Potential Factors Associated with Cognitive Improvement of Individuals Diagnosed with Mild Cognitive Impairment or Dementia in Longitudinal Studies. - Hadjichrysanthou, Christoforos; McRae-McKee, Kevin; Evans, Stephanie; De Wolf, Frank; Anderson, Roy M (J Alzheimers Dis, 2018)
Despite the progressive nature of Alzheimer's disease and other dementias, it is observed that many individuals that are diagnosed with mild cognitive impairment (MCI) in one clinical assessment, may return back to normal cognition (CN) in a subsequent assessment. Less frequently, such 'back-transitions' are also observed in people that had already been diagnosed with later stages of dementia. In this study, an analysis was performed on two longitudinal cohort datasets provided by 1) the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 2) the National Alzheimer's Coordinating Centre (NACC). The focus is on the observed improvement of individuals' clinical condition recorded in these datasets to explore potential associations with different factors. It is shown that, in both datasets, transitions from MCI to CN are significantly associated with younger age, better cognitive function, and the absence of ApoE ɛ4 alleles. Better cognitive function and in some cases the absence of ApoE ɛ4 alleles are also significantly associated with transitions from types of dementia to less severe clinical states. The effect of gender and education is not clear-cut in these datasets, although highly educated people who reach MCI tend to be more likely to show an improvement in their clinical state. The potential effect of other factors such as changes in symptoms of depression is also discussed. Although improved clinical outcomes can be associated with many factors, better diagnostic tools are required to provide insight into whether such improvements are a result of misdiagnosis, and if they are not, whether they are linked to improvements in the underlying neuropathological condition.

Potential Novel Approaches to Understand the Pathogenesis and Treat Alzheimer's Disease. - Drummond, Eleanor; Goñi, Fernando; Liu, Shan; Prelli, Frances; Scholtzova, Henrieta; Wisniewski, Thomas (J Alzheimers Dis, 2018)
There is growing genetic and proteomic data highlighting the complexity of Alzheimer's disease (AD) pathogenesis. Greater use of unbiased "omics" approaches is being increasingly recognized as essential for the future development of effective AD research, that need to better reflect the multiple distinct pathway abnormalities that can drive AD pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. We highlight our recent efforts to increase use of human tissue to gain a better understanding of the AD pathogenesis subtype variety and to develop several distinct therapeutic approaches tailored to address this diversity. These therapeutic approaches include the blocking of the Aβ/apoE interaction, stimulation of innate immunity, and the simultaneous blocking of Aβ/tau oligomer toxicity. We believe that future successful therapeutic approaches will need to be combined to better reflect the complexity of the abnormal pathways triggered in AD pathogenesis.

Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial. - Wilcock, Gordon K; Gauthier, Serge; Frisoni, Giovanni B; Jia, Jianping; Hardlund, Jiri H; Moebius, Hans J; Bentham, Peter; Kook, Karin A; Schelter, Bjoern O; Wischik, Damon J; Davis, Charles S; Staff, Roger T; et al. (J Alzheimers Dis, 2018)
BACKGROUND: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. OBJECTIVES: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. METHODS: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. RESULTS: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. CONCLUSIONS: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Antipsychotic Agents; Cohort Studies; Double-Blind Method; Female; Humans; International Cooperation; Male; Mental Status and Dementia Tests; Methylene Blue; Middle Aged; Treatment Outcome

Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer's Disease. - Tao, Qiushan; Zhu, Haihao; Chen, Xi; Stern, Robert A; Kowall, Neil; Au, Rhoda; Blusztajn, Jan Krzysztof; Qiu, Wei Qiao (J Alzheimers Dis, 2018)
Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer's disease (AD) biomarkers in the blood of AD mouse models and AD patients. The aim of this study was to examine whether a pramlintide challenge combined with a phosphatidylcholine (PC) profile diagnoses of AD and mild cognitive impairment (MCI) better than PC alone. Non-diabetic subjects with cognitive status were administered a single subcutaneous injection of 60 mcg of pramlintide under fasting condition. A total of 71 PCs, amyloid-β peptide (Aβ), and total tau (t-tau) in plasma at different time points were measured and treated as individual variables. A single injection of pramlintide altered the levels of 7 PCs in the blood, while a pramlintide injection plus food modulated the levels of 10 PCs in the blood (p < 0.05). The levels of 2 PCs in MCI and 12 PCs in AD in the pramlintide challenge were significantly lower than the ones in controls. We found that while some PCs were associated with only Aβ levels, other PCs were associated with both Aβ and t-tau levels. A receiver operating characteristic analysis of the PCs was combined with the Aβ and t-tau data to produce an area under the curve predictive value of 0.9799 between MCI subjects and controls, 0.9794 between AD subjects and controls, and 0.9490 between AD and MCI subjects. A combination of AD biomarkers and a group of PCs post a pramlintide challenge may provide a valuable diagnostic and prognostic test for AD and MCI.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction; Female; Humans; Islet Amyloid Polypeptide; Logistic Models; Male; Middle Aged; Phosphatidylcholines; ROC Curve; tau Proteins

A Precision Medicine Model for Targeted NSAID Therapy in Alzheimer's Disease. - O'Bryant, Sid E; Zhang, Fan; Johnson, Leigh A; Hall, James; Edwards, Melissa; Grammas, Paula; Oh, Esther; Lyketsos, Constantine G; Rissman, Robert A (J Alzheimers Dis, 2018)
BACKGROUND: To date, the therapeutic paradigm for Alzheimer's disease (AD) has focused on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy. OBJECTIVE: To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy. METHODS: Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo. RESULTS: 474 participants with mild-to-moderate AD were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm. CONCLUSION: Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD.

Preclinical Alzheimer's Disease: Implications for Refinement of the Concept. - Vos, Stephanie J B; Visser, Pieter Jelle (J Alzheimers Dis, 2018)
Increasing interest in clinical trials and clinical research settings to identify Alzheimer's disease (AD) in the earliest stages of the disease has led to the concept of preclinical AD. Individuals with preclinical AD have AD pathology without clinical symptoms yet. Accumulating evidence has shown that biomarkers can identify preclinical AD and that preclinical AD is associated with a poor clinical outcome. Little is known yet about the role of vascular and lifestyle risk factors in the development of preclinical AD. In order to better understand preclinical AD pathology and clinical progression rates, there is a need to refine the concept of preclinical AD. This will be of great value for advancements in future research, clinical trials, and eventually clinical practice.

Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease: Structural Brain Biomarkers. - Marizzoni, Moira; Ferrari, Clarissa; Jovicich, Jorge; Albani, Diego; Babiloni, Claudio; Cavaliere, Libera; Didic, Mira; Forloni, Gianluigi; Galluzzi, Samantha; Hoffmann, Karl-Titus; Molinuevo, José Luis; Nobili, Flavio; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. OBJECTIVE: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. METHODS: APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. RESULTS: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction). CONCLUSION: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs.

Predicting Imminent Progression to Clinically Significant Memory Decline Using Volumetric MRI and FDG PET. - Stonnington, Cynthia M; Chen, Yinghua; Savage, Cary R; Lee, Wendy; Bauer Iii, Robert J; Sharieff, Sameen; Thiyyagura, Pradeep; Alexander, Gene E; Caselli, Richard J; Locke, Dona E C; Reiman, Eric M; Chen, Kewei (J Alzheimers Dis, 2018)
BACKGROUND: Brain imaging measurements can provide evidence of possible preclinical Alzheimer's disease (AD). Their ability to predict individual imminent clinical conversion remains unclear. OBJECTIVE: To investigate the ability of pre-specified volumetric magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) measurements to predict which cognitively unimpaired older participants would subsequently progress to amnestic mild cognitive impairment (aMCI) within 2 years. METHODS: From an apolipoprotein E4 (APOE4) enriched prospective cohort study, 18 participants subsequently progressed to the clinical diagnosis of aMCI or probable AD dementia within 1.8±0.8 years (progressors); 20 participants matched for sex, age, education, and APOE allele dose remained cognitively unimpaired for at least 4 years (nonprogressors). A complementary control group not matched for APOE allele dose included 35 nonprogressors. Groups were compared on baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD and by voxel-wise differences in regional gray matter volume and glucose metabolism. Receiver Operating Characteristic, binary logistic regression, and leave-one-out procedures were used to predict clinical outcome for the a priori measures. RESULTS: Compared to non-progressors and regardless of APOE-matching, progressors had significantly reduced baseline MRI and PET measurements in brain regions preferentially affected by AD and reduced hippocampal volume was the strongest predictor of an individual's imminent progression to clinically significant memory decline (79% sensitivity/78% specificity among APOE-matched cohorts). CONCLUSION: Regional MRI and FDG-PET measurements may be useful in predicting imminent progression to clinically significant memory decline.

Prediction and Early Detection of Alzheimer's Dementia: Professional Disclosure Practices and Ethical Attitudes. - Schweda, Mark; Kögel, Anna; Bartels, Claudia; Wiltfang, Jens; Schneider, Anja; Schicktanz, Silke (J Alzheimers Dis, 2018)
BACKGROUND: Biomarker-supported testing for preclinical and prodromal Alzheimer's disease (AD) finds its way into clinical practice. Professional attitudes and practices regarding disclosure and ethical issues are controversial in many countries. OBJECTIVES: Against this background, the objective was to survey the actual practice and the attitudes of physicians in German hospitals and memory clinics in order to explore possible practical insecurities and ethical concerns. METHODS: A detailed survey with 37 items was conducted among medical professionals at German hospitals and memory clinics (n = 108). Analyses were performed using SPSS 21.0 (IBM). Findings were based on frequency and percentage distribution. RESULTS: Nearly half of the respondents stated that persons with mild cognitive impairment and pathological cerebrospinal fluid biomarkers were informed they had or would soon develop AD. While 81% acknowledged a 'right not to know', 75% said that results were always communicated. A majority agreed there was a benefit of prediction or later life planning [end-of-life, financial, family, housing (73-75%)] but also expected high psychological stress (82%) and self-stigmatization (70%) for those tested. CONCLUSIONS: There is considerable heterogeneity and insecurity regarding prediction and early detection in the context of AD in Germany. Information of professionals and standardization of professional testing and disclosure practices are needed.

Prediction of Alzheimer's Dementia in Patients with Amnestic Mild Cognitive Impairment in Clinical Routine: Incremental Value of Biomarkers of Neurodegeneration and Brain Amyloidosis Added Stepwise to Cognitive Status. - Lange, Catharina; Suppa, Per; Pietrzyk, Uwe; Makowski, Marcus R; Spies, Lothar; Peters, Oliver; Buchert, Ralph (J Alzheimers Dis, 2018)
The aim of this study was to evaluate the incremental benefit of biomarkers for prediction of Alzheimer's disease dementia (ADD) in patients with mild cognitive impairment (MCI) when added stepwise in the order of their collection in clinical routine. The model started with cognitive status characterized by the ADAS-13 score. Hippocampus volume (HV), cerebrospinal fluid (CSF) phospho-tau (pTau), and the FDG t-sum score in an AD meta-region-of-interest were compared as neurodegeneration markers. CSF-Aβ1-42 was used as amyloidosis marker. The incremental prognostic benefit from these markers was assessed by stepwise Kaplan-Meier survival analysis in 402 ADNI MCI subjects. Predefined cutoffs were used to dichotomize patients as 'negative' or 'positive' for AD characteristic alteration with respect to each marker. Among the neurodegeneration markers, CSF-pTau provided the best incremental risk stratification when added to ADAS-13. FDG PET outperformed HV only in MCI subjects with relatively preserved cognition. Adding CSF-Aβ provided further risk stratification in pTau-positive subjects, independent of their cognitive status. Stepwise integration of biomarkers allows stepwise refinement of risk estimates for MCI-to-ADD progression. Incremental benefit strongly depends on the patient's status according to the preceding diagnostic steps. The stepwise Kaplan-Meier curves might be useful to optimize diagnostic workflow in individual patients.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloidosis; Brain; Cognitive Dysfunction; Female; Fluorodeoxyglucose F18; Humans; Imaging, Three-Dimensional; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Survival Analysis; tau Proteins

Predictors of Age of Diagnosis and Survival of Alzheimer's Disease in Down Syndrome. - Sinai, Amanda; Mokrysz, Claire; Bernal, Jane; Bohnen, Ingrid; Bonell, Simon; Courtenay, Ken; Dodd, Karen; Gazizova, Dina; Hassiotis, Angela; Hillier, Richard; McBrien, Judith; McCarthy, Jane; et al. (J Alzheimers Dis, 2018)
BACKGROUND: People with Down syndrome (DS) are an ultra-high risk population for Alzheimer's disease (AD). Understanding the factors associated with age of onset and survival in this population could highlight factors associated with modulation of the amyloid cascade. OBJECTIVE: This study aimed to establish the typical age at diagnosis and survival associated with AD in DS and the risk factors associated with these. METHODS: Data was obtained from the Aging with Down Syndrome and Intellectual Disabilities (ADSID) research database, consisting of data extracted from clinical records of patients seen by Community Intellectual Disability Services (CIDS) in England. Survival times when considering different risk factors were calculated. RESULTS: The mean age of diagnosis was 55.80 years, SD 6.29. Median survival time after diagnosis was 3.78 years, and median age at death was approximately 60 years. Survival time was associated with age of diagnosis, severity of intellectual disability, living status, anti-dementia medication status, and history of epilepsy. Age at diagnosis and treatment status remained predictive of survival time following adjustment. CONCLUSION: This study provides the best estimate of survival in dementia within the DS population to date, and is in keeping with previous estimates from smaller studies in the DS population. This study provides important estimates and insights into possible predictors of survival and age of diagnosis of AD in adults with DS, which will inform selection of participants for treatment trials in the future.
Keywords: Age of Onset; Alzheimer Disease; Down Syndrome; England; Female; Humans; Male; Middle Aged; Risk Factors; Survival Analysis

Predictors of Delirium Development in Older Medical Inpatients: Readily Identifiable Factors at Admission. - O'Regan, Niamh A; Fitzgerald, James; Adamis, Dimitrios; Molloy, David William; Meagher, David; Timmons, Suzanne (J Alzheimers Dis, 2018)
BACKGROUND: Identifying patients at high risk of delirium is crucial to facilitate prevention. Although dementia is the most consistent risk factor across populations, it remains under-diagnosed. Hence understanding other markers of delirium vulnerability on admission is important. OBJECTIVE: We aimed to identify predictors of incident delirium development in older medical inpatients that were readily identifiable at presentation to the emergency department. METHODS: Medical inpatients of ≥70 years were assessed on admission for delirium using the Revised Delirium Rating Scale (DRS-R98) and those with prevalent delirium were excluded. Consenting non-delirious patients were then assessed daily using the DRS-R98. Data pertaining to multiple baseline delirium risk factors were collected, including pre-morbid dementia. Multivariable logistic regression was used to examine which factors predicted the development of incident delirium. RESULTS: Of 555 patients approached, 184 (33.1%) had prevalent delirium. Following other exclusions, 191 were included in the study and 61 developed incident delirium. Predictors of incident delirium on multivariable analysis, controlling for confounders, were dementia (OR 2.54, 95% CI 1.01-6.43, p = 0.048); Barthel Index score (OR 1.15 for each unit decrease in score, 95% CI 1.06-1.25, p = 0.001), and Modified Cumulative Illness Rating Scale score (OR 1.13 for each unit increase in score, 95% CI 1.05-1.22, p = 0.001). CONCLUSION: Dementia is a well-known risk factor for delirium; however, it too is under-recognized and on admission can be missed. Conversely, the Barthel Index is a simple and widely used measure of functional ability that may prove useful in stratifying those at risk of in-hospital delirium on admission.

Preoperative Phosphorylated Tau Concentration in the Cerebrospinal Fluid Can Predict Cognitive Function Three Years after Shunt Surgery in Patients with Idiopathic Normal Pressure Hydrocephalus. - Nakajima, Madoka; Miyajima, Masakazu; Ogino, Ikuko; Akiba, Chihiro; Kawamura, Kaito; Kamohara, Chihiro; Fusegi, Keiko; Harada, Yoshinao; Hara, Takeshi; Sugano, Hidenori; Tange, Yuichi; Karagiozov, Kostadin; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer's disease (AD) pathology is debated. OBJECTIVE: To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH. METHODS: Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (≥30 pg/mL) p-Tau groups and followed up for three years after lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low (n = 24; mean age 75.7 years [SD 5.3]) and high (n = 11; mean age 76.0 years [SD 5.6]) p-Tau groups. RESULTS: Cognitive function improved early in the low p-Tau group and was maintained thereafter (p = 0.005). In contrast, the high p-Tau group showed a gradual decline to baseline levels by the third postoperative year (p = 0.040). Although the p-Tau concentration did not correlate with the preoperative MMSE score, a negative correlation appeared and strengthened during follow-up (R2 = 0.352, p < 0.001). Furthermore, the low p-Tau group showed rapid and sustained mRS grade improvement, whereas mRS performance gradually declined in the high p-Tau group. CONCLUSIONS: Preoperative CSF p-Tau concentration predicted some aspects of cognitive function after shunt intervention in patients with iNPH. The therapeutic effects of shunt treatment were shorter-lasting in patients with coexisting AD pathology.

Preserved Structural Network Organization Mediates Pathology Spread in Alzheimer's Disease Spectrum Despite Loss of White Matter Tract Integrity. - Powell, Fon; Tosun, Duygu; Sadeghi, Roksana; Weiner, Michael; Raj, Ashish (J Alzheimers Dis, 2018)
Models of Alzheimer's disease (AD) hypothesize stereotyped progression via white matter (WM) fiber connections, most likely via trans-synaptic transmission of toxic proteins along neuronal pathways. An important question in the field is whether and how organization of fiber pathways is affected by disease. It remains unknown whether fibers act as conduits of degenerative pathologies, or if they also degenerate with the gray matter network. This work uses graph theoretic modeling in a longitudinal design to investigate the impact of WM network organization on AD pathology spread. We hypothesize if altered WM network organization mediates disease progression, then a previously published network diffusion model will yield higher prediction accuracy using subject-specific connectomes in place of a healthy template connectome. Neuroimaging data in 124 subjects from ADNI were assessed. Graph topology metrics show preserved network organization in patients compared to controls. Using a published diffusion model, we further probe the effect of network alterations on degeneration spread in AD. We show that choice of connectome does not significantly impact the model's predictive ability. These results suggest that, despite measurable changes in integrity of specific fiber tracts, WM network organization in AD is preserved. Further, there is no difference in the mediation of putative pathology spread between healthy and AD-impaired networks. This conclusion is somewhat at variance with previous results, which report global topological disturbances in AD. Our data indicates the combined effect of edge thresholding, binarization, and inclusion of subcortical regions to network graphs may be responsible for previously reported effects.

Prevalence and Determinants of Agonistic Autoantibodies Against α1-Adrenergic Receptors in Patients Screened Positive for Dementia: Results from the Population-Based DelpHi-Study. - Thyrian, Jochen René; Hertel, Johannes; Schulze, Lara N; Dörr, Marcus; Prüss, Harald; Hempel, Petra; Bimmler, Marion; Kunze, Rudolf; Grabe, Hans Jörgen; Teipel, Stefan; Hoffmann, Wolfgang (J Alzheimers Dis, 2018)
BACKGROUND: There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation. OBJECTIVE: 1) Describe prevalence of agAAB directed against GPCR, especially agABB against α1-adrenergic receptors (α1-AR-agAAB) and agABB directed against β2-adrenergic receptors (β2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care. METHODS: Blood samples and data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked. RESULTS: In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing α1-AR-agAAB and n = 21 (22%) β2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have α1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment. DISCUSSION: For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between α1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB.

Prevalence of Delirium in a Population of Elderly Outpatients with Dementia: A Retrospective Study. - Addesi, Desirée; Maio, Raffaele; Smirne, Nicoletta; Laganà, Valentina; Altomari, Natalia; Puccio, Gianfranco; Colao, Rosanna; Cupidi, Chiara; Perticone, Francesco; Bruni, Amalia Cecilia (J Alzheimers Dis, 2018)
BACKGROUND: Delirium is a multifactorial geriatric syndrome and often occurs in patients with cognitive impairment. It also remains under-recognized, specifically in elderly outpatients, because signs of delirium might overlap with symptoms of dementia. OBJECTIVE: The aim of the present study is to retrospectively apply the chart-based delirium instrument on a cohort of elderly outpatients with dementia, to assess prevalence and features of delirium in this population. METHODS: We randomly selected 650 medical records of outpatients referred to the "Neurogenetic Regional Centre" (CRN) of Lamezia Terme. Each evaluation included demographics, medical history, drugs, type and severity of dementia, and cognitive and functional status. Delirium was identified by the application of the chart-based delirium instrument. RESULTS: The prevalence of delirium was 13.3%. The study population was divided, according to the presence of delirium, into two subgroups. Compared to the no delirium group, the delirium group was significantly older and had greater cognitive impairment with lower MMSE scores both at baseline and at the end of the follow up. They also had a significant lower score on the ADL and IADL. In this group, a higher intake of antihypertensive and antipsychotic drugs, together with a lower intake of cholinesterase inhibitors and memantine, was observed. CONCLUSIONS: In this study, the chart-based delirium instrument was applied to an outpatient population affected by dementia and followed for a long time. Our data confirm the importance that age and frailty play on the genesis of delirium and suggest attention should be paid to the pharmacological treatment of these patients.
Keywords: Aged; Aged, 80 and over; Antipsychotic Agents; Cohort Studies; Delirium; Dementia; Female; Geriatric Assessment; Humans; Male; Outpatients; Prevalence; Severity of Illness Index

Prevalence of Dementia and Associated Risk Factors: A Population-Based Study in the Philippines. - Dominguez, Jacqueline; Fe de Guzman, Ma; Reandelar, Macario; Thi Phung, Thien Kieu (J Alzheimers Dis, 2018)
BACKGROUND: The Philippines is experiencing rapid demographic aging and with it, the dementia epidemic. Prevalence of dementia and associated risk factors have not been studied in the Philippines. OBJECTIVES: The study aimed to provide a reliable estimate of dementia prevalence and identify associated risk factors in the Filipino population. METHODS: 1460 participants 60 years and older were randomly selected from the Marikina City's senior registry. A multidisciplinary team (nurse, psychologist, and neurologist) administered a comprehensive assessment to the study population: health history, neurological examination, Geriatric Depression Scale, Neuropsychiatric Inventory, Disability Assessment for Dementia, Alzheimer's Disease 8, and Clinical Dementia Rating Scale. The neurologist analyzed all clinical data to diagnose dementia based on the DSM-IV criteria, Alzheimer's Disease (AD) on the NINCDS-ADRDA criteria, vascular dementia (VaD) on the Hachinski Ischemic Scale, cognitive impairment no dementia (CIND) on a CDR score of 0.5 and not fulfilling DSM-IV criteria for dementia. Risk factors were correlated with dementia prevalence using multivariate binary logistic regression. RESULTS: 1460 persons were randomly selected. 1367 agreed to participate and underwent all assessments. The response rate was 93.6%. Dementia prevalence was found to be 10.6% (95% CI 9.0 to 12.4) with the breakdown 85.5% AD, 11.7% VaD, and 2.7% other dementias. In this population, 82.0% of men and 70.4% of women had at least one cardiovascular risk factor (hypertension, diabetes, dyslipidemia, smoking), which was associated with VaD prevalence but not AD. CONCLUSION: The prevalence of dementia, CIND, and cardiovascular risk factors are high in the Philippines.

Prevalence of Potentially Inappropriate Medication Use in Older Inpatients with and without Cognitive Impairment: A Systematic Review. - Redston, Mitchell R; Hilmer, Sarah N; McLachlan, Andrew J; Clough, Alexander J; Gnjidic, Danijela (J Alzheimers Dis, 2018)
BACKGROUND: Older people with cognitive impairment, including dementia and delirium, are high users of acute care services internationally. Potentially inappropriate medication (PIM) use may be associated with adverse outcomes, including hospital re-admission, functional disability, and mortality. OBJECTIVE: This systematic review aimed to quantify and compare the prevalence of PIMs in older inpatients with and without cognitive impairment. METHODS: A systematic search of observational studies was performed independently assessed by two reviewers in Embase, Medline, PsycINFO, International Pharmaceutical Abstracts, Scopus, and Informit. Articles published in English during the period January 2007-June 2017 that reported PIM prevalence in hospital inpatients ≥ 65 years were included. PIMs were defined as the presence of polypharmacy (multiple medication use) and using implicit or explicit tools, such as the Beers criteria, and 'Screening Tool of Older Person's Prescriptions' (STOPP). RESULTS: 47 articles were included. In studies measuring polypharmacy (n = 15), the prevalence of PIMs ranged from 53.2% to 89.8% and 30.4% to 97.1% for inpatients with and without cognitive impairment, respectively, and 24.0% to 80.0% when cognitive status was unreported. In studies employing explicit and implicit tools (n = 35), the prevalence of PIMs when cognitive impairment was reported ranged from 20.6% to 80.5% using the Beers criteria, and 39.3% to 88.5% using STOPP. When cognitive status was unreported, the prevalence of PIMs ranged from 7.0% to 79.2% using the Beers criteria, and 20.0% to 63.4% using STOPP. CONCLUSION: Our findings suggest a high prevalence of PIMs in older inpatients with and without cognitive impairment. Future studies should investigate the impact of PIM use on patient-centered outcomes, such as functional status and quality of life, to inform enhanced acute care services.
Keywords: Aged; Cognitive Dysfunction; Dementia; Humans; Inpatients; Polypharmacy; Potentially Inappropriate Medication List; Prevalence; Quality of Life

Prevalence, Safety, and Effectiveness of Oral Anticoagulant Use in People with and without Dementia or Cognitive Impairment: A Systematic Review and Meta-Analysis. - Fanning, Laura; Ryan-Atwood, Taliesin E; Bell, J Simon; Meretoja, Atte; McNamara, Kevin P; Dārziņš, Pēteris; Wong, Ian C K; Ilomäki, Jenni (J Alzheimers Dis, 2018)
BACKGROUND: Differences in management and outcomes of oral anticoagulant (OAC) use may exist for people with and without dementia or cognitive impairment (CI). OBJECTIVE: To systematically review the prevalence and safety and effectiveness outcomes of OAC use in people with and without dementia or CI. METHODS: MEDLINE, EMBASE, and CINAHL were searched for studies reporting prevalence or safety and effectiveness outcomes of OAC use for people with and without dementia, published between 2000 to September 2017. Study selection, data extraction, and quality assessment were performed by two reviewers. RESULTS: studies met pre-specified inclusion criteria (21 prevalence studies, 6 outcomes studies). People with dementia had 52% lower odds of receiving OAC compared to people without dementia. Mean OAC prevalence was 32% for people with dementia, compared to 48% without dementia. There was no difference in the composite outcome of embolic events, myocardial infarction, and all-cause death between dementia and non-dementia groups (adjusted hazard ratio (HR) 0.72, 95% CI, 0.45-1.14, p = 0.155). Bleeding rate was lower for people without dementia (HR 0.56, 95% CI, 0.37-0.85). Adverse warfarin events were more common for residents of long-term care with dementia (adjusted incidence rate ratio 1.48, 95% CI, 1.20-1.82). Community-dwelling people with dementia treated with warfarin had poorer anticoagulation control than those without dementia (mean time in therapeutic range (TTR) % ±SD, 38±26 (dementia), 61±27 (no dementia), p < 0.0001). CONCLUSION: A lower proportion of people with dementia received oral anticoagulation compared with people without dementia. People with dementia had higher bleeding risk and poorer anticoagulation control when treated with warfarin.

Prevalence, Semiology, and Risk Factors of Epilepsy in Alzheimer's Disease: An Ambulatory EEG Study. - Horváth, András; Szűcs, Anna; Hidasi, Zoltán; Csukly, Gábor; Barcs, Gábor; Kamondi, Anita (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is the primary cause of cognitive decline. A growing body of evidence suggests that AD patients have a higher risk to develop epileptic seizures; however, results are contradictory due to different methodological approaches of previous studies. OBJECTIVE: We aimed to identify the prevalence, semiology, and risk factors of epilepsy in AD using long-term EEG. METHODS: We selected forty-two AD patients and examined them using 24-hour ambulatory EEG. Neurological and epileptological data were collected with retro- and prospective methods. We analyzed the semiology of the identified seizures and the possible risk factors using logistic regression analysis. RESULTS: We identified seizures confirmed by EEG in 24%. The majority of the seizures were aware focal (72%) without any motor activity (55%). We found epileptiform discharges without seizures in 28%. Patients with seizures and only with epileptic EEG activity showed similar clinical and demographical features. Higher education (OR:1.8) and lower Addenbrooke Examination Score (OR: 0.9) were identified as risk factors of epilepsy. Increase of 0.1 point in the Verbal-Language/Orientation-Memory ratio (VLOM) was associated with higher epilepsy risk as well (OR:2.9). CONCLUSION: Epilepsy is a frequent comorbidity of AD. Since most of the seizures are aware non-motor focal seizures, sensitive EEG techniques are required for precise diagnosis of epilepsy. Long-term ambulatory EEG is a safe and well-tolerated option. Epileptiform EEG in AD signals the presence of concomitant epilepsy. Clinicians have to pay attention to comorbid epilepsy in dementia patients with high education, with high VLOM ratio and severe stage.

The Price of Stress: High Bedtime Salivary Cortisol Levels Are Associated with Brain Atrophy and Cognitive Decline in Stroke Survivors. Results from the TABASCO Prospective Cohort Study. - Tene, Oren; Hallevi, Hen; Korczyn, Amos D; Shopin, Ludmila; Molad, Jeremy; Kirschbaum, Clemens; Bornstein, Natan M; Shenhar-Tsarfaty, Shani; Kliper, Efrat; Auriel, Eitan; Usher, Sali; Stalder, Tobias; et al. (J Alzheimers Dis, 2018)
BACKGROUND AND OBJECTIVE: Previous studies suggest that excessive cortisol levels after stroke are associated with cognitive dysfunction. However, limited data exist regarding associations between post-stroke cortisol levels, brain abnormalities, genetic factors, and cognitive outcome. We sought to study these issues in a longitudinal stroke survivors cohort. METHODS: Data from 182 cognitively intact ischemic stroke patients from the TABASCO study were available. Saliva cortisol levels (bedtime and post-awakening) and cognitive assessments were obtained on admission, and 6, 12, and 24 months thereafter. During hospitalization, patients underwent 3T MRI scans and APOE genotyping. RESULTS: Higher bedtime cortisol levels immediately post-stroke were associated with larger neurological deficits (p < 0.001), brain atrophy (p = 0.025), worse white matter integrity (p = 0.003), and worse cognitive results up to 24 months post-stroke. These findings remained significant when adjusted for age, gender, education, smoking, stroke severity, apolipoprotein E4 (ApoE4) status, and body mass index. ApoE4 negatively modified the relation between cortisol and memory. As a group, participants who presented with high admission bedtime cortisol levels continued to present relatively elevated bedtime levels across all examined time-points, and this group had inferior memory and executive functioning scores compared to the lower cortisol group 24 months post-stroke (p = 0.05, p = 0.035, respectively). Post-awakening cortisol levels were not associated with neuroimaging findings or cognitive scores. CONCLUSIONS: High bedtime salivary cortisol levels post-stroke may provide information about dysregulation of diurnal HPA-axis activity under acute challenge conditions, and predict worse cognitive outcome. ApoE4 genotype might modify this association. These findings call for specific stress management interventions in stroke survivors.

Prodromal Alzheimer's Disease Demonstrates Increased Errors at a Simple and Automated Anti-Saccade Task. - Holden, John G; Cosnard, Alexandre; Laurens, Brice; Asselineau, Julien; Biotti, Damien; Cubizolle, Stéphanie; Dupouy, Sandrine; Formaglio, Maıté; Koric, Lejla; Seassau, Magali; Tilikete, Caroline; Vighetto, Alain; et al. (J Alzheimers Dis, 2018)
Saccade alterations are potential early signs of Alzheimer's disease. However, uncertainty persists in how early and reliably automated saccade recording systems detect impairments. This multicenter pathophysiological case-control transversal study explored saccade execution in carefully diagnosed amnestic mild cognitive impairment patients fulfilling research criteria for prodromal Alzheimer's disease (n = 29), as compared to both aged-matched mild Alzheimer's disease patients (n = 23) and controls (n = 27). Auto-coded saccades from horizontal (gap) vertical (step) stimulus elicited pro-saccades, and anti-saccade (gap) tasks were compared across the 3 groups. Mild cognitive impairment patients committed significantly more anti-saccade errors compared to controls (46.9 versus 24.3%, p < 0.001). Conventional analyses of the auto-coded stimulus elicited saccades parameters did not distinguish the amnestic mild cognitive impairment from controls or the mild Alzheimer's disease group. However, an offline analysis of manually coded saccade latencies, using resampling statistics did reveal subtle differences among the groups. Analysis of the manually coded data revealed that the mild Alzheimer's disease group had a reliably larger self-corrected error-rate than in amnestic mild cognitive impairment and controls (p = 0.003). Analysis of the manually coded saccade latencies, using more sensitive lognormal bootstrap analysis revealed a continuum, from amnestic mild cognitive impairment to mild Alzheimer's disease, of an increased severity of impaired inhibition of stimulus elicited saccades and correct voluntary saccade initiation. Anti-saccade error rates and psychometric measures of executive and several other cognitive functions were moderately and negatively correlated. Overall, inhibitory impairments in stimulus elicited saccades, characteristic of Alzheimer's disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task.

Profiling of Specific Gene Expression Pathways in Peripheral Cells from Prodromal Alzheimer's Disease Patients. - Serpente, Maria; Fenoglio, Chiara; Cioffi, Sara Maria Giulia; Oldoni, Emanuela; Arcaro, Marina; Arighi, Andrea; Fumagalli, Giorgio Giulio; Ghezzi, Laura; Scarpini, Elio; Galimberti, Daniela (J Alzheimers Dis, 2018)
Herein, we performed a gene expression profiling in a cohort of 10 mild cognitive impairment (MCI), subdivided, according to the analysis of cerebrospinal fluid biomarkers, in prodromal Alzheimer's disease (AD) and non-AD MCI, as compared with 27 AD patients and 24 controls, in order to detect early gene expression alterations. We observed a significant upregulation of insulin (INS) and INS Receptor (INSR) expression levels in AD both prodromal and fully symptomatic, as compared with controls, but not in MCI subjects. Our results suggest an early dysregulation of INS and INSR in AD pathogenesis and pave the way to a possible utility of these transcripts as peripheral biomarkers.
Keywords: Aged; Alzheimer Disease; Antigens, CD; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Female; Gene Expression Profiling; Humans; Insulin; Male; Middle Aged; Receptor, Insulin

Progress and Challenges in Frontotemporal Dementia Research: A 20-Year Review. - Hodges, John R; Piguet, Olivier (J Alzheimers Dis, 2018)
The landscape of frontotemporal dementia (FTD) has evolved remarkably in recent years and is barely recognizable from two decades ago. Knowledge of the clinical phenomenology, cognition, neuroimaging, genetics, pathology of the different subtypes of FTD, and their relations to other neurodegenerative conditions, has increased rapidly, due in part, to the growing interests into these neurodegenerative brain conditions. This article reviews the major advances in the field of FTD over the past 20 years, focusing primarily on the work of Frontier, the frontotemporal dementia clinical research group, based in Sydney, Australia. Topics covered include clinical presentations (cognition, behavior, neuroimaging), pathology, genetics, and disease progression, as well as interventions and carer directed research. This review demonstrates the improvement in diagnostic accuracy and capacity to provide advice on genetic risks, prognosis, and outcome. The next major challenge will be to capitalize on these research findings to develop effective disease modifying drugs, which are currently lacking.

Progress of Brain Amyloid Deposition in Familial Alzheimer's Disease with Taiwan D678H APP Mutation. - Weng, Yi-Ching; Hsiao, Ing-Tsung; Huang, Chu-Yun; Huang, Kuo-Lun; Liu, Chi-Hung; Chang, Ting-Yu; Yen, Tzu-Chen; Lin, Kun-Ju; Huang, Chin-Chang (J Alzheimers Dis, 2018)
BACKGROUND: The amyloid AV-45 (florbetapir) positron emission tomography (PET) has been used in the study of the familial Alzheimer's disease (FAD) with the D678H amyloid precursor protein (APP) mutation. In addition, the progress of the disease remains unknown. OBJECTIVE: We aim to investigate the progression rate of amyloid accumulation in FAD patients with this mutation by neuroimages analysis. METHODS: The clinical course, changes in cognitive function, brain magnetic resonance imaging (MRI) and 18F-AV-45 PET scan were investigated in FAD patients and sporadic AD (sAD) patients. We compared the amyloid deposition pattern in serial brain 18F-AV-45 PET scan among the FAD, familial mild cognitive impairment (FMCI), and sMCI and sAD patients. RESULTS: Seven familial patients received a follow-up survey. The follow up duration for brain AV-45 PET was from 1.54 to 3.61 years. In 4 FMCI patients, an increased regional SUVR was noted, and the annual change rates were increased from 1.03% to 18.82%. However, a decreased regional SUVR was noted in 3 FAD patients and the annual change rates were from -2.62% to -16.03%. As compared with the sAD and sMCI patients, the annual change rate is statistically significant in FAD and FMCI patients respectively. CONCLUSIONS: The data indicate a biphasic course with an initial increase and then a decrease of SUVR in brain amyloid PET scan in familial APP mutation patients. The data also reveal that the novel Taiwan APP (D678H) mutation has a more amyloid burden than the sAD patients, particularly in an MCI stage.

Progression of Alzheimer's Disease: A Longitudinal Study in Norwegian Memory Clinics. - Eldholm, Rannveig Sakshaug; Barca, Maria Lage; Persson, Karin; Knapskog, Anne-Brita; Kersten, Hege; Engedal, Knut; Selbæk, Geir; Brækhus, Anne; Skovlund, Eva; Saltvedt, Ingvild (J Alzheimers Dis, 2018)
BACKGROUND: The course of Alzheimer's disease (AD) varies considerably between individuals. There is limited evidence on factors important for disease progression. OBJECTIVE: The primary aim was to study the progression of AD, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary aims were to investigate whether baseline characteristics are important for differences in progression, and to examine the correlation between progression assessed using three different instruments: CDR-SB (0-18), the cognitive test Mini-Mental State Examination (MMSE, 0-30), and the functional measure Instrumental Activities of Daily Living (IADL, 0-1). METHODS: The Progression of AD and Resource use (PADR) study is a longitudinal observational study in three Norwegian memory clinics. RESULTS: In total, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16-37) months. The mean annual increase in CDR-SB was 1.6 (SD 1.8), the mean decrease in MMSE score 1.9 (SD 2.6), and the mean decrease in IADL score 0.13 (SD 0.14). Of the 282 patients, 132 (46.8%) progressed slowly, with less than 1 point yearly increase in CDR-SB. Cognitive test results at baseline predicted progression rate, and together with age, ApoE, history of hypertension, and drug use could explain 17% of the variance in progression rate. The strongest correlation of change was found between CDR-SB and IADL scores, the weakest between MMSE and IADL scores. CONCLUSION: Progression rate varied considerably among AD patients; about half of the patients progressed slowly. Cognitive test results at baseline were predictors of progression rate.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Disease Progression; Female; Humans; Linear Models; Longitudinal Studies; Male; Memory; Neuropsychological Tests; Norway

Progression of Alzheimer's Disease-Related Pathology and Cell Counts in a Patient with Idiopathic Normal Pressure Hydrocephalus. - Libard, Sylwia; Laurell, Katarina; Cesarini, Kristina Giuliana; Alafuzoff, Irina (J Alzheimers Dis, 2018)
We had an opportunity to assess the change observed in the brain regarding Alzheimer's disease (AD)-related alterations, cell count, and inflammation that took place during a period of 21 months in a subject with a definite diagnosis of AD and idiopathic Normal Pressure Hydrocephalus (iNPH). Four neuronal markers, i.e., synaptophysin, microtubule associated protein 2, non-phosphorylated neurofilament H (SMI32), and embryonic lethal abnormal visual system proteins 3/4 HuC/HuD (HuC/HuD); three microglial markers CD68, Human Leucocytic Antigen DR, ionized calcium-binding adaptor molecule 1, glial fibrillary acidic protein (GFAP); and AD-related markers, hyperphosphorylated τ (HPτ) and amyloid-β (Aβ, Aβ40, Aβ42) were assessed. Morphometrically assessed immunoreactivity of all neuronal and all microglial markers and Aβ42 decreased parallel with an increase in the HPτ in the frontal cortex. The expression of GFAP was stable with time. The first sample was obtained during the therapeutic shunting procedure for iNPH, and the second sample was obtained postmortem. Negligible reactive changes were observed surrounding the shunt channel. In conclusion, in the late stage of AD with time, a neuronal loss, increase in the HPτ, and decrease in Aβ42 and microglia was observed, whereas the expression of GFAP was rather stable. The observations described here suggest that when a brain biopsy has been obtained from an adult subject with iNPH, the assessment of postmortem brain is of major significance.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Biopsy; Brain; Cell Count; Disease Progression; Female; Glial Fibrillary Acidic Protein; Humans; Hydrocephalus, Normal Pressure; Microglia; tau Proteins

The Progression of Dementia and Cognitive Decline in a Dutch 2-Year Cohort Study of People with Young-Onset Dementia. - Gerritsen, Adrie A J; Bakker, Christian; Verhey, Frans R J; Bor, Hans; Pijnenburg, Yolande A L; de Vugt, Marjolein E; Koopmans, Raymond T C M (J Alzheimers Dis, 2018)
BACKGROUND: The progression of dementia in people with young-onset dementia (YOD) is relatively unknown. OBJECTIVE: To investigate the progression of dementia and cognitive decline in the three most common subtypes in YOD and to explore which factors are associated with this course. METHODS: The course of dementia was examined in 198 people with YOD. The primary outcomes were cognitive function, as assessed by the Mini-Mental State Examination (MMSE) and dementia severity, as assessed by the Global Deterioration Scale (GDS). Mixed-model analyses were used to explore factors associated with the course of dementia of the diagnostic sub-types. RESULTS: The mean overall two-year progression of dementia severity was 0.9 GDS points, this was a statistically significant change (p = 0.012) and was not significant different for the three dementia subtypes. The mean overall two-year decline in cognitive function was 1.6 points on the MMSE. The differences in cognitive decline were statistically significant (p = 0.046) among the three diagnosis groups, AD participants showed the greatest decline, of 2.3 points. In addition to lower education (p = 0.010), higher scores on the Neuropsychiatric Inventory (NPI) sub-syndromes psychosis (p < 0.001) and hyperactivity (p = 0.002) were associated with higher rates of cognitive decline. In contrast, higher scores on the NPI affect cluster were associated with lower levels of cognitive decline (p < 0.001). CONCLUSION: Different YOD subtypes show different rates of decline in cognitive functioning, and this decline seems less progressive compared to those observed in studies in late-onset AD. Further research is needed to evaluate whether managing neuropsychiatric symptoms can positively influence the decline of cognitive function.

The Progression of Neuropsychiatric Symptoms in Alzheimer's Disease During a Five-Year Follow-Up: Kuopio ALSOVA Study. - Hallikainen, Ilona; Hongisto, Kristiina; Välimäki, Tarja; Hänninen, Tuomo; Martikainen, Janne; Koivisto, Anne M (J Alzheimers Dis, 2018)
BACKGROUND: An improved understanding of the role of neuropsychiatric symptoms (NPS) in the course of Alzheimer's disease (AD) has recently emerged. NPS lead to hospitalization and caregiver stress, but are more variable during the course of the disease than other symptoms. Knowledge about the role of specific NPS in disease progression and prognosis is especially limited. OBJECTIVES: To examine the relationship between specific NPS and AD severity during a 5-year follow-up period, and to determine which baseline NPS predict AD progression. METHODS: 236 persons with very mild (CDR 0.5) or mild (CDR 1) AD at baseline and their caregivers were followed up for five years as part of the ALSOVA study. The Neuropsychiatric Inventory was used to assess NPS, and AD severity progression was measured with the Clinical Dementia Rating Sum of Boxes. Data was analyzed with Generalized Estimated Equations and Linear Mixed Models. RESULTS: The baseline NPS that best predicted AD progression were delusions, agitation, and aberrant motor behavior, while AD severity during follow-up was associated with hallucinations, delusions, agitation, apathy, aberrant motor behavior, and sleep and appetite disturbances. CONCLUSIONS: Persons with mild AD presenting delusions, agitation, and aberrant motor behavior at the time of diagnosis could have a more rapidly progressing disease, and some NPS are associated with AD severity. These results highlight the importance of evaluating NPS at the time of AD diagnosis, and the need to offer additional support to persons presenting delusions, agitation and aberrant motor behavior, and their caregivers.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Anxiety; Caregivers; Delusions; Disease Progression; Female; Finland; Hallucinations; Humans; Linear Models; Male; Motor Activity; Multivariate Analysis; Neuropsychological Tests; Severity of Illness Index

The Progressive Acalculia Presentation of Parietal Variant Alzheimer's Disease. - Mendez, Mario F; Moheb, Negar; Desarzant, Randy E; Teng, Edmond H (J Alzheimers Dis, 2018)
BACKGROUND: Many patients with early-onset Alzheimer's disease (EOAD; age of onset <65 years) have non-amnestic presentations involving language (logopenic primary progressive aphasia, lvPPA), visuospatial abilities (posterior cortical atrophy, PCA), and even asymmetric symptoms consistent with corticobasal syndrome (CBS). An inferior parietal lobule variant of EOAD commonly presents with progressive difficulty with calculations. METHODS: We reviewed 276 EOAD patients for presentations with predominant acalculia. These patients were diagnosed with clinically probable Alzheimer's disease (AD) verified by positron emission tomography (PET) or cerebrospinal fluid amyloid-β or tau biomarkers. RESULTS: We identified 18 (9M/9F) (6.5%) EOAD patients with progressive acalculia that did not meet most criteria for lvPPA, visual PCA, or CBS. Their ages of onset and presentation were 56.6 (5.0) and 59.4 (6.5), respectively. Their acalculia was consistent with a primary acalculia ("anarithmetia") not explained by language or visuospatial impairments. Many also had anomia (14/18), ideomotor apraxia (13/18), and the complete Gerstmann's syndrome (7/18). Visual analysis of their diverse magnetic resonance imaging disclosed biparietal atrophy, disproportionately worse on the left. CONCLUSIONS: Primary acalculia may be the most common manifestation of an inferior parietal presentation of EOAD affecting the left intraparietal sulcus. This parietal variant also commonly involves progressive anomia, ideomotor apraxia, and other elements of Gerstmann's syndrome. The early recognition of patients with this variant, which is distinguishable from lvPPA, visual PCA, or CBS, would be facilitated by its recognition as a unique subtype of EOAD.

Prominent Non-Memory Deficits in Alzheimer's Disease Are Associated with Faster Disease Progression. - Scheltens, Nienke M E; Tijms, Betty M; Heymans, Martijn W; Rabinovici, Gil D; Cohn-Sheehy, Brendan I; Miller, Bruce L; Kramer, Joel H; Wolfsgruber, Steffen; Wagner, Michael; Kornhuber, Johannes; Peters, Oliver; Scheltens, Philip; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is a heterogeneous disorder. OBJECTIVE: To investigate whether cognitive AD subtypes are associated with different rates of disease progression. METHODS: We included 1,066 probable AD patients from the Amsterdam Dementia Cohort (n = 290), Alzheimer's Disease Neuroimaging Initiative (n = 268), Dementia Competence Network (n = 226), and University of California, San Francisco (n = 282) with available follow-up data. Patients were previously clustered into two subtypes based on their neuropsychological test results: one with most prominent memory impairment (n = 663) and one with most prominent non-memory impairment (n = 403). We examined associations between cognitive subtype and disease progression, as measured with repeated Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale sum of boxes (CDR sob), using linear mixed models. Furthermore, we investigated mortality risk associated with subtypes using Cox proportional hazard analyses. RESULTS: Patients were 71±9 years old; 541 (51%) were female. At baseline, pooled non-memory patients had worse MMSE scores (23.1±0.1) and slightly worse CDR sob (4.4±0.1) than memory patients (MMSE 24.0±0.1; p < 0.001; CDR sob 4.1±0.1; p < 0.001). During follow-up, pooled non-memory patients showed steeper annual decline in MMSE (-2.8±0.1) and steeper annual increase in CDR sob (1.8±0.1) than memory patients (MMSE - 1.9±0.1; pinteraction<0.001; CDR sob 1.3±0.1; pinteraction<0.001). Furthermore, the non-memory subtype was associated with an increased risk of mortality compared with the memory subtype at trend level (HR = 1.36, CI = 1.00-1.85, p = 0.05). CONCLUSIONS: AD patients with most prominently non-memory impairment show faster disease progression and higher risk of mortality than patients with most prominently memory impairment.

Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer's Disease. - Reddy, P Hemachandra; Manczak, Maria; Yin, XiangLing; Grady, Mary Catherine; Mitchell, Andrew; Tonk, Sahil; Kuruva, Chandra Sekhar; Bhatti, Jasvinder Singh; Kandimalla, Ramesh; Vijayan, Murali; Kumar, Subodh; Wang, Rui; et al. (J Alzheimers Dis, 2018)
The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer's disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on Aβ and curcumin has revealed that curcumin prevents Aβ aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and Aβ in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin's bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Curcumin; Disease Models, Animal; Humans; Mice; Neuroprotective Agents; Randomized Controlled Trials as Topic; Spices

Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau. - Chen, Mei; Song, Hailong; Cui, Jiankun; Johnson, Catherine E; Hubler, Graham K; DePalma, Ralph G; Gu, Zezong; Xia, Weiming (J Alzheimers Dis, 2018)
Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.

Protofibrillar and Fibrillar Amyloid-β Binding Proteins in Cerebrospinal Fluid. - Rahman, M Mahafuzur; Westermark, Gunilla T; Zetterberg, Henrik; Härd, Torleif; Sandgren, Mats (J Alzheimers Dis, 2018)
Aggregation and deposition of misfolded amyloid-β (Aβ) peptide in the brain is central to Alzheimer's disease (AD). Oligomeric, protofibrillar, and fibrillar forms of Aβ are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve Aβ-interacting molecular partners. In a previous study, we identified potential Aβ42 protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of Aβ42 (Aβ42CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to Aβ42 fibrils in AD and non-AD CSF and compared these with protofibrillar Aβ42CC-binding partners. Aβ42 fibrils sequestered 2.4-fold more proteins than Aβ42CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar Aβ-binding proteins represent distinct functional categories. Aβ42CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while Aβ42 fibrils were more likely involved in binding to proteoglycans, growth factors and neuron-associated proteins, e.g., neurexin-1, -2, and -3. Interestingly, 10 brain-enriched proteins were identified among the fibril-binding proteins, while protofibril-extracted proteins had more general expression patterns. Both types of Aβ aggregates bound several extracellular proteins. Additionally, we list a set of CSF proteins that might have potential to discriminate between AD and non-AD CSF samples. The results may be of relevance both for biomarker studies and for studies of Aβ-related toxicity mechanisms.

A Prototype for the Voice Analysis Diagnosis of Alzheimer's Disease. - Martínez-Sánchez, Francisco; Meilán, Juan José G; Carro, Juan; Ivanova, Olga (J Alzheimers Dis, 2018)
BACKGROUND: Speech variations enable us to map the performance of cognitive processes of syntactic, semantic, phonological, and articulatory planning and execution. Speaking is one of the first functions to be affected by neurodegenerative complaints such as Alzheimer's disease (AD), which makes the speech a highly promising biomarker for detecting the illness before the first preclinical symptoms appear. OBJECTIVE: This paper has sought to develop and validate a technological prototype that adopts an automated approach to speech analysis among older people. METHODS: It uses a mathematical algorithm based on certain discriminatory variables to estimate the probability of developing AD. RESULTS AND CONCLUSION: This device may be used at a preclinical stage by non-expert health professionals to determine the likelihood of the onset of AD.

Psychological and Mnemonic Benefits of Nostalgia for People with Dementia. - Ismail, Sanda; Christopher, Gary; Dodd, Emily; Wildschut, Tim; Sedikides, Constantine; Ingram, Tom A; Jones, Roy W; Noonan, Krist A; Tingley, Danielle; Cheston, Richard (J Alzheimers Dis, 2018)
BACKGROUND: Studies with non-clinical populations show that nostalgia increases psychological resources, such as self-esteem and social connectedness. OBJECTIVES: Our objectives were to find out if the benefits of nostalgia in non-clinical populations generalize to people with dementia and if nostalgia facilitates recall of dementia-related information. METHODS: All three experiments recruited participants with mild or moderate levels of dementia. Experiment 1 tested whether nostalgia (compared to control) enhances psychological resources among 27 participants. Experiment 2 used music to induce nostalgia (compared to control) in 29 participants. Experiment 3 compared recall for self-referent dementia statements among 50 participants randomized to either a nostalgia or control condition. Findings across experiments were synthesized with integrative data analysis. RESULTS: Nostalgia (compared to control) significantly increased self-reported social connectedness, meaning in life, self-continuity, optimism, self-esteem, and positive (but not negative) affect (Experiments 1-3). Compared to controls, nostalgic participants also recalled significantly more self-referent dementia-related information (Experiment 3). CONCLUSION: This series of experiments extends social psychological research with non-clinical populations into dementia care, providing evidence that nostalgia significantly enhances psychological resources. The finding that nostalgia increased recall of self-referent statements about dementia suggests that this emotion lends participants the fortitude to face the threat posed by their illness. The finding has potentially important clinical implications both for the development of reminiscence therapy and for facilitating adjustment to a diagnosis of dementia.

Psychological Distress, Self-Beliefs, and Risk of Cognitive Impairment and Dementia. - Sutin, Angelina R; Stephan, Yannick; Terracciano, Antonio (J Alzheimers Dis, 2018)
Depressive symptoms and a history of mental disorders are associated with increased risk for dementia. Less is known about whether other aspects of psychological distress and negative self-beliefs also increase risk. The purpose of this research is to examine 1) whether eight aspects of psychological distress and self-beliefs (anxiety, negative affect, hostility, anger-in, anger-out, hopelessness, pessimism, perceived constraints) are associated with risk of incident dementia and cognitive impairment not dementia (CIND), 2) whether the associations are independent of depressive symptoms and history of a mental health diagnosis, and 3) whether the associations are also independent of behavioral, clinical, and genetic risk factors. A total of 9,913 participants (60% female) from the Health and Retirement Study completed the baseline measures, scored in the non-impaired range of cognition at baseline, and had cognitive status assessed across the 6-8-year follow-up. Baseline measures included eight aspects of psychological distress and self-beliefs, cognitive performance, depressive symptoms, and genetic, clinical, and behavioral risk factors. Participants who scored higher on anxiety, negative affect, hostility, pessimism, hopelessness, and perceived constraints were at a 20-30% increased risk of dementia and a 10-20% increased risk of CIND. The associations held controlling for baseline depressive symptoms, history of a mental health diagnosis, clinical and behavioral risk factors, and genetic risk. Anger-in and anger-out were unrelated to risk of either dementia or CIND. Independent of the core experience of depressed affect, other aspects of negative emotionality and self-beliefs increase risk of mild and severe cognitive impairment, which suggests additional targets of intervention.

Psychometric Properties of Apathy Scales in Dementia: A Systematic Review. - Mohammad, Dana; Ellis, Courtney; Rau, Allison; Rosenberg, Paul B; Mintzer, Jacobo; Ruthirakuhan, Myuri; Herrmann, Nathan; Lanctôt, Krista L (J Alzheimers Dis, 2018)
Apathy is a prevalent and problematic neuropsychiatric symptom in those with dementia that is emerging as a treatment target, necessitating accurate assessment. While many apathy scales are available, not all have been developed for use exclusively in dementia, and psychometric properties may vary across different populations. This systematic review aimed to provide an overview of the psychometric properties of apathy scales used in Alzheimer's disease (AD) and related dementias, as well as rate the methodological quality of supporting studies. In addition, for those scales identified, performance in clinical trials was reviewed. A search was conducted through Medline, Psychinfo, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Articles that reported psychometric properties of an apathy scale in an AD or mixed dementia population were included. Of 15 articles, the methodological quality ratings of the studies ranged from adequate to excellent. Three clinical trials and two pooled analyses of clinical trials were included that used apathy scales evaluated in this review. Three scales emerged. The Neuropsychiatric Inventory apathy subscale (NPI-apathy) and the Apathy Evaluation Scale (AES) had the greatest number of studies evaluating psychometric properties and were also used in the clinical trials and have shown sensitivity to change. The Dementia Apathy Interview and Rating demonstrated excellent values of internal consistency, validity, and reliability for use in an AD population. Future research should address comparative scale performance and assess ability to distinguish subtypes of apathy. Validation may include evaluation of performance against specific imaging defined deficits.

Putative Dementia Cases Fluctuate as a Function of Mini-Mental State Examination Cut-Off Points. - Rosa, Ilka M; Henriques, Ana G; Wiltfang, Jens; da Cruz E Silva, Odete A B (J Alzheimers Dis, 2018)
As the population ages, there is a growing need to quickly and accurately identify putative dementia cases. Many cognitive tests are available; among those commonly used are the Cognitive Dementia Rating (CDR) and the Mini-Mental Status Examination (MMSE). The aim of this work was to compare the validity and reliability of these cognitive tests in a primary care based cohort (pcb-Cohort). The MMSE and the CDR were applied to 568 volunteers in the pcb-Cohort. Distinct cut-off points for the MMSE were considered, namely MMSE 27, MMSE 24, and MMSE PT (adapted for the Portuguese population). The MMSE 27 identified the greatest number of putative dementia cases, and, as determined by the ROC curve, it was the most sensitive and specific of the MMSE cut-offs considered. Putative predictive or risk factors identified included age, literacy, depression, and diabetes mellitus (DM). DM has previously been indicated as a risk factor for dementia and Alzheimer's disease. Comparatively, the MMSE 27 cut-off has the greatest sensibility (94.9%) and specificity (66.3%) when compared to MMSE PT and MMSE 24. Upon comparing MMSE and CDR scores, the latter identified a further 146 putative dementia cases, thus permitting one to propose that in an ideal situation, both tests should be employed. This increases the likelihood of identifying putative dementia cases for subsequent follow up work, thus these cognitive tests represent important tools in patient care. Further, this is a significant study for Portuguese populations, where few of these studies have been carried out.
Keywords: Age Factors; Aged; Aged, 80 and over; Cohort Studies; Community Health Planning; Cross-Sectional Studies; Dementia; Female; Humans; Male; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; ROC Curve

Putative Gonadotropin-Releasing Hormone Agonist Therapy and Dementia: An Application of Medicare Hospitalization Claims Data. - Smith, Mark A; Bowen, Richard L; Nguyen, Richard Q; Perry, George; Atwood, Craig S; Rimm, Alfred A (J Alzheimers Dis, 2018)
BACKGROUND: Estrogen and hormone replacement therapies to reduce Alzheimer's disease (AD) have yielded conflicting results. However, this study proposes that the well-characterized increase in serum gonadotropins following menopause or andropause are accountable for the increased risk of developing AD among the elderly population. OBJECTIVE: To determine the role of gonadotropins in the development of AD and investigate gonadotropin-releasing hormone (GnRH) agonist therapy as a potential preventative and/or disease-modifying approach to AD management. METHODS: Male Medicare beneficiaries aged 67 to 75 and hospitalized with prostate cancer (n = 115,789) were compared to three control groups: men of the same demographics undergoing a cholecystectomy (n = 97,267), herniorrhaphy (n = 68,778), or transurethral prostatectomy (n = 267,691). A proportion of the patients hospitalized with prostate cancer were assumed to have low concentrations of serum gonadotropins and sex steroids as a result of GnRH agonist therapy, while those in the control groups were assumed to have elevated gonadotropin but lowered sex steroid levels that are associated with andropause in this age group. RESULTS: The rates of development of select diagnoses of dementia, including AD, over a twelve-year follow-up period following surgery. When compared to control patients, men hospitalized with prostate cancer have a protection against dementia after twelve years of follow-up, with relative risks ranging from 0.48 to 0.83. CONCLUSION: Patients with prostate cancer are treated with the GnRH analogue leuprolide acetate, our data suggest that leuprolide acetate may be therapeutic for AD via its downregulation of serum gonadotropins.

Pyk2 is a Novel Tau Tyrosine Kinase that is Regulated by the Tyrosine Kinase Fyn. - Li, Chuanzhou; Götz, Jürgen (J Alzheimers Dis, 2018)
The protein tyrosine kinase Pyk2 is encoded by PTK2B, a novel Alzheimer's disease (AD) susceptibility variant, with the PTK2B risk allele being associated with increased mRNA levels, suggestive of increased Pyk2 levels. However, the role of Pyk2, a member of the focal adhesion kinase (FAK) family, in AD pathology and its regulation are largely unknown. To address this, we generated mice with neuronal expression of human Pyk2. Because we had previously reported an association of Pyk2 and hyperphosphorylated tau (a hallmark feature of AD) in human tau transgenic pR5 mice, we also generated Pyk2/tau double-transgenic mice, which exhibit increased tyrosine phosphorylation and accumulation of tau. We further demonstrated that Pyk2 colocalizes, interacts with, and phosphorylates tau in vivo and in vitro. Importantly, although Pyk2 interacts with the established tyrosine-directed tau kinase Fyn, we identified an increased Pyk2 activity in mice which constitutively overexpress Fyn (FynCA), and a decreased activity in mice lacking Fyn (FynKO). Together, our study reveals a novel role for Pyk2 as a direct tyrosine kinase of tau that is active downstream of Fyn. Our analysis may enhance the understanding of how the PTK2B risk allele contributes to tauopathy.

Quality of Life, Care Resource Use, and Costs of Dementia in 8 European Countries in a Cross-Sectional Cohort of the Actifcare Study. - Handels, Ron L H; Sköldunger, Anders; Bieber, Anja; Edwards, Rhiannon Tudor; Gonçalves-Pereira, Manuel; Hopper, Louise; Irving, Kate; Jelley, Hannah; Kerpershoek, Liselot; Marques, Maria J; Meyer, Gabriele; Michelet, Mona; et al. (J Alzheimers Dis, 2018)
BACKGROUND: With 10.5 million people with dementia in Europe and $301 billion associated costs, governments face challenges organizing access to care. OBJECTIVE: To examine the costs related to formal and informal care use and quality of life for people with dementia in eight European countries, and explore the association with unmet needs. METHODS: Cross-sectional data from 451 persons with dementia and their informal caregivers of the Actifcare cohort study were obtained. Formal and informal care use was multiplied by country specific unit prices of services. Needs were measured using the CANE and health-related quality of life (HRQOL) of the person with dementia (both self- and proxy-rated) and informal caregiver's quality of life using EQ-5D-5L, ICECAP-O, DEMQOL-U, and CarerQol utility scores. The association between costs and country, European region, and unmet needs was assessed using multi-level linear regression. RESULTS: Self-rated EQ-5D-5L utility score was higher than proxy-rated (0.84 and 0.71, respectively). Informal caregivers' utility score was 0.84. Across eight countries annual mean costs of formal and informal care were approximately € 17,000. Unmet needs were not associated with annual costs of care, nor with proxy-rated HRQOL, but were associated with self-rated HRQOL. CONCLUSION: We found varying relationships between unmet needs and quality of life, and no association between unmet needs and care costs, although the results were sensitive to various factors. Future research should further investigate the relation between unmet needs, quality of life and costs to generate a better understanding of the effects of (un)timely access to care.

Quantifying the Diagnostic Pathway for Patients with Cognitive Impairment: Real-World Data from Seven European and North American Countries. - Ritchie, Craig W; Black, Christopher M; Khandker, Rezaul K; Wood, Robert; Jones, Eddie; Hu, Xiaohan; Ambegaonkar, Baishali M (J Alzheimers Dis, 2018)
To ensure that patients with dementia and their caregivers receive appropriate treatment and support, early diagnosis is essential but remains challenging. Real-world data from a multi-national, cross-sectional survey of physicians and their patients were analyzed to quantify the diagnostic pathway for dementia, including a focus on severity of patients' cognitive impairment (CI) at the time of symptom onset, referral and subsequent diagnosis. Data were collected for 7,620 patients with CI. Most patients saw a healthcare professional within 1 year of first symptoms and received a diagnosis within 3-7 months of initial consultation. However, only 20% of patients received a diagnosis before their disease progressed beyond the prodromal stage and 23.5% already had moderate CI at diagnosis. These findings show that the goal of identifying and diagnosing CI at the earliest stages of disease is, for many patients, not achieved. Efforts toward public awareness and proactive, earlier detection and intervention, must be maintained-indeed where possible invigorated.

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers. - Ramos de Matos, Mafalda; Ferreira, Catarina; Herukka, Sanna-Kaisa; Soininen, Hilkka; Janeiro, André; Santana, Isabel; Baldeiras, Ines; Almeida, Maria Rosário; Lleo, Alberto; Dols-Icardo, Oriol; Alcolea, Daniel; Benussi, Luisa; et al. (J Alzheimers Dis, 2018)
Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

Quantitative Magnetization Transfer of White Matter Tracts Correlates with Diffusion Tensor Imaging Indices in Predicting the Conversion from Mild Cognitive Impairment to Alzheimer's Disease. - Makovac, Elena; Serra, Laura; Di Domenico, Carlotta; Marra, Camillo; Caltagirone, Carlo; Cercignani, Mara; Bozzali, Marco (J Alzheimers Dis, 2018)
Patients with amnestic mild cognitive impairment (aMCI) have higher probability to develop Alzheimer's disease (AD) than elderly controls. The detection of subtle changes in brain structure associated with disease progression and the development of tools to identify patients at high risk for dementia in a short time is crucial. Here, we used probabilistic white matter (WM) tractography to explore microstructural alterations within the main association, limbic, and commissural pathways in aMCI patients who converted to AD after 1 year follow-up (MCIconverters) and those who remained stable (MCIstable). Both diffusion tensor imaging (DTI) and quantitative magnetization transfer (qMT) parameters have been considered for a comprehensive pathophysiological characterization of the WM damage. Overall, tract-specific parameters derived from qMT and DTI at baseline were able to differentiate aMCI patients who converted to AD from those who remained stable in time. In particular, the qMT exchange rate, RMB0, of the right uncinate fasciculus was significantly decreased in MCIconverters, whereas fractional anisotropy was significantly decreased in the bilateral superior cingulum in MCIconverters compared to MCIstable. These results confirm the involvement of WM and particularly of association fibers in the progression of AD, highlighting disconnection as a potential mechanism.

Quantitative PET and Histology of Brain Biopsy Reveal Lack of Selective Pittsburgh Compound-B Binding to Intracerebral Amyloidoma. - Groot, Colin; Tolboom, Nelleke; Ikonomovic, Milos D; Lammertsma, Adriaan A; Boon, Baayla D C; Barkhof, Frederik; Scheltens, Philip; Klunk, William E; Rozemuller, Annemieke J M; Ossenkoppele, Rik; van Berckel, Bart N M (J Alzheimers Dis, 2018)
This single case study examines selective Pittsburgh compound-B (PiB) binding to an intracerebral light-chain amyloidoma using a 90-minute dynamic [11C]PiB-PET scan and brain biopsy tissue. Parametric non-displaceable binding potential (BPND) images showed low specific binding in the amyloidoma (BPND = 0.23), while relative tracer delivery was adequate (R1 = 0.44). Histology of the tissue revealed strong coloring with Congo-red, thioflavin-S, and X-34, indicating presence of amyloid. However, immunological staining with 6F/3D revealed absence of amyloid-β and histofluorescence of 6-CN-PiB, a highly fluorescent derivative of PiB, was at background levels. Our results suggest that PiB does not detect the atypical amyloid pathology associated with an intracerebral light-chain amyloidoma. These findings are of interest to clinicians and researchers applying [11C]PiB-PET to detect atypical forms of amyloid pathology.

Quantitative Susceptibility Mapping of Amyloid-β Aggregates in Alzheimer's Disease with 7T MR. - Tiepolt, Solveig; Schäfer, Andreas; Rullmann, Michael; Roggenhofer, Elisabeth; Gertz, Hermann-Josef; Schroeter, Matthias L; Patt, Marianne; Bazin, Pierre-Louis; Jochimsen, Thies H; Turner, Robert; Sabri, Osama; Barthel, Henryk (J Alzheimers Dis, 2018)
BACKGROUND: PET imaging is an established technique to detect cerebral amyloid-β (Aβ) plaques in vivo. Some preclinical and postmortem data report an accumulation of redox-active iron near Aβ plaques. Quantitative susceptibility mapping (QSM) at high-field MRI enables iron deposits to be depicted with high spatial resolution. OBJECTIVE: Aim of this study was to examine whether iron and Aβ plaque accumulation is related and thus, whether 7T MRI might be an additive diagnostic tool to Aβ PET imaging. METHODS: Postmortem human Alzheimer's disease (AD) and healthy control (HC) frontal gray matter (GM) was imaged with 7T MRI which resulted in T1 maps and QSM. Aβ plaque load was determined by histopathology. In vivo, 10 Aβ PET-positive AD patients (74.1±6.0a) and 10 Aβ PET-negative HCs (67.1±4.4a) underwent 7T MR examination and QSM maps were analyzed. Severity of cognitive deficits was determined by MMSE. RESULTS: Postmortem, the susceptibility of Aβ plaque-containing GM were higher than those of Aβ plaque-free GM (0.011±0.002 versus - 0.008±0.003 ppm, p < 0.001). In vivo, only the bilateral globus pallidus showed significantly higher susceptibility in AD patients compared to HCs (right: 0.277±0.018 versus - 0.009±0.009 ppm; left: 0.293±0.014 versus - 0.007±0.012 ppm, p < 0.0001). The pallidal QSM values were negatively correlated with those of the MMSE (r = - 0.69, p = 0.001). CONCLUSION: The postmortem study revealed significant susceptibility differences between the Aβ plaque-containing and Aβ plaque-free GM, whereas in vivo only the QSM values of the globus pallidus differed significantly between AD and HC group. The pallidal QSM values correlated with the severity of cognitive deficits. These findings encourage efforts to optimize the 7T-QSM methodology.

Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer's Disease. - Yan, Tingxiang; Wang, Luwen; Gao, Ju; Siedlak, Sandra L; Huntley, Mikayla L; Termsarasab, Pichet; Perry, George; Chen, Shu G; Wang, Xinglong (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles (NFTs), senile plaques (SPs), and a progressive loss of neuronal cells in selective brain regions. Rab10, a small Rab GTPase involved in vesicular trafficking, has recently been identified as a novel protein associated with AD. Interestingly, Rab10 is a key substrate of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine protein kinase genetically associated with the second most common neurodegenerative disease Parkinson's disease. However, the phosphorylation state of Rab10 has not yet been investigated in AD. Here, using a specific antibody recognizing LRRK2-mediated Rab10 phosphorylation at the amino acid residue threonine 73 (pRab10-T73), we performed immunocytochemical analysis of pRab10-T73 in hippocampal tissues of patients with AD. pRab10-T73 was prominent in NFTs in neurons within the hippocampus in all cases of AD examined, whereas immunoreactivity was very faint in control cases. Other characteristic AD pathological structures including granulovacuolar degeneration, dystrophic neurites and neuropil threads also contained pRab10-T73. The pRab10-T73 immunoreactivity was diminished greatly following dephosphorylation with alkaline phosphatase. pRab10-T73 was further found to be highly co-localized with hyperphosphorylated tau (pTau) in AD, and demonstrated similar pathological patterns as pTau in Down syndrome and progressive supranuclear palsy. Although pRab10-T73 immunoreactivity could be noted in dystrophic neurites surrounding SPs, SPs were largely negative for pRab10-T73. These findings indicate that Rab10 phosphorylation could be responsible for aberrations in the vesicle trafficking observed in AD leading to neurodegeneration.

Rapidly Progressive Alzheimer's Disease: Contributions to Clinical-Pathological Definition and Diagnosis. - Abu-Rumeileh, Samir; Capellari, Sabina; Parchi, Piero (J Alzheimers Dis, 2018)
Rapidly progressive Alzheimer's disease (rpAD) has recently been recognized as a clinical disease subtype characterized by rapidly progressive cognitive decline and/or short disease duration, and the possible occurrence of early focal neurological signs. Consistently, rpAD represents a relatively frequent alternative diagnosis among cases referred as possible or probable Creutzfeldt-Jakob disease (CJD) to surveillance centers for prion disease worldwide. Indeed, the early clinical differential diagnosis between the two disorders can be challenging given the partial overlap in clinical features and cerebrospinal fluid (CSF) levels of the protein surrogate markers 14-3-3 and total-tau. Although typical AD and rpAD seem to share the neuropathological core features, recent evidence suggests that a distinctive molecular signature involving the structure of amyloid-β aggregates and the proteomic landscape of amyloid plaques may distinguish rpAD from typical AD. Here we review clinical, neuropathologic, and molecular features and diagnostic findings, including CSF biomarker data, reported to date in rpAD. Furthermore, we summarize the main clinic-pathological and laboratory features of 27 autopsy confirmed cases of rpAD referred to our center. The results of this retrospective analysis, while largely confirming previously published genetic, clinical, and neuropathologic data, suggest a higher prevalence of moderate to severe cerebral amyloid angiopathy in rpAD compared to typical AD, a finding to explore further and validate in a larger patient group.

Rapidly Progressive Alzheimer's Disease in Two Distinct Autopsy Cohorts. - Pillai, Jagan A; Appleby, Brian S; Safar, Jiri; Leverenz, James B (J Alzheimers Dis, 2018)
BACKGROUND: A rapidly progressive phenotype of Alzheimer's disease (AD) has been described in some prion disease cohorts. Limited information regarding rapidly progressive AD (rpAD) is available from longitudinal national cohorts. OBJECTIVE: To compare the clinical characteristics of rpAD in two different national cohorts. METHODS: A retrospective analysis was performed on AD subjects with available neuropathology in the National Alzheimer's Coordinating Center (NACC) database and among neuropathologically characterized AD cases from the National Prion Disease Pathology Surveillance Center (NPDPSC) that were evaluated for suspected prion disease. In the NACC cohort, rpAD was delineated by the lower 10th percentile of follow up duration from pre-dementia to death duration among subjects meeting pathological diagnosis of AD. RESULTS: rpAD from the NPDPSC had a shorter mean symptom duration than the NACC identified rpAD cases (11.6 months versus 62.4 months) and were also younger at the time of their death (60.0 versus 81.8 years). NACC identified rpAD subjects, beginning from a predementia stage, had slower rate of MMSE change per year than NPDPSC cases (2.5 versus 6.0 points). CONCLUSIONS: rpAD constitute an important subset of AD subjects in whom a rapid course of symptomatic clinical decline is noted, as confirmed in both national cohorts. rpAD was best characterized by survival time (≤3 years), as there were clear differences between the rpAD cohorts in terms of symptom duration, age at death, and MMSE change per year, likely due to the strong selection biases. rpAD could shed light on the biology of rate of progression in AD.

Rare Variants in PLD3 Increase Risk for Alzheimer's Disease in Han Chinese. - Tan, Meng-Shan; Zhu, Jun-Xia; Cao, Xi-Peng; Yu, Jin-Tai; Tan, Lan (J Alzheimers Dis, 2018)
Next-generation sequencing studies had reported that a rare coding variant p.V232M in PLD3 was associated with Alzheimer's disease (AD) and a two-fold increased AD risk in European cohorts. To test whether coding region variants of PLD3 were associated with AD in a large Han Chinese cohort, we performed sequencing to analyze all exons of PLD3, and demonstrated that rare variants p.I163M and c.1020-8G>A conferred considerable risk of late-onset AD (LOAD) in our cohort. Meanwhile, the previously reported p.V232M variant was identified in our AD group. These findings indicate that rare variants of PLD3 may play an important role in LOAD in northern Han Chinese.

Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer's (HEART) Trial. - Wharton, Whitney; Goldstein, Felicia C; Tansey, Malú G; Brown, Alexandra L; Tharwani, Sonum D; Verble, Danielle D; Cintron, Amarallys; Kehoe, Patrick G (J Alzheimers Dis, 2018)
Research indicates that certain antihypertensive medications alter Alzheimer's disease (AD) biomarkers in Caucasians. The renin angiotensin system (RAS) regulates blood pressure (BP) in the body and the brain and may directly influence AD biomarkers, including amyloid-β (Aβ) neuropathology, cerebral blood flow (CBF), and inflammatory markers. This hypothesis is supported by studies, including ours, showing that antihypertensives targeting the RAS reduce the risk and slow the progression of AD in Caucasians. While mounting evidence supports a protective role of RAS medications in Caucasians, this mechanism has not been explored in African Americans. To assess the mechanism by which RAS medications modify the brain RAS, cerebrospinal fluid (CSF) Aβ, CBF, and inflammatory markers in African Americans, we are conducting an eight month, Phase Ib randomized, placebo controlled trial, enrolling 60 middle-aged (45-70 years), non-demented individuals, at risk for AD by virtue of a parental history. Participants include normotensive and treated hypertensives that have never been exposed to a RAS medication. Participants are randomized (1 : 1:1) by gender and BP medication use (yes/no) to one of three groups: placebo, or 20 mg, or 40 mg telmisartan (Micardis), to determine the dose required to penetrate the CNS. Our overarching hypothesis is that, compared to placebo, both doses of telmisartan will penetrate the CNS and produce salutary, dose dependent effects on the brain RAS as well as CSF Aβ, CBF, and CSF inflammatory markers in African Americans, over eight months. This manuscript describes the trial rationale and design.
Keywords: African Americans; Aged; Alzheimer Disease; Amyloid beta-Peptides; Antihypertensive Agents; Biomarkers; Blood Pressure; Brain; Clinical Trials, Phase I as Topic; Female; Georgia; Humans; Linear Models; Male; Middle Aged; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Telmisartan

The Rationale and Design of the Reducing Pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR) Trial. - Kehoe, Patrick G; Blair, Peter S; Howden, Beth; Thomas, David L; Malone, Ian B; Horwood, Jeremy; Clement, Clare; Selman, Lucy E; Baber, Hannah; Lane, Athene; Coulthard, Elizabeth; Passmore, Anthony Peter; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Anti-hypertensives that modify the renin angiotensin system may reduce Alzheimer's disease (AD) pathology and reduce the rate of disease progression. OBJECTIVE: To conduct a phase II, two arm, double-blind, placebo-controlled, randomized trial of losartan to test the efficacy of Reducing pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR). METHODS: Men and women aged at least 55 years with mild-to-moderate AD will be randomly allocated 100 mg encapsulated generic losartan or placebo once daily for 12 months after successful completion of a 2-week open-label phase and 2-week placebo washout to establish drug tolerability. 228 participants will provide at least 182 subjects with final assessments to provide 84% power to detect a 25% difference in atrophy rate (therapeutic benefit) change over 12 months at an alpha level of 0.05. We will use intention-to-treat analysis, estimating between-group differences in outcomes derived from appropriate (linear or logistic) multivariable regression models adjusting for minimization variables. RESULTS: The primary outcome will be rate of whole brain atrophy as a surrogate measure of disease progression. Secondary outcomes will include changes to 1) white matter hyperintensity volume and cerebral blood flow; 2) performance on a standard series of assessments of memory, cognitive function, activities of daily living, and quality of life. Major assessments (for all outcomes) and relevant safety monitoring of blood pressure and bloods will be at baseline and 12 months. Additional cognitive assessment will also be conducted at 6 months along with safety blood pressure and blood monitoring. Monitoring of blood pressure, bloods, and self-reported side effects will occur during the open-label phase and during the majority of the post-randomization dispensing visits. CONCLUSION: This study will identify whether losartan is efficacious in the treatment of AD and whether definitive Phase III trials are warranted.
Keywords: Activities of Daily Living; Alzheimer Disease; Antihypertensive Agents; Atrophy; Blood Pressure Monitors; Brain; Clinical Trials, Phase II as Topic; Disease Progression; Double-Blind Method; Female; Humans; Losartan; Magnetic Resonance Imaging; Male; Multivariate Analysis; Quality of Life; Randomized Controlled Trials as Topic; Regression Analysis; Renin-Angiotensin System

The Rationale Behind the New Alzheimer's Disease Conceptualization: Lessons Learned During the Last Decades. - Molinuevo, José Luis; Minguillon, Carolina; Rami, Lorena; Gispert, Juan Domingo (J Alzheimers Dis, 2018)
In the last decades, progress in neuroimaging techniques and cerebrospinal fluid assays has enabled the characterization of several Alzheimer's disease (AD) biomarkers. This knowledge has shifted the conceptualization of AD from a clinical-pathological construct, where its diagnosis required the presence of dementia with distinct pathologic features, toward a clinical-biological one that recognizes AD as a pathological continuum with a clinical picture that ranges from normal cognition to a dementia stage. Specifically, AD is now divided into three stages: preclinical (abnormal biomarkers and no or only subtle cognitive impairment), mild cognitive impairment or prodromal AD (abnormal pathophysiological biomarkers and episodic memory impairment), and dementia (abnormal biomarkers and clear cognitive and functional impairment). The possibility of assessing AD pathophysiology in vivo before the onset of clinical symptoms in the preclinical stage provides the unprecedented opportunity to intervene at earlier stages of the continuum in secondary prevention trials. Currently, large cohort studies of cognitively healthy participants are undergoing with the main aim of disentangling the natural history of AD to identify individuals with an increased risk of developing AD in the near future to be recruited in these clinical trials. In this paper, we review how the concept of AD has changed over the years as well as discuss the implications of this conceptual change.

Rbfox3/NeuN Regulates Alternative Splicing of Tau Exon 10. - Gu, Jianlan; Chen, Feng; Chu, Dandan; Lu, Ying; Iqbal, Khalid; Gong, Cheng-Xin; Liu, Fei (J Alzheimers Dis, 2018)
Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau or 4R-tau, which are under developmental regulation. Dysregulation of tau exon 10 splicing is sufficient to cause neurodegenerative disorders. The RNA-binding Fox3 (Rbfox3), identified as NeuN, regulates RNA processing. However, whether Rbfox3/NeuN regulates tau exon 10 splicing is unknown. In the present study, we found that the developmental expression of 4R-tau coincided with the expression of Rbfox3 in rat brains. Rbfox3 enhanced tau exon 10 inclusion. Tau intron 10 contains UGCAUG, the conservative binding sequence of Rbfox3. Intron 10 of tau pre-mRNA was co-immunoprecipitated by Rbfox3/NeuN. Deletion mutants of the RNA recognition motif (RRM) or three RNA-binding sites of the RRM in Rbfox3/NeuN failed to enhance tau exon 10 inclusion. Rbfox3, specifically expressed in the fetal brain, did not affect tau exon 10 splicing. The level of Rbfox3/NeuN was reduced and was associated with the ratio of 4R-tau/3R-tau in the excitotoxic mouse brains induced by kainic acid. These findings suggest that Rbfox3/NeuN regulates the alternative splicing of tau exon 10 and that decreased Rbfox3/NeuN may lower the ratio of 4R-tau/3R-tau.

Reaction of Amyloid-β Peptide Antibody with Different Infectious Agents Involved in Alzheimer's Disease. - Vojdani, Aristo; Vojdani, Elroy; Saidara, Evan; Kharrazian, Datis (J Alzheimers Dis, 2018)
As early as the 1980s, molecular virologist Ruth Itzhaki began to investigate if there was a causal connection between infections and neurodegenerative disorder. Although the theory has yet to be universally embraced, in 2016 Itzhaki and 33 other scientists from all over the world published a review article in this very journal presenting evidence for the causal role of pathogens in Alzheimer's disease (AD). Exactly how and in what way pathogens affect the induction of AD has yet to be determined, but one possible answer may involve the cross-reactivity of different pathogens with amyloid-β (Aβ). Aβ autoantibodies have been detected in the serum and cerebrospinal fluid of AD patients and in some healthy individuals. In the present study our major goal was to investigate whether antibodies made against Aβ would react both with other brain proteins as well as pathogens associated with AD as a result of molecular mimicry or the binding of bacterial toxins to Aβ42. Our study used a specific monoclonal antibody made against Aβ42, which not only reacted strongly with Aβ42, tau protein, and α-synuclein, but also had from weak to strong reactions with 25 different pathogens or their molecules, some of which have been associated with AD. The homology between peptide stretches of microbial origin and proteins involved in AD could be a mechanism by which antibodies to homologous peptides mount attacks against autoantigens in AD. We concluded that bacterial molecules bind to Aβ protein, forming small oligomers, then encasing pathogens and their molecules to form amyloid plaques, the tell-tale markers of AD. Conversely, these same Aβ peptides induce the production of antibodies to both Aβ42 and bacterial molecules, which may inhibit bacterial pathogenesis, but in the process may promote amyloid plaque formation.

Real World Recruiting of Older Subjects with Mild Cognitive Impairment for Exercise Trials: Community Readiness is Pivotal. - Sanders, Marit L; Stuckenschneider, Tim; Devenney, Kate E; Lawlor, Brian; Schneider, Stefan; Olde Rikkert, Marcel G M (J Alzheimers Dis, 2018)
Prevention trials in subjects with mild cognitive impairment (MCI), especially lifestyle interventions, can be difficult to carry out, particularly the recruitment and retention of subjects. We experienced these challenges in our multi-site one-year exercise trial in MCI, NeuroExercise. Trial recruitment rates differed significantly across sites; the non-medical sport university site, providing free access to a range of group exercise in a sports environment, proved far more successful than memory clinics linked to hospitals. This suggests that non-medical settings and a non-medical research community facilitating physical activities may be important factors in recruitment of subjects with MCI for large prevention trials.
Keywords: Aged; Cognitive Dysfunction; Europe; Exercise; Female; Humans; Life Style; Male; Middle Aged; Patient Selection

Real-World, Multinational, Retrospective Observational Survey of the ADAS-Cog and Associations with Healthcare Resource Utilization in Patients with Alzheimer's Disease. - Ritchie, Craig W; Khandker, Rezaul K; Pike, James; Black, Christopher M; Jones, Eddie; Ambegaonkar, Baishali M (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is one of the most costly conditions, both economically and regarding patient disability and dependency. The huge costs coupled with the predicted increase in prevalence worldwide are likely to challenge healthcare systems in the future. The classic version of the Alzheimer's Disease Assessment Scale-Cognition subscale (ADAS-Cog) is generally seen as the current gold standard primary outcome measure of cognitive symptom progression in dementia clinical trials. OBJECTIVE: This study evaluated the relationship between ADAS-Cog scores as a measure of clinical progression and the healthcare resource utilization (HCRU)-measured burden of cognitive impairment in patients with mild cognitive impairment, AD, or suspected AD in the real world. METHODS: A retrospective observational survey of physicians and their consulting patients with multiple ADAS-Cog scores. Regression models were constructed for HCRU variables (e.g., consultations, hospitalizations, caregiving requirements) with ADAS-Cog rate of change, baseline ADAS-Cog, and their interaction included as exposure variables. RESULTS: 651 patient records were completed by 154 physicians. Approximately 70% of patients had mild to moderate dementia. In 56.7% of patients, clinical progression was maintained/stable from baseline. Mean change in ADAS-Cog (adjusted to 12 months) was 2.8 points and change scores increased with increasing dementia severity. Most HCRU variables increased significantly (p < 0.05; joint test) with increasing ADAS-Cog scores (indexing clinical deterioration). CONCLUSION: The results suggest that further understanding the relationship between HCRU and ADAS-Cog changes in real-world clinical practice could potentially provide a baseline upon which the success of disease-modifying, as well as newer symptomatic, dementia therapies can be judged.

Reappraisal of Aβ40 and Aβ42 Peptides Measurements in Cerebrospinal Fluid of Patients with Alzheimer's Disease. - Fiorini, Michele; Bongianni, Matilde; Benedetti, Maria Donata; Monaco, Salvatore; Zanusso, Gianluigi (J Alzheimers Dis, 2018)
Cerebrospinal fluid (CSF) biomarkers are currently included in the diagnostic criteria for Alzheimer's disease (AD), in particular, decreased concentrations of amyloid-β peptide 1-42 (Aβ42) in the CSF, coupled with increased levels of tau and phosphorylated tau proteins, are supportive of AD diagnosis. To date, the quantification of Aβ42 levels with antibody-dependent immunoassay shows a marked variability among different laboratories and is also affected by different pre-analytical factors, suggesting that part of Aβ42 peptides might be aggregated and thus undetected by antibodies. To bypass an antibody-dependent measurement, we determined the Aβ40 and Aβ42 levels by immunoblot. We analyzed CSF samples from 35 patients with clinical diagnosis of probable AD and from 15 age-matched normal controls; CSF Aβ levels were determined by two different ELISA kits and by immunoblot analysis. Aβ40 levels measured by ELISA were comparable to those obtained by immunoblot, whereas CSF concentrations of Aβ42 measured by ELISA were significantly lower compared to values obtained by immunoblot quantification. Biochemical analysis, following 1D- and 2D-PAGE analysis, showed that the qualitative composition of Aβ peptides in the CSF is similar in AD and controls but different from that of AD brain tissues. Moreover, sedimentation velocity in sucrose gradient of CSF and brain homogenate from AD demonstrated that Aβ42 in CSF is different from Aβ42 in brain in terms of solubility and aggregation state.

Reduced Cerebrovascular Reserve Capacity as a Biomarker of Microangiopathy in Alzheimer's Disease and Mild Cognitive Impairment. - Urbanova, Barbora Soukupova; Schwabova, Jaroslava Paulasova; Magerova, Hana; Jansky, Petr; Marková, Hana; Vyhnálek, Martin; Laczó, Jan; Hort, Jakub; Tomek, Ales (J Alzheimers Dis, 2018)
BACKGROUND: Cerebral microangiopathy in Alzheimer's disease (AD) causes chronic hypoperfusion and probably accelerates neurodegenerative changes. OBJECTIVE: We hypothesize microvascular impairment could be present already in mild cognitive impairment (MCI) and can be revealed using transcranial color-coded sonography (TCCS) and the breath-holding maneuver. METHODS: Three groups of subjects (AD in the stage of dementia, MCI, and cognitively normal controls) with detailed neuropsychological testing and low cerebrovascular burden (no history of stroke, no intra- or extracranial artery stenoses, and no severe vascular lesions on brain MRI), underwent a TCCS assessment of peak systolic (PSV), mean flow (MFV), and end diastolic velocities (EDV) and resistance and pulsatility indices (RI, PI) in large intracranial vessels bilaterally. Cerebrovascular reserve capacity was assessed using the breath-holding index (BHI) in middle cerebral artery (MCA) bilaterally. The ultrasound parameters were compared between the groups, correlated with neuropsychological tests, and compared between amnestic and non-amnestic MCI subtypes. RESULTS: Fourteen AD (3 males, 67.9±11.1 years, MMSE 18.0±4.6), 24 MCI (13 males, 71.9±7.3 years, MMSE 28.0±1.6), and 24 risk factor-matched controls (14 males, 67.8±6.4 years, MMSE 29.1±1.2) were enrolled. Significant differences were found between AD and controls in MFV, EDV, RI, PI in right MCA after breath holding, in PSV, MFV, EDV in left MCA after breath holding, and in BHI on the left side. The left BHI correlated positively with verbal memory test. CONCLUSION: Results show decreased cerebrovascular reserve capacity in AD as a sign of impaired cerebral hemodynamic status without severe underlying atherosclerosis. This can be identified using TCCS and BHI.

Reduced Gray Matter Volume of the Thalamus and Hippocampal Region in Elderly Healthy Adults with no Impact of APOE ɛ4: A Longitudinal Voxel-Based Morphometry Study. - Squarzoni, Paula; Duran, Fabio Luis Souza; Busatto, Geraldo F; Alves, Tania Correa Toledo de Ferraz (J Alzheimers Dis, 2018)
BACKGROUND: Many cross-sectional voxel-based morphometry (VBM) investigations have shown significant inverse correlations between chronological age and gray matter (GM) volume in several brain regions in healthy humans. However, few VBM studies have documented GM decrements in the healthy elderly with repeated MRI measurements obtained in the same subjects. Also, the extent to which the APOE ɛ4 allele influences longitudinal findings of GM reduction in the healthy elderly is unclear. OBJECTIVE: Verify whether regional GM changes are associated with significant decrements in cognitive performance taking in account the presence of the APOE ɛ4 allele. METHODS: Using structural MRI datasets acquired in 55 cognitively intact elderly subjects at two time-points separated by approximately three years, we searched for voxels showing significant GM reductions taking into account differences in APOE genotype. RESULTS: We found global GM reductions as well as regional GM decrements in the right thalamus and left parahippocampal gyrus (p < 0.05, family-wise error corrected for multiple comparisons over the whole brain). These findings were not affected by APOE ɛ4. CONCLUSIONS: Irrespective of APOE ɛ4, longitudinal VBM analyses show that the hippocampal region and thalamus are critical sites where GM shrinkage is greater than the degree of global volume reduction in healthy elderly subjects.
Keywords: Aged; Aging; Apolipoprotein E4; Atrophy; Cross-Sectional Studies; Female; Gray Matter; Healthy Volunteers; Hippocampus; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Organ Size; Thalamus

Regional Distribution, Asymmetry, and Clinical Correlates of Tau Uptake on [18F]AV-1451 PET in Atypical Alzheimer's Disease. - Tetzloff, Katerina A; Graff-Radford, Jonathan; Martin, Peter R; Tosakulwong, Nirubol; Machulda, Mary M; Duffy, Joseph R; Clark, Heather M; Senjem, Matthew L; Schwarz, Christopher G; Spychalla, Anthony J; Drubach, Daniel A; Jack, Clifford R; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Despite common pathology, Alzheimer's disease (AD) can have multiple clinical presentations which pathological studies suggest result from differences in the regional distribution of tau pathology. Positron emission tomography (PET) ligands are now available that can detect tau proteins in vivo and hence can be used to investigate the biological mechanisms underlying atypical AD. OBJECTIVE: To assess regional patterns of tau uptake on PET imaging in two atypical AD variants, posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA). METHODS: Eighteen PCA and 19 lvPPA subjects that showed amyloid-β deposition on PET underwent tau-PET imaging with [18F]AV-1451. Group comparisons of tau uptake in PCA and lvPPA were performed using voxel-level and regional-level analyses. We also assessed the degree of lobar tau asymmetry and correlated regional tau uptake to age and performance on clinical evaluations. RESULTS: Both syndromes showed diffuse tau uptake throughout all cortical regions, although PCA showed greater uptake in occipital regions compared to lvPPA, and lvPPA showed greater uptake in left frontal and temporal regions compared to PCA. While lvPPA showed predominant left-asymmetric tau deposition, PCA was more bilateral. Younger subjects showed greater tau uptake bilaterally in frontal and parietal lobes than older subjects, and sentence repetition, Boston naming test, simultanagnosia, and visuoperceptual function showed specific regional tau correlates. CONCLUSION: Tau deposition is closely related to clinical presentation in atypical AD with age playing a role in determining the degree of cortical tau deposition.

Regional White Matter Hyperintensity Influences Grey Matter Atrophy in Mild Cognitive Impairment. - Vipin, Ashwati; Foo, Heidi Jing Ling; Lim, Joseph Kai Wei; Chander, Russell Jude; Yong, Ting Ting; Ng, Adeline Su Lyn; Hameed, Shahul; Ting, Simon Kang Seng; Zhou, Juan; Kandiah, Nagaendran (J Alzheimers Dis, 2018)
The association between cerebrovascular disease pathology (measured by white matter hyperintensities, WMH) and brain atrophy in early Alzheimer's disease (AD) remain to be elucidated. Thus, we investigated how WMH influence neurodegeneration and cognition in prodromal and clinical AD. We examined 51 healthy controls, 35 subjects with mild cognitive impairment (MCI), and 30 AD patients. We tested how total and regional WMH is related to specific grey matter volume (GMV) reductions in MCI and AD compared to controls. Stepwise regression analysis was further performed to investigate the association of GMV and regional WMH volume with global cognition. We found that total WMH volume was highest in AD but showed the strongest association with lower GMV in MCI. Frontal and parietal WMH had the most extensive influence on GMV loss in MCI. Additionally, parietal lobe WMH volume (but not hippocampal atrophy) was significantly associated with global cognition in MCI while smaller hippocampal volume (but not WMH volume) was associated with lower global cognition in AD. Thus, although WMH volume was highest in AD subjects, it had a more pervasive influence on brain structure and cognitive impairment in MCI. Our study thus highlights the importance of early detection of cerebrovascular disease, as its intervention at the MCI stage might potentially slow down neurodegeneration.

Relationship Between Amyloid-β Positivity and Progression to Mild Cognitive Impairment or Dementia over 8 Years in Cognitively Normal Older Adults. - Dang, Christa; Harrington, Karra D; Lim, Yen Ying; Ames, David; Hassenstab, Jason; Laws, Simon M; Yassi, Nawaf; Hickey, Martha; Rainey-Smith, Stephanie; Robertson, Joanne; Sohrabi, Hamid R; Salvado, Olivier; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Preclinical Alzheimer's disease (AD) is defined by cerebral amyloid-β positivity (Aβ+) in cognitively normal (CN) older adults. OBJECTIVE: To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study. METHODS: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ+, APOEɛ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years. RESULTS: 17.7% Aβ+ and 8.1% Aβ-progressed over 8 years (OR: 2.43). Risk of progression for Aβ+ was 65-104% greater than Aβ-. Aβ+ APOEɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ4 carriage (HR: 2.63); only age was a significant risk factor in Aβ-(HR: 1.09). Aβ-progressors were not near the threshold for Aβ+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. CONCLUSION: Aβ+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOEɛ4 carriage provides further predictive value in the presence of Aβ+. These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age.

Relationship Between Body Mass Index, ApoE4 Status, and PET-Based Amyloid and Neurodegeneration Markers in Amyloid-Positive Subjects with Normal Cognition or Mild Cognitive Impairment. - Blautzik, Janusch; Kotz, Sebastian; Brendel, Matthias; Sauerbeck, Julia; Vettermann, Franziska; Winter, Yaroslav; Bartenstein, Peter; Ishii, Kazunari; Rominger, Axel (J Alzheimers Dis, 2018)
Body weight loss in late-life is known to occur at a very early stage of Alzheimer's disease (AD). Apolipoprotein E4 (ApoE4) represents a major genetic risk factor for AD and is linked to an increased cortical amyloid-β (Aβ) accumulation. Since the relationship between body weight, ApoE4, and AD pathology is poorly investigated, we aimed to evaluate whether ApoE4 allelic status modifies the association of body mass index (BMI) with markers of AD pathology. A total of 368 Aβ-positive cognitively healthy or mild cognitive impaired subjects had undergone [18F]-AV45-PET, [18F]-FDG-PET, and T1w-MRI examinations. Composite cortical [18F]-AV45 uptake and [18F]-FDG uptake in posterior cingulate cortex were calculated as surrogates of cortical Aβ load and glucose metabolism, respectively. Multiple linear regressions were performed to assess the relationships between these PET biomarkers with BMI, present cognitive performance, and cognitive changes over time. Multivariate analysis of covariance was conducted to test for statistical differences between ApoE4/BMI categories on the PET markers and cognitive scores. In carriers of the ApoE4 allele only, BMI was inversely associated with cortical amlyoid load (β= -0.193, p < 0.005) and recent cognitive decline (β= -0.209, p < 0.05), and positively associated with cortical glucose metabolism in an AD-vulnerable region (β= 0.145, p < 0.05). ApoE4/BMI category analyses demonstrated lower Aβ load, higher posterior cingulate glucose metabolism, improved cognitive performance, and lower progression of cognitive decline in obese ApoE4 carriers. The effect of ApoE4 in promoting the accumulation of cortical amyoid, which may itself be a driver for weight loss, may be moderated by altering leptin signaling in the hypothalamus.

The Relationship between Obstructive Sleep Apnea and Alzheimer's Disease. - Andrade, Andreia G; Bubu, Omonigho M; Varga, Andrew W; Osorio, Ricardo S (J Alzheimers Dis, 2018)
Obstructive sleep apnea (OSA) and Alzheimer's disease (AD) are highly prevalent conditions with growing impact on our aging society. While the causes of OSA are now better characterized, the mechanisms underlying AD are still largely unknown, challenging the development of effective treatments. Cognitive impairment, especially affecting attention and executive functions, is a recognized clinical consequence of OSA. A deeper contribution of OSA to AD pathogenesis is now gaining support from several lines of research. OSA is intrinsically associated with disruptions of sleep architecture, intermittent hypoxia and oxidative stress, intrathoracic and hemodynamic changes as well as cardiovascular comorbidities. All of these could increase the risk for AD, rendering OSA as a potential modifiable target for AD prevention. Evidence supporting the relevance of each of these mechanisms for AD risk, as well as a possible effect of AD in OSA expression, will be explored in this review.

Relationship of Area of Soft Drusen in Retina with Cerebral Amyloid-β Accumulation and Blood Amyloid-β Level in the Elderly. - Shoda, Chiho; Kitagawa, Yorihisa; Shimada, Hiroyuki; Yuzawa, Mitsuko; Tateno, Amane; Okubo, Yoshiro (J Alzheimers Dis, 2018)
BACKGROUND: Histopathological studies have confirmed that soft drusen contains amyloid-β (Aβ). OBJECTIVE: To examine the relationship between the area of soft drusen in the macular area and cerebral Aβ accumulation or plasma Aβ level in elderly persons without dementia. METHODS: Fourteen consecutive patients (18 eyes) aged ≥50 years with macular soft drusen were studied prospectively. From color fundus photographs, the area of soft drusen (pixel) within a 6,000 μm diameter with the macula as center was measured. Standard uptake value ratio (SUVR) was obtained from positron emission tomography using florbetapir, which indicates the ratio of cerebral cortical-to-cerebellar Aβ accumulation. Ratio of plasma Aβ1-42 to Aβ1-40 level was calculated. RESULTS: Mean age was 73.3±7.6 years. The soft drusen area was 4.32±2.42 mm2. The SUVR was 1.08±0.15. Plasma Aβ1-42/Aβ1-40 ratio was 0.17±0.08. When SUVR ≥1.10 was defined as positive and <1.10 as negative, the soft drusen area in SUVR-positive patients (6.19±1.14 mm2) was significantly (p = 0.0043) larger than that in SUVR-negative patients (3.13±2.27 mm2). Multivariate regression analysis showed that SUVR positivity correlated with soft drusen area (p = 0.0484) and with Voxel-based Specific Regional Analysis System for Alzheimer's Disease score (p = 0.0360). However, there was no correlation with gender (p = 0.1921), age (p = 0.2361), Alzheimer's Disease Assessment Scale score (p = 0.6310), Mini-Mental State Examination score (p = 0.4246), or plasma Aβ1-42/Aβ1-40 ratio (p = 0.8398). CONCLUSION: Among elderly persons without dementia, the area of soft drusen was larger in those with more extensive cerebral Aβ accumulation. The area of soft drusen may be a biomarker of cerebral Aβ accumulation.

Relationships between Cognition and Activities of Daily Living in Alzheimer's Disease During a 5-Year Follow-Up: ALSOVA Study. - Saari, Toni; Hallikainen, Ilona; Hänninen, Tuomo; Räty, Hannu; Koivisto, Anne (J Alzheimers Dis, 2018)
BACKGROUND: Impaired cognition and activities of daily living (ADL) are core symptoms of Alzheimer's disease (AD), but their relationship is unclear. OBJECTIVES: To explore relationships between cognitive domains and functional ability during 5-year follow-up in persons with AD. METHODS: We analyzed ALSOVA study data from 236 individuals with very mild or mild AD at baseline. The CERAD Neuropsychological Battery (CERAD-NB) was used as a cognitive measure and Alzheimer's Disease Cooperative Study ADL (ADCS-ADL) as a functional measure, analyzing the IADL and BADL sub-scores separately. Annual regression models and linear mixed-effect models (LMMs) covering a 5-year follow-up period were used. RESULTS: Annually, the CERAD-NB total and especially Verbal Fluency, Clock Drawing, and Constructional Praxis were associated with the total ADCS-ADL and IADL scores increasingly yet modestly, and to a lesser extent the BADL score. In the LMMs, the same measures and MMSE were associated with ADL. CONCLUSION: Measures of executive function and visuoconstructive skills appear to be associated with caregiver-interview based ADL measure during the progression of AD.

Relationships Between Lower Olfaction and Brain White Matter Lesions in Elderly Subjects with Mild Cognitive Impairment. - Heinrich, Juliette; Vidal, Jean-Sébastien; Simon, Axelle; Rigaud, Anne-Sophie; Hanon, Olivier; Epelbaum, Jacques; Viollet, Cécile; Duron, Emmanuelle (J Alzheimers Dis, 2018)
BACKGROUND: Olfactory impairment is reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and is associated with hippocampal atrophy. In elderly people, dementia with AD neuropathology and white matter lesions (WML) is common. In this context, olfactory impairment could also depend on the presence of WML. OBJECTIVE: To assess the cross-sectional relationship between olfaction and WML in elderly subjects with MCI. METHODS: Consecutive subjects, >65 years old, diagnosed as MCI after a comprehensive neuropsychological assessment in an expert memory center, with a brain MRI performed within a year and without major depressive state, were included. Olfaction was assessed by the Brief Smell Identification Test (BSIT). Two trained neuroradiologists, blind to cognitive and olfaction status, visually assessed hippocampal atrophy according to Scheltens' scale and WML according to Fazekas criteria. RESULTS: Seventy-five MCI subjects (mean age (SD) = 77.1 (6.2) years, 74.7% of women) were included. After adjustment for age and sex, factors associated with low BSIT scores were older age (p = 0.007), lower BMI (p = 0.08), lower MMSE score (p = 0.05), lower FCRST (p = 0.008), hippocampal atrophy (p = 0.04), periventricular WML (p = 0.007), and deep WML burden (p = 0.005). In multivariate analysis, severe deep WML (OR (95% CI) = 6.29 (1.4-35.13), p = 0.02) remained associated with low BSIT score independently from hippocampal atrophy. CONCLUSION: In elderly MCI subjects, low olfactory performances are associated with WML, whose progression may be slowed by vascular treatments. A longitudinal study to evaluate whether the progression of WML, hippocampal atrophy and low olfactory function, can predict accurately conversion from MCI to dementia is ongoing.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Atrophy; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Female; Humans; Logistic Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Multivariate Analysis; Neuropsychological Tests; Olfaction Disorders; Severity of Illness Index; White Matter

Relevance of Coded Prodromal Mild Cognitive Impairment in the Routine Treatment of Patients with Dementia in Germany. - Bohlken, Jens; Kostev, Karel (J Alzheimers Dis, 2018)
Little is known about the impact of prior mild cognitive impairment (MCI, ICD-10: F06.7) diagnosis on the time to dementia diagnosis, anti-dementia drug therapy, and treatment persistence in patients with dementia (PWD). Patients with dementia diagnoses who started anti-dementia therapy between January 2010 and December 2016 were selected from 203 neurological/psychiatric practices in the Disease Analyzer databank (IQVIA). Patients with a history of MCI were compared to non-MCI controls in terms of demographic characteristics, anti-dementia therapy, and the rate of persistence with anti-dementia drugs. For persistence analyses, a 1:1 matching procedure was used based on age, gender, type of residence, and depression and dementia diagnosis. Persistence was represented using Kaplan-Meier curves. A Cox regression analysis was used to determine the influence of MCI diagnosis on persistence with anti-dementia drugs. 339 PWD with MCI diagnoses and 339 controls were available for analysis. PWD with MCI were younger (78.9 versus 80.4 years), less likely to live in a nursing home (8.5% versus 22.5%), more frequently received donepezil (40.1% versus 33.7%), and more likely to exhibit comorbid depression (29.6% versus 16.9%). There was no association between the risk of treatment discontinuation and prior MCI diagnosis. After 24 months, 40% versus 41.1% of patients had discontinued treatment. The prior MCI diagnosis presumably led to an earlier diagnosis of dementia and earlier anti-dementia treatment. Treatment continuity did not differ, which would suggest that it does not depend on prior MCI diagnosis but on the behavior of patients and their caregiving relatives.

The Relevance of Iron in the Pathogenesis of Multiple System Atrophy: A Viewpoint. - Kaindlstorfer, Christine; Jellinger, Kurt A; Eschlböck, Sabine; Stefanova, Nadia; Weiss, Günter; Wenning, Gregor K (J Alzheimers Dis, 2018)
Iron is essential for cellular development and maintenance of multiple physiological processes in the central nervous system. The disturbance of its homeostasis leads to abnormal iron deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Iron toxicity has been established in the pathogenesis of Parkinson's disease; however, its contribution to multiple system atrophy (MSA) remains elusive. MSA is characterized by cytoplasmic inclusions of misfolded α-synuclein (α-SYN) in oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs). Remarkably, the oligodendrocytes possess high amounts of iron, which together with GCI pathology make a contribution toward MSA pathogenesis likely. Consistent with this observation, the GCI density is associated with neurodegeneration in central autonomic networks as well as olivopontocerebellar and striatonigral pathways. Iron converts native α-SYN into a β-sheet conformation and promotes its aggregation either directly or via increasing levels of oxidative stress. Interestingly, α-SYN possesses ferrireductase activity and α-SYN expression underlies iron mediated translational control via RNA stem loop structures. Despite a correlation between progressive putaminal atrophy and iron accumulation as well as clinical decline, it remains unclear whether pathologic iron accumulation in MSA is a secondary event in the cascade of neuronal degeneration rather than a primary cause. This review summarizes the current knowledge of iron in MSA and gives evidence for perturbed iron homeostasis as a potential pathogenic factor in MSA-associated neurodegeneration.
Keywords: alpha-Synuclein; Brain; Humans; Inclusion Bodies; Iron; Magnetic Resonance Imaging; Multiple System Atrophy; Oligodendroglia; Parkinsonian Disorders

Religious Orders Study and Rush Memory and Aging Project. - Bennett, David A; Buchman, Aron S; Boyle, Patricia A; Barnes, Lisa L; Wilson, Robert S; Schneider, Julie A (J Alzheimers Dis, 2018)
BACKGROUND: The Religious Orders Study and Rush Memory and Aging Project are both ongoing longitudinal clinical-pathologic cohort studies of aging and Alzheimer's disease (AD). OBJECTIVES: To summarize progress over the past five years and its implications for understanding neurodegenerative diseases. METHODS: Participants in both studies are older adults who enroll without dementia and agree to detailed longitudinal clinical evaluations and organ donation. The last review summarized findings through the end of 2011. Here we summarize progress and study findings over the past five years and discuss new directions for how these studies can inform on aging and AD in the future. RESULTS: We summarize 1) findings on the relation of neurobiology to clinical AD; 2) neurobiologic pathways linking risk factors to clinical AD; 3) non-cognitive AD phenotypes including motor function and decision making; 4) the development of a novel drug discovery platform. CONCLUSION: Complexity at multiple levels needs to be understood and overcome to develop effective treatments and preventions for cognitive decline and AD dementia.

REM Sleep Behavior Disorder and Alzheimer's Disease: Definitely No Relationship? - Galbiati, Andrea; Carli, Giulia; Hensley, Michael; Ferini-Strambi, Luigi (J Alzheimers Dis, 2018)
Rapid eye movement (REM) sleep behavior disorder (RBD) is a REM sleep parasomnia characterized by the loss of the typical muscular atonia present during healthy REM sleep. RBD can occur in the absence of other neurological conditions or in association with a neurodegenerative disorder. It is now well established that RBD is a strong predictor of neurodegeneration, in particular synucleinopathies, such as Parkinson's disease, Lewy body dementia (LBD), or multiple system atrophy. However, some longitudinal studies report that a minority of patients develop either overlapping form of dementia or Alzheimer disease's (AD). Although AD is reported as a possible development in patients with RBD, it is in a limited number of cases and there are concerns about the accuracy of the diagnostic criteria. Neuropsychological impairments identified in cross-sectional studies of RBD patients describe a profile similar to that observed in dementia related to synucleinopathies. However, only deficits in executive function predict the development of neurodegeneration. Longitudinal studies reported the development of AD in RBD patients in about 7% of cases with variability ranging from 3% and 11%. Since the majority of longitudinal investigations do not report AD as a possible development for RBD patients the proportion may be overestimated. The study of the relationship between RBD and AD may be confounded by two factors that lead to misdiagnosis: the use of clinical criteria alone and the overlap between the clinical features and neuropathology of AD and LBD. Future studies to investigate this association must use updated diagnostic criteria incorporating ancillary investigations.

Reproducibility of Alzheimer's Disease Cerebrospinal Fluid-Biomarker Measurements under Clinical Routine Conditions. - Vogelgsang, Jonathan; Wedekind, Dirk; Bouter, Caroline; Klafki, Hans-W; Wiltfang, Jens (J Alzheimers Dis, 2018)
Analysis of cerebrospinal fluid (CSF) is one of the key tools for the state-of-the-art differential diagnosis of dementias. Dementia due to Alzheimer's disease (AD) is characterized by elevated CSF levels of total Tau (tTau) and phospho-181-Tau (pTau) and low CSF amyloid-β42 (Aβ42). Discrepancies in the laboratory analysis of human materials are well known and much effort has been put into harmonization procedures. In this study, we measured CSF biomarkers of more than 100 patients obtained under clinical routine conditions in two different clinical laboratories. The CSF biomarker levels obtained from the two different sites were significantly correlated: R2 = 0.7129 (tTau, p < 0.001), 0.7914 (pTau, p < 0.001), 0.5078 (Aβ42, p < 0.001), 0.5739 (Aβ40, p < 0.001), and 0.4308 (Aβ42/40, p < 0.001). However, the diagnostic classifications of the Aβ42, tTau, and pTau levels of identical subjects into normal versus pathological range made by the two different sites showed substantial discrepancies (31.5%, 29.6%, and 25.0% discordant cases, respectively). Applying Aβ42/40, instead of CSF Aβ42 alone, lead to a reduction of the discordant cases to 16.8%. Our findings suggest that CSF Aβ42/40 can outperform Aβ42 as a biomarker for AD neuropathology, not only under well-controlled study conditions but also in real life clinical routine. Thus, we recommend the inclusion of Aβ42/40 as a CSF biomarker in the diagnostic procedure.

Rethinking the Reserve with a Translational Approach: Novel Ideas on the Construct and the Interventions. - Serra, Laura; Gelfo, Francesca; Petrosini, Laura; Di Domenico, Carlotta; Bozzali, Marco; Caltagirone, Carlo (J Alzheimers Dis, 2018)
The concept of brain, cognitive, and neural reserves has been introduced to account for the apparent discrepancies between neurological damage and clinical manifestations. However, these ideas are yet theoretical suggestions that are not completely assimilated in the clinical routine. The mechanisms of the reserves have been extensively studied in neurodegenerative pathologies, in particular in Alzheimer's disease. Both human and animal studies addressed this topic by following two parallel pathways. The specific aim of the present review is to attempt to combine the suggestions derived from the two different research fields to deepen the knowledge about reserves. In fact, the achievement of a comprehensive theoretical framework on reserve mechanisms is an essential step to propose well-timed interventions tailored to the clinical characteristics of patients. The present review highlights the importance of addressing three main aspects: the definition of reserve proxy measures, the interaction between reserve level and therapeutic interventions, and the specific time-window of reserve efficacy.

Retinoic Acid Enhances Apolipoprotein E Synthesis in Human Macrophages. - Clemens, Vera; Regen, Francesca; Le Bret, Nathalie; Heuser, Isabella; Hellmann-Regen, Julian (J Alzheimers Dis, 2018)
Apolipoprotein E (ApoE) represents a pivotal target in Alzheimer's disease (AD) and is modulated through retinoic acid (RA), an endogenous neuroprotective and anti-inflammatory compound. A major source of ApoE are microglia, which are pathologically activated in AD. Activated microglia are known to block RA signaling. This suggests a vicious cycle between inflammation, RA signaling, and ApoE homeostasis in AD pathogenesis. To test this hypothesis, we investigated effects of RA and proinflammatory activation on ApoE synthesis in primary human macrophage-derived microglial-like cells. Our results indicate that proinflammatory activation attenuates ApoE synthesis, an effect blocked by RA.
Keywords: Alzheimer Disease; Apolipoproteins E; Cells, Cultured; Humans; Macrophages; Signal Transduction; Tretinoin

A Retrospective Belgian Multi-Center MRI Biomarker Study in Alzheimer's Disease (REMEMBER). - Niemantsverdriet, Ellis; Ribbens, Annemie; Bastin, Christine; Benoit, Florence; Bergmans, Bruno; Bier, Jean-Christophe; Bladt, Roxanne; Claes, Lene; De Deyn, Peter Paul; Deryck, Olivier; Hanseeuw, Bernard; Ivanoiu, Adrian; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer's disease (AD). OBJECTIVE: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression. METHODS: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available. RESULTS: The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment. CONCLUSION: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.

A Review of the Familial Alzheimer's Disease Locus PRESENILIN 2 and Its Relationship to PRESENILIN 1. - Jiang, Haowei; Jayadev, Suman; Lardelli, Michael; Newman, Morgan (J Alzheimers Dis, 2018)
PRESENILIN 1 (PSEN1) and PRESENILIN 2 (PSEN2) genes are loci for mutations causing familial Alzheimer's disease (fAD). However, the function of these genes and how they contribute to fAD pathogenesis has not been fully determined. This review provides a summary of the overlapping and independent functions of the PRESENILINS with a focus on the lesser studied PSEN2. As a core component of the γ-secretase complex, the PSEN2 protein is involved in many γ-secretase-related physiological activities, including innate immunity, Notch signaling, autophagy, and mitochondrial function. These physiological activities have all been associated with AD progression, indicating that PSEN2 plays a particular role in AD pathogenesis.

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology. - Hampel, Harald; Toschi, Nicola; Babiloni, Claudio; Baldacci, Filippo; Black, Keith L; Bokde, Arun L W; Bun, René S; Cacciola, Francesco; Cavedo, Enrica; Chiesa, Patrizia A; Colliot, Olivier; Coman, Cristina-Maria; et al. (J Alzheimers Dis, 2018)
The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an "omics"-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical, and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer's disease. The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group "Alzheimer Precision Medicine" (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development toward breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.
Keywords: Alzheimer Disease; Animals; Brain; Humans; Neurology; Neurophysiology; Precision Medicine; Systems Biology; Translational Medical Research

Risk Factors Associated with Cortical Thickness and White Matter Hyperintensities in Dementia Free Okinawan Elderly. - Silbert, Lisa C; Lahna, David; Promjunyakul, Nutta-On; Boespflug, Erin; Ohya, Yusuke; Higashiuesato, Yasushi; Nishihira, Junko; Katsumata, Yuriko; Tokashiki, Takashi; Dodge, Hiroko H (J Alzheimers Dis, 2018)
BACKGROUND: Cortical gray matter (GM) and white matter (WM) deterioration are signals of neurodegeneration and increased dementia risk; however, their specific etiologies in dementia-free aging is unclear. OBJECTIVE: The objective of this study was to examine potentially modifiable risk factors of GM and WM degeneration in a well-characterized cohort of dementia-free elderly. METHODS: 96 Okinawan elderly participants (age 83.6) from the Keys to Optimal Cognitive Aging Project (KOCOA) underwent MRI and cognitive evaluation. Serum markers of inflammation (interleukin-6 (IL-6), high sensitivity C-reactive protein), cerebrovascular disease (systolic blood pressure (SBP) 140+, hemoglobin A1C (HgbA1C), total cholesterol), and essential minerals (copper (Cu), magnesium, and calcium) were examined in relation to mean cortical thickness (MCT) and white matter hyperintensities (WMH), adjusting for age and gender. Voxel-based morphometry (VBM) analyses identified relationships between regional GM density and the above markers. RESULTS: Decreased MCT was associated with SBP 140 + (p = 0.029) and increased serum IL-6 (p = 0.036), HgbA1C (p = 0.002), and Cu (p = 0.025). In VBM analyses, increased IL-6, HgbA1C, and Cu were associated with decreased GM density in temporal lobe regions. HgbA1C (p = 0.004) was associated with greater WMH volume. CONCLUSIONS: Peripheral markers of Cu, CVD risk, and inflammation are associated with MRI-markers of decreased brain health in dementia-free Okinawan elderly, with regional cortical thinning in areas involved in early accumulation of Alzheimer's disease pathology. Results identify potentially modifiable biomarkers as targets in the prevention of dementia in older individuals.

Risk Factors of Rapid Cognitive Decline in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. - Song, Ya-Nan; Wang, Ping; Xu, Wei; Li, Jie-Qiong; Cao, Xi-Peng; Yu, Jin-Tai; Tan, Lan (J Alzheimers Dis, 2018)
BACKGROUND: The conclusions about risk factors for rapid cognitive decline (RCD) in Alzheimer's disease (AD) and mild cognitive impairment (MCI) remain contradictory. OBJECTIVE: To explore the factors predicting RCD in AD and MCI. METHODS: We searched the PubMed, EMBASE, and the Cochrane Library from inception to May 27, 2017 for studies investigating factors associated with faster cognitive progression in AD and MCI. Effect sizes were meta-analyzed using fixed-effects and random-effects models. RESULTS: Fifty-three studies with 14,330 patients (12,396 AD and 1,934 MCI) were included in the systematic review. The following factors were identified to increase the risk of RCD in AD: Apolipoprotein E4 (ApoE4) (SMD [95% CI]: 0.52 [0.06,0.98]), early age at onset (SMD [95% CI]: -0.42 [-0.71, -0.13]), high level of education (RR = 2.05, 95% CI = 1.26 to 3.33), early appearance of extrapyramidal signs (RR = 2.18; 95% CI = 1.30 to 3.67), and neuropsychiatric conditions including hallucination (RR = 2.01, 95% CI = 1.40 to 2.87), strolling (RR = 1.99, 95% CI = 1.38 to 2.86), agitation (RR = 1.66, 95% CI = 1.23 to 2.24), and psychosis (RR = 1.42, 95% CI = 1.07 to 1.89). Instead, advanced age (≥75 years) (RR = 0.96, 95% CI = 0.93 to 0.99), diabetes (RR = 0.57; 95% CI = 0.35 to 0.93), and multidrug therapy (RR = 0.61, 95% CI = 0.60 to 0.62) would lower the risk of RCD. Furthermore, systematic research also reviewed seven risk factors associated with RCD in MCI. CONCLUSION: ApoE4, early onset, early appearance of extrapyramidal signs, high education level, and neuropsychiatric conditions might increase the risk of RCD while older age, diabetes, and multidrug therapy were the protective factors for AD.

Risk of Alzheimer's Disease in Obstructive Sleep Apnea Syndrome: Amyloid-β and Tau Imaging. - Elias, Alby; Cummins, Tia; Tyrrell, Regan; Lamb, Fiona; Doré, Vincent; Williams, Robert; Rosenfeld, J V; Hopwood, Malcolm; Villemagne, Victor L; Rowe, Christopher C (J Alzheimers Dis, 2018)
BACKGROUND: An association between obstructive sleep apnea (OSA) and Alzheimer's disease has been suggested but little is known about amyloid-β and tau deposition in this syndrome. OBJECTIVE: To determine amyloid and tau burden and cognitive function in OSA in comparison with those without a diagnosis of OSA. METHODS: The status of OSA was determined by asking participants about history of polysomnographic diagnosis of OSA and the use of Continuous Positive Airway Pressure (CPAP). A comprehensive neuropsychological battery measured cognitive function. Positron emission tomography (PET) was used to measure standardized uptake value ratio (SUVR) of 18F-florbetaben and 18F-AV1451, to quantify amyloid and tau burden. RESULTS: 119 male Vietnam veterans completed assessment. Impairment in visual attention and processing speed and increased body mass index (BMI) were seen in subjects with OSA compared with those without a diagnosis OSA. The cortical uptake of 18F-florbetaben was higher in the OSA group than in the control group (SUVR: 1.35±0.21 versus 1.27±0.16, p = 0.04). There were more apolipoprotein E ɛ4 allele (APOE ɛ4) carriers in the OSA group than in the control group. In multilinear regression analysis, the significance of OSA in predicting 18F-florbetaben uptake remained independent of age and vascular risk factors but not when BMI or APOE ɛ4 was adjusted. The reported use of CPAP (n = 14) had no effect on cognitive or amyloid PET findings. There was no significant difference in 18F-AV1451 uptake between the two groups. CONCLUSIONS: Obstructive sleep apnea is associated with Alzheimer's disease pathology, but this relationship is moderated by APOE ɛ4 and BMI.

Risk of Conversion to Dementia in a Mild Behavioral Impairment Group Compared to a Psychiatric Group and to a Mild Cognitive Impairment Group. - Taragano, Fernando E; Allegri, Ricardo F; Heisecke, Silvina L; Martelli, María I; Feldman, Mónica L; Sánchez, Viviana; García, Virginia A; Tufro, Graciela; Castro, Diego M; Leguizamón, Patricio Perez; Guelar, Verónica; Ruotolo, Eva; et al. (J Alzheimers Dis, 2018)
BACKGROUND: There is insufficient available information on behavioral changes in the absence of cognitive impairment as factors increasing the risk of conversion to dementia. OBJECTIVE: To observe and analyze patients with mild behavioral impairment (MBI), mild cognitive impairment (MCI), and a psychiatry group (PG) to compare the risk of progression to dementia. METHODS: From 677 initially assessed ≥60-year-old patients, a series of 348 patients was studied for a five-year period until censoring or conversion to dementia: 96 with MBI, 87 with MCI, and 165 with general psychiatry disorders, including 4 subgroups: Anxiety, Depression, Psychosis and Others. All patients were assessed with clinical, psychiatric, neurological, neuropsychological, and neuroimaging studies. RESULTS: From 348 patients, 126 evolved to dementia (36.2%). Conversion was significantly higher in MBI (71.5%), followed by the MCI-MBI overlap (59.6%) and MCI (37.8%) groups, compared to PG (13.9%) (Log-rank p < 0.001). MCI patients mostly converted to Alzheimer's dementia, while MBI converted to frontotemporal dementia and Lewy body dementia. Patients in PG converted to Lewy body dementia and frontotemporal dementia. CONCLUSION: Conversion to dementia is significantly higher in patients with neuropsychiatric symptoms. The MBI concept generates a new milestone in the refining of diagnosis of neurodegenerative diseases and the possibility of creating neuropsychiatric profiles. Its earlier identification will allow new possibilities for therapeutic intervention.

Role of Amyloid-β and Tau Proteins in Alzheimer's Disease: Confuting the Amyloid Cascade. - Gulisano, Walter; Maugeri, Daniele; Baltrons, Marian A; Fà, Mauro; Amato, Arianna; Palmeri, Agostino; D'Adamio, Luciano; Grassi, Claudio; Devanand, D P; Honig, Lawrence S; Puzzo, Daniela; Arancio, Ottavio (J Alzheimers Dis, 2018)
The "Amyloid Cascade Hypothesis" has dominated the Alzheimer's disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies.

Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer's Disease and Brain Aging. - Hasegawa, Yu; Toyama, Kensuke; Uekawa, Ken; Ichijo, Hidenori; Kim-Mitsuyama, Shokei (J Alzheimers Dis, 2018)
To examine the role of ASK1 in Alzheimer's disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24-month-old 5XFAD mice, which was associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade seems to play some role in the pathogenesis of AD in mice. In 24-month-old wild-type mice, ASK1 deficiency increased cerebral vasoreactivity to acetazolamide and significantly reduced brain soluble Aβ, which were also associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade may contribute to brain aging of wild-type mice. Collectively, our present results provided the evidence suggesting the involvement of ASK1/p38 cascade in AD and brain aging.
Keywords: Aging; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Avoidance Learning; Disease Models, Animal; Gene Expression Regulation; MAP Kinase Kinase Kinase 5; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Transgenic; Presenilin-1; Reaction Time

Role of Blood-Brain Barrier in Alzheimer's Disease. - Cai, Zhiyou; Qiao, Pei-Feng; Wan, Cheng-Qun; Cai, Min; Zhou, Nan-Kai; Li, Qin (J Alzheimers Dis, 2018)
The blood-brain barrier (BBB) is involved in the pathogenesis of Alzheimer's disease (AD). BBB is a highly selective semipermeable structural and chemical barrier which ensures a stable internal environment of the brain and prevents foreign objects invading the brain tissue. BBB dysfunction induces the failure of Aβ transport from brain to the peripheral circulation across the BBB. Especially, decreased levels of LRP-1 (low density lipoprotein receptor-related protein 1) and increased levels of RAGE (receptor for advanced glycation endproducts) at the BBB can cause the failure of Aβ transport. The pathogenesis of AD is related to the BBB structural components, including pericytes, astrocytes, vascular endothelial cells, and tight junctions. BBB dysfunction will trigger neuroinflammation and oxidative stress, then enhance the activity of β-secretase and γ-secretase, and finally promote Aβ generation. A progressive accumulation of Aβ in brain and BBB dysfunction may become a feedback loop that gives rise to cognitive impairment and the onset of dementia. The correlation between BBB dysfunction and tau pathology has been well-reported. Therefore, regulating BBB function may be a new therapeutic target for treating AD.

The Role of Cognitive Reserve in Alzheimer's Disease and Aging: A Multi-Modal Imaging Review. - Menardi, Arianna; Pascual-Leone, Alvaro; Fried, Peter J; Santarnecchi, Emiliano (J Alzheimers Dis, 2018)
Comforts in modern society have generally been associated with longer survival rates, enabling individuals to reach advanced age as never before in history. With the increase in longevity, however, the incidence of neurodegenerative diseases, especially Alzheimer's disease, has also doubled. Nevertheless, most of the observed variance, in terms of time of clinical diagnosis and progression, often remains striking. Only recently, differences in the social, educational and occupational background of the individual, as proxies of cognitive reserve (CR), have been hypothesized to play a role in accounting for such discrepancies. CR is a well-established concept in literature; lots of studies have been conducted in trying to better understand its underlying neural substrates and associated biomarkers, resulting in an incredible amount of data being produced. Here, we aimed to summarize recent relevant published work addressing the issue, gathering evidence for the existence of a common path across research efforts that might ease future investigations by providing a general perspective on the actual state of the arts. An innovative model is hereby proposed, addressing the role of CR across structural and functional evidences, as well as the potential implementation of non-invasive brain stimulation techniques in the causal validation of such theoretical frame.

Role of Genetics and Epigenetics in the Pathogenesis of Alzheimer's Disease and Frontotemporal Dementia. - Fenoglio, Chiara; Scarpini, Elio; Serpente, Maria; Galimberti, Daniela (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) and frontotemporal dementia (FTD) represent the first cause of dementia in senile and pre-senile population, respectively. A percentage of cases have a genetic cause, inherited with an autosomal dominant pattern of transmission. The majority of cases, however, derive from complex interactions between a number of genetic and environmental factors. Gene variants may act as risk or protective factors. Their combination with a variety of environmental exposures may result in increased susceptibility to these diseases or may influence their course. The scenario is even more complicated considering the effect of epigenetics, which encompasses mechanisms able to alter the expression of genes without altering the DNA sequence. In this review, an overview of the current genetic and epigenetic progresses in AD and FTD will be provided, with particular focus on 1) causative genes, 2) genetic risk factors and disease modifiers, and 3) epigenetics, including methylation, non-coding RNAs and chromatin remodeling.
Keywords: Alzheimer Disease; Animals; Epigenesis, Genetic; Frontotemporal Dementia; Genetic Predisposition to Disease; Humans

The Role of Lifestyle Factors and Sleep Duration for Late-Onset Dementia: A Cohort Study. - Larsson, Susanna C; Wolk, Alicja (J Alzheimers Dis, 2018)
BACKGROUND: The role of lifestyle factors and sleep for dementia is uncertain. OBJECTIVE: To examine the associations of major lifestyle factors and sleep duration with risk of late-onset dementia. METHODS: We used data from a population-based cohort of 28,775 Swedish adults who were ≥65 years of age and completed a questionnaire about lifestyle and other modifiable factors in the autumn of 1997. Dementia cases were ascertained by linkage with the Swedish National Patient Register. RESULTS: During a mean follow-up of 12.6 years, dementia was diagnosed among 3,755 participants (mean age at diagnosis 83.2±5.1 years). There were no associations of an overall healthy diet (defined by a modified Dietary Approaches to Stop Hypertension Diet score or a Mediterranean diet score), alcohol and coffee consumption, or physical activity with dementia incidence. Compared with never smokers, dementia risk was increased in former and current smokers (hazard ratio [95% confidence interval] = 1.13 [1.04-1.23] and 1.10 [1.00-1.21], respectively). Extended time of sleep (>9 h per night) was associated with an increased risk of dementia. However, this association appeared to be related to a reverse causation effect since the association did not remain after exclusion of cases diagnosed within the first five or ten years of follow-up. CONCLUSIONS: This study found no evidence that major lifestyle factors, aside from smoking, or sleep duration influence the risk of dementia.

Role of Neuroinflammation in the Trajectory of Alzheimer's Disease and in vivo Quantification Using PET. - Edison, Paul; Brooks, David J (J Alzheimers Dis, 2018)
Recent evidence suggests that neuroinflammation and immunity play a significant role in Alzheimer's disease and other neurodegenerative diseases. It has also been observed that, independent of the presence of aggregated proteins, neuroinflammation could be present in different neurodegenerative diseases. It has also been suggested that neuroinflammation could occur well ahead of amyloid deposition in AD. Recent genetic studies and other preclinical studies specifically point to a role of neuroinflammation and, in this review, we evaluate the evidence of neuroinflammation in the Alzheimer's disease trajectory and the different imaging modalities by which we could monitor neuroinflammation in vivo in humans.

Role of Noradrenergic Brain Nuclei in the Regulation of Carotid Artery Blood Flow: Pharmacological Evidence from Anesthetized Pigs with Alpha-2 Adrenergic Receptor Modulator Drugs. - Wirth, Klaus J (J Alzheimers Dis, 2018)
BACKGROUND: Cerebral hypoperfusion and degeneration of the noradrenergic locus coeruleus (LC) occur early in Alzheimer's disease (AD). Cerebral blood vessels are densely innervated by noradrenergic projections from the LC suggesting a functional role for the regulation of cerebral blood flow (CBF). Experimental LC stimulation, however, has provided no clarity as decreases or increases in CBF were reported from different experimental settings and investigators. OBJECTIVE: To find out with pharmacological methods whether endogenously released norepinephrine (NE) increases or decreases carotid artery blood flow (CABF) in anesthetized pigs by investigating the effect of centrally acting alpha-2 adrenergic drugs, which increase (atipamezole) or decrease (xylazine) NE in the brain. METHODS: CABF was measured by a Doppler-flow probe placed around the left carotid artery in pentobarbital anesthetized young pigs. RESULTS: Neither current antihypertensive drugs nor pharmacological stimulation of dopamine, histamine, serotonin or acetylcholine receptors changed CABF. The alpha-2 adrenergic-receptor agonist xylazine decreased, while the antagonist atipamezole raised CABF. This rise was abolished by a combined treatment with endothelial NO-synthase inhibitor Nω-Nitro-L-arginine methyl ester (L-NAME) and the non-selective β-receptor antagonist propranolol. Propranolol alone did not decrease CABF in contrast to L-NAME but decreased CABF after L-NAME, surprisingly. CONCLUSION: Pharmacological evidence suggests that NE released in the brain of anesthetized pigs raises CABF involving β-adrenergic mechanisms and nitric oxide. If in awake humans NE released from the LC had vasodilator effects early LC degeneration could be involved in early cerebral hypoperfusion of AD. Moreover, a cerebral adrenergic vascular innervation deficit, possibly resulting from LC degeneration, and systemic endothelial dysfunction together may act synergistically to reduce CBF.

Role of the Glyoxalase System in Alzheimer's Disease. - Jiang, Lianying; Wang, Jiafeng; Wang, Zhigang; Huang, Wenhui; Yang, Yixia; Cai, Zhiyou; Li, Keshen (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disease. The main pathological features of AD are the formation of amyloid-β deposits in the anterior cerebral cortex and hippocampus as well as the formation of intracellular neurofibrillary tangles. Thus far, accumulating evidence shows that glycation is closely related to AD. As a final product resulting from the crosslinking of a reducing sugar or other reactive carbonyls and a protein, the advanced glycation end products have been found to be associated with the formation of amyloid-β and neurofibrillary tangles in AD. As a saccharification inhibitor, the glyoxalase system and its substrate methylglyoxal (MG) were certified to be associated with AD onset and development. As an active substance of AGEs, MG could cause direct or indirect damage to nerve cells and tissues. MG is converted to D-lactic acid after decomposition by the glyoxalase system. Under normal circumstances, MG metabolism is in a dynamic equilibrium, whereas MG accumulates in cells in the case of aging or pathological states. Studies have shown that increasing glyoxalase activity and reducing the MG level can inhibit the generation of oxidative stress and AGEs, thereby alleviating the symptoms and signs of AD to some extent. This paper focuses on the relevant mechanisms of action of the glyoxalase system and MG in the pathogenesis of AD, as well as the potential of inhibiting the production of advanced glycation end products in the treatment of AD.

The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic Mice. - Pasinetti, Giulio Maria; Singh, Risham; Westfall, Susan; Herman, Francis; Faith, Jeremiah; Ho, Lap (J Alzheimers Dis, 2018)
A growing body of experimental data suggests that microbes in the gut influence behavior and can alter brain physiology and neurochemistry. Although promising, researchers are only starting to understand the potential of the gut microbiota for use in neurological disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metabolism and bioavailability of certain dietary compounds and synthetic drugs. Based on this evidence, this review article will discuss the implications of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compounds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms associated with the promotion of resilience against psychological and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline.

The Role of Verb Fluency in the Detection of Early Cognitive Impairment in Alzheimer's Disease. - Alegret, Montserrat; Peretó, Mar; Pérez, Alba; Valero, Sergi; Espinosa, Ana; Ortega, Gemma; Hernandez, Isabel; Mauleón, Ana; Rosende-Roca, Maitee; Vargas, Liliana; Rodríguez-Gómez, Octavio; Abdelnour, Carla; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Verb fluency (VF) is the less commonly used fluency test, despite several studies suggesting its potential as a neuropsychological assessment tool. OBJECTIVE: To investigate the presence of VF deficits in mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) dementia; to assess the usefulness of VF in the detection of cognitively healthy (CH) people who will convert to MCI, and from MCI to dementia; and to establish the VF cut-offs useful in the cognitive assessment of Spanish population. METHODS: 568 CH, 885 MCI, and 367 mild AD dementia individuals were administered the VF test and a complete neuropsychological battery. Longitudinal analyses were performed in 231 CH and 667 MCI subjects to search for VF predictors of diagnosis conversion. RESULTS: A worsening on VF performance from CH, MCI to AD dementia groups was found. Lower performances on VF were significantly related to conversion from CH to MCI/MCI to dementia. When the effect of time to conversion was analyzed, a significant effect of VF was found on the faster conversion from CH to MCI, but not from MCI to dementia. Moreover, VF cut-off scores and sensitivity/specificity values were calculated for 6 conditions (3 age ranges by 2 educational levels). CONCLUSION: The VF test may be a useful tool for the differential diagnosis of cognitive failure in the elderly. Since VF deficits seem to take place in early stages of the disease, it is a suitable neuropsychological tool for the detection not only of CH people who will convert to MCI, but also from MCI to dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cognitive Dysfunction; Cross-Sectional Studies; Early Diagnosis; Executive Function; Female; Humans; Language Tests; Logistic Models; Longitudinal Studies; Male; Middle Aged; Proportional Hazards Models; Sensitivity and Specificity; Spain

Roles of Mitochondrial 17β-Hydroxysteroid Dehydrogenase Type 10 in Alzheimer's Disease. - He, Xue-Ying; Isaacs, Charles; Yang, Song-Yu (J Alzheimers Dis, 2018)
17β-Hydroxysteroid dehydrogenase type 10 is a multifunctional, homotetrameric, mitochondrial protein encoded by the HSD17B10 gene at Xp 11.2. This protein, 17β-HSD10, is overexpressed in brain cells of Alzheimer's disease (AD) patients. It was reported to be involved in AD pathogenesis as the endoplasmic reticulum-associated amyloid-β binding protein (ERAB) and as amyloid-β binding alcohol dehydrogenase (ABAD). However, the exaggerated catalytic efficiencies for ERAB/ABAD in these reports necessitated the re-characterization of the catalytic functions of this brain enzyme. In addition to isoleucine metabolism, 17β-HSD10 is also responsible for the mitochondrial metabolism of neurosteroids such as 5α-androstane-3α,17β-diol and 17β-estradiol. These neurosteroids are inactivated by the oxidation catalyzed by 17β-HSD10. Since neurosteroid homeostasis is presumably essential for cognitive function, analysis of the impact of 17β-HSD10 and its inhibitor, amyloid-β peptide (Aβ), on the metabolism of neuroactive steroids offers a new approach to AD pathogenesis.
Keywords: 3-Hydroxyacyl CoA Dehydrogenases; Alzheimer Disease; Amyloid beta-Peptides; Brain; Endoplasmic Reticulum; Humans; Mitochondria; Neurotransmitter Agents; Oxidation-Reduction

S-[18F]THK-5117-PET and [11C]PIB-PET Imaging in Idiopathic Normal Pressure Hydrocephalus in Relation to Confirmed Amyloid-β Plaques and Tau in Brain Biopsies. - Leinonen, Ville; Rauramaa, Tuomas; Johansson, Jarkko; Bottelbergs, Astrid; Tesseur, Ina; van der Ark, Peter; Pemberton, Darrel; Koivisto, Anne M; Jääskeläinen, Juha E; Hiltunen, Mikko; Herukka, Sanna-Kaisa; Blennow, Kaj; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer's disease (AD) and monitor drug effects in clinical trials. S-[18F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[18F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo. OBJECTIVE: Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[18F]THK-5117, and [11C]PIB PET against tau and amyloid lesions in brain biopsy. METHODS: Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF Aβ1 - 42, total tau, and P-tau181 measures, underwent brain MRI, [11C]PIB PET, and S-[18F]THK-5117 PET imaging. RESULTS: Seven patients had amyloid-β (Aβ, 4G8) plaques, two both Aβ and phosphorylated tau (Pτ, AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aβ was well associated with higher [11C]PIB uptake in PET. However, S-[18F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau. CONCLUSIONS: S-[18F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aβ and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology.

Sally-Anne Test in Patients with Alzheimer's Disease Dementia. - Takenoshita, Shintaro; Terada, Seishi; Yokota, Osamu; Kutoku, Yumiko; Wakutani, Yosuke; Nakashima, Makoto; Maki, Yohko; Hattori, Hideyuki; Yamada, Norihito (J Alzheimers Dis, 2018)
Social cognition has recently been recognized as one of the essential cognitive domains. Some reports suggested that patients with Alzheimer's disease dementia (ADD) presented significant theory of mind deficits even in the mild condition. However, most previous studies included only small numbers of patients with ADD. The present study administered the first-order false belief (Sally-Anne) test to 116 consecutive patients with ADD from the outpatient units of the Memory Clinic and compared the characteristics of the two groups with correct and incorrect answers on the test. Then various clinical characteristics were evaluated. Only 37.1% of patients with ADD correctly answered the Sally-Anne test with the right explanation. Comparison between the two groups of correct and incorrect answers revealed a significant association between the frontal assessment battery score and the result of the Sally-Anne test in the multiple logistic regression analyses. Thus, patients with ADD presented a significant deficit in social cognition even in the mild condition. Frontal dysfunction was thought to be related to the deficits in mild ADD.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Disease Progression; Female; Humans; Logistic Models; Male; Neuropsychological Tests; Social Behavior Disorders; Theory of Mind

Secular Trends in Dementia Prevalence and Incidence Worldwide: A Systematic Review. - Stephan, Blossom C M; Birdi, Ratika; Tang, Eugene Yee Hing; Cosco, Theodore D; Donini, Lorenzo M; Licher, Silvan; Ikram, M Arfan; Siervo, Mario; Robinson, Louise (J Alzheimers Dis, 2018)
BACKGROUND: Time trends for dementia prevalence and incidence rates have been reported over the past seven decades in different countries and some have reported a decline. OBJECTIVE: To undertake a systematic review to critically appraise and provide an evidence-based summary of the magnitude and direction of the global changes in dementia prevalence and incidence across time. METHODS: Medline, EMBASE, and PsychINFO were searched for studies focused on secular trends in dementia prevalence and/or incidence until 18 December 2017. In total, 10,992 articles were identified and 43 retained. RESULTS: Overall, prevalence rates are largely increasing (evidence primarily from record-based surveys and cohort studies in Japan, Canada, and France) or have remained stable (evidence primarily from cohort studies in Sweden, Spain and China). A significant decline in prevalence has however been reported in more recent studies (i.e., from 2010 onwards) from Europe (e.g., UK and Sweden) and the USA. Incidence rates have generally remained stable or decreased in China, Canada, France, Germany, Denmark, Sweden, the Netherlands, UK, and USA. An increase has only been reported in five countries: Italy, Japan, Wales, Germany, and the Netherlands. Only one study reported findings (stability in incidence) from a low and middle-income country using data from Nigeria. CONCLUSIONS: The evidence on secular trends in the prevalence and incidence of dementia is mixed including contradictory findings using different (and in some cases the same) datasets in some countries (e.g., the USA, UK, and Sweden). This making it difficult to draw concrete conclusions. However, declining trends recently observed in some high-income Western countries in the most recent two decades including the UK, USA, and Sweden are encouraging. Updated dementia prevalence and incidence estimates will inform public health and financial planning as well as development of prevention strategies.

A Selection of Important Genes and Their Correlated Behavior in Alzheimer's Disease. - Cruz-Rivera, Yazeli E; Perez-Morales, Jaileene; Santiago, Yaritza M; Gonzalez, Valerie M; Morales, Luisa; Cabrera-Rios, Mauricio; Isaza, Clara E (J Alzheimers Dis, 2018)
In 2017, approximately 5 million Americans were living with Alzheimer's disease (AD), and it is estimated that by 2050 this number could increase to 16 million. In this study, we apply mathematical optimization to approach microarray analysis to detect differentially expressed genes and determine the most correlated structure among their expression changes. The analysis of GSE4757 microarray dataset, which compares expression between AD neurons without neurofibrillary tangles (controls) and with neurofibrillary tangles (cases), was casted as a multiple criteria optimization (MCO) problem. Through the analysis it was possible to determine a series of Pareto efficient frontiers to find the most differentially expressed genes, which are here proposed as potential AD biomarkers. The Traveling Sales Problem (TSP) model was used to find the cyclical path of maximal correlation between the expression changes among the genes deemed important from the previous stage. This leads to a structure capable of guiding biological exploration with enhanced precision and repeatability. Ten genes were selected (FTL, GFAP, HNRNPA3, COX1, ND2, ND3, ND4, NUCKS1, RPL41, and RPS10) and their most correlated cyclic structure was found in our analyses. The biological functions of their products were found to be linked to inflammation and neurodegenerative diseases and some of them had not been reported for AD before. The TSP path connects genes coding for mitochondrial electron transfer proteins. Some of these proteins are closely related to other electron transport proteins already reported as important for AD.

Self- and Informant-Reported Memory Complaints: Frequency and Severity in Cognitively Intact Individuals and those with Mild Cognitive Impairment and Neurodegenerative Dementias. - Rahman-Filipiak, Annalise M; Giordani, Bruno; Heidebrink, Judith; Bhaumik, Arijit; Hampstead, Benjamin M (J Alzheimers Dis, 2018)
BACKGROUND: Subjective memory complaints (SMCs) are incorporated into the diagnosis of mild cognitive impairment (MCI) and neurodegenerative dementias; however, the relative frequency of SMCs in cognitively intact older adults and those with different types of dementia is poorly understood. Similarly, the concordance between self- versus informant-reported SMCs has not been compared across different diagnostic groups. OBJECTIVE: This study aimed to evaluate the frequency of self-reported (Objective 1) and informant-reported (Objective 2) SMCs in cognitively intact adults or those diagnosed with MCI or a neurodegenerative dementia. Agreement between participant and informant complaints was also evaluated (Objective 3). METHODS: Baseline evaluation data were drawn from 488 participants (Mage = 70.49 years; Medu = 15.62 years) diagnosed as cognitively intact, non-amnestic MCI, amnestic single domain MCI, amnestic multi-domain MCI, possible/probable Alzheimer's disease, dementia with Lewy bodies, or frontotemporal dementia. Participants and their informants completed the Memory Assessment Clinic Questionnaire. RESULTS: One-way ANCOVAs controlling for age, education, and depression revealed no group differences in severity of self-reported SMCs. In contrast, informant memory ratings followed the expected clinical pattern, with comparable and most impaired ratings given to participants with any dementia diagnosis, followed by those with any MCI diagnosis, followed by cognitively intact participants. There was inconsistent agreement between self- and informant-reported SMC ratings in any of the impaired groups. CONCLUSIONS: Given greater diagnostic specificity and internal consistency of informant report, clinicians should weigh this information more heavily than self-report in the diagnostic process.

Self-Reported Physical Activity is Associated with Tau Burden Measured by Positron Emission Tomography. - Brown, Belinda M; Rainey-Smith, Stephanie R; Doré, Vincent; Peiffer, Jeremiah J; Burnham, Samantha C; Laws, Simon M; Taddei, Kevin; Ames, David; Masters, Colin L; Rowe, Christopher C; Martins, Ralph N; Villemagne, Victor L (J Alzheimers Dis, 2018)
Numerous animal studies have reported exercise reduces the accumulation of Alzheimer's disease pathology, including amyloid-β (Aβ) and tau. Furthermore, we previously reported a relationship between higher levels of physical activity (PA) and lower brain Aβ burden in a human population. The recent advent of tau positron emission tomography (PET) tracers enables us to extend our investigations into the evaluation of the relationship between PA and brain tau burden. Utilizing data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we have examined the cross-sectional relationship between habitual PA and PET-quantified tau burden. Forty-three cognitively healthy older adults were categorized into low-moderate PA (LMPA; n = 16) or high PA (HPA; n = 27), based on self-reported PA levels. Tau PET imaging with the AV1451 tracer was conducted on all participants. The LMPA group had significantly higher neocortical tau burden (presented as a z-score; 1.22±1.98), compared to the HPA group (z-score: - 0.28±1.18). The difference between the LMPA and HPA groups was also evident when examining regional tau burden in the temporoparietal cortex and the prefrontal cortex. Our results suggest an association between self-reported PA level and brain tau burden. Future longitudinal and interventional studies utilizing larger samples sizes are vital to further investigate the nature of the relationship between tau and PA.

Separating Symptomatic Alzheimer's Disease from Depression based on Structural MRI. - Klöppel, Stefan; Kotschi, Maria; Peter, Jessica; Egger, Karl; Hausner, Lucrezia; Frölich, Lutz; Förster, Alex; Heimbach, Bernhard; Normann, Claus; Vach, Werner; Urbach, Horst; Abdulkadir, Ahmed (J Alzheimers Dis, 2018)
Older patients with depression or Alzheimer's disease (AD) at the stage of early dementia or mild cognitive impairment may present with objective cognitive impairment, although the pathology and thus therapy and prognosis differ substantially. In this study, we assessed the potential of an automated algorithm to categorize a test set of 65 T1-weighted structural magnetic resonance images (MRI). A convenience sample of elderly individuals fulfilling clinical criteria of either AD (n = 28) or moderate and severe depression (n = 37) was recruited from different settings to assess the potential of the pattern recognition method to assist in the differential diagnosis of AD versus depression. We found that our algorithm learned discriminative patterns in the subject's grey matter distribution reflected by an area under the receiver operator characteristics curve of up to 0.83 (confidence interval ranged from 0.67 to 0.92) and a balanced accuracy of 0.79 for the separation of depression from AD, evaluated by leave-one-out cross validation. The algorithm also identified consistent structural differences in a clinically more relevant scenario where the data used during training were independent from the data used for evaluation and, critically, which included five possible diagnoses (specifically AD, frontotemporal dementia, Lewy body dementia, depression, and healthy aging). While the output was insufficiently accurate to use it directly as a means for classification when multiple classes are possible, the continuous output computed by the machine learning algorithm differed between the two groups that were investigated. The automated analysis thus could complement, but not replace clinical assessments.

Serotonin Selective Reuptake Inhibitor Treatment Improves Cognition and Grey Matter Atrophy but not Amyloid Burden During Two-Year Follow-Up in Mild Cognitive Impairment and Alzheimer's Disease Patients with Depressive Symptoms. - Brendel, Matthias; Sauerbeck, Julia; Greven, Sonja; Kotz, Sebastian; Scheiwein, Franziska; Blautzik, Janusch; Delker, Andreas; Pogarell, Oliver; Ishii, Kazunari; Bartenstein, Peter; Rominger, Axel (J Alzheimers Dis, 2018)
Late-life depression, even when of subsyndromal severity, has shown strong associations with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Preclinical studies have suggested that serotonin selective reuptake inhibitors (SSRIs) can attenuate amyloidogenesis. Therefore, we aimed to investigate the effect of SSRI medication on amyloidosis and grey matter volume in subsyndromal depressed subjects with MCI and AD during an interval of two years. 256 cognitively affected subjects (225 MCI/ 31 AD) undergoing [18F]-AV45-PET and MRI at baseline and 2-year follow-up were selected from the ADNI database. Subjects with a positive depression item (DEP(+); n = 73) in the Neuropsychiatric Inventory Questionnaire were subdivided to those receiving SSRI medication (SSRI(+); n = 24) and those without SSRI treatment (SSRI(-); n = 49). Longitudinal cognition (Δ-ADAS), amyloid deposition rate (standardized uptake value, using white matter as reference region (SUVRWM), and changes in grey matter volume were compared using common covariates. Analyses were performed separately in all subjects and in the subgroup of amyloid-positive subjects. Cognitive performance in DEP(+)/SSRI(+) subjects (Δ-ADAS: -5.0%) showed less deterioration with 2-year follow-up when compared to DEP(+)/SSRI(-) subjects (Δ-ADAS: +18.6%, p < 0.05), independent of amyloid SUVRWM at baseline. With SSRI treatment, the progression of grey matter atrophy was reduced (-0.9% versus -2.7%, p < 0.05), notably in fronto-temporal cortex. A slight trend towards lower amyloid deposition rate was observed in DEP(+)/SSRI(+) subjects versus DEP(+)/SSRI(-). Despite the lack of effect to amyloid PET, SSRI medication distinctly rescued the declining cognitive performance in cognitively affected patients with depressive symptoms, and likewise attenuated grey matter atrophy.

Serum Copper is not Altered in Frontotemporal Lobar Degeneration. - Squitti, Rosanna; Fostinelli, Silvia; Siotto, Mariacristina; Ferrari, Clarissa; Binetti, Giuliano; Benussi, Luisa; Rongioletti, Mauro; Ghidoni, Roberta (J Alzheimers Dis, 2018)
Meta-analyses show copper dyshomeostasis in Alzheimer's disease. However, a study evaluating copper changes in other neurodegenerative forms of dementia has not yet been performed. In this study, we assessed copper, ceruloplasmin, copper not bound to ceruloplasmin, and copper to ceruloplasmin ratio in 85 patients affected by frontotemporal lobar degeneration (FTLD) and 55 healthy controls. Data were analyzed through multivariate ANOVA models taking into account age and sex as covariates and the stratification for FTLD variants, after calculating power analysis to ensure the reliability of the conclusions drawn. The study revealed no difference between the groups.

Serum C-Peptide, Visfatin, Resistin, and Ghrelin are Altered in Sporadic and GRN-Associated Frontotemporal Lobar Degeneration. - Zanardini, Roberta; Benussi, Luisa; Fostinelli, Silvia; Saraceno, Claudia; Ciani, Miriam; Borroni, Barbara; Padovani, Alessandro; Binetti, Giuliano; Ghidoni, Roberta (J Alzheimers Dis, 2018)
Frontotemporal lobar degeneration (FTLD) is a group of complex neurodegenerative disease characterized by progressive deterioration of the frontal and anterior temporal lobes of the brain resulting in different heterogeneous conditions, mainly characterized by personality changes, behavioral disturbances, such as binge eating, and deficits in language and executive functions. Null mutations in progranulin gene (GRN) are one of the most frequent genetic determinants in familial frontotemporal dementia. Recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance revealing its metabolic function. Increasing evidence suggests that neurodegenerative dementias are associated with a higher prevalence of metabolic changes than in the general population. According to these findings, the aim of this study is to investigate putative alterations in markers linked to metabolic functions (i.e., C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon, insulin, resistin, and three adipokines as visfatin, leptin, and plasminogen activator inhibitor-1 total) in sporadic and GRN-related FTLD. We found that 1) C-peptide is increased in sporadic and GRN-mutated FTLD patients; in addition, we demonstrated an anticipation of the disease in patients with the highest C-peptide concentrations; 2) visfatin is slightly reduced in the whole FTLD group; 3) resistin, an adipokine involved in inflammatory-related diseases, is specifically increased in FTLD due to GRN null mutations; 4) ghrelin concentration is specifically increased in pre-symptomatic subjects and FTLD patients with GRN mutations. These findings support the hypothesis that alterations in metabolic pattern are involved in FTLD progression highlighting novel putative targets for the development of preventive and personalized therapies.
Keywords: Aged; Biomarkers; C-Peptide; Female; Frontotemporal Lobar Degeneration; Ghrelin; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Nicotinamide Phosphoribosyltransferase; Progranulins; Resistin

Serum Non-Ceruloplasmin Non-Albumin Copper Elevation in Mild Cognitive Impairment and Dementia due to Alzheimer's Disease: A Case Control Study. - Rozzini, Luca; Lanfranchi, Francesco; Pilotto, Andrea; Catalani, Simona; Gilberti, Maria Enrica; Paganelli, Matteo; Apostoli, Pietro; Padovani, Alessandro (J Alzheimers Dis, 2018)
Several studies showed high serum copper levels in Alzheimer's disease (AD). The present study applied a newly developed method to detect serum copper free from proteins (free-Cu). Forty-four patients affected by dementia due to AD, thirty-six patients affected by mild cognitive impairment (MCI) due to AD, and twenty-eight healthy controls underwent clinical, cognitive, and MRI assessment. The new method showed higher free-Cu concentrations in MCI and dementia due to AD compared to controls (p < 0.0001). No correlation between copper levels, cognitive or MRI measures were found.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cognitive Dysfunction; Copper; Female; Humans; Magnetic Resonance Imaging; Male; Psychiatric Status Rating Scales

Severe Agitation in Dementia: An Explorative Secondary Data Analysis on the Prevalence and Associated Factors in Nursing Home Residents. - Palm, Rebecca; Sorg, Christian G G; Ströbel, Armin; Gerritsen, Debby L; Holle, Bernhard (J Alzheimers Dis, 2018)
BACKGROUND: The phenomena of severe agitation is not well understood and often not adequately treated. OBJECTIVE: This article determines the prevalence and associated factors of severe agitation in nursing home residents with dementia. METHODS: Secondary data analysis within an observational study in German nursing homes with n = 1,967 participants. We assessed severity of agitation with the Neuropsychiatric Inventory Questionnaire (NPI-Q) and defined the construct of agitation as a composite score of the NPI-Q items agitation/aggression, disinhibition, and irritability/lability; the dependent variable of severe agitation was considered as being present in residents who scored 'severe' in at least one of these symptoms. A binary logistic regression model was calculated to estimate associations. RESULTS: The prevalence of severe agitation was 6.3% (n = 124). The strongest associations were found for elation/euphoria (OR 7.6, CI 3.1-18.5), delusions (OR 7.3, CI 4.0-13.2), apathy/indifference (OR 2.8, CI 1.7-4.7), anxiety (OR 2.2, CI 1.2-3.8), nighttime behaviors (OR 2.4, CI 1.4-4.2), motor disturbances (OR 2.4, CI 1.4-4.1), and male sex (OR 2.4. CI 1.3-4.2). CONCLUSION: Severe agitation in nursing home residents with dementia is a relevant clinical issue as approximately 70% of residents have a dementia. Residents with elation/euphoria and delusions may have a stronger risk of showing severe agitation. We consider delusions as a possible cause of agitation and therefore a prelude to agitation. Although it might be possible that elation/euphoria follows from agitation, we hypothesize that the residents first experience elation/ euphoria and exhibit agitation afterwards.

Severity-Related Increase and Cognitive Correlates of Serum VEGF Levels in Alzheimer's Disease ApoE4 Carriers. - Alvarez, X Anton; Alvarez, Irene; Aleixandre, Manuel; Linares, Carlos; Muresanu, Dafin; Winter, Stefan; Moessler, Herbert (J Alzheimers Dis, 2018)
Vascular endothelial growth factor (VEGF) is an angioneurin involved in the regulation of vascular and neural functions relevant for the pathophysiology of Alzheimer's disease (AD), but the influence of AD severity and ApoE4 status on circulating VEGF and its relationship with cognition has not been investigated. We assessed serum VEGF levels and cognitive performance in AD, amnestic mild cognitive impairment (MCI), and control subjects. VEGF levels were higher in AD patients than in MCI cases and controls (p < 0.05) and showed a progressive increase with clinical severity in the whole study population (p < 0.01). Among AD patients, severity-related VEGF elevations were significant in ApoE4 carriers (p < 0.05), but not in non-carriers. Increased VEGF levels were associated with disease severity and showed mild correlations with cognitive impairment that were only consistent for the ADAS-cog+ items remembering test instructions (memory) and maze task (executive functions) in the group of AD patients (p < 0.05). On the other hand, higher VEGF values were related to better memory and language performance in ApoE4 carriers with moderately-severe AD. According to these results showing severity- and ApoE4-related differences in serum VEGF and its cognitive correlates, it is suggested that increases in VEGF levels might represent an endogenous response driven by pathological factors and could entail cognitive benefits in AD patients, particularly in ApoE4 carriers. Our findings support the notion that VEGF constitutes a relevant molecular target to be further explored in AD pathology and therapy.

Sex Influences the Accuracy of Subjective Memory Complaint Reporting in Older Adults. - Sundermann, Erin E; Edmonds, Emily C; Delano-Wood, Lisa; Galasko, Douglas R; Salmon, David P; Rubin, Leah H; Bondi, Mark W (J Alzheimers Dis, 2018)
Subjective memory complaints (SMC) are required when diagnosing amnestic mild cognitive impairment (aMCI), although their relationship with objective memory performance and Alzheimer's disease (AD) pathology remains unclear. We investigated whether the sex of the patient/participant moderates these associations. Participants were 940 normal control (NC) and aMCI participants from the Alzheimer's Disease Neuroimaging Initiative. SMC were assessed via the memory scale of the Everyday Cognition questionnaire. Discrepancy scores were calculated between self- and informant-reports and categorized into "overestimates," "comparable estimates", and "underestimates" of SMC. We conducted linear and logistic regressions to examine the interaction of sex with self- and informant-reported SMC and discrepancy group on the Rey Auditory Verbal Learning Test (RAVLT) Immediate and Delayed Recall and on PET measures of amyloid-β (Aβ) positivity. Diagnosis-stratified analyses were also conducted. Overall, there were sex by self- and informant-reported SMC interactions for Immediate and Delayed Recall. Despite a higher proportion of "overestimates" in women, greater self- and informant-reported SMC showed a stronger relationship to poorer RAVLT scores in women versus men. Diagnosis-stratified analyses revealed that results were driven by aMCI participants. Conversely, overall, greater self- and informant-reported SMC related to greater odds of Aβ positivity regardless of sex. In diagnosis-stratified analyses, only informant-reported SMC related to Aβ positivity in aMCI. Relative to "comparable estimates," "underestimates" of SMC were associated with poorer RAVLT scores across sexes in the overall sample and in aMCI. The predictive utility of self-report SMC may be limited to women in aMCI. Sex differences should be considered when evaluating SMC.
Keywords: Aged; Cognitive Dysfunction; Female; Humans; Logistic Models; Male; Memory Disorders; Mental Recall; Neuropsychological Tests; Self Report; Sex Factors

Sex Moderates the Impact of Diagnosis and Amyloid PET Positivity on Hippocampal Subfield Volume. - Caldwell, Jessica Z K; Berg, Jody-Lynn; Shan, Guogen; Cummings, Jeffrey L; Banks, Sarah J (J Alzheimers Dis, 2018)
We examined moderation effects of sex and diagnosis on the effect of positive florbetapir positron emission tomography (PET) amyloid-β (Aβ) scan (A+) on hippocampus subfield volumes in 526 normal control (NC) and early mild cognitive impairment (eMCI) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI2; ADNI-GO). Regression moderation models showed that women- but not men- with NC designation did not show reduced subiculum volumes despite A+. At the eMCI stage, A+ was detrimental across sexes. Findings were significant while accounting for the effects of age, cognition at screening, education, and APOE4 carrier status. These findings suggest that women with A+ have early neural resistance to Alzheimer's disease-related amyloid burden.

Sex-Dependent Differences in Spontaneous Autoimmunity in Adult 3xTg-AD Mice. - Kapadia, Minesh; Mian, M Firoz; Michalski, Bernadeta; Azam, Amber B; Ma, Donglai; Salwierz, Patrick; Christopher, Adam; Rosa, Elyse; Zovkic, Iva B; Forsythe, Paul; Fahnestock, Margaret; Sakic, Boris (J Alzheimers Dis, 2018)
The triple-transgenic (3xTg-AD) mouse strain is a valuable model of Alzheimer's disease (AD) because it develops both amyloid-β (Aβ) and tau brain pathology. However, 1-year-old 3xTg-AD males no longer show plaques and tangles, yet early in life they exhibit diverse signs of systemic autoimmunity. The current study aimed to address whether females, which exhibit more severe plaque/tangle pathology at 1 year of age, show similar autoimmune phenomena and if so, whether these immunological changes coincide with prodromal markers of AD pathology, markers of learning and memory formation, and epigenetic markers of neurodegenerative disease. Six-month-old 3xTg-AD and wild-type mice of both sexes were examined for T-cell phenotype (CD3+, CD8+, and CD4+ populations), serological measures (autoantibodies, hematocrit), soluble tau/phospho-tau and Aβ levels, brain-derived neurotrophic factor (BDNF) expression, and expression of histone H2A variants. Although no significant group differences were seen in tau/phospho-tau levels, 3xTg-AD mice had lower brain mass and showed increased levels of soluble Aβ and downregulation of BDNF expression in the cortex. Splenomegaly, depleted CD+ T-splenocytes, increased autoantibody levels and low hematocrit were more pronounced in 3xTg-AD males than in females. Diseased mice also failed to exhibit sex-specific changes in histone H2A variant expression shown by wild-type mice, implicating altered nucleosome composition in these immune differences. Our study reveals that the current 3xTg-AD model is characterized by systemic autoimmunity that is worse in males, as well as transcriptional changes in epigenetic factors of unknown origin. Given the previously observed lack of plaque/tangle pathology in 1-year-old males, an early, sex-dependent autoimmune mechanism that interferes with the formation and/or deposition of aggregated protein species is hypothesized. These results suggest that more attention should be given to studying sex-dependent differences in the immunological profiles of human patients.

Sex-Related Reserve Hypothesis in Alzheimer's Disease: Changes in Cortical Thickness with a Five-Year Longitudinal Follow-Up. - Lee, Juyoun; Cho, Hanna; Jeon, Seun; Kim, Hee Jin; Kim, Yeo Jin; Lee, Jeongmin; Kim, Sung Tae; Lee, Jong-Min; Chin, Juhee; Lockhart, Samuel N; Lee, Ae Young; Na, Duk L; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Sex effects on the progression of Alzheimer's disease (AD) have received less attention than other demographic factors, including onset age and education. OBJECTIVE: The aim of this study was to investigate whether sex affected cortical thinning in the disease progression of AD. METHODS: We prospectively recruited 36 patients with early-stage AD and 14 people with normal cognition. All subjects were assessed with magnetic resonance imaging at baseline, Year 1, Year 3, and Year 5. We performed cortical thickness analyses using surface-based morphometry on magnetic resonance imaging. RESULTS: Women with AD showed more rapid cortical thinning in the left dorsolateral frontal cortex, left superior temporal gyrus, bilateral temporo-parietal association cortices, bilateral anterior cingulate gyri, bilateral medial frontal cortices, and bilateral occipital cortices over 5 years than men with AD, even though there was no difference in cortical thickness at baseline. In contrast, there were no regions of significantly more rapid atrophy in men with AD. CONCLUSIONS: Our findings suggest that women deteriorate faster than men in the progression of AD.

Shear-Induced Amyloid Formation in the Brain: III. The Roles of Shear Energy and Seeding in a Proposed Shear Model. - Trumbore, Conrad N (J Alzheimers Dis, 2018)
If cerebrospinal and interstitial fluids move through very narrow brain flow channels, these restrictive surroundings generate varying levels of fluid shear and different shear rates, and dissolved amyloid monomers absorb different shear energies. It is proposed that dissolved amyloid-β protein (Aβ) and other amyloid monomers undergo shear-induced conformational changes that ultimately lead to amyloid monomer aggregation even at very low brain flow and shear rates. Soluble Aβ oligomers taken from diseased brains initiate in vivo amyloid formation in non-diseased brains. The brain environment is apparently responsible for this result. A mechanism involving extensional shear is proposed for the formation of a seed Aβ monomer molecule that ultimately promotes templated conformational change of other Aβ molecules. Under non-quiescent, non-equilibrium conditions, gentle extensional shear within the brain parenchyma, and perhaps even during laboratory preparation of Aβ samples, may be sufficient to cause subtle conformational changes in these monomers. These result from brain processes that significantly lower the high activation energy predicted for the quiescent Aβ dimerization process. It is further suggested that changes in brain location and changes brought about by aging expose Aβ molecules to different shear rates, total shear, and types of shear, resulting in different conformational changes in these molecules. The consequences of such changes caused by variable shear energy are proposed to underlie formation of amyloid strains causing different amyloid diseases. Amyloid researchers are urged to undertake studies with amyloids, anti-amyloid drugs, and antibodies while all of these are under shear conditions similar to those in the brain.

Shear-Induced Amyloid Formation in the Brain: IV. Effects on Synapses Surrounding Senile Plaque and in Plaque-Free Regions. - Trumbore, Conrad N (J Alzheimers Dis, 2018)
Amyloid-β oligomers (AβO) have been proposed as neurotoxins in the synaptic dysfunction that precedes Alzheimer's disease symptoms. Human and animal model studies report that senile plaques contain a halo of AβO molecules surrounding these plaques. A far smaller number of oligomers are distributed widely in plaque-free regions. It has been suggested that oligomers migrate from halos to nearby synapses and are incorporated into both pre- and postsynaptic terminals. These two types of oligomers have two different toxicities when extracted and injected in animal models. This paper proposes a shear-energy based explanation for the data in these studies. Shear hypotheses in the preceding three papers in this series are applied to suggest how the hydrodynamics and resulting shear patterns explain the spatial distribution of both AβO types, the apparent synapse loss in the vicinity of plaque particles, and possible reasons for the differing toxicities. A shear-based mechanism is proposed for the preferential migration of locally shear-excited Aβ molecules into the synaptic cleft. It is proposed that high energy laminar shear generated by the forced diversion of interstitial fluid around the flow-impeding plaque particle is responsible for the formation of AβOs around the plaque. It is suggested that in plaque-free regions, a different type of AβO with different toxicity is generated by lower energy shear flow around synapses, depositing AβO within the synapse from either the neuron membrane surface or by prion-like seeding within the synaptic cleft by locally-sheared Aβ molecules near the synapse entry.

Short-Term Effects of Microglia-Specific Mitochondrial Dysfunction on Amyloidosis in Transgenic Models of Alzheimer's Disease. - Steffen, Johannes; Stenzel, Jan; Ibrahim, Saleh; Pahnke, Jens (J Alzheimers Dis, 2018)
Reduction of mitochondrial activity is a subtle and early event in the pathogenesis of Alzheimer's disease. Mitochondrial damage and consequentially enhanced production of reactive oxygen species is particularly occurring in the vicinity of amyloid plaques. Since all cells are affected by mitochondrial damage, analyses of cell type-specific effects are challenging. To study the impact of mitochondrial alterations on microglial activity in a homogeneous genetic background, we generated bone marrow chimeras of irradiated 46-days-old APP-transgenic mice. For reconstitution, bone marrow from CX3CR1-eGFP mice with mitochondria of either non-obese diabetic or C57BL/6J animals was utilized. Successful reconstitution was evident in 100-day-old animals, by the presence of eGFP-positive cells in liver and spleen. In the brain, one-third of IBA1-positive microglia cells were newly recruited eGFP-expressing cells. Although donor-derived microglia were equally located in the proximity of amyloid plaques, no difference was observed in either the amyloid level, total number, or microglial coverage of plaques. These results indicate that during this brief and early phase of amyloid deposition, beneficial mitochondrial alterations in the newly recruited third of microglial cells were not sufficient to affect the amyloidosis in APP-transgenic mice.

Simultaneous Aerobic Exercise and Memory Training Program in Older Adults with Subjective Memory Impairments. - McEwen, Sarah C; Siddarth, Prabha; Abedelsater, Berna; Kim, Yena; Mui, Wenli; Wu, Pauline; Emerson, Natacha D; Lee, Jacob; Greenberg, Shayna; Shelton, Tiffany; Kaiser, Scott; Small, Gary W; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Several modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance. OBJECTIVE: The aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults. METHODS: 55 older adults (aged 60- 75) with subjective memory impairments (non-demented and non-MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) or sequentially after the stationary cycling (SEQ). Standardized neurocognitive measures of memory, executive functioning, speed of processing, attention, and cognitive flexibility were assessed at baseline and post-intervention. RESULTS: The SIM group, but not the SEQ group, had a significant improvement on composite memory following the intervention (t(51) = 2.7, p = 0.01, effect size (ES) = 0.42) and transfer to non-trained reasoning abilities (t(51) = 6.0, ES = 0.49) and complex attention (t(51) = 3.1, p = 0.003, ES = 0.70). Conversely, the SEQ group, but not the SIM, showed significant improvement in executive functioning (t(51) = 5.0, p = 0.0001, ES = 0.96). CONCLUSION: These findings indicate that a 4-week simultaneous memory training and aerobic exercise program is sufficient to improve memory, attention, and reasoning abilities in older adults.
Keywords: Aged; Attention; California; Cognition; Executive Function; Exercise; Female; Humans; Learning; Male; Memory; Memory Disorders; Middle Aged; Treatment Outcome

Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging. - Bouts, Mark J R J; Möller, Christiane; Hafkemeijer, Anne; van Swieten, John C; Dopper, Elise; van der Flier, Wiesje M; Vrenken, Hugo; Wink, Alle Meije; Pijnenburg, Yolande A L; Scheltens, Philip; Barkhof, Frederik; Schouten, Tijn M; et al. (J Alzheimers Dis, 2018)
BACKGROUND/OBJECTIVE: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known. METHODS: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC). RESULTS: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41). CONCLUSION: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI.

SIRT1 Deacetylates SC35 and Suppresses Its Function in Tau Exon 10 Inclusion. - Yin, Xiaomin; Jiang, Xiaosu; Wang, Jia; Qian, Shuo; Liu, Fei; Qian, Wei (J Alzheimers Dis, 2018)
Approximately equal amounts of 3R-tau and 4R-tau resulting from alternative splicing of tau exon 10 is necessary to maintain normal brain function. Dysregulation of alternative splicing of tau exon 10 and the imbalance of 3R-tau/4R-tau have been seen in inherited and sporadic tauopathies. Splicing factor SC35 (also name as SRSF2) plays an important role in promoting tau exon 10 inclusion. SC35 is post-translationally modified by phosphorylation and acetylation, but the role of acetylation in SC35-medicated tau exon 10 inclusion is unknown. Sirtuin type 1 (SIRT1) is an enzyme that deacetylates proteins and associates with age-related disease such as Alzheimer's disease. In the present study, we determined the role of SIRT1 in SC35 acetylation and in the alternative splicing of tau exon 10. We found that SIRT1 interacts with and deacetylates SC35, and inhibits SC35-promoted tau exon 10 inclusion. Substituting K52 residue of SC35 by arginine impairs the role of SC35 in tau exon 10 inclusion. These results suggest that SIRT1 may serve as a therapeutic target for tauopathy by regulating SC35-mediated tau exon 10 splicing.
Keywords: Alternative Splicing; Alzheimer Disease; Exons; HEK293 Cells; HeLa Cells; Humans; Phosphorylation; Ribonucleoproteins; Serine-Arginine Splicing Factors; Sirtuin 1; tau Proteins; Tauopathies

Sleep and EEG Power Spectral Analysis in Three Transgenic Mouse Models of Alzheimer's Disease: APP/PS1, 3xTgAD, and Tg2576. - Kent, Brianne A; Strittmatter, Stephen M; Nygaard, Haakon B (J Alzheimers Dis, 2018)
BACKGROUND: Sleep disturbances have long been associated with Alzheimer's disease (AD), and there is a growing interest in how these disturbances might impact AD pathophysiology. Despite this growing interest, surprisingly little is known about how sleep architecture and the broader neuronal network are affected in widely used transgenic mouse models of AD. OBJECTIVE: We analyzed sleep and electroencephalography (EEG) power in three transgenic mouse models of AD, using identical and commercially available hardware and analytical software. The goal was to assess the suitability of these mouse lines to model sleep and the broader neuronal network dysfunction measured by EEG in AD. METHODS: Tg2576, APP/PS1, and 3xTgAD transgenic AD mice were studied using in vivo EEG recordings for sleep/wake time and power spectral analysis. RESULTS: Both the APP/PS1 model at 8- 10 months and the Tg2576 model at 12 months of age exhibited stage-dependent decreases in theta and delta power, and shifts in the power spectra toward higher frequencies. Stage-dependent power spectral analyses showed no changes in the 3xTgAD model at 18 months of age. The percentage of time spent awake, in non-rapid eye movement sleep (NREM), or in rapid-eye-movement sleep (REM) was not different between genotypes in any of the transgenic lines. CONCLUSION: Our findings are consistent with data from several other transgenic AD models as well as certain studies in patients with mild cognitive impairment. Further studies will be needed to better understand the correlation between EEG spectra and AD pathophysiology, both in AD models and the human condition.

A Small Molecule Inhibitor of Plasminogen Activator Inhibitor-1 Reduces Brain Amyloid-β Load and Improves Memory in an Animal Model of Alzheimer's Disease. - Akhter, Hasina; Huang, Wen-Tan; van Groen, Thomas; Kuo, Hui-Chien; Miyata, Toshio; Liu, Rui-Ming (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aβ load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aβ load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, as well as plasma Aβ42 are increased, whereas the expression and processing of full-length amyloid-β protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aβ40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aβ accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aβ in the brain.

Small Vessel Cerebrovascular Pathology Identified by Magnetic Resonance Imaging Is Prevalent in Alzheimer's Disease and Mild Cognitive Impairment: A Potential Target for Intervention. - Scott, Tammy M; Bhadelia, Rafeeque A; Qiu, Wei Qiao; Folstein, Marshal F; Rosenberg, Irwin H (J Alzheimers Dis, 2018)
BACKGROUND: There is evidence that Alzheimer's disease (AD) has significant cerebrovascular etiopathogenesis. Understanding potentially modifiable risk factors for vascular disease can help design long-term intervention strategies for controlling or preventing cognitive dysfunction attributable to cerebrovascular disease. OBJECTIVE: To evaluate the presence and severity of markers of cerebrovascular pathology, its relationship to diagnostic categories of dementia, including AD, and association with the metabolic biomarker homocysteine. METHODS: In a cross-sectional observational study, 340 community-dwelling elders received a clinical evaluation including brain MRI and neuropsychological tests. Dementia and mild cognitive impairment (MCI) were diagnosed by consensus committee. Fasting total plasma homocysteine was measured. Statistical analyses were adjusted for demographics and cerebrovascular risk factors. RESULTS: Nearly 25% of those diagnosed with AD had small vessel infarcts (SVI). Periventricular white matter hyperintensity (pvWMHI) was prevalent in participants with AD (61%) or MCI (amnesic 61% and non-amnesic 54%, respectively). Participants with SVI and/or pvWMHI also had greater brain atrophy. Homocysteine concentrations were higher in individuals with cerebrovascular findings than in those without. In individuals with cerebrovascular disease, homocysteine was inversely related to executive function (p = 0.022) and directly related to degree of brain atrophy (p = 0.009). CONCLUSIONS: We demonstrated a significant prevalence of small vessel markers of cerebrovascular pathology in individuals diagnosed with AD, with a significant concurrence between cerebrovascular disease and brain and ventricular atrophy. While current research on AD has focused on amyloid-βpeptide deposition, tau-pathology, and microglial activation and inflammation, greater attention to the cerebrovascular contribution to this neurodegenerative disease presents an additional target for therapeutic prevention and intervention.

Social Dysfunction in Older Age and Relationships with Cognition, Depression, and Apathy: The GreatAGE Study. - Lozupone, Madia; Panza, Francesco; Piccininni, Marco; Copetti, Massimiliano; Sardone, Rodolfo; Imbimbo, Bruno P; Stella, Eleonora; D'Urso, Francesca; Barulli, Maria Rosaria; Battista, Petronilla; Grasso, Alessandra; Tortelli, Rosanna; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Most studies focused on only one measure of social dysfunction in older age, without proper validation and distinction across different dimensions including subjectivity, structural, and functional aspects. OBJECTIVE: We sought to validate the Social Dysfunction Rating Scale (SDRS) and its factorial structure, also determining the association of SDRS with cognitive functions, global psychopathology, and social deprivation. METHODS: The SDRS was administered to 484 Italian community-dwelling elderly, recruited in the GreatAGE study, a population-based study on aging conducted in Castellana Grotte, Bari, Southern Italy. We determined objective and subjective psychometric properties of SDRS against the gold standard evaluation of social dysfunction according to the Semi-structured Clinical Diagnostic Interview for DSM-IV-TR Axis I Disorders (SCID-I) criterion. RESULTS: The SDRS showed a moderate accuracy with an optimal cut-off of 26 maximized with higher sensitivity (0.74,95% CI:0.63-0.84) than specificity (0.57,95% CI:0.50-0.64). A five-factor structure was carried out and five dimensions of SDRS were identified (loneliness; social isolation; feeling of contribution/uselessness; lack of leisure activities; anxiety for the health). Education and global cognitive functions were inversely correlated to SDRS, while a direct association with global psychopathology, depression, and apathy was found. The prevalence of higher SDRS scores was major in subjects with current psychiatric disorders versus other subjects.∥Conclusion: The SDRS could be a valid instrument to capture both size and quality of social dysfunction, both in subjects with psychiatric disorders and in normal subjects. Several categories of social dysfunction differed only in the degree of health deprivation, not in social or material deprivation.

Some Methodological Characteristics of Alzheimer-Associated Urine Neuronal Thread Protein Detected by Enzyme-Linked Immunosorbent Assay. - Jin, He; Wang, Rong; Liu, Zhaohui; Jia, Qiang; Wu, Yanchuan; Zhao, Zhiwei; Wang, Yulan; Zhang, Xu (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a candidate biomarker of Alzheimer's disease (AD). OBJECTIVE: To investigate the effects of urine collected time, different preservatives addition, and storage condition on the measurement of urine AD7c-NTP by enzyme-linked immunosorbent assay (ELISA). METHODS: Three hundred urine samples were collected from 20 participants at three time points on five consecutive days. These samples were immediately placed at 4°C and detected within 2 h. The single spot samples of the first day morning were split into eleven duplicate aliquots (a-k) of 1 ml each, (a) without any preservative (untreated), (b) containing boric acid (2 g/L), (c) containing NaHCO3 (5 g/L), (a-c) were detected at six different time points. For the other eight preservative-free samples, (d-g) were stored at -20°C and (h-k) were stored at -70°C, respectively, detected at different time points. All of the results were compared with the baseline urine. RESULTS: The urine AD7c-NTP levels at different time points behaved stably (p > 0.05). Urine samples without any preservative increased over time, and compared with the NaHCO3 addition group, boric acid addition group behaved stably. Samples stored at -20°C and -70°C led to an obviously false positive. CONCLUSIONS: AD7c-NTP can be tested using random urine instead of the first morning urine. If the specimen cannot be tested in time, boric acid appears to be an acceptable preservative with storage at 4°C, freezing is not recommended.

SORL1 Variants in Familial Alzheimer's Disease. - Gómez-Tortosa, Estrella; Ruggiero, María; Sainz, Ma José; Villarejo-Galende, Alberto; Prieto-Jurczynska, Cristina; Venegas Pérez, Begoña; Ordás, Carlos; Agüero, Pablo; Guerrero-López, Rosa; Pérez-Pérez, Julián (J Alzheimers Dis, 2018)
The SORL1 gene encodes a protein involved in the amyloidogenic process, and its variants have been associated with Alzheimer's disease (AD) physiopathology. We screened for SORL1 variants in 124 familial (44 early- and 80 late-onset) dementia of Alzheimer type (DAT) cases. Nine potentially pathogenic changes (three not previously reported and six rare variants) were found in nine probands (7%). After screening the control population and siblings (presence in at least 1/200 controls and/or absence of segregation pattern), a causal relationship with the disease was considered unlikely in six variants and uncertain in one. The change Trp848Ter and a splice-site variant remained likely correlated with the disease. SORL1 mutations are present in 7% of our familial DAT cohort, though in most cases cannot be considered the direct cause of the disease.
Keywords: Aged; Alzheimer Disease; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; LDL-Receptor Related Proteins; Male; Membrane Transport Proteins; Middle Aged; Mutation; Polymorphism, Single Nucleotide; Siblings; Spain

SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging. - Seddighi, Sahba; Varma, Vijay R; An, Yang; Varma, Sudhir; Beason-Held, Lori L; Tanaka, Toshiko; Kitner-Triolo, Melissa H; Kraut, Michael A; Davatzikos, Christos; Thambisetty, Madhav (J Alzheimers Dis, 2018)
We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.
Keywords: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Brain; Calcium-Binding Proteins; Cerebrovascular Circulation; Cognition Disorders; Extracellular Matrix Proteins; Female; Humans; Independent Living; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Polymorphism, Single Nucleotide; Positron-Emission Tomography

Spatial Navigation in the Elderly with Alzheimer's Disease: A Cross-Sectional Study. - Zanco, Marcos; Plácido, Jessica; Marinho, Valeska; Ferreira, José Vinicius; de Oliveira, Felipe; Monteiro-Junior, Renato; Barca, Maria; Engedal, Knut; Laks, Jerson; Deslandes, Andrea (J Alzheimers Dis, 2018)
BACKGROUND: Spatial navigation is a fundamental cognitive ability that allows an individual to maintain independence by facilitating the safe movement from one place to another. It emerges as one of the first deficits in patients with Alzheimer's disease (AD). OBJECTIVE: To compare spatial navigation performance in the healthy elderly and AD patients through use of the Floor Maze Test (FMT)- an easy-to-apply two-dimensional (2D) maze- and determine which cognitive and functional capacities were associated with performance in this task. METHODS: The FMT was administered to 24 AD patients and 36 healthy controls. Spatial navigation was evaluated through the FMT. Functional capacity was evaluated through the Senior Fitness Test battery of tests. Cognitive functions were evaluated through the Mini-Mental State Examination (MMSE), verbal fluency, digit span test, and the Rey Auditory Verbal Learning Test (RAVLT). RESULTS: The group with AD was significantly slower and presented more errors at all stages of the FMT. Planning Time (PT) performance was associated with cardiorespiratory resistance (Step test) and delayed memory according to the RAVLT (R2 = 0.395, p < 0.001). Performance in the Immediate Maze Time (IMT) and Delayed Maze Time (DMT) was associated with global cognitive status (MMSE) (R2 = 0.509) and delayed memory (R2 = 0.540). CONCLUSION: Patients with AD present significant spatial navigation deficits. Their performance on the FMT is influenced by cardiorespiratory capacity, memory, and global cognitive function. As exercise helps to improve executive function and functional capacity, future intervention studies should be carried out to analyze the possible effects of physical exercise on spatial navigation.

Stabilized Low-n Amyloid-β Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat. - Watremez, William; Jackson, Joshua; Almari, Bushra; McLean, Samantha L; Grayson, Ben; Neill, Joanna C; Fischer, Nicolas; Allouche, Ahmad; Koziel, Violette; Pillot, Thierry; Harte, Michael K (J Alzheimers Dis, 2018)
BACKGROUND: With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. OBJECTIVE: The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. METHODS: Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). RESULTS: Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. CONCLUSION: Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.

Statins and Brain Health: Alzheimer's Disease and Cerebrovascular Disease Biomarkers in Older Adults. - Ramanan, Vijay K; Przybelski, Scott A; Graff-Radford, Jonathan; Castillo, Anna M; Lowe, Val J; Mielke, Michelle M; Roberts, Rosebud O; Reid, Robert I; Knopman, David S; Jack, Clifford R; Petersen, Ronald C; Vemuri, Prashanthi (J Alzheimers Dis, 2018)
BACKGROUND: Statins have been proposed to reduce the risk of Alzheimer's disease (AD). OBJECTIVE: Assess whether long-term statin use was associated with neuroimaging biomarkers of aging and dementia. METHODS: Methods: We analyzed neuroimaging biomarkers in 1,160 individuals aged 65+ from the Mayo Clinic Study of Aging, a population-based prospective longitudinal study of cognitive aging. RESULTS: Statin-treated (5+ years of therapy) individuals had greater burden of mid-and late-life cardiovascular disease (p < 0.001) than statin-untreated (≤3 months) individuals. Lower fractional anisotropy in the genu of the corpus callosum, an early marker of cerebrovascular disease, was associated with long-term statin exposure (p < 0.035). No significant associations were identified between long-term statin exposure and cerebral amyloid or tau burden, AD pattern neurodegeneration, or white matter hyperintensity burden. CONCLUSIONS: Long-term statin therapy was not associated with differences in AD biomarkers. Individuals with long-term statin exposure had worse white matter integrity in the genu of the corpus callosum, consistent with the coexistence of higher cerebrovascular risk factor burden in this group.

Stereological Investigation of the Effects of Treadmill Running Exercise on the Hippocampal Neurons in Middle-Aged APP/PS1 Transgenic Mice. - Chao, Fenglei; Jiang, Lin; Zhang, Yi; Zhou, Chunni; Zhang, Lei; Tang, Jing; Liang, Xin; Qi, Yingqiang; Zhu, Yanqing; Ma, Jing; Tang, Yong (J Alzheimers Dis, 2018)
The risk of cognitive decline during Alzheimer's disease (AD) can be reduced if physical activity is maintained; however, the specific neural events underlying this beneficial effect are still uncertain. To quantitatively investigate the neural events underlying the effect of running exercise on middle-aged AD subjects, 12-month-old male APP/PS1 mice were randomly assigned to a control group or running group, and age-matched non-transgenic littermates were used as a wild-type group. AD running group mice were subjected to a treadmill running protocol (regular and moderate intensity) for four months. Spatial learning and memory abilities were assessed using the Morris water maze. Hippocampal amyloid plaques were observed using Thioflavin S staining and immunohistochemistry. Hippocampal volume, number of neurons, and number of newborn cells (BrdU+ cells) in the hippocampus were estimated using stereological techniques, and newborn neurons were observed using double-labelling immunofluorescence. Marked neuronal loss in both the CA1 field and dentate gyrus (DG) and deficits in both the neurogenesis and survival of new neurons in the DG of middle-aged APP/PS1 mice were observed. Running exercise could improve the spatial learning and memory abilities, reduce amyloid plaques in the hippocampi, delay neuronal loss, induce neurogenesis, and promote the survival of newborn neurons in the DG of middle-aged APP/PS1 mice. Exercise-induced protection of neurons and adult neurogenesis within the DG might be part of the important structural basis of the improved spatial learning and memory abilities observed in AD mice.

Stereological Quantification of Plaques and Tangles in Neocortex from Alzheimer's Disease Patients. - Madsen, Jes Buster; Folke, Jonas; Pakkenberg, Bente (J Alzheimers Dis, 2018)
We estimated by stereological methods the neocortical volume occupied by plaques and tangles in females dying with severe Alzheimer's disease (AD), age-matched female subjects with severe vascular dementia (VaD), and normal control brains. Stereological investigations include a uniform sampling of the tissue in the whole of neocortex and its subdivisions. Resultant volume estimates provide information about the overall burden of these two pathological changes and their volume fractions and allow for correlational studies between the pathological changes and factors such as the total neocortical neuronal cell numbers, dementia test scores, and age. We estimated the volume of plaques and tangles in the entire neocortex and frontal-, temporal-, parietal-, and occipital cortex in nine female AD brains, four female patients dying with VaD, and six neurologically normal female control brains using point-counting in uniform samples of neocortex. The volume occupied by plaques comprised approximately 1% of neocortex, while the neocortical tangles made up approximately 0.1% of neocortex of AD patients but were scarcely present in the other study groups. The individual tangle and plaque volumes did not correlate to the ultimate dementia score of the AD subjects, despite correlating with reduced neocortical volume. In neocortex of AD patients, the burden of plaques and tangles is much higher than that in patients with severe vascular dementia or normal older women but only occupy a small fraction of the neocortical volume.

Stimulation of SIRT1 Attenuates the Level of Oxidative Stress in the Brains of APP/PS1 Double Transgenic Mice and in Primary Neurons Exposed to Oligomers of the Amyloid-β Peptide. - Dong, Yang-Ting; Cao, Kun; Tan, Long-Chun; Wang, Xiao-Ling; Qi, Xiao-Lan; Xiao, Yan; Guan, Zhi-Zhong (J Alzheimers Dis, 2018)
In the study, we examined whether the silent information regulator 1 (SIRT1) can attenuate oxidative stress in the brains of mice carrying the APP/PS1 double mutation and/or in primary neonatal rat neurons exposed to oligomers of amyloid-β peptide (AβOs). Starting at 4 or 8 months of age, the transgenic mice were treated with resveratrol (RSV, a stimulator of SIRT1) or suramin (an inhibitor) (each 20 mg/kg BW/day) for two months. The primary neurons were exposed to AβOs (0.5 μM) for 48 h and thereafter RSV (20 μM) or suramin (300 mg/ml) for 24 h. Cell viability was assessed by the CCK-8 assay; SIRT1 protein and mRNA determined by western blotting and real-time PCR, respectively; senile plaques examined immunohistochemically; ROS monitored by flow cytometry; and the contents of OH-, H2O2, O2·-, and MDA, and the activities of SOD and GSH-Px measured by standard biochemical procedures. In comparison to wild-type mice or untreated primary neurons, the expression of SIRT1 was significantly lower in the brains of APP/PS1 mice or neurons exposed to AβOs. In these same systems, increased numbers of senile plaques and a high level of oxidative stress were apparent. Interestingly, these two latter changes were attenuated by treatment with RSV, but enhanced by suramin. These findings indicate that SIRT1 may be neuroprotective.

Structural Anatomical Investigation of Long-Term Memory Deficit in Behavioral Frontotemporal Dementia. - Bertoux, Maxime; Flanagan, Emma C; Hobbs, Matthew; Ruiz-Tagle, Amparo; Delgado, Carolina; Miranda, Marcelo; Ibáñez, Agustín; Slachevsky, Andrea; Hornberger, Michael (J Alzheimers Dis, 2018)
Although a growing body of work has shown that behavioral variant frontotemporal dementia (bvFTD) could present with severe amnesia in approximately half of cases, memory assessment is currently the clinical standard to distinguish bvFTD from Alzheimer's disease (AD). Thus, the concept of "relatively preserved episodic memory" in bvFTD remains the basis of its clinical distinction from AD and a criterion for bvFTD's diagnosis. This view is supported by the idea that bvFTD is not characterized by genuine amnesia and hippocampal degeneration, by contrast to AD. In this multicenter study, we aimed to investigate the neural correlates of memory performance in bvFTD as assessed by the Free and Cued Selective Reminding Test (FCSRT). Imaging explorations followed a two-step procedure, first relying on a visual rating of atrophy of 35 bvFTD and 34 AD patients' MRI, contrasted with 29 controls; and then using voxel-based morphometry (VBM) in a subset of bvFTD patients. Results showed that 43% of bvFTD patients presented with a genuine amnesia. Data-driven analysis on visual rating data showed that, in bvFTD, memory recall & storage performances were significantly predicted by atrophy in rostral prefrontal and hippocampal/perihippocampal regions, similar to mild AD. VBM results in bvFTD (pFWE<0.05) showed similar prefrontal and hippocampal regions in addition to striatal and lateral temporal involvement. Our findings showed the involvement of prefrontal as well as medial/lateral temporal atrophy in memory deficits of bvFTD patients. This contradicts the common view that only frontal deficits explain memory impairment in this disease and plead for an updated view on memory dysfunctions in bvFTD.

Structural Connectivity Alterations Along the Alzheimer's Disease Continuum: Reproducibility Across Two Independent Samples and Correlation with Cerebrospinal Fluid Amyloid-β and Tau. - Tucholka, Alan; Grau-Rivera, Oriol; Falcon, Carles; Rami, Lorena; Sánchez-Valle, Raquel; Lladó, Albert; Gispert, Juan Domingo; Molinuevo, José Luis (J Alzheimers Dis, 2018)
BACKGROUND: Gray matter changes associated with the progression of Alzheimer's disease (AD) have been thoroughly studied. However, alterations in white matter tracts have received less attention, particularly during early or preclinical stages of the disease. OBJECTIVE: To identify the structural connectivity changes across the AD continuum. METHODS: We performed probabilistic tractography in a total of 183 subjects on two independent samples that include control (n = 68) and preclinical AD individuals (n = 28), patients diagnosed with mild cognitive impairment (MCI) due to AD (n = 44), and AD patients (n = 43). We compared the connectivity between groups, and with CSF Aβ42 and tau biomarkers. RESULTS: We observed disconnections in preclinical individuals, mainly located in the temporal lobe. This pattern of disconnection spread to the parietal and frontal lobes at the MCI stage and involved almost all the brain in AD. These findings were not driven by gray matter atrophy. DISCUSSION: Using tractography, we were able to identify white matter changes between subsequent disease stages and, notably, also in preclinical AD. Therefore, this method may be useful for detecting early and specific brain structural changes during preclinical AD stage.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Atrophy; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Cohort Studies; Disease Progression; Female; Gray Matter; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Reproducibility of Results; Spain; tau Proteins; White Matter

A Study of a Supplement Containing Huperzine A and Curcumin in Dementia Patients and Individuals with Mild Cognitive Impairment. - Tabira, Takeshi; Kawamura, Nobutoshi (J Alzheimers Dis, 2018)
Extracts from Huperzia serrata (HS) function as a cholinesterase inhibitor and a glutamic acid receptor antagonist. We tested a supplement containing HS extracts, curcumin, and others in dementia patients and individuals with mild cognitive impairment (MCI) in an open label study. Most patients with Alzheimer's disease, dementia with Lewy bodies, and MCI individuals exhibited improvements in cognitive functions, as assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale Japanese version. The scores were significantly improved at 6-12 weeks compared with baseline scores (p = 0.007) and at 22-28 weeks (p = 0.004). Thus, this supplement may be administered to dementia patients as well as MCI individuals.

A Study of Amyloid-β and Phosphotau in Plaques and Neurons in the Hippocampus of Alzheimer's Disease Patients. - Furcila, Diana; DeFelipe, Javier; Alonso-Nanclares, Lidia (J Alzheimers Dis, 2018)
The main pathological hallmarks in Alzheimer's disease (AD) are the presence of extracellular amyloid plaques, primarily consisting of amyloid-β (Aβ) peptide, and the accumulation of paired helical filaments of hyperphosphorylated tau protein (PHF-Tau) within neurons. Since CA1 is one of the most affected regions in AD, mainly at early stages, we have performed a detailed analysis of the CA1 region from 11 AD patients (demented and clinically similar; Braak stages IV-VI) to better understand the possible relationship between the presence and distribution of different neurochemical types of Aβ plaques and PHF-Tau immunoreactive  (- ir)  neurons. Hence, we have examined hippocampal sections in confocal microscopy images from double and triple-immunostained sections, to study labeled plaques and PHF-Tau-ir neurons using specific software tools. There are four main findings in the present study. First, the pyramidal layer of proximal CA1 (close to CA2) contains the smallest number of both plaques and PHF-Tau-ir neurons. Second, a large proportion of Aβ-ir plaques were also characterized by the presence of PHF-Tau-ir. Third, all plaques containing one of the two PHF-Tau isoforms also express the other isoform, that is, if a plaque contains PHFpS396, it also contains PHFAT8, and vice versa. Fourth, the coexpression study of both PHF-Tau isoforms in CA1 neurons revealed that most of the labeled neurons express only PHFpS396. Our findings further support the idea that AD is not a unique entity even within the same neuropathological stage, since the microanatomical/neurochemical changes that occur in the hippocampus greatly vary from one patient to another.

Subjective Cognitive Decline and APOE ɛ4: A Systematic Review. - Ali, Jordan I; Smart, Colette M; Gawryluk, Jodie R (J Alzheimers Dis, 2018)
Individuals with subjective cognitive decline (SCD) report self-perceived declines in cognitive function but perform within normal limits on standardized tests. However, for some, these self-perceived changes may herald eventual decline to Alzheimer's disease (AD). In light of this, the relationship between SCD and APOE ɛ4, a known genetic risk factor for AD, has garnered interest; however, no systematic review of this literature exists. The current review (n = 36 articles) examined the prevalence of APOE ɛ4 in SCD samples relative to healthy and objectively impaired samples, and summarized APOE ɛ4-related risk of conversion from SCD to AD. Univariate ANOVA indicated that APOE ɛ4 frequency was comparable between healthy control and SCD samples, yet significantly higher in objectively impaired samples (i.e., MCI, AD) relative to either of these groups. Narrative review provided mixed evidence linking coincident APOE ɛ4-positive genotype and SCD to structural neuropathology. Though there was little evidence to suggest that APOE ɛ4 predisposes individuals to developing SCD, both APOE ɛ4 and SCD were found to confer individual and multiplicative risk of conversion to objective cognitive impairment. Combined, it is likely that a relationship between APOE ɛ4, SCD, and AD exists, though its exact nature remains undetermined. A clearer understanding of these relationships is hindered by a lack of standardization in SCD classification and a dearth of longitudinal outcome research. Wide-scale adoption of genetic screening for dementia risk in persons with SCD is considered premature at this time. Ethical considerations and clinical implications of genetic testing for dementia risk are discussed.

Subjective Cognitive Decline Is Associated with Greater White Matter Hyperintensity Volume. - van Rooden, Sanneke; van den Berg-Huysmans, Annette A; Croll, Pauline H; Labadie, Gerda; Hayes, Jessica M; Viviano, Raymond; van der Grond, Jeroen; Rombouts, Serge A R B; Damoiseaux, Jessica S (J Alzheimers Dis, 2018)
BACKGROUND: Research in older adults with subjective cognitive decline (SCD) has mainly focused on Alzheimer's disease (AD)-related MRI markers, such as hippocampal volume. However, small vessel disease (SVD) is currently established as serious comorbidity in dementia and its preliminary stages. It is therefore important to examine SVD markers in addition to AD markers in older adults presenting with SCD. OBJECTIVE: The aim of our study was to elucidate the role of SVD markers in late middle-aged to older adults with and without SCD in addition to the commonly found role of AD markers (hippocampal volume). METHODS: 67 healthy late middle-aged to older adults participated in this study (mean age 68 years); 25 participants with SCD and 42 participants without SCD. We evaluated quantitative as well as qualitative AD markers (i.e., hippocampal volume and medial temporal lobe atrophy (MTA) scale) and SVD markers (i.e., white matter hyperintensities (WMH) volume, Fazekas scale, microbleeds, and lacunar infarcts), and neuropsychological function and amount of memory complaints. RESULTS: We found a significant effect of SCD on hippocampal atrophy, as assessed using the MTA scale, but not on hippocampal volume. In addition, we found a significant effect of SCD, and amount of memory complaints, on WMH volume and Fazekas score, suggesting larger WMH volumes in participants with SCD. CONCLUSION: SVD MRI markers are related to amount of memory complaints, in addition to the commonly observed AD MRI markers, as demonstrated by the greater WMHs in healthy late middle-aged to older adults with SCD.

Subjective Cognitive Decline, Objective Cognition, and Depression in Older Hispanics Screened for Memory Impairment. - Zlatar, Zvinka Z; Muniz, Martha C; Espinoza, Sarah G; Gratianne, Roberto; Gollan, Tamar H; Galasko, Douglas; Salmon, David P (J Alzheimers Dis, 2018)
Subjective cognitive decline (SCD) is common in older adults and may be an early marker of future cognitive decline. Research suggest that SCD is more closely related to concurrent symptoms of depression than to objective cognitive performance in non-Hispanic Whites, but it is unknown whether the associations of SCD, cognition, and depression manifest differently in Hispanic older adults. We examined if SCD is associated with objective cognitive performance or with depression symptoms in 145 Hispanic individuals ages 60 or older referred by community health clinics for screening of cognitive complaints. All participants lived near the U.S.-Mexico border, spoke Spanish only, or were Spanish-English bilingual. Memory-only and global cognitive composites were created from scores on Spanish versions of several neuropsychological tests. The Geriatric Depression Scale (GDS) and a five-item SCD questionnaire developed by our group were also completed. Multiple regression analyses showed no significant associations between SCD and memory or global cognitive composite scores after adjusting for age, sex, education, and GDS score. In contrast, there was a significant association between GDS and SCD after adjusting for age, sex, education, global and memory composite scores. Findings suggest that SCD does not accurately reflect current cognitive status in older Hispanics who present to their primary care physician with cognitive complaints. Clinicians should interpret SCD in this population within the context of information about symptoms of depression. Longitudinal research is needed in older Hispanics to better characterize SCD in this population and to determine if it can predict future cognitive decline.

Subjective Cognitive Decline Prediction of Mortality: Results from the Einstein Aging Study. - Katz, Mindy J; Wang, Cuiling; Derby, Carol A; Lipton, Richard B; Zimmerman, Molly E; Sliwinski, Martin J; Rabin, Laura A (J Alzheimers Dis, 2018)
BACKGROUND: The relation of pre-dementia stages to mortality has not been fully explored. Previous work examining subjective cognitive decline (SCD) and mortality is limited and mixed regarding methods used and consistency of findings. OBJECTIVE: To examine SCD and mortality in a longitudinal, community-based cohort, using item response theory (IRT) methodology to form a composite SCD measure. Also, to assess whether this relationship was independent of clinical cognitive status. METHODS: The Einstein Aging Study is a diverse longitudinal cohort of adults aged ≥70. SCD items were extracted from baseline CERAD questionnaires and a composite score was formed using IRT methodology. A total of 1,741 participants with complete data were clinically diagnosed as cognitively normal, or as having amnestic mild cognitive impairment (aMCI), nonamnestic mild cognitive impairment (naMCI), or dementia. 645 deaths occurred over a period of 8,912 person-years of follow-up. Cox proportional hazard models predicted time to death adjusting for covariates. RESULTS: A one standard deviation unit increase in level of SCD was associated with >20% higher risk of mortality. However, when models were adjusted for clinical cognitive status, the association was no longer significant. Both dementia and aMCI predicted mortality. Furthermore, when analyses focused only on those without cognitive impairment, SCD level did not predict mortality. CONCLUSIONS: The association of SCD with mortality may be due to the association of SCD with clinical cognitive status. Thus, SCD may be used as a community-based screen to initially identify those with cognitive impairment who may be at greatest risk for death.

Subjective Sleep Quality is not Associated with Incident Dementia: The Rotterdam Study. - Lysen, Thom S; Wolters, Frank J; Luik, Annemarie I; Ikram, M Kamran; Tiemeier, Henning; Ikram, M Arfan (J Alzheimers Dis, 2018)
BACKGROUND: Poor sleep is related to higher dementia risk, but this association is more equivocal for subjective sleep quality specifically. This study investigates the link between subjective sleep quality and dementia risk in the general population. OBJECTIVE: To study the role of subjective sleep quality in the risk of dementia in the general population. METHODS: In the prospective population-based Rotterdam Study, 4,835 persons (mean age 72 years, 58% women) underwent a home interview (2002- 2006) that included the validated Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality. Participants were followed until 2015 for incident dementia, through in-person screening and continuous monitoring of medical records. We used Cox regression models to associate sleep quality with dementia risk, adjusting for age, sex, education, smoking, employment, coffee consumption, alcohol consumption, activities of daily living, cardiovascular risk factors, anxiety, depressive symptoms, cognition, and snoring. RESULTS: During 41,385 person-years (8.5 years mean), 420 participants developed dementia, of whom 320 Alzheimer's disease (AD). Poorer subjective sleep quality was not associated with the risk of all-cause dementia (hazard ratio [HR] per SD increase in PSQI score: 0.91, 95% CI 0.82- 1.02) or AD (HR 0.92, 95% CI 0.81- 1.05). Similarly, individual components of the PSQI were also not associated with dementia. Several sensitivity analyses, i.e., excluding last years of the follow-up time duration or restricting to those with best MMSE scores at baseline, did not reveal subgroups with increased risks. CONCLUSION: In this study, we found no association of poor subjective sleep quality with higher risk of dementia.

Subtle Cognitive Impairment and Alzheimer's Disease-Type Pathological Changes in Cerebrospinal Fluid are Common Among Neurologically Healthy Subjects. - Haapalinna, Fanni; Kokki, Merja; Jääskeläinen, Olli; Hallikainen, Merja; Helisalmi, Seppo; Koivisto, Anne; Kokki, Hannu; Paajanen, Teemu; Penttinen, Janne; Pikkarainen, Maria; Rautiainen, Minna; Soininen, Hilkka; et al. (J Alzheimers Dis, 2018)
BACKGROUND: The neuropathology of Alzheimer's disease (AD) has previously been shown to be rather common among the elderly. OBJECTIVE: The aim of this study was to inspect the associations between cerebrospinal fluid (CSF) AD biomarker concentrations, age, the APOEɛ4 allele, cardiovascular diseases, diabetes, and cognitive performance in a cohort of a neurologically healthy population. METHODS: This study included 93 subjects (42 men, mean age 67 years) without previous neurological symptoms or subjective cognitive complaints. Their cognition was assessed, and CSF biomarkers and APOEɛ4 status were analyzed. RESULTS: Of the studied subjects, 8.6% (n = 8) had a pathological CSF AD biomarker profile. An increase in age correlated positively with CSF tau pathology and negatively with global cognitive performance. CONCLUSION: AD-type pathological changes in CSF and subtle cognitive impairment are common within a population with no previous memory complaints. Age was the main risk factor for the changes.

Subtypes Based on Neuropsychological Performance Predict Incident Dementia: Findings from the Rush Memory and Aging Project. - Zammit, Andrea R; Muniz-Terrera, Graciela; Katz, Mindy J; Hall, Charles B; Ezzati, Ali; Bennett, David A; Lipton, Richard B (J Alzheimers Dis, 2018)
BACKGROUND: In a previous report, we used latent class analysis (LCA) to identify natural subgroups of older adults in the Einstein Aging Study (EAS) based on neuropsychological performance. These subgroups differed in demographics, genetic profile, and prognosis. Herein, we assess the generalizability of these findings to an independent sample, the Rush Memory and Aging Project (MAP), which used an overlapping, but distinct neuropsychological battery. OBJECTIVE: Our aim was to identify the association of natural subgroups based on neuropsychological performance in the MAP cohort with incident dementia and compare them with the associations identified in the EAS. METHODS: MAP is a community-dwelling cohort of older adults living in the northeastern Illinois, Chicago. Latent class models were applied to baseline scores of 10 neuropsychological measures across 1,662 dementia-free MAP participants. Results were compared to prior findings from the EAS. RESULTS: LCA resulted in a 5-class model: Mixed-Domain Impairment (n = 71, 4.3%), Memory-specific-Impairment (n = 274, 16.5%), Average (n = 767, 46.1%), Frontal Impairment (n = 222, 13.4%), and a class of Superior Cognition (n = 328, 19.7%). Similar to the EAS, the Mixed-Domain Impairment, the Memory-Specific Impairment, and the Frontal Impairment classes had higher risk of incident Alzheimer's disease when compared to the Average class. By contrast, the Superior Cognition had a lower risk of Alzheimer's disease when compared to the Average class. CONCLUSIONS: Natural cognitive subgroups in MAP are similar to those identified in EAS. These similarities, despite study differences in geography, sampling strategy, and cognitive tests, suggest that LCA is capable of identifying classes that are not limited to a single sample or a set of cognitive tests.

Sulforaphane Inhibits the Generation of Amyloid-β Oligomer and Promotes Spatial Learning and Memory in Alzheimer's Disease (PS1V97L) Transgenic Mice. - Hou, Ting-Ting; Yang, He-Yun; Wang, Wei; Wu, Qiao-Qi; Tian, Yuan-Ruhua; Jia, Jian-Ping (J Alzheimers Dis, 2018)
Abnormal amyloid-β (Aβ) aggregates are a striking feature of Alzheimer's disease (AD), and Aβ oligomers have been proven to be crucial in the pathology of AD. Any intervention targeting the generation or aggregation of Aβ can be expected to be useful in AD treatment. Oxidative stress and inflammation are common pathological changes in AD that are involved in the generation and aggregation of Aβ. In the present study, 6-month-old PS1V97L transgenic (Tg) mice were treated with sulforaphane, an antioxidant, for 4 months, and this treatment significantly inhibited the generation and aggregation of Aβ. Sulforaphane also alleviated several downstream pathological changes that including tau hyperphosphorylation, oxidative stress, and neuroinflammation. Most importantly, the cognition of the sulforaphane-treated PS1V97L Tg mice remained normal compared to that of wild-type mice at 10 months of age, when dementia typically emerges in PS1V97L Tg mice. Pretreating cultured cortical neurons with sulforaphane also protected against neuronal injury caused by Aβ oligomers in vitro. These findings suggest that sulforaphane may be a potential compound that can inhibit Aβ oligomer production in AD.

Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. - Power, Rebecca; Coen, Robert F; Beatty, Stephen; Mulcahy, Riona; Moran, Rachel; Stack, Jim; Howard, Alan N; Nolan, John M (J Alzheimers Dis, 2018)
BACKGROUND: There is a biologically plausible rationale whereby the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which are collectively referred to as macular pigment (MP) in the central retina (macula), support the maintenance of cognition via their antioxidant and anti-inflammatory properties. OBJECTIVE: To investigate the impact of supplemental L, Z, and MZ on memory, executive function, and verbal fluency among healthy individuals with low MP levels. METHODS: In this double-blind, placebo-controlled, randomized clinical trial, subjects (n = 91; mean±SD age = 45.42±12.40; % male = 51.6) consumed a daily formulation of 10 mg L, 10 mg MZ, and 2 mg Z (n = 45) or placebo (n = 46) for 12 months. Cognitive domains assessed included verbal and visual learning, immediate and delayed memory, executive function, and verbal fluency. MP and serum carotenoid concentrations of L, Z, and MZ were also measured. RESULTS: Following 12-month supplementation, individuals in the active group exhibited statistically significant improvements in memory when compared to the placebo group (paired associated learning [PAL] memory score [rANOVA, p = 0.009]; PAL errors [rANOVA, p = 0.017]). Furthermore, the observed reduction in the number of errors made in the PAL task among those in the intervention group was positively and significantly related to observed increases in MP volume (p = 0.005) and observed increases in serum concentrations of L (p = 0.009). CONCLUSION: This randomized, double-blind, placebo-controlled clinical trial demonstrates a memory-enhancing effect of daily supplementation with L, Z, and MZ in healthy subjects with low MP at baseline. The implications of these findings for intellectual performance throughout life, and for risk of cognitive decline in later life, warrant further study.
Keywords: Adult; Cognition; Dietary Supplements; Double-Blind Method; Executive Function; Female; Healthy Volunteers; Humans; Lutein; Macular Pigment; Male; Memory, Episodic; Middle Aged; Retina; Vision Tests; Zeaxanthins

A Survey of Patient and Partner Outcome and Treatment Preferences in Mild Cognitive Impairment. - Smith, Glenn E; Chandler, Melanie; Fields, Julie A; Aakre, Jeremiah; Locke, Dona E C (J Alzheimers Dis, 2018)
BACKGROUND: The patient-centered movement in health care is increasing efforts to design studies and interventions that address the outcomes that matter most to patients and their families. Research has not adequately addressed Alzheimer's disease patient and caregiver preferences. OBJECTIVE: To survey the outcome and treatment preferences of patients and caregivers who had completed a multicomponent behavioral intervention for mild cognitive impairment (MCI). METHODS: Extending prior work, we conducted an online survey regarding outcome and intervention preferences. Participants were patients with MCI and partners who completed the HABIT Healthy Action to Benefit Independence & Thinking ® program. RESULTS: Both patient and partner respondents ranked patient quality of life as the highest priority, followed by patient self-efficacy, functional status, patient mood, and patient memory performance. Distressing behaviors and caregiver outcomes (burden, mood, and self-efficacy) had low rankings. Regarding the importance of HABIT ® program components, memory compensation training was ranked highest and wellness education lowest by all groups. CONCLUSION: Additional research should compare patient preference for patient reported outcomes, traditional neuropsychological and clinician outcomes, and modern biomarker outcomes.

Sweet Mitochondria: A Shortcut to Alzheimer's Disease. - Moreira, Paula I (J Alzheimers Dis, 2018)
A growing body of evidence supports a clear association between Alzheimer's disease and diabetes and several mechanistic links have been revealed. This paper is mainly devoted to the discussion of the role of diabetes-associated mitochondrial defects in the pathogenesis of Alzheimer's disease. The research experience and views of the author on this subject will be highlighted.

Synergistic Protective Effects of Mitochondrial Division Inhibitor 1 and Mitochondria-Targeted Small Peptide SS31 in Alzheimer's Disease. - Reddy, P Hemachandra; Manczak, Maria; Yin, XiangLing; Reddy, Arubala P (J Alzheimers Dis, 2018)
The purpose of our study was to determine the synergistic protective effects of mitochondria-targeted antioxidant SS31 and mitochondria division inhibitor 1 (Mdivi1) in Alzheimer's disease (AD). Using biochemical methods, we assessed mitochondrial function by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity, mitochondrial ATP, and GTPase Drp1 enzymatic activity in mutant AβPP cells. Using biochemical methods, we also measured cell survival and apoptotic cell death. Amyloid-β (Aβ) levels were measured using sandwich ELISA, and using real-time quantitative RT-PCR, we assessed mtDNA (mtDNA) copy number in relation to nuclear DNA (nDNA) in all groups of cells. We found significantly reduced levels of Aβ40 and Aβ42 in mutant AβPP cells treated with SS31, Mdivi1, and SS31+Mdivi1, and the reduction of Aβ42 levels were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. The levels of mtDNA copy number and cell survival were significantly increased in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the increased levels of mtDNA copy number and cell survival were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. Mitochondrial dysfunction is significantly reduced in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the reduction is much higher in cells treated with both SS31+Mdvi1. Similarly, GTPase Drp1 activity is reduced in all treatments, but reduced much higher in SS31+Mdivi1 treated cells. These observations strongly suggest that combined treatment of SS31+Mdivi1 is effective than individual treatments of SS31 and Mdivi1. Therefore, we propose that combined treatment of SS31+Mdivi1 is a better therapeutic strategy for AD. Ours is the first study to investigate combined treatment of mitochondria-targeted antioxidant SS31 and mitochondrial division inhibitor 1 in AD neurons.

Synthetic Fragment of Receptor for Advanced Glycation End Products Prevents Memory Loss and Protects Brain Neurons in Olfactory Bulbectomized Mice. - Volpina, Olga M; Samokhin, Alexandr N; Koroev, Dmitriy O; Nesterova, Inna V; Volkova, Tatyana D; Medvinskaya, Natalia I; Nekrasov, Pavel V; Tatarnikova, Olga G; Kamynina, Anna V; Balasanyants, Samson M; Voronina, Tamara A; Kulikov, Alexey M; et al. (J Alzheimers Dis, 2018)
Activation of receptor for advanced glycation end products (RAGE) plays an essential role in the development of Alzheimer's disease (AD). It is known that the soluble isoform of the receptor binds to ligands and prevents negative effects of the receptor activation. We proposed that peptide fragments from RAGE prevent negative effects of the receptor activation during AD neurodegeneration. We have synthesized peptide fragments from surface-exposed regions of RAGE. Peptides were intranasally administrated into olfactory bulbectomized (OBX) mice, which developed some characteristics similar to AD neurodegeneration. We have found that only insertion of fragment (60-76) prevents the memory of OBX mice. Immunization of OBX mice with peptides showed that again only (60-76) peptide protected the memory of animals. Both intranasal insertion and immunization decreased the amyloid-β (Aβ) level in the brain. Activity of shortened fragments of (60-76) peptide was tested and showed only the (60-70) peptide is responsible for manifestation of activity. Intranasal administration of (60-76) peptide shows most protective effect on morpho-functional characteristics of neurons in the cortex and hippocampal areas. Using Flu-(60-76) peptide, we revealed its penetration in the brain of OBX mice as well as colocalization of Flu-labeled peptide with Aβ in the brain regions in transgenic mice. Flu-(60-76) peptide complex with trimer of Aβ was detected by SDS-PAGE. These data indicate that Aβ can be one of the molecular target of (60-70) peptide. These findings provide a new peptide molecule for design of anti-AD drug and for investigation of RAGE activation ways in progression of AD neurodegeneration.
Keywords: Administration, Intranasal; Animals; Behavior, Animal; Brain; Disease Models, Animal; Male; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Neurons; Olfactory Bulb; Peptide Fragments; Receptor for Advanced Glycation End Products

A Systematic Review and Aggregated Analysis on the Impact of Amyloid PET Brain Imaging on the Diagnosis, Diagnostic Confidence, and Management of Patients being Evaluated for Alzheimer's Disease. - Fantoni, Enrico R; Chalkidou, Anastasia; O' Brien, John T; Farrar, Gill; Hammers, Alexander (J Alzheimers Dis, 2018)
BACKGROUND: Amyloid PET (aPET) imaging could improve patient outcomes in clinical practice, but the extent of impact needs quantification. OBJECTIVE: To provide an aggregated quantitative analysis of the value added by aPET in cognitively impaired subjects. METHODS: Systematic literature searches were performed in Embase and Medline until January 2017. 1,531 cases over 12 studies were included (1,142 cases over seven studies in the primary analysis where aPET was the key biomarker; the remaining cases included as defined groups in the secondary analysis). Data was abstracted by consensus among two observers and assessed for bias. Clinical utility was measured by diagnostic change, diagnostic confidence, and patient management before and after aPET. Three groups were further analyzed: control patients for whom feedback of aPET scan results was delayed; aPET Appropriate Use Criteria (AUC+) cases; and patients undergoing additional FDG/CSF testing. RESULTS: For 1,142 cases with only aPET, 31.3% of diagnoses were revised, whereas 3.2% of diagnoses changed in the delayed aPET control group (p < 0.0001). Increased diagnostic confidence following aPET was found for 62.1% of 870 patients. Management changes with aPET were found in 72.2% of 740 cases and in 55.5% of 299 cases in the control group (p < 0.0001). The diagnostic value of aPET in AUC+ patients or when FDG/CSF were additionally available did not substantially differ from the value of aPET alone in the wider population. CONCLUSIONS: Amyloid PET contributed to diagnostic revision in almost a third of cases and demonstrated value in increasing diagnostic confidence and refining management plans.

A Systematic Review and Meta-Analysis on the Prevalence of Dementia in Europe: Estimates from the Highest-Quality Studies Adopting the DSM IV Diagnostic Criteria. - Bacigalupo, Ilaria; Mayer, Flavia; Lacorte, Eleonora; Di Pucchio, Alessandra; Marzolini, Fabrizio; Canevelli, Marco; Di Fiandra, Teresa; Vanacore, Nicola (J Alzheimers Dis, 2018)
BACKGROUND: Dementia, including Alzheimer's disease (AD), is one of the most burdensome medical conditions. Usually, the reviews that aim at calculating the prevalence of dementia include estimates from studies without assessing their methodological quality. Alzheimer's Disease International (ADI) proposed a score to assess the methodological quality of population-based studies aimed at estimating the prevalence of dementia. During the last three years, the European Commission has funded three projects (Eurodem, EuroCoDe, and ALCOVE) in order to estimate the prevalence of dementia in Europe. OBJECTIVE: The aim of this study was to perform a systematic review and meta-analysis of data on the prevalence of dementia in Europe derived from studies that included only subjects with a diagnosis of dementia according to the DSM IV criteria, and that had a high quality score according to ADI criteria. METHODS: We considered the studies selected by the two projects EuroCoDe (1993-2007) and Alcove (2008-2011), and we performed a new bibliographic search. For the systematic review, we only selected the subset of articles that included subjects with a diagnosis of dementia according to the DSM IV criteria. The studies were qualitatively assessed using the ADI tool. RESULTS: The meta-analysis considered 9 studies that were carried out in Europe between 1993 and 2018 including a total of 18,263 participants, of which 2,137 were diagnosed with dementia. The prevalence rate standardized for age and sex resulted 7.1%. DISCUSSION: This is the first systematic review on the prevalence of dementia in Europe considering only high-quality studies adopting the same diagnostic criteria (i.e., DSM IV).

Targeted Assessment of Enlargement of the Perivascular Space in Alzheimer's Disease and Vascular Dementia Subtypes Implicates Astroglial Involvement Specific to Alzheimer's Disease. - Boespflug, Erin L; Simon, Matthew J; Leonard, Emmalyn; Grafe, Marjorie; Woltjer, Randall; Silbert, Lisa C; Kaye, Jeffrey A; Iliff, Jeffrey J (J Alzheimers Dis, 2018)
Waste clearance from the brain parenchyma occurs along perivascular pathways. Enlargement of the perivascular space (ePVS) is associated with pathologic features of Alzheimer's disease (AD), although the mechanisms and implications of this dilation are unclear. Fluid exchange along the cerebral vasculature is dependent on the perivascular astrocytic water channel aquaporin-4 (AQP4) and loss of perivascular AQP4 localization is found in AD. We directly measured ePVS in postmortem samples of pathologically characterized tissue from participants who were cognitively intact or had AD or mixed dementia (vascular lesions with AD). We found that both AD and mixed dementia groups had significantly increased ePVS compared to cognitively intact subjects. In addition, we found increased global AQP4 expression of the AD group over both control and mixed dementia groups and a qualitative reduction in perivascular localization of AQP4 in the AD group. Among these cases, increasing ePVS burden was associated with the presence of tau and amyloid-β pathology. These findings are consistent with the existing evidence of ePVS in AD and provide novel information regarding differences in AD and vascular dementia and the potential role of astroglial pathology in ePVS.

Targeting Alzheimer's Disease at the Right Time and the Right Place: Validation of a Personalized Approach to Diagnosis and Treatment. - Gauthier, Serge; Ng, Kok Pin; Pascoal, Tharick A; Zhang, Hua; Rosa-Neto, Pedro (J Alzheimers Dis, 2018)
Cautious optimism is appropriate for a near future (five years) time frame for a number of drugs acting on the different pathophysiological components of Alzheimer's disease (amyloid deposition, tau hyperphosphorylation, neuroinflammation, vascular changes, to name the most important known so far). Since the relative weight of these components will be different between individuals and will even change over time for each individual, a 'one drug fit for all' approach is no longer defensible. Precision medicine using biomarkers in the diagnosis and treatment of Alzheimer's disease is the new strategy.

Targeting Insulin for Alzheimer's Disease: Mechanisms, Status and Potential Directions. - Lee, Jung Hyun; Jahrling, Jordan B; Denner, Larry; Dineley, Kelly T (J Alzheimers Dis, 2018)
Insulin resistance can occur when the body is unable to respond to insulin even in excess. In the brain, insulin manages glucose metabolism in regions such as the hippocampus and plays a key role in directly regulating ERK, a kinase required for the type of memory compromised in early Alzheimer's disease (AD). Human imaging studies show that brain glucose utilization declines with age and is notably impaired in subjects with early AD. Likewise, animal models of AD or insulin resistance, or both, demonstrate that dysfunctional insulin signaling and insulin resistance in the brain have reciprocity with neuroinflammation and aberrant accumulation of amyloid-β (Aβ), pathological hallmarks in AD. As such, the association between brain insulin activity and AD has led to clinical trials testing the efficacy of insulin and insulin-sensitizing drugs to intervene in AD. Based on recent inquiries to ClinicalTrials.gov, we evaluated thirty-three clinical studies related to AD and insulin. The search filtered for interventional clinical trials to test FDA-approved drugs or substances that impinge upon the insulin signaling pathway. Insulin, metformin, and thiazolidinediones were the three main interventions assessed. Overall, these strategies are expected to negate the effects of brain insulin resistance by targeting insulin signaling pathways involved in neuroinflammation, metabolic homeostasis, synaptic functional and structural integrity. The goal of this review is to provide an update on insulin and ERK signaling in relation to memory, its decline in early AD, and provide an overview of clinical trials related to insulin for early AD intervention.

Tau and Amyloid Positron Emission Tomography Imaging Predict Driving Performance Among Older Adults with and without Preclinical Alzheimer's Disease. - Roe, Catherine M; Babulal, Ganesh M; Mishra, Shruti; Gordon, Brian A; Stout, Sarah H; Ott, Brian R; Carr, David B; Ances, Beau M; Morris, John C; Benzinger, Tammie L S (J Alzheimers Dis, 2018)
Abnormal levels of Alzheimer's disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving performance.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid; Automobile Driving; Biomarkers; Carbolines; Female; Humans; Logistic Models; Male; Neuroimaging; Positron-Emission Tomography; tau Proteins

Tau Conformation as a Target for Disease-Modifying Therapy: The Role of Truncation. - Novak, Petr; Cehlar, Ondrej; Skrabana, Rostislav; Novak, Michal (J Alzheimers Dis, 2018)
Tau protein plays a major role in the pathogenesis of Alzheimer's disease. Despite many decades of intensive research, the cause of the conformational switch that leads to the remodeling of the highly flexible conformational ensemble of intrinsically disordered protein tau into insoluble filaments is still elusive. We show here that truncation of tau may play a causative role in this conformational change, as evidenced by results obtained from in vitro experiments and from transgenic animal models. This conformational change is a common denominator of pathological tau protein assemblies, and a salient drug target. The long-running research of truncated tau has led to the generation of the first active tau vaccine that has entered clinical trials.

Tau Immunotherapies for Alzheimer's Disease and Related Tauopathies: Progress and Potential Pitfalls. - Sigurdsson, Einar M (J Alzheimers Dis, 2018)
Tau immunotherapies have now advanced from proof-of-concept studies to Phase II clinical trials. This review briefly outlines developments in the field and discusses how these therapies may work, which involves multiple variables that are connected in complex ways. These various factors are likely to define therapeutic success in humans and have not been thoroughly investigated, at least based on published reports.

Tau Protein Dysfunction after Brain Ischemia. - Pluta, Ryszard; Ułamek-Kozioł, Marzena; Januszewski, Sławomir; Czuczwar, Stanisław J (J Alzheimers Dis, 2018)
Brain ischemia comprises blood-brain barrier, glial, and neuronal cells. The blood-brain barrier controls permeability of different substances and the composition of the neuronal cells 'milieu', which is required for their physiological functioning. Recent evidence indicates that brain ischemia itself and ischemic blood-brain barrier dysfunction is associated with the accumulation of neurotoxic molecules within brain tissue, e.g., different parts of amyloid-β protein precursor and changed pathologically tau protein. All these changes due to ischemia can initiate and progress neurodegeneration of the Alzheimer's disease-type. This review presents brain ischemia and ischemic blood-brain barrier as a trigger for tau protein alterations. Thus, we hypothesize that the changes in pattern of phosphorylation of tau protein are critical to microtubule function especially in neurons, and contribute to the neurodegeneration following brain ischemia-reperfusion episodes with Alzheimer's disease phenotype.

Tau Proteolysis in the Pathogenesis of Tauopathies: Neurotoxic Fragments and Novel Biomarkers. - Quinn, James P; Corbett, Nicola J; Kellett, Katherine A B; Hooper, Nigel M (J Alzheimers Dis, 2018)
With predictions showing that 131.5 million people worldwide will be living with dementia by 2050, an understanding of the molecular mechanisms underpinning disease is crucial in the hunt for novel therapeutics and for biomarkers to detect disease early and/or monitor disease progression. The metabolism of the microtubule-associated protein tau is altered in different dementias, the so-called tauopathies. Tau detaches from microtubules, aggregates into oligomers and neurofibrillary tangles, which can be secreted from neurons, and spreads through the brain during disease progression. Post-translational modifications exacerbate the production of both oligomeric and soluble forms of tau, with proteolysis by a range of different proteases being a crucial driver. However, the impact of tau proteolysis on disease progression has been overlooked until recently. Studies have highlighted that proteolytic fragments of tau can drive neurodegeneration in a fragment-dependent manner as a result of aggregation and/or transcellular propagation. Proteolytic fragments of tau have been found in the cerebrospinal fluid and plasma of patients with different tauopathies, providing an opportunity to develop these fragments as novel disease progression biomarkers. A range of therapeutic strategies have been proposed to halt the toxicity associated with proteolysis, including reducing protease expression and/or activity, selectively inhibiting protease-substrate interactions, and blocking the action of the resulting fragments. This review highlights the importance of tau proteolysis in the pathogenesis of tauopathies, identifies putative sites during tau fragment-mediated neurodegeneration that could be targeted therapeutically, and discusses the potential use of proteolytic fragments of tau as biomarkers for different tauopathies.

Tauopathies: Mechanisms and Therapeutic Strategies. - Tan, Chen-Chen; Zhang, Xiao-Yan; Tan, Lan; Yu, Jin-Tai (J Alzheimers Dis, 2018)
Tauopathies are morphologically, biochemically, and clinically heterogeneous neurodegenerative diseases defined by the accumulation of abnormal tau proteins in the brain. There is no effective method to prevent and reverse the tauopathies, but this gloomy picture has been changed by recent research advances. Evidences from genetic studies, experimental animal models, and molecular and cell biology have shed light on the main mechanisms of the diseases. The development of radiology and biochemistry, especially the development of PET imaging, will provide important biomarkers for the clinical diagnosis and treatment. Given the central role of tau in tauopathies, many treatments have constantly emerged, including targeting phosphorylation, targeting aggregation, increasing microtubule stabilization, tau immunization, clearance of tau, anti-inflammatory treatment, and other therapeutics. There is still a long way to go before we obtain drug therapy targeted at multifactor mechanisms.
Keywords: Animals; Biomarkers; Brain; Disease Models, Animal; Humans; Neuroimaging; Phosphorylation; Positron-Emission Tomography; tau Proteins; Tauopathies

TDP-43 and Alzheimer's Disease Pathologic Subtype in Non-Amnestic Alzheimer's Disease Dementia. - Sahoo, Aradhana; Bejanin, Alexandre; Murray, Melissa E; Tosakulwong, Nirubol; Weigand, Stephen D; Serie, Amanda M; Senjem, Matthew L; Machulda, Mary M; Parisi, Joseph E; Boeve, Bradley F; Knopman, David S; Petersen, Ronald C; et al. (J Alzheimers Dis, 2018)
BACKGROUND: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer's disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown. OBJECTIVE: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD. METHODS: All cases with pathologically confirmed intermediate-high probability AD from 1996-2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features. RESULTS: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43. CONCLUSION: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43.

TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study. - Flanagan, Margaret E; Cholerton, Brenna; Latimer, Caitlin S; Hemmy, Laura S; Edland, Steven D; Montine, Kathleen S; White, Lon R; Montine, Thomas J (J Alzheimers Dis, 2018)
Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p < 0.0001, 95% CI 3.57-34.13). In the NS, there were significant associations between TDP-43 and HS (OR = 16.44, p > 0.001 95%, CI 7.10-38.00) and Alzheimer's disease (AD) severity (OR = 1.74, p = 0.009, 95% CI 1.15-2.64). When cognitive scores were added to the model, HS remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR = 2.11, p = 0.022, 95% CI 1.11-4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p = 0.005, 95% CI 1.22-3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p < 0.001, 95% CI 1.58-3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort-specific features.

Testamentary Capacity Assessment Tool (TCAT): A Brief Instrument for Patients with Dementia. - Papageorgiou, Sokratis G; Voskou, Panagiota; Economou, Alexandra; Beratis, Ion; Douzenis, Athanasios (J Alzheimers Dis, 2018)
BACKGROUND: In current practice, it is common for the medical practitioner to assess a person's testamentary capacity (TC) and give evidence to the Courts about a potential will contest. TC is an advanced cognitive activity that is both situation- and task-specific. OBJECTIVE: The aim of the present study was the development of a brief, specialized instrument for TC assessment in patients with dementia. METHOD: We developed a short tool consisting of four subtests, assessing the person's core functions which are required for TC: memory (orientation, autobiographical memory and realistic perception of beneficiaries), absence of serious psychopathology, knowledge of financial parameters (value of assets, everyday life products, bills), and intention (vignettes, theory of mind). For its validation, we examined 64 outpatients from the Cognitive Disorders/Dementia Unit, 2nd Department of Behavioral Neurology, University of Athens. The decision of the expert served as the gold standard for the evaluation of TC. RESULTS: Of the 64 participants, 39 were judged by the expert as capable of TC and the remaining 25 as incapable. For the total scale (maximum score of 48), the best combination of sensitivity (82.6%) and specificity (100%) was obtained for a cut-off score of 32/33. Cronbach's alpha showed high levels of internal reliability for the scale (α= 0.86) and the point-biserial correlation coefficients showed high levels of criterion-related validity (rbp = 0.797, p < 0.001). CONCLUSION: The new instrument appears to be a reliable screening tool for the evaluation of TC in dementia, which can be used by both the expert and the non-expert. Further research is needed to confirm these promising findings.
Keywords: Adult; Aged; Cognition Disorders; Dementia; Female; Humans; Male; Memory; Mental Competency; Middle Aged; Neuropsychological Tests; Reproducibility of Results; Sensitivity and Specificity; Wills

Testing Hippocampal Memory in Prodromal Dementia with Lewy Bodies. - Bussè, Cinzia; Caffarra, Paolo; Rossi, Alice; Zorzi, Giovanni; Fragiacomo, Federica; Camporese, Giulia; Pompanin, Sara; Di Bernardo, Gian Antonio; Cagnin, Annachiara (J Alzheimers Dis, 2018)
The Free and Cued Selective Reminding test (FCSRT) was used to assess memory in 19 patients with prodromal dementia with Lewy bodies (DLB) and 25 Alzheimer's disease (AD) patients. DLB scored better than AD in selective measures of the FCSRT: immediate total recall (p = 0.01) and index of sensitivity of cueing (p = 0.001), while free delayed and total memory scores were similarly impaired. The index of sensitivity of cueing held a sensitivity of 76% and specificity of 79% in distinguishing DLB. FCSRT could help in disentangling hippocampal memory deficits from memory impairment due to ineffective recall strategies.

Is There a Characteristic Clinical Profile for Patients with Dementia and Sundown Syndrome? - Angulo Sevilla, David; Carreras Rodríguez, María Teresa; Heredia Rodríguez, Patricia; Fernández Sánchez, Marisa; Vivancos Mora, José Aurelio; Gago-Veiga, Ana Beatriz (J Alzheimers Dis, 2018)
BACKGROUND: Sundown syndrome (SS) is the onset or worsening of behavioral symptoms in the evening in patients with dementia. OBJECTIVE: To identify the differential clinical profile of patients with dementia who present SS. METHODS: A cross-sectional, case-control observational study was conducted by retrospectively reviewing the medical records of patients with dementia in a specialized Memory Unit. We compared the characteristics of patients with and without SS, including sociodemographic variables, etiology, and severity of the dementia, behavioral symptoms, sleep disorders (considering insomnia and hypersomnia), other diseases and treatments employed. We identified the factors related to SS and conducted a logistic regression analysis to establish a predictive nomogram. RESULTS: Of the 216 study patients with dementia, 41 (19%) had SS. There was a predominance of women (2.4:1), advanced age (p = 0.0001), dependence (p < 0.0001), institutionalization (p < 0.0001), caregiver burden (p < 0.0001), anxiety (p < 0.0001), delirium (p < 0.0001), hallucinations (p < 0.0001), wandering (p < 0.0001), Lewy body dementia (p = 0.05), higher Global Deterioration Scale score (GDS; p < 0.0001), and sleep disorders (p < 0.0001). The multivariate analysis revealed that age (p = 0.048), GDS score (p = 0.01), and the presence of insomnia or hypersomnia (p < 0.0001) independently defined the presence of SS. We established a predictive nomogram for developing SS in patients with dementia, with a predictive capacity of 80.1%. CONCLUSION: In our study, age, a higher score on the GDS, and the presence of insomnia or hypersomnia are differential clinical characteristics of patients with SS. We defined a nomogram that helps predicting the occurrence of SS in patients with dementia.

Three Decades of Dementia Research: Insights from One Small Community of Indomitable Rotterdammers. - Wolters, Frank J; Adams, Hieab H H; Bos, Daniel; Licher, Silvan; Ikram, M Arfan (J Alzheimers Dis, 2018)
The most commonly encountered opening sentence in scientific publications about dementia undoubtedly relates to the overwhelming burden of disease. Finding an effective preventive or therapeutic intervention against dementia has been considered the most important unmet need in contemporary medicine. While efforts on tackling this devastating disease have increased exponentially, it is difficult to imagine that in the 1980s and early-1990s, the disease did not feature prominently on any public health report. Yet, it was already then that epidemiologists recognized the growing societal burden of dementia and rationalized that dementia is not necessarily part of aging. Indeed, the conviction that dementia is pathologically distinct from aging led to various efforts in search of unravelling its risk factors and understanding its pre-clinical phase. Among the early pioneers, the population-based Rotterdam Study was initiated in 1990 clearly aiming on chronic diseases including dementia, and among this Alzheimer's disease, as one of its focus points. Ever since, the Rotterdam Study has been an important cornerstone in increasing our knowledge about dementia from an epidemiological perspective. Here, we summarize the main findings originating from this study, and put these into perspective with previous and current work in the field. With an expanding scope of the Rotterdam Study over the years, we discuss findings on occurrence, modifiable risk factors, imaging, and its genetic underpinnings. Importantly, we conclude with recommendations- or, perhaps better stated, a wish list- for future research which may help us reach our finish line: finding an effective preventive or therapeutic intervention against dementia.

Three VCP Mutations in Patients with Frontotemporal Dementia. - Wong, Tsz Hang; Pottier, Cyril; Hondius, David C; Meeter, Lieke H H; van Rooij, Jeroen G J; Melhem, Shami; van Minkelen, Rick; van Duijn, Cornelia M; Rozemuller, Annemieke J M; Seelaar, Harro; Rademakers, Rosa; van Swieten, John C (J Alzheimers Dis, 2018)
Valosin-containing protein (VCP) is involved in multiple cellular activities. Mutations in VCP lead to heterogeneous clinical presentations including inclusion body myopathy with Paget's disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis, even in patients carrying the same mutation. We screened a cohort of 48 patients with familial frontotemporal dementia (FTD) negative for MAPT, GRN, and C9orf72 mutations for other known FTD genes by using whole exome sequencing. In addition, we carried out targeted sequencing of a cohort of 37 patients with frontotemporal lobar degeneration with Transactive response DNA-binding protein 43 (TDP-43) subtype from the Netherlands Brain bank. Two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD were identified, and were absence in population-match controls. All three patients presented with behavioral changes, with additional semantic deficits in one. No signs of Paget or muscle disease were observed. Pathological examination of the patient with VCP p.Arg159Ser mutation showed numerous TDP-43 immunoreactive (IR) neuronal intranuclear inclusions (NII) and dystrophic neurites (DN), while a lower number of NII and DN were observed in the patient with the VCP p.Thr262Ser mutation. Pathological findings of both patients were consistent with FTLD-TDP subtype D. Furthermore, only rare VCP-IR NII was observed in both cases. Our study expands the clinical heterogeneity of VCP mutations carriers, and indicates that other additional factors, such as genetic modifiers, may determine the clinical phenotype.

A Three-Factor Structure of Cognitive Functioning Among Unimpaired Carriers and Non-Carriers of Autosomal-Dominant Alzheimer's Disease. - Guzmán-Vélez, Edmarie; Jaimes, Sehily; Aguirre-Acevedo, Daniel C; Norton, Daniel J; Papp, Kathryn V; Amariglio, Rebecca; Rentz, Dorene; Baena, Ana; Henao, Eliana; Tirado, Victoria; Munoz, Claudia; Giraldo, Margarita; et al. (J Alzheimers Dis, 2018)
BACKGROUND: There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline. OBJECTIVE: We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. METHODS: 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). RESULTS: The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset. CONCLUSIONS: The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

Time Trends in the Prevalence of Neurocognitive Disorders and Cognitive Impairment in the United States: The Effects of Disease Severity and Improved Ascertainment. - Akushevich, Igor; Yashkin, Arseniy P; Kravchenko, Julia; Ukraintseva, Svetlana; Stallard, Eric; Yashin, Anatoliy I (J Alzheimers Dis, 2018)
BACKGROUND: Trends in the prevalence of cognitive impairment (CI) based on cognitive assessment instruments are often inconsistent with those of neurocognitive disorders (ND) based on Medicare claims records. OBJECTIVE: We hypothesized that improved ascertainment and resulting decrease in disease severity at the time of diagnosis are responsible for this phenomenon. METHODS: Using Medicare data linked to the Health and Retirement Study (1992-2012), we performed a joint analysis of trends in CI and ND to test our hypothesis. RESULTS: We identified two major contributors to the divergent directions in CI and ND trends: reductions in disease severity explained more than 60% of the differences between CI and ND prevalence over the study period; the remaining 40% was explained by a decrease in the fraction of undiagnosed individuals. DISCUSSION: Improvements in the diagnoses of ND diseases were a major contributor to reported trends in ND and CI. Recent forecasts of CI and ND trends in the U.S. may be overly pessimistic.

TLR4 Gene Expression and Pro-Inflammatory Cytokines in Alzheimer's Disease and in Response to Hippocampal Deafferentation in Rodents. - Miron, Justin; Picard, Cynthia; Frappier, Josée; Dea, Doris; Théroux, Louise; Poirier, Judes (J Alzheimers Dis, 2018)
One important aspect in Alzheimer's disease pathology is the presence of chronic inflammation. Considering its role as a key receptor in the microglial innate immune system, TLR4 was shown to regulate the binding and phagocytosis of amyloid plaques by microglia in several mouse models of amyloidosis, as well as the production of pro-inflammatory cytokines. To our knowledge, TLR4 and its association with cytokines have not been thoroughly examined in the brains of subjects affected with Alzheimer's disease. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in postmortem human brains, we observed increased expression for the TLR4 and TNF genes (p = 0.001 and p = 0.025, respectively), as well as a trend for higher IL6 gene expression in the frontal cortex of AD subjects when compared to age-matched controls. Similarly, using a mouse model of hippocampal deafferentation without amyloidosis, (i.e., the entorhinal cortex lesioned mouse), we observed significant increases in the expression of both the Tlr4 (p = 0.0367 and p = 0.0193 compared to sham-lesioned mice or to the contralateral side, respectively) and Il1b (p = 0.0055 and p = 0.0066 compared to sham-lesioned mice or to the contralateral side, respectively) genes in the deafferentation phase, but not during the ensuing reinnervation process. In conclusion, we suggest that the modulation of cytokines by TLR4 is differentially regulated whether by the presence of amyloid plaques or by the ongoing deafferentation process.

Tocotrienol-Rich Fraction of Palm Oil Improves Behavioral Impairments and Regulates Metabolic Pathways in AβPP/PS1 Mice. - Durani, Lina Wati; Hamezah, Hamizah Shahirah; Ibrahim, Nor Faeizah; Yanagisawa, Daijiro; Nasaruddin, Muhammad Luqman; Mori, Masaki; Azizan, Kamalrul Azlan; Damanhuri, Hanafi Ahmad; Makpol, Suzana; Wan Ngah, Wan Zurinah; Tooyama, Ikuo (J Alzheimers Dis, 2018)
We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo. However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer's disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction.

Total MRI Small Vessel Disease Burden Correlates with Cognitive Performance, Cortical Atrophy, and Network Measures in a Memory Clinic Population. - Banerjee, Gargi; Jang, Hyemin; Kim, Hee Jin; Kim, Sung Tae; Kim, Jae Seung; Lee, Jae Hong; Im, Kiho; Kwon, Hunki; Lee, Jong Min; Na, Duk L; Seo, Sang Won; Werring, David John (J Alzheimers Dis, 2018)
BACKGROUND: Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures. OBJECTIVE: We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden. METHODS: We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11C] PiB-PET scanning and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition. RESULTS: Total SVD score was associated with the performance of frontal (β - 4.31, SE 2.09, p = 0.040) and visuospatial (β - 0.95, SE 0.44, p = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness. CONCLUSION: Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption.

Trajectories of Physiological Brain Aging and Related Factors in People Aged from 20 to over-80. - Lee, Jin San; Kim, Seonwoo; Yoo, Heejin; Park, Seongbeom; Jang, Young Kyoung; Kim, Hee Jin; Kim, Ko Woon; Kim, Yeshin; Jang, Hyemin; Park, Key-Chung; Yaffe, Kristine; Yang, Jin-Ju; et al. (J Alzheimers Dis, 2018)
BACKGROUND/OBJECTIVE: In this study, we investigated a long-term trajectory of brain aging (from the 20 s to over-80) in cognitively normal (CN) individuals. We further determined whether differences in sex, education years, and apolipoprotein E ε 4 status affect age-related cortical thinning. METHODS: A total of 2,944 CN individuals who underwent high-resolution (3.0-Tesla) magnetic resonance imaging were included in this study. Cortical thickness was measured using a surface-based method. Multiple linear regression analyses were performed to evaluate age-related cortical thinning and related factors. RESULTS: Compared to those in their 20 s/30 s, participants in their 40 s showed thinning primarily in the medial and lateral frontal and inferior parietal regions, and cortical thinning occurred across most of the cortices with increasing age. Notably, the precuneus, inferior temporal and lateral occipital regions were relatively spared until later in life. Male and lower education years were associated with greater cortical thinning with distinct regional specificity. CONCLUSION: Our findings provide an important clue to understanding the mechanism of age-related cognitive decline and new strategies for preventing the acceleration of pathological brain aging.

Transcranial Sonography in Neurodegenerative Diseases with Cognitive Decline. - Favaretto, Silvia; Walter, Uwe; Baracchini, Claudio; Cagnin, Annachiara (J Alzheimers Dis, 2018)
Transcranial sonography (TCS) of the brain parenchyma detects alterations in the substantia nigra (SN), raphe nuclei and basal ganglia; this technique has been established as a tool for the early diagnosis of Parkinson's disease and differential diagnosis from atypical parkinsonian syndromes. Here, we aimed to review the main applications of TCS in neurodegenerative diseases presenting with dementia syndrome, focusing on Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal lobar degeneration, idiopathic normal pressure hydrocephalus, and atypical and secondary parkinsonisms. The finding of bilaterally marked hyperechogenicity of the SN appears as a characteristic feature of DLB, while it is found only in a minority of AD patients. SN hyperechogenicity is also detected in most patients with corticobasal degeneration and in about one third of patients with progressive supranuclear palsy, in which is constantly associated with hyperechogenic alterations of the basal ganglia. In conclusion, TCS is a valid supportive tool in the diagnostic workup of patients with dementia due to different neurodegenerative conditions. A promising new application is the differentiation of DLB from AD even at the early stages of these diseases.
Keywords: Cognition Disorders; Humans; Neurodegenerative Diseases; Ultrasonography, Doppler, Transcranial

Translational Research in Alzheimer's and Prion Diseases. - Di Fede, Giuseppe; Giaccone, Giorgio; Salmona, Mario; Tagliavini, Fabrizio (J Alzheimers Dis, 2018)
Translational neuroscience integrates the knowledge derived by basic neuroscience with the development of new diagnostic and therapeutic tools that may be applied to clinical practice in neurological diseases. This information can be used to improve clinical trial designs and outcomes that will accelerate drug development, and to discover novel biomarkers which can be efficiently employed to early recognize neurological disorders and provide information regarding the effects of drugs on the underlying disease biology. Alzheimer's disease (AD) and prion disease are two classes of neurodegenerative disorders characterized by incomplete knowledge of the molecular mechanisms underlying their occurrence and the lack of valid biomarkers and effective treatments. For these reasons, the design of therapies that prevent or delay the onset, slow the progression, or improve the symptoms associated to these disorders is urgently needed. During the last few decades, translational research provided a framework for advancing development of new diagnostic devices and promising disease-modifying therapies for patients with prion encephalopathies and AD. In this review, we provide present evidence of how supportive can be the translational approach to the study of dementias and show some results of our preclinical studies which have been translated to the clinical application following the 'bed-to-bench-and-back' research model.

Traumatic Brain Injury and Age of Onset of Dementia with Lewy Bodies. - Nguyen, Trung P; Schaffert, Jeff; LoBue, Christian; Womack, Kyle B; Hart, John; Cullum, C Munro (J Alzheimers Dis, 2018)
BACKGROUND: Traumatic brain injury (TBI) with loss of consciousness (LOC) has been associated with earlier onset of mild cognitive impairment, frontotemporal dementia, Parkinson's disease, and Alzheimer's disease (AD), but has not been examined as a risk factor for earlier onset of dementia with Lewy bodies (DLB). OBJECTIVE: The purpose of this study was to assess the association between a history of TBI and the age of onset of DLB. METHOD: Data from 576 subjects with a clinical diagnosis of DLB were obtained from the National Alzheimer's Coordinating Center (NACC). Analyses of Covariance examined whether self-reported history of remote TBI with LOC (i.e., >1 year prior to the first Alzheimer's Disease Center visit) was associated with earlier DLB symptom onset. RESULTS: Controlling for sex, those with a history of remote TBI had an approximately 1.5-year earlier clinician-estimated age of onset (F = 0.87, p = 0.35) and 0.75-years earlier age of diagnosis (F = 0.14, p = 0.71) of DLB compared to those without a history of TBI, though the differences did not reach statistical significance. Analysis of subjects with autopsy-confirmed diagnoses was underpowered due to the low number of TBI+ subjects. CONCLUSIONS: Remote TBI with LOC was not significantly associated with DLB onset, despite being a significant risk factor for cognitive decline and earlier age of onset in other neurodegenerative conditions. Replication of these results using a larger cohort of DLB subjects with and without a TBI history who have undergone autopsy is indicated, as our TBI+ subjects did show a slightly earlier onset of about 1.5 years. Further investigations into other potential DLB risk factors are also warranted.

Treatment of Atrial Fibrillation in Patients with Dementia: A Cohort Study from the Swedish Dementia Registry. - Subic, Ana; Cermakova, Pavla; Religa, Dorota; Han, Shuang; von Euler, Mia; Kåreholt, Ingemar; Johnell, Kristina; Fastbom, Johan; Bognandi, Liselia; Winblad, Bengt; Kramberger, Milica G; Eriksdotter, Maria; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Patients with dementia might have higher risk for hemorrhagic complications with anticoagulant therapy prescribed for atrial fibrillation (AF). OBJECTIVE: This study assesses the risks and benefits of warfarin, antiplatelets, and no treatment in patients with dementia and AF. METHODS: Of 49,792 patients registered in the Swedish Dementia Registry 2007-2014, 8,096 (16%) had a previous diagnosis of AF. Cox proportional hazards models were used to calculate the risk for ischemic stroke (IS), nontraumatic intracranial hemorrhage, any-cause hemorrhage, and death. RESULTS: Out of the 8,096 dementia patients with AF, 2,143 (26%) received warfarin treatment, 2,975 (37%) antiplatelet treatment, and 2,978 (37%) had no antithrombotic treatment at the time of dementia diagnosis. Patients on warfarin had fewer IS than those without treatment (5.2% versus 8.7%; p < 0.001) with no differences compared to antiplatelets. In adjusted analyses, warfarin was associated with a lower risk for IS (HR 0.76, CI 0.59-0.98), while antiplatelets were associated with increased risk (HR 1.25, CI 1.01-1.54) compared to no treatment. For any-cause hemorrhage, there was a higher risk with warfarin (HR 1.28, CI 1.03-1.59) compared to antiplatelets. Warfarin and antiplatelets were associated with a lower risk for death compared to no treatment. CONCLUSIONS: Warfarin treatment in Swedish patients with dementia is associated with lower risk of IS and mortality, and a small increase in any-cause hemorrhage. This study supports the use of warfarin in appropriate cases in patients with dementia. The low percentage of patients on warfarin treatment indicates that further gains in stroke prevention are possible.
Keywords: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dementia; Female; Hemorrhage; Humans; Longitudinal Studies; Male; Registries; Risk Factors; Stroke; Survival Analysis; Sweden; Warfarin

TREM1 mRNA Expression in Leukocytes and Cognitive Function in Japanese Patients with Alzheimer's Disease. - Sao, Tomoko; Yoshino, Yuta; Yamazaki, Kiyohiro; Ozaki, Yuki; Mori, Yoko; Ochi, Shinichiro; Yoshida, Taku; Mori, Takaaki; Iga, Jun-Ichi; Ueno, Shu-Ichi (J Alzheimers Dis, 2018)
BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) activates the innate immune system, promotes phagocytosis by microglia, and is associated with Alzheimer's disease (AD). The possible role of a related molecule, TREM1, in AD remains unknown. OBJECTIVE: We investigated a possible role for TREM1 in AD by determining the gene expression and methylation levels of TREM1 in leukocytes from AD patients. METHODS: Fifty patients with AD and 50 age-matched healthy controls were enrolled. AD patients underwent a battery of neuropsychiatric tests. Peripheral blood samples were obtained from each participant, RNA and DNA were extracted, and samples were assessed for TREM1 mRNA expression and methylation rates at three CpG sites in the TREM1 promoter. RESULTS: TREM1 mRNA expression levels in AD patients were significantly higher than those in controls (p = 0.008). TREM1 mRNA expression levels were not correlated with sex, age, duration of illness, APOE genotype, donepezil treatment, or scores of most neuropsychiatric tests. TREM1 mRNA expression levels in AD patients were correlated with the total score of the Montgomery-Åsberg Depression Rating Scale (p = 0.047, r = - 0.344). Methylation rates at the three CpG sites were significantly lower in AD patients than in controls. We also found a significant correlation between TREM1 mRNA expression and TREM1 DNA methylation rates (p < 0.001). CONCLUSION: TREM1 may be associated with the immune responses in AD, and along with hypomethylation at CpG sites in the TREM1 promoter, may become part of a biomarker panel for AD pathogenesis.

TRPC1 Null Exacerbates Memory Deficit and Apoptosis Induced by Amyloid-β. - Li, Mengzhu; Liu, Enjie; Zhou, Qiuzhi; Li, Shihong; Wang, Xin; Liu, Yanchao; Wang, Lin; Sun, Dongsheng; Ye, Jinwang; Gao, Yuan; Yang, Xifei; Liu, Jianjun; et al. (J Alzheimers Dis, 2018)
The transient receptor potential cation (TRPC) channels are widely expressed in nervous system but their functions remain largely unclear. Here, we found that TRPC1 deletion did not affect learning and memory in physiological conditions, while it aggravated learning and memory deficits induced by amyloid-β (Aβ), the major component of the senile plaques observed in the brains of Alzheimer's disease (AD). Further studies demonstrated that TRPC1 deletion did not affect cell apoptosis in physiological condition, but it exacerbated the Aβ-induced cell death in mouse hippocampus. Moreover, the level of TRPC1 was decreased in AD cell and mouse models, and upregulation of TRPC1 decreased Aβ levels with attenuation of apoptosis in the cells stably overexpressing amyloid-β protein precursor (AβPP). Finally, the transmembrane domain of TRPC1 could bind to AβPP and thus decreased Aβ production. These findings indicate that loss of TRPC1 exacerbates Aβ-induced memory deficit and cell apoptosis, though it does not impair cognitive function or induce cell death in physiological conditions.

TTC7 and Hyccin Regulate Neuronal Aβ42 Accumulation and its Associated Neural Deficits in Aβ42-Expressing Drosophila. - Sun, Minghao; Zhao, Yinghui; Han, Men; Zhang, Baozhu; Zhang, Xiao; Zhang, Qichao; Lim, Nastasia K-H; Wang, Wen-An; Huang, Fu-De (J Alzheimers Dis, 2018)
Neuronal amyloid-β (Aβ) accumulation plays an important role in the pathogenesis of Alzheimer's disease (AD). The conformation and toxicity of Aβ are regulated by lipids on the plasma membrane. Previously, we found downregulation of Rolling Blackout (RBO) or phosphatidylinositol-4-kinase type IIIα (PI4KIIIα) reduces neuronal Aβ accumulation and associated neural deficits in a Drosophila model expressing Aβ42. In mammals, the homologs of RBO and PI4KIIIα were reported to form a plasma membrane-localized complex with a scaffold protein TTC7 and cytosolic protein Hyccin/FAM126A to tightly control the plasmalemmal level of phosphatidylinositol-4-phosphate. Here, we show genetic downregulation of Drosophila TTC7 and Hyccin also reduces neuronal Aβ accumulation and associated synaptic and motor defects as well as premature death in Aβ42-expressing flies, while overexpression of TTC7 and Hyccin produced the opposite effect. These results, together with our previous study, demonstrate that RBO/TTC7/PI4KIIIα/Hyccin regulate neuronal Aβ accumulation and associated neural deficits in the Drosophila model, further supporting the RBO/Efr3-PI4KIIIα complex as a potential therapeutic target for AD.

Ubisol-Q10 (a Nanomicellar Water-Soluble Formulation of CoQ10) Treatment Inhibits Alzheimer-Type Behavioral and Pathological Symptoms in a Double Transgenic Mouse (TgAPEswe, PSEN1dE9) Model of Alzheimer's Disease. - Muthukumaran, Krithika; Kanwar, Annie; Vegh, Caleb; Marginean, Alexandra; Elliott, Austin; Guilbeault, Nicholas; Badour, Alexander; Sikorska, Marianna; Cohen, Jerome; Pandey, Siyaram (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused by neurotoxins or oxidative stress both in vitro and in vivo. In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ∼6 mg/kg/day) reduced circulating amyloid-β (Aβ) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Aβ plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Transgenic; Microglia; Mutation; Nerve Tissue Proteins; Peptide Fragments; Presenilin-1; Ubiquinone; Vitamins

Underlying Biological Processes in Mild Cognitive Impairment: Amyloidosis Versus Neurodegeneration. - Santana, Isabel; Baldeiras, Ines; Santiago, Beatriz; Duro, Diana; Freitas, Sandra; Pereira, Miguel Tábuas; Almeida, Maria Rosário; Oliveira, Catarina Resende (J Alzheimers Dis, 2018)
The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer's disease (AD), but this mandatory "amyloid-first pathway" has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n = 165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42, and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR = 6.1, 95% CI = 2.1-18.0, p = 0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7-9.3, p = 0.141; SNAP: HR = 3.1, 95% CI = 1.1-9.6; p = 0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative "neurodegeneration-first pathway" for further investigation.

Understanding Epigenetics in the Neurodegeneration of Alzheimer's Disease: SAMP8 Mouse Model. - Griñán-Ferré, Christian; Corpas, Rubén; Puigoriol-Illamola, Dolors; Palomera-Ávalos, Verónica; Sanfeliu, Coral; Pallas, Merce (J Alzheimers Dis, 2018)
Epigenetics is emerging as the missing link among genetic inheritance, environmental influences, and body and brain health status. In the brain, specific changes in nucleic acids or their associated proteins in neurons and glial cells might imprint differential patterns of gene activation that will favor either cognitive enhancement or cognitive loss for more than one generation. Furthermore, derangement of age-related epigenetic signaling is appearing as a significant risk factor for illnesses of aging, including neurodegeneration and Alzheimer's disease (AD). In addition, better knowledge of epigenetic mechanisms might provide hints and clues in the triggering and progression of AD. Intense research in experimental models suggests that molecular interventions for modulating epigenetic mechanisms might have therapeutic applications to promote cognitive maintenance through an advanced age. The SAMP8 mouse is a senescence model with AD traits in which the study of epigenetic alterations may unveil epigenetic therapies against the AD.

The Unexpected Role of Aβ1-42 Monomers in the Pathogenesis of Alzheimer's Disease. - Tamagno, Elena; Guglielmotto, Michela; Monteleone, Debora; Manassero, Giusi; Vasciaveo, Valeria; Tabaton, Massimo (J Alzheimers Dis, 2018)
Amyloid-β (Aβ) has been proposed as a biomarker and a drug target for the therapy of Alzheimer's disease (AD). The neurotoxic entity and relevance of each conformational form of Aβ to AD pathology is still under debate; Aβ oligomers are considered the major killer form of the peptide whereas monomers have been proposed to be involved in physiological process. Here we reviewed some different effects mediated by monomers and oligomers on mechanisms involved in AD pathogenesis such as autophagy and tau aggregation. Data reported in this review demonstrate that Aβ monomers could have a major role in sustaining the pathogenesis of AD and that AD therapy should be focused not only in the removal of oligomers but also of monomers.

The Uniform Data Set, Czech Version: Normative Data in Older Adults from an International Perspective. - Nikolai, Tomas; Stepankova, Hana; Kopecek, Miloslav; Sulc, Zdenek; Vyhnálek, Martin; Bezdicek, Ondrej (J Alzheimers Dis, 2018)
BACKGROUND: Outside of the United States, international perspectives on normative data for neuropsychological test performance, within diverse populations, have been scarce. The neuropsychological test battery from the Uniform Data Set (UDS) of the Alzheimer's Disease Centers (ADC) program of the United States National Institute on Aging (NIA) is one of the most sensitive batteries for the evaluation of both normal cognitive aging and pathological cognitive decline. OBJECTIVE: This study aimed to determine the feasibility of the Czech Neuropsychological Test Battery from the Uniform Data Set (UDS-Cz 2.0), while also evaluating the results obtained from an international perspective. METHODS: This paper describes data from 520 cognitively normal participants. Regression analyses were used to describe the influence of demographic variables on UDS-Cz test performance. RESULTS: Cognitive performance on all measures declined with age, with patient education level serving as a protective factor. Therefore, the present study provides normative data for the UDS-Cz, adjusted for the demographic variables of age and education. CONCLUSION: The present study determines the psychometric properties of the UDS-Cz and establishes normative values in the aging Czech population, which can be used in clinical settings.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Cognition; Czech Republic; Female; Humans; Internationality; Male; Middle Aged; National Institute on Aging (U.S.); Neuropsychological Tests; Psychometrics; Reference Values; Regression Analysis; United States

Untold New Beginnings: Adult Hippocampal Neurogenesis and Alzheimer's Disease. - Teixeira, Catia M; Pallas-Bazarra, Noemí; Bolós, Marta; Terreros-Roncal, Julia; Avila, Jesús; Llorens-Martín, María (J Alzheimers Dis, 2018)
Neurogenesis occurs in a limited number of brain regions during adulthood. Of these, the hippocampus has attracted great interest due to its involvement in memory processing. Moreover, both the hippocampus and the main area that innervates this structure, namely the entorhinal cortex, show remarkable atrophy in patients with Alzheimer's disease (AD). Adult hippocampal neurogenesis is a process that continuously gives rise to newborn granule neurons in the dentate gyrus. These cells coexist with developmentally generated granule neurons in this structure, and both cooperative and competition phenomena regulate the communication between these two types of cells. Importantly, it has been revealed that GSK-3β and tau proteins, which are two of the main players driving AD pathology, are cornerstones of adult hippocampal neurogenesis regulation. We have shown that alterations either promoting or impeding the actions of these two proteins have detrimental effects on the structural plasticity of granule neurons. Of note, these impairments occur both under basal conditions and in response to detrimental and neuroprotective stimuli. Thus, in order to achieve the full effectiveness of future therapies for AD, we propose that attention be turned toward identifying the pathological and physiological actions of the proteins involved in the pathogenesis of this condition.

Unusual Clinical Presentations Challenging the Early Clinical Diagnosis of Creutzfeldt-Jakob Disease. - Baiardi, Simone; Capellari, Sabina; Bartoletti Stella, Anna; Parchi, Piero (J Alzheimers Dis, 2018)
The introduction of prion RT-QuIC, an ultrasensitive specific assay for the in vivo detection of the abnormal prion protein, has significantly increased the potential for an early and accurate clinical diagnosis of Creutzfeldt-Jakob disease (CJD). However, in the clinical setting, the early identification of patients with possible CJD is often challenging. Indeed, CJD patients may present with isolated symptoms that remain the only clinical manifestation for some time, or with neurological syndromes atypical for CJD. To enhance awareness of unusual disease presentations and promote earlier diagnosis, we reviewed the entire spectrum of atypical early manifestations of CJD, mainly reported to date as case descriptions or small case series. They included sensory either visual or auditory disturbances, seizures, isolated psychiatric manifestations, atypical parkinsonian syndromes (corticobasal syndrome, progressive supranuclear palsy-like), pseudobulbar syndrome, isolated involuntary movements (dystonia, myoclonus, chorea, blepharospasm), acute or subacute onsets mimicking a stroke, isolated aphasia, and neuropathy. Since CJD is a rare disease and its clinical course rapidly progressive, an in-depth understanding and awareness of early clinical features are mandatory to enhance the overall diagnostic accuracy in its very early stages and to recruit optimal candidates for future therapeutic trials.

Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease. - Wallin, Anders; Román, Gustavo C; Esiri, Margaret; Kettunen, Petronella; Svensson, Johan; Paraskevas, George P; Kapaki, Elisabeth (J Alzheimers Dis, 2018)
Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer's disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.
Keywords: Animals; Cerebrovascular Disorders; Dementia; Humans

Urine-Based Biomarkers for Alzheimer's Disease Identified Through Coupling Computational and Experimental Methods. - Yao, Fang; Hong, Xiaoyu; Li, Shuiming; Zhang, Yan; Zhao, Qing; Du, Wei; Wang, Yong; Ni, Jiazuan (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a chronic neurodegenerative disorder contributing to nearly 70% of dementia cases. However, no diagnostic protein biomarkers are available in urine. In this study, we combined computational and experimental methods to identify urinary biomarkers for AD. First, by analyzing brain tissue-based gene expression data of AD, 2,754 differentially expressed genes were identified, 559 of which were predicted to encode urine-excretory proteins that might act as candidate protein biomarkers of AD. GO enrichment analyses implied that they were mainly involved in microtubule-based process, myelin sheath, and calcium ion binding, suggesting that they might be associated with AD pathogenesis. In order to verify these proteins in urine, an iTRAQ experiment was carried out to analyze urine samples from AD patients and healthy controls, and 15 proteins were detected. Based on the expression changes of these proteins, 4 proteins were chosen for further validation by ELISA experiment, and SPP1, GSN, and IGFBP7 were found to be differentially expressed in the urine of AD patients. After a literature survey, we found that they were involved in AD pathophysiology and might serve as new urine biomarkers for AD. To our knowledge, this is the first time that urine biomarkers for AD were identified by combining computational and experimental methods. Furthermore, this is the first time SPP1, GSN, and IGFBP7 have been reported as potential urine protein biomarkers for AD. Therefore, our findings might provide significant guidance for finding early biomarkers of AD in urine.

The Use of Mobile Games to Assess Cognitive Function of Elderly with and without Cognitive Impairment. - Bonnechère, Bruno; Van Vooren, Mélissa; Bier, Jean-Christophe; De Breucker, Sandra; Van Hove, Olivier; Van Sint Jan, Serge; Feipel, Véronique; Jansen, Bart (J Alzheimers Dis, 2018)
BACKGROUND: In the past few years numerous mobile games have been developed to train the brain. There is a lack of information about the relation between the scores obtained in these games and the cognitive abilities of the patients. OBJECTIVE: The aim of this study was to determine whether or not mobile games can be used to assess cognitive abilities of elderly. METHODS: Twenty healthy young adults, 29 old patients with cognitive impairments (Mini-Mental State Exam (MMSE) [20- 24]) and 27-aged controls participated in this study. Scores obtained in 7 mobile games were correlated with MMSE and the Addenbrooke's Cognitive Evaluation revised (ACE-R). RESULTS: Statistically significant differences were found for all games between patients with cognitive impairments and the aged controls. Correlations between the average scores of the games and the MMSE and ACE-R are significant (R = 0.72 [p < 0.001] and R = 0.81 [p < 0.001], respectively). CONCLUSION: Scores of cognitive mobile games could be used as an alternative to MMSE and ACE-R to evaluate cognitive function of aged people with and without cognitive impairment at least when MMSE is higher than 20/30.

Usefulness of Dual-Point Amyloid PET Scans in Appropriate Use Criteria: A Multicenter Study. - Segovia, Fermín; Gómez-Río, Manuel; Sánchez-Vañó, Raquel; Górriz, Juan Manuel; Ramírez, Javier; Triviño-Ibáñez, Eva; Carnero-Pardo, Cristóbal; Martínez-Lozano, María Dolores; Sopena-Novales, Pablo (J Alzheimers Dis, 2018)
BACKGROUND: Biomarkers of neurodegeneration play a major role in the diagnosis of Alzheimer's disease (AD). Information on both amyloid-β accumulation, e.g., from amyloid positron emission tomography (PET), and downstream neuronal injury, e.g., from 18F-fluorodeoxyglucose (FDG) PET, would ideally be obtained in a single procedure. OBJECTIVE: On the basis that the parallelism between brain perfusion and glucose metabolism is well documented, the objective of this work is to evaluate whether brain perfusion estimated in a dual-point protocol of 18F-florbetaben (FBB) PET can be a surrogate of FDG PET in appropriate use criteria (AUC) for amyloid PET. METHODS: This study included 47 patients fulfilling international AUC for amyloid PET. FDG PET, early FBB (pFBB) PET (0-10 min post injection), and standard FBB (sFBB) PET (90-110 min post injection) scans were acquired. Results of clinical subjective reports and of quantitative region of interest (ROI)-based analyses were compared between procedures using statistical techniques such as Pearson's correlation coefficients and t-tests. RESULTS: pFBB and FDG visual reports on the 47 patients showed good agreement (k  >  0.74); ROI quantitative analysis indicated that both data modalities are highly correlated; and the t-test analysis does not reject the null hypothesis that data from pFBB and FDG examinations comes from independent random samples from normal distributions with equal means and variances. CONCLUSIONS: A good agreement was found between pFBB and FDG data as obtained by subjective visual and quantitative analyses. Dual-point FBB PET scans could offer complementary information (similar to that from FDG PET and FBB PET) in a single procedure, considering pFBB as a surrogate of FDG.

Using Neuropsychological Process Scores to Identify Subtle Cognitive Decline and Predict Progression to Mild Cognitive Impairment. - Thomas, Kelsey R; Edmonds, Emily C; Eppig, Joel; Salmon, David P; Bondi, Mark W (J Alzheimers Dis, 2018)
BACKGROUND: We previously operationally-defined subtle cognitive decline (SCD) in preclinical Alzheimer's disease (AD) using total scores on neuropsychological (NP) tests. NP process scores (i.e., provide information about how a total NP score was achieved) may be a useful tool for identifying early cognitive inefficiencies prior to objective impairment seen in mild cognitive impairment (MCI) and dementia. OBJECTIVE: We aimed to integrate process scores into the SCD definition to identify stages of SCD and improve early detection of those at risk for decline. METHODS: Cognitively "normal" participants from the Alzheimer's Disease Neuroimaging Initiative were classified as "early" SCD (E-SCD; >1 SD below norm-adjusted mean on 2 process scores or on 1 process score plus 1 NP total score), "late" SCD (L-SCD; existing SCD criteria of >1 SD below norm-adjusted mean on 2 NP total scores in different domains), or "no SCD" (NC). Process scores considered in the SCD criteria were word-list intrusion errors, retroactive interference, and learning slope. Cerebrospinal fluid AD biomarkers were used to examine pathologic burden across groups. RESULTS: E-SCD and L-SCD progressed to MCI 2.5-3.4 times faster than the NC group. Survival curves for E-SCD and L-SCD converged at 7-8 years after baseline. The combined (E-SCD+L-SCD) group had improved sensitivity to detect progression to MCI relative to L-SCD only. AD biomarker positivity increased across NC, SCD, and MCI groups. CONCLUSIONS: Process scores can be integrated into the SCD criteria to allow for increased sensitivity and earlier identification of cognitively normal older adults at risk for decline prior to frank impairment on NP total scores.

Utility of Amyloid and FDG-PET in Clinical Practice: Differences Between Secondary and Tertiary Care Memory Units. - Lage, Carmen; Suarez, Andrea Gonzalez; Pozueta, Ana; Riancho, Javier; Kazimierczak, Martha; Bravo, María; Jimenez Bonilla, Julio; de Arcocha Torres, Marıa; Quirce, Remedios; Banzo, Ignacio; Vázquez-Higuera, José Luis; Rabinovici, Gil D; et al. (J Alzheimers Dis, 2018)
The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer's disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using χ2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p = 0.0002). Changes in treatment were associated with concordant PiB (p = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating <1 were more likely to benefit from amyloid PET due to a higher likelihood of diagnostic change. We found that changes in diagnosis after PET in our secondary center almost doubled those of our previous analysis of a tertiary unit (9% versus 17.2%). Our results offer some clues about the rational use of amyloid PET in a secondary care memory unit stressing its utility in mild cognitive impairment patients.

Utility of Amyloid PET Scans in the Evaluation of Patients Presenting with Diverse Cognitive Complaints. - Shea, Yat-Fung; Barker, Warren; Greig-Gusto, Maria T; Loewenstein, David A; DeKosky, Steven T; Duara, Ranjan (J Alzheimers Dis, 2018)
BACKGROUND: The impact of amyloid positron emission tomography (Aβ-PET) in a "real-world" memory disorders clinic remains poorly studied. OBJECTIVE: We studied the impact of Aβ-PET in diagnosis and management in the memory clinic and factors making the most impact in diagnosis and management. METHODS: We studied 102 patients who had presented at a memory disorders clinic (the Wien Center for Alzheimer's Disease and Memory Disorders, Miami Beach, FL) and had a diagnostic work-up for cognitive complaints, including Aβ-PET scans. RESULTS: Following Aβ-PET, changes were made in diagnosis (37.3%), in specific treatments for Alzheimer's disease (26.5%) and in psychiatric treatments (25.5%). The agreement between diagnosis pre-Aβ-PET versus post-Aβ-PET diagnosis was only fair, with a Cohen's kappa of 0.23 (95% CI 0-0.42). Patients with MRI findings suggestive of AD (medial temporal and/or parietal atrophy) were more frequently amyloid positive than amyloid negative (66.2% versus 33.8%, p = 0.04). Among patients with atypical clinical features for AD, but with MRI findings suggestive of AD, an amyloid negative PET scan had a greater impact than an amyloid positive PET scan on diagnosis (84.2% versus 17.1%, p < 0.001), management (84.2% versus 40%, p < 0.01) and discussion of results and advice on lifestyle (73.7% versus 22.9%, p < 0.001). CONCLUSIONS: We conclude that MRI features suggestive of AD predict a positive amyloid PET scan. However, among those with MRI features suggestive of AD but with atypical clinical features of AD, the clinical impact on diagnosis and management is greater for an amyloid negative than an amyloid positive Aβ-PET scans.

Utility of an Alzheimer's Disease Risk-Weighted Polygenic Risk Score for Predicting Rates of Cognitive Decline in Preclinical Alzheimer's Disease: A Prospective Longitudinal Study. - Porter, Tenielle; Burnham, Samantha C; Milicic, Lidija; Savage, Greg; Maruff, Paul; Lim, Yen Ying; Li, Qiao-Xin; Ames, David; Masters, Colin L; Rainey-Smith, Stephanie; Rowe, Christopher C; Salvado, Olivier; et al. (J Alzheimers Dis, 2018)
BACKGROUND: With the exception of APOE, genetic variants associated with increased Alzheimer's disease (AD) risk are characterized by small effect sizes. Polygenic risk scores (PRS) have shown utility in predicting AD risk; however, their utility for predicting decline in cognition at preclinical stages of AD is poorly understood. OBJECTIVE: To validate associations of a 22-variant AD-risk-weighted PRS with AD risk and related biomarkers and to assess its utility to predict cognitive decline. METHODS: The PRS was evaluated with respect to brain amyloid-β (Aβ) burden, cerebrospinal fluid (CSF) Aβ42, total-tau, and phospho-tau, and decline in cognition in 643 (570 cognitively normal (CN), 73 AD) PET-imaged participants from the longitudinal Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. Cognition was assessed using three composite measures; global cognition, verbal episodic memory, and a Pre-Alzheimer's Cognitive Composite (PACC). RESULTS: PRS, both with and without APOE, were positively correlated with brain Aβ burden, CSF total-tau, and phospho-tau in CN older adults. Further, in CN biomarker positive (Aβhigh) participants, significant associations were observed with baseline and longitudinal cognition. However, this association was not observed after the removal of APOE. Partitioning the PRS into quartiles revealed that the PRS associations with cognitive decline in Aβhigh CN older adults is due to a saturating effect of APOE genotype. CONCLUSIONS: An AD-risk-weighted PRS is associated with cognitive decline in CN older adults. However, this association is absent when APOE genotype is excluded from the PRS, suggesting that associations with cognitive decline in this model of polygenic risk are driven by APOE genotype alone. Further research is needed to define appropriate PRSs with greater utility for predicting preclinical AD cognitive decline.

Utility of the LIBRA Index in Relation to Cognitive Functioning in a Clinical Health Seeking Sample. - Pons, Anke; LaMonica, Haley M; Mowszowski, Loren; Köhler, Sebastian; Deckers, Kay; Naismith, Sharon L (J Alzheimers Dis, 2018)
BACKGROUND: Dementia prevalence is expected to increase substantially over the next few decades. Since there is currently no cure for dementia available, there is an urgent need for the early identification of individuals at high risk for dementia, so that primary and secondary prevention strategies can be implemented. Recently, the LIfestyle for BRAin health (LIBRA) index was developed as a new dementia risk algorithm. It specifically focuses on modifiable risk and protective factors that can be targeted in midlife. OBJECTIVE: The objective of this study was to evaluate the LIBRA index in relation to markers of cognitive functioning in a clinical, health-seeking sample of community-based older adults. METHODS: 484 participants (mean age 62.7 years) were recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney. Participants underwent comprehensive clinical and neuropsychological assessment and completed a self-report survey pack. Participants were rated via consensus as having either subjective cognitive complaints (SCC) or meeting criteria for mild cognitive impairment (MCI). The LIBRA score was calculated based on 11 available risk and protective factors. RESULTS: 65.4% of the sample met criteria for MCI. People with MCI showed a significantly higher LIBRA score compared to people with SCC. Furthermore, multiple cognitive domains, in particular executive functioning, were associated with a higher LIBRA score, with stronger correlations in people with MCI. CONCLUSION: The LIBRA index might be a useful tool to determine lifestyle-attributable risk of cognitive decline in an older health-seeking population, including people with MCI.

Validation of the Delayed Matching-to-Sample Task 48 (DMS48) in Elderly Chinese. - Feng, Xueyan; Zhou, Aihong; Liu, Zhixin; Li, Fangyu; Wei, Cuibai; Zhang, Guili; Jia, Jianping (J Alzheimers Dis, 2018)
BACKGROUND: Delayed Matching-to-Sample Task 48 (DMS48), a brief tool measuring visual recognition memory, is valid to identify the early stage of Alzheimer's disease (AD) in Caucasians. However, little data is available in Chinese. OBJECTIVE: To develop norms and optimal cutoff points for the DMS48 in Chinese elders. METHODS: A cross-sectional study was conducted in seven memory clinics from five cities across China. DMS48 was applied to 369 Chinese aged 50 or older (138 cognitively normal [CN], 112 mild cognitive impairment due to AD (MCI-A), and 119 mild AD dementia). The demographic factors which influence DMS48 scores were investigated and the norms were established considering those factors. Receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff points. RESULTS: Age was shown to influence DMS48 scores (r = -0.36, p < 0.05), and we presented the age-stratified normative data for the DMS48. The optimal cutoff point is 42/43 for identifying cognitive impairment (MCI-A and AD dementia) against CN (sensitivity 97.80% and specificity 89.13%) and MCI-A against CN (sensitivity 86.60% and specificity 94.20%). A cutoff of 39/40 obtained good sensitivity (100.00%) and specificity (94.90%) in discriminating AD dementia from CN. The age-stratified optimal cutoff points for identifying MCI-A were 43/44 for individuals aged 50 to 59 years old, 42/43 for 60 to 69 years old, 41/42 for 70 to 79 years old, and 40/41 for 80 or older, respectively (sensitivity 84.80% and specificity 95.70%). CONCLUSION: This study proved that DMS48 is of good validation in screening MCI-A in elderly Chinese.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; China; Cognitive Dysfunction; Cross-Sectional Studies; Female; Humans; Linear Models; Male; Memory Disorders; Middle Aged; Neuropsychological Tests; ROC Curve; Sensitivity and Specificity; Severity of Illness Index

Validation of the Spanish Version of the Dementia Knowledge Assessment Tool 2. - Parra-Anguita, Laura; Moreno-Cámara, Sara; López-Franco, María Dolores; Pancorbo-Hidalgo, Pedro L (J Alzheimers Dis, 2018)
BACKGROUND: There are currently no questionnaires to measure the knowledge of nurses about dementia or Alzheimer's disease care in the Spanish language. OBJECTIVE: To validate the Spanish version of the Dementia Knowledge Assessment Tool 2 (DKAT2-Sp). METHODS: The DKAT2 was translated into Spanish and then back-translated. The new Spanish version was validated in a sample of 361 members of the nursing staff from 24 nursing homes and a sample of 297 nursing students in Spain. Psychometric properties were assessed through an item analysis, a Rasch analysis, differential item functioning analysis, construct validity (known groups), and internal consistency (Cronbach's alpha). RESULTS: The 21 items of the DKAT2-Sp fit the model well, showing a wide range of difficulty. Four items have differential items functioning between nursing professionals and students. The DKAT2-Sp shows acceptable internal consistency (Cronbach's alpha = 0.76 for nursing professionals and 0.83 for students). Scores obtained in the known groups test were as hypothesized (Nursing home staff mean = 15.57 versus Nursing student mean = 12.85; p < 0.0001 for mean difference), supporting construct validity. CONCLUSION: The DKAT2-Sp is a reliable and valid questionnaire to measure knowledge about dementia in both nursing professionals and nursing students in Spanish-speaking contexts.

Vascular Cognitive Impairment and the Gut Microbiota. - Li, Sinian; Shao, Yiming; Li, Kanglan; HuangFu, Changmei; Wang, Wenjie; Liu, Zhou; Cai, Zhiyou; Zhao, Bin (J Alzheimers Dis, 2018)
Vascular cognitive impairment (VCI), the second most common cause of dementia in elderly people, is a term that refers to all forms of cognitive disorders that can be attributed to cerebrovascular disease such as manifestations of discrete infarctions, brain hemorrhages, and white matter lesions. The gut microbiota (GM) has emerged recently as an essential player in the development of VCI. The GM may affect the brain's physiological, behavioral, and cognitive functions through the brain-gut axis via neural, immune, endocrine, and metabolic pathways. Therefore, microbiota dysbiosis may mediate or affect atherosclerosis, cerebrovascular disease, and endothelial dysfunction, which are the predominant risk factors for VCI. Moreover, the composition of the GM includes the bacterial component lipopolysaccharides and their metabolic products including trimethylamine-N-oxide and short-chain fatty acids. These products may increase the permeability of the intestinal epithelium, leading to systemic immune responses, low-grade inflammation, and altered signaling pathways that are associated with the pathogenesis of VCI. In this review, we discuss the proposed mechanisms of the GM in the maintenance of VCI and how it is implicated in acquired metabolic diseases, particularly in VCI regulation.

Vascular Effects on Depressive Symptoms in Cognitive Impairment. - Kim, Yeshin; Jang, Hyemin; Kim, Seung Joo; Cho, Soo Hyun; Kim, Si Eun; Kim, Sung Tae; Kim, Hee Jin; Moon, Seung Hwan; Ewers, Michael; Im, Kiho; Kwon, Hunki; Na, Duk L; et al. (J Alzheimers Dis, 2018)
Late life depression is related to pathologic burdens, such as cerebral small vascular disease (CSVD) and amyloid, which are associated with brain network changes and cortical thinning. To examine the associations of various CSVD imaging markers, amyloid, and network changes with depression in cognitively impaired patients, we prospectively recruited 228 cognitively impaired patients having various degrees of amyloid and CSVD who underwent diffuse tensor image and PiB PET. Greater CSVD burden was associated with greater Geriatric Depression Scale (GDS) (white matter hyperintensities, WMH: p = 0.025, lacunes: p < 0.001) but not with amyloid (p = 0.095), and cortical thinning (p = 0.630) was not associated with greater GDS. The changes in white matter networks were related to GDS with decreasing integration (global efficiency: p < 0.001) and increasing segregation (clustering coefficient: p = 0.009). The network changes mediated the relationships of WMH and lacunes with GDS. Our findings provide insight to better understand how CSVD burdens contribute to depression in cognitively impaired patients having varying degrees of amyloid and vascular burdens.

The Vascular Hypothesis of Alzheimer's Disease: A Key to Preclinical Prediction of Dementia Using Neuroimaging. - de la Torre, Jack (J Alzheimers Dis, 2018)
The vascular hypothesis of Alzheimer's disease (VHAD) was proposed 24 years ago from observations made in our laboratory using aging rats subjected to chronic brain hypoperfusion. In recent years, VHAD has become a mother-lode to numerous neuroimaging studies targeting cerebral hemodynamic changes, particularly brain hypoperfusion in elderly patients at risk of developing Alzheimer's disease (AD). There is a growing consensus among neuroradiologists that brain hypoperfusion is likely involved in the pathogenesis of AD and that disturbed cerebral blood flow (CBF) can serve as a key biomarker for predicting conversion of mild cognitive impairment to AD. The use of cerebral hypoperfusion as a preclinical predictor of AD is becoming decisive in stratifying low and high risk patients that may develop cognitive decline and for assessing the effectiveness of therapeutic interventions. There is currently an international research drive from neuroimaging groups to seek new perspectives that can broaden our understanding of AD and improve lifestyle. Diverse neuroimaging methods are currently being used to monitor normal and dyscognitive brain activity. Some techniques are very powerful and can detect, diagnose, quantify, prognose, and predict cognitive decline before AD onset, even from a healthy cognitive state. Multimodal imaging offers new insights in the treatment and prevention of cognitive decline during advanced aging and better understanding of the functional and structural organization of the human brain. This review discusses the impact the VHAD and CBF are having on the neuroimaging technology that can usher practical strategies to help prevent AD.