Impact of Olfactory Priming on Food Intake in an Alzheimer's Disease Unit. - Sulmont-Rossé, Claire; Gaillet, Marie; Raclot, Carine; Duclos, Michel; Servelle, Maud; Chambaron, Stéphanie (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is often associated with feeding difficulties and changes in eating behavior with may lead to malnutrition. In French nursing homes, AD patients may live in special care units that better meet dementia residents' needs. However, meals are often delivered to AD patients by using meal trays coming from central kitchens. This led to the disappearance of cues that could help residents to foresee mealtime, such as the smell of food odors. The aim of the present study was to assess the impact of odorizing the dining room of AD Units with a meat odor before lunch on subsequent food intake and eating behavior. Thirty-two residents (>75 years old) from three AD Units were included in the study. They participated in two control lunches and two primed lunches, for which a meat odor was diffused in the dining room 15 minutes before the arrival of the meal tray (olfactory priming). Results of the first replication showed a significant effect of olfactory priming, with a 25% increase in meat and vegetable consumption compared to the control condition. Behavioral measurements also showed a significant increase of resident's interest toward the meal in the primed lunch. However, this effect was no longer observed when the priming session was replicated two weeks later with the same priming odor and the same menu. Although further research is needed to understand why this priming effect cannot be replicated, our experiment is one of the very first to investigate the effect of food odor priming on subsequent food intake in AD patients in a real-life setting.

Impact of Osteoporosis on the Risk of Dementia in Almost 60,000 Patients Followed in General Practices in Germany. - Kostev, Karel; Hadji, Peyman; Jacob, Louis (J Alzheimers Dis, 2018)
BACKGROUND: There has been in recent decades a growing interest in the relationship between osteoporosis and cognitive decline. OBJECTIVE: The goal of this study was to analyze the impact of osteoporosis on the risk of dementia in patients followed for up to 20 years in general practices in Germany. METHODS: This study included patients who received an initial diagnosis of osteoporosis and were followed by 1,215 general practitioners in Germany between January 1993 and December 2012 (index date). Controls were matched (1:1) to osteoporosis patients using propensity scores based on age, gender, index year, comorbidities, and co-therapies. Kaplan-Meier curves were performed to study the development of dementia separately in men and women with or without osteoporosis within 20 years of the index date. Cox proportional regression models were used to estimate the relationship between osteoporosis and dementia in men and women. RESULTS: The present study included 29,983 cases and 29,983 controls. After 20 years of follow-up, 20.5% of women with osteoporosis and 16.4% of controls had been diagnosed with dementia (log-rank p-value <0.001). At the end of the follow-up period, dementia was found in 22.0% of men previously diagnosed with osteoporosis and 14.9% of men without this chronic condition (log-rank p-value <0.001). Osteoporosis was associated with a 1.2-fold increase in the risk of being diagnosed with dementia in women and a 1.3-fold increase in the risk of being diagnosed with dementia in men. CONCLUSIONS: There was a positive association between osteoporosis and dementia in patients followed in general practices in Germany.

Impact of Total Knee Arthroplasty with General Anesthesia on Brain Networks: Cognitive Efficiency and Ventricular Volume Predict Functional Connectivity Decline in Older Adults. - Huang, Haiqing; Tanner, Jared; Parvataneni, Hari; Rice, Mark; Horgas, Ann; Ding, Mingzhou; Price, Catherine (J Alzheimers Dis, 2018)
Using resting state functional magnetic resonance imaging (RS-fMRI), we explored: 1) pre- to post-operative changes in functional connectivity in default mode, salience, and central executive networks after total knee arthroplasty (TKA) with general anesthesia, and 2) the contribution of cognitive/brain reserve metrics these resting state functional declines. Individuals age 60 and older electing unilateral total knee arthroplasty (TKA; n = 48) and non-surgery peers with osteoarthritis (n = 45) completed baseline cognitive testing and baseline and post-surgery (post-baseline, 48-h post-surgery) brain MRI. We acquired cognitive and brain estimates for premorbid (vocabulary, reading, education, intracranial volume) and current (working memory, processing speed, declarative memory, ventricular volume) reserve. Functional network analyses corrected for pain severity and pain medication. The surgery group declined in every functional network of interest (p < 0.001). Relative to non-surgery peers, 23% of surgery participants declined in at least one network and 15% of the total TKA sample declined across all networks. Larger preoperative ventricular volume and lower scores on preoperative metrics of processing speed and working memory predicted default mode network connectivity decline. Premorbid cognitive and premorbid brain reserve did not predict decline. Within 48 hours after surgery, at least one fourth of the older adult sample showed significant functional network decline. Metrics of current brain status (ventricular volume), working memory, and processing speed predicted the severity of default mode network connectivity decline. These findings demonstrate the relevance of preoperative cognition and brain integrity on acute postoperative functional network change.

Impact of Untimely Access to Formal Care on Costs and Quality of Life in Community Dwelling People with Dementia. - Janssen, Niels; Handels, Ron L; Sköldunger, Anders; Woods, Bob; Jelley, Hannah; Edwards, Rhiannon Tudor; Orrell, Martin; Selbæk, Geir; Røsvik, Janne; Gonçalves-Pereira, Manuel; Marques, Maria J; Zanetti, Orazio; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Access to formal care is not always timely and a better understanding on the impact of untimely access is needed. OBJECTIVE: To examine, from a societal perspective, the impact of untimely access to formal care in terms of total costs and quality of life over one year in community dwelling people with dementia. METHODS: Within the Actifcare study, needs, resource use, and quality of life were observed for one year in a cohort of 451 community dwelling people with dementia in 8 European countries. Untimely access to care was operationalized as having at least one unmet need for care identified by the Camberwell Assessment of Need for the Elderly (CANE) instrument. Two regression models were built for both total costs and quality of life measured by the EQ-5D-5L, one using sum of unmet needs and one using a predefined selection of need items. RESULTS: Unmet needs were not associated with higher total costs but they were associated with a lower quality of life of people with dementia. Of all CANE items, only an unmet need for "company" was significantly related to lower total costs. CONCLUSION: Total costs did not seem to differ between participants with unmet and met needs. Only few associations between specific unmet needs and costs and quality of life were found. Furthermore, quality of life of people with dementia decreases when multiple unmet needs are experienced, indicating that assessing and meeting needs is important to improve quality of life.

Impaired IL-17 Production in Gut-Residing Immune Cells of 5xFAD Mice with Alzheimer's Disease Pathology. - Saksida, Tamara; Koprivica, Ivan; Vujičić, Milica; Stošić-Grujičić, Stanislava; Perović, Milka; Kanazir, Selma; Stojanović, Ivana (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is characterized by accumulation of amyloid-β plaques that further promotes microglia-mediated neuroinflammatory responses and inflammation in the brain. Emerging data are revealing the relation between gut-associated lymphoid tissue (GALT) cells and CNS, as effector cells primed in the gut might home to the brain. This study aimed to determine cell composition of GALT in 5xFAD mice, an established model for AD. Immune cells isolated from Peyer's patches (PP) and mesenteric lymph nodes (MLN) were stained with surface and intracellular markers for T helper (Th) subpopulations, B lymphocytes and macrophages and analyzed cytofluorimetrically, while cytokine expression and production were determined by qPCR and ELISA, respectively. Inflammation was detected in GALT of 5xFAD mice with established AD pathology. Although the production of IFN-γ, IL-4, and IL-10 was comparable between the strains, lower IL-17 production was observed in PP and MLN cells. This phenomenon could not be attributed to a lower abundance of Th17 cells, or cytokines that initiate their formation or propagation (TGF-β, IL-6, and IL-23). Also, reduced IL-17 production was not a consequence of altered Il-17 mRNA transcription or deficiency of Rorγt, a key transcription factor for IL-17. However, the expression of miR-155 (a non-coding micro RNA that promotes the development of Th17 cells), was significantly lower in MLN cells of 5xFAD mice. In contrast, mice without AD neuropathology did not have inflammation in GALT or altered Th17 numbers, nor decreased IL-17 production. In conclusion, the observed changes in GALT of 5xFAD mice mirror the disease progression and might reflect inadequate immune surveillance in the gut and lead to enhanced AD pathology.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; B-Lymphocytes; Disease Models, Animal; Female; Interleukin-17; Lymph Nodes; Male; Mice; Mice, Transgenic; MicroRNAs; Peyer's Patches; Th17 Cells

Impaired Spike Timing Dependent Cortico-Cortical Plasticity in Alzheimer's Disease Patients. - Di Lorenzo, Francesco; Ponzo, Viviana; Motta, Caterina; Bonní, Sonia; Picazio, Silvia; Caltagirone, Carlo; Bozzali, Marco; Martorana, Alessandro; Koch, Giacomo (J Alzheimers Dis, 2018)
BACKGROUND: Mechanisms of cortical plasticity have been recently investigated in Alzheimer's disease (AD) patients with transcranial magnetic stimulation protocols showing a clear impairment of long-term potentiation (LTP) cortical-like plasticity mechanisms. OBJECTIVE: We aimed to investigate mechanisms of cortico-cortical spike-timing dependent plasticity (STDP) in AD patients investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1). METHODS: We used a cortico-cortical paired associative stimulation (cc-PAS) protocol to repeatedly activate the connection between PPC and M1 of the left-dominant hemisphere in a sample of fifteen AD patients and ten age-matched healthy subjects. PPC transcranial magnetic stimulation preceded (ccPAS +5) or followed M1 stimulation (ccPAS - 5) by 5 ms. Motor-evoked potentials (MEPs) were collected to assess the time course of the after effects of cc-PAS protocol measuring MEP amplitude as index of cortico-cortical associative plasticity. RESULTS: In healthy subjects, ccPAS - 5 protocol induced the expected long-lasting increase of MEP amplitude compatible with LTP-like cortical plasticity while PAS +5 protocol induced the opposite effect. AD patients did not show any significant modification of the amplitude of MEP after both ccPAS protocols. CONCLUSIONS: Our study shows that in AD patients the time-locked activation of human cortico-cortical connections is not able to form STDP, reflecting an impairment of a multi-factor plasticity process.

Implementation of an Occupational Therapy Program for Alzheimer's Disease Patients in France: Patients' and Caregivers' Perspectives. - Corvol, Aline; Netter, Alix; Campeon, Arnaud; Somme, Dominique (J Alzheimers Dis, 2018)
BACKGROUND: The French National Alzheimer Plan 2008-2012 created specialized Alzheimer teams, which provide up to 15 sessions of cognitive rehabilitation in the patient's home for 3 months. Sessions are conducted by an occupational therapist and a gerontological nursing assistant. OBJECTIVES: As the patient's experience is one determinant of successful implementation, we explored the usefulness of these teams as viewed by the patient and his or her main caregiver. METHODS: Thirteen patients and their caregiver, previously assisted by a specialized Alzheimer team, were individually given semi-structured interviews (n = 26, duration 20 to 180 minutes). RESULTS: Our study showed that although patients and caregiver had no initial expectations, most of them appreciated the support provided by the specialized Alzheimer teams. Patients valued the "human" component, and favored interventions that improved quality of life over those intended to maintain functional capacities. Caregivers observed improved mood and behavior in patients. Those involved in sessions felt empowered by contact with a specialized Alzheimer team. We discuss how patients' and caregivers' feedback influenced the implementation process through comprehensive use of the five dimensions of the RE-AIM framework. CONCLUSION: Whereas intervention by specialized Alzheimer teams was largely accepted by health care professionals, patients, and caregivers, its effectiveness is questioned in view of its deviation from the evidence-based model. Interviews with patients and caregivers shed light on some reasons for this deviation, as what they value in the intervention differs from the functional focus of the model.

Improvement of Main Cognitive Functions in Patients with Alzheimer's Disease after Treatment with Coconut Oil Enriched Mediterranean Diet: A Pilot Study. - de la Rubia Ortí, Jose Enrique; García-Pardo, María Pilar; Drehmer, Eraci; Sancho Cantus, David; Julián Rochina, Mariano; Aguilar, Maria Asunción; Hu Yang, Iván (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder (mainly in women), and new therapies are needed. In this way, ketone bodies are a direct source of cellular energy and can be obtained from coconut oil, postulating that coconut oil could be a new non-pharmacological alternative in AD patients. OBJECTIVE: The aim of this study is to detect changes in the main cognitive functions of patients with AD after following a coconut oil enriched Mediterranean diet, and to determine whether there are differences in function of stage or sex. METHODS: A prospective, longitudinal, qualitative, analytic, experimental study was carried out in 44 patients with AD, who were randomly divided into two homogenous groups of 22 patients each: an experimental group of patients who followed a coconut oil enriched Mediterranean diet for 21 days and a control group. In order to determine the cognitive changes after the intervention, we carried out the 7 Minute Screen, which analyses temporal orientation, visuospatial and visuoconstructive abilities, and semantic and episodic memory. RESULTS: After intervention with coconut oil, improvements in episodic, temporal orientation, and semantic memory were observed, and it seems that the positive effect is more evident in women with mild-moderate state, although other improvements in males and severe state were also shown. CONCLUSIONS: The isocaloric coconut oil enriched Mediterranean diet seems to improve cognitive functions in patients with AD, with differences according to patient sex and degree of severity of the disease, although more studies in this line are needed.

In Vitro Potency and Preclinical Pharmacokinetic Comparison of All-D-Enantiomeric Peptides Developed for the Treatment of Alzheimer's Disease. - Schartmann, Elena; Schemmert, Sarah; Niemietz, Nicole; Honold, Dominik; Ziehm, Tamar; Tusche, Markus; Elfgen, Anne; Gering, Ian; Brener, Oleksandr; Shah, Nadim Joni; Langen, Karl-Josef; Kutzsche, Janine; et al. (J Alzheimers Dis, 2018)
Diffusible amyloid-β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer's disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely D-enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the D-peptides' potencies to inhibit Aβ aggregation, eliminate Aβ oligomers, and reduce Aβ-induced cytotoxicity revealed that all three D-peptides efficiently target Aβ. Subsequent preclinical pharmacokinetic studies of the three all-D-peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides' potencies to lower Aβ toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.

In vivo Depiction of α7 Nicotinic Receptor Loss for Cognitive Decline in Alzheimer's Disease. - Nakaizumi, Kyoko; Ouchi, Yasuomi; Terada, Tatsuhiro; Yoshikawa, Etsuji; Kakimoto, Akihiro; Isobe, Takashi; Bunai, Tomoyasu; Yokokura, Masamichi; Suzuki, Katsuaki; Magata, Yasuhiro (J Alzheimers Dis, 2018)
BACKGROUND: The α7 subtype of the nicotinic acetylcholine receptor (nAChR) is considered important in higher cognitive functions, and cholinergic loss underpins the pathophysiology of Alzheimer's disease (AD). However, the relationships between α7 nAChR function and clinical functions or amyloid-β (Aβ) deposition remain to be explored in the living AD brain. OBJECTIVE: We aimed to elucidate the relationship between α7 nAChR availability in the specific cholinergic region and cognitive decline in the Aβ-confirmed AD brain. METHODS: Twenty AD patients and ten age-matched healthy subjects were examined. The α7-nAChR availability and Aβ deposition were evaluated using positron emission tomography with an α7 nAChR radiotracer 11C-(R)-MeQAA and 11C-Pittsburg compound B (11C-PiB), respectively. Semi-quantified values of tracer binding were estimated with a simplified reference tissue method for BPND of 11C-(R)-MeQAA and a tissue ratio method for SUVR of 11C-PiB. These parameters and clinical scores were compared voxel-wise using a statistical parametric mapping method. RESULTS: The levels of 11C-(R)-MeQAA BPND in the temporal and prefrontal cholinergic projection regions were significantly lower in AD, and negative correlations were found between 11C-PiB SUVR and 11C-(R)-MeQAA BPND in the region of the nucleus basalis magnocellularis and medial prefrontal cortex. Levels of 11C-(R)-MeQAA BPND were significantly correlated with memory and frontal function scores in AD. CONCLUSION: The association between Aβ burden and α7-nAChR reduction in the basal forebrain cholinergic system was highlighted in relation to cognitive decline in AD. This suggests that Aβ-linked α7-nAChR reduction is clinico-pathophyisologically important for considering a good therapeutic target in AD.
Keywords: Adult; Aged; alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Brain; Case-Control Studies; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Young Adult

In Vivo MRI of Amyloid Plaques in a Cholesterol-Fed Rabbit Model of Alzheimer's Disease. - Chen, Yuanxin; Lim, Patrick; Rogers, Kem A; Rutt, Brian K; Ronald, John A (J Alzheimers Dis, 2018)
Hypercholesterolemia has been identified as a risk factor for Alzheimer's disease. In this study, rabbits were fed either a cholesterol diet or normal chow diet for 24 months. At endpoint, in vivo MRI was performed at the field strength of 3 Tesla using fast imaging employing steady state acquisition without (FIESTA) or with susceptibility-weighted post-processing (SWI-FIESTA) and susceptibility-weighted imaging with multi-echo acquisition (SWAN). This imaging revealed signal voids/hypointensities throughout the cortex, sub-cortex, and hippocampus of cholesterol-fed animals compared to control animals. Quantitative image analysis corroborated these qualitative findings and highlighted that SWI processing of FIESTA images significantly improved the detectability of plaques (p < 0.05). Aβ immunostaining and Prussian blue staining for iron demonstrated that the voids in MR images corresponded to iron-laden Aβ-positive plaques. This study demonstrates non-invasive in vivo visualization of Aβ plaques in a diet-induced large animal model of Alzheimer's disease. This work lays the foundation for future work focusing on longitudinal monitoring of plaque formation in this model and the effects of diet or drug interventions.

In Vivo Visualization of Tau Accumulation, Microglial Activation, and Brain Atrophy in a Mouse Model of Tauopathy rTg4510. - Ishikawa, Ai; Tokunaga, Masaki; Maeda, Jun; Minamihisamatsu, Takeharu; Shimojo, Masafumi; Takuwa, Hiroyuki; Ono, Maiko; Ni, Ruiqing; Hirano, Shigeki; Kuwabara, Satoshi; Ji, Bin; Zhang, Ming-Rong; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Tau imaging using PET is a promising tool for the diagnosis and evaluation of tau-related neurodegenerative disorders, but the relationship among PET-detectable tau, neuroinflammation, and neurodegeneration is not yet fully understood. OBJECTIVE: We aimed to elucidate sequential changes in tau accumulation, neuroinflammation, and brain atrophy by PET and MRI in a tauopathy mouse model. METHODS: rTg4510 transgenic (tg) mice expressing P301L mutated tau and non-tg mice were examined with brain MRI and PET imaging (analyzed numbers: tg = 17, non-tg = 13; age 2.5∼14 months). As PET probes, [11C]PBB3 (Pyridinyl-Butadienyl-Benzothiazole 3) and [11C]AC-5216 were used to visualize tau pathology and 18-kDa translocator protein (TSPO) neuroinflammation. Tau pathology and microglia activation were subsequently analyzed by histochemistry. RESULTS: PET studies revealed age-dependent increases in [11C]PBB3 and [11C]AC-5216 signals, which were correlated with age-dependent volume reduction in the forebrain on MRI. However, the increase in [11C]PBB3 signals reached a plateau at age 7 months, and therefore its significant correlation with [11C]AC-5216 disappeared after age 7 months. In contrast, [11C]AC-5216 showed a strong correlation with both age and volume reduction until age 14 months. Histochemical analyses confirmed the relevance of pathological tau accumulation and elevated TSPO immunoreactivity in putative microglia. CONCLUSION: Our results showed that tau accumulation is associated with neuroinflammation and brain atrophy in a tauopathy mouse model. The time-course of the [11C]PBB3- and TSPO-PET finding suggests that tau deposition triggers progressive neuroinflammation, and the sequential changes can be evaluated in vivo in mouse brains.
Keywords: Animals; Atrophy; Benzothiazoles; Brain; Disease Models, Animal; Female; Magnetic Resonance Imaging; Male; Mice; Mice, Transgenic; Microglia; Positron-Emission Tomography; Receptors, GABA; tau Proteins; Tauopathies

Incidence and Prevalence of Antiepileptic Medication Use in Community-Dwelling Persons with and without Alzheimer's Disease. - Sarycheva, Tatyana; Taipale, Heidi; Lavikainen, Piia; Tiihonen, Jari; Tanskanen, Antti; Hartikainen, Sirpa; Tolppanen, Anna-Maija (J Alzheimers Dis, 2018)
BACKGROUND: Although antiepileptic drugs (AEDs) have a potential for adverse drug reactions in older populations, little is known about their use in relation to Alzheimer's disease (AD) diagnosis. OBJECTIVES: In this study, we investigated the incidence and prevalence of AED use in relation to AD diagnosis. METHODS: The MEDALZ-study includes all Finnish persons who received clinically verified AD diagnoses (n = 70,718) during 2005-2011 and a matched comparison cohort without AD (n = 70,718). AD diagnoses were identified from the Special Reimbursement Register. We used the Prescription Register to identify dispensed AEDs. Incident AED users were identified with a one-year washout period 9-10 years before AD diagnosis, and incidence rates per 100 person-years were calculated for each six-month period from nine years before to five years after AD diagnosis. Prevalence was assessed as proportion using AEDs during each six-month time period for incident use. RESULTS: Persons with AD were more likely to use AEDs during the study period (4.3%) than persons without AD (3.2%). The incidence and prevalence of AED use was higher among persons with AD and increased around the time of AD diagnosis. Epilepsy diagnoses did not explain these differences. Persons with AD were more likely to use older AEDs. CONCLUSION: Our study highlights the need to balance effective symptom control with the possible risks of treatment.

Increased Albumin Oxidation in Cerebrospinal Fluid and Plasma from Alzheimer's Disease Patients. - Costa, Montserrat; Horrillo, Raquel; Ortiz, Ana María; Pérez, Alba; Mestre, Anna; Ruiz, Agustin; Boada, Merce; Grancha, Salvador (J Alzheimers Dis, 2018)
BACKGROUND: Oxidative stress in the brain and peripheral systems is considered a major player in Alzheimer's disease (AD). Albumin is the main transporter and the main extracellular antioxidant in the human body. OBJECTIVE: Here we explore for the first time the oxidation status of cerebrospinal fluid (CSF) and plasma albumin in AD in comparison to healthy subjects. METHODS: Plasma and CSF samples were obtained from mild-moderate AD patients and control healthy age-matched donors. Albumin redox state forms (reduced: HMA; reversibly oxidized: HNA1; irreversibly oxidized: HNA2) were determined by HPLC. Albumin post-translational modifications (PTM) analysis was performed by mass spectrometry. RESULTS: HPLC showed less HMA in AD plasma than in controls (54.1% versus 65.2% ; p < 0.0001), mainly at expense of HNA1 (42.8% versus 32.5% ; p < 0.0001). In AD CSF, HMA was drastically decreased compared to controls (9.6% versus 77.4% ; p < 0.0001), while HNA2 was increased (52.8% versus 7.4% ; p < 0.0001). In AD patients but not in healthy controls, CSF albumin was much more irreversibly oxidized than in plasma (close to 20-fold increase in HNA2). PTM analysis showed that AD CSF albumin samples behave as a differentiated cluster, thus confirming the albumin oxidative pattern observed by HPLC. CONCLUSION: CSF albumin oxidation in AD patients was dramatically increased comparing to healthy controls, while in plasma this increase was smaller. CSF albumin in AD patients was much more oxidized than in plasma, but this effect was not observed in healthy controls. These results suggest that albumin oxidation, especially in CSF, and its role in AD deserves further investigation.

Increased Foxo3a Nuclear Translocation and Activity is an Early Neuronal Response to βγ-Secretase-Mediated Processing of the Amyloid-β Protein Precursor: Utility of an AβPP-GAL4 Reporter Assay. - Law, Bernard M; Guest, Amy L; Pullen, Matthew W J; Perkinton, Michael S; Williams, Robert J (J Alzheimers Dis, 2018)
Sequential cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (β-secretase) followed by theγ-secretase complex, is strongly implicated in Alzheimer's disease (AD) but the initial cellular responses to these cleavage events are not fully defined. β-secretase-mediated AβPP processing yields an extracellular domain (sAβPPβ) and a C-terminal fragment of AβPP of 99 amino acids (C99). Subsequent cleavage by γ-secretase produces amyloid-β (Aβ) and an AβPP intracellular domain (AICD). A cellular screen based on the generation of AICD from an AβPP-Gal4 fusion protein was adapted by introducing familial AD (FAD) mutations into the AβPP sequence and linking the assay to Gal4-UAS driven luciferase and GFP expression, to identify responses immediately downstream of AβPP processing in neurons with a focus on the transcription factor Foxo3a which has been implicated in neurodegeneration. The K670N/M671L, E682K, E693G, and V717I FAD mutations and the A673T protective mutation, were introduced into the AβPP sequence by site directed mutagenesis. When expressed in mouse cortical neurons, AβPP-Gal4-UAS driven luciferase and GFP expression was substantially reduced by γ-secretase inhibitors, lowered by β-secretase inhibitors, and enhanced by α-secretase inhibitors suggesting that AICD is a product of the βγ-secretase pathway. AβPP-Gal4-UAS driven GFP expression was exploited to identify individual neurons undergoing amyloidogenic AβPP processing, revealing increased nuclear localization of Foxo3a and enhanced Foxo3a-mediated transcription downstream of AICD production. Foxo3a translocation was not driven by AICD directly but correlated with reduced Akt phosphorylation. Collectively this suggests that βγ-secretase-mediated AβPP processing couples to Foxo3a which could be an early neuronal signaling response in AD.
Keywords: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Disease Models, Animal; Forkhead Box Protein O3; Mice; Mutagenesis, Site-Directed; Mutation; Neurons; Phosphorylation; Protein Transport; Signal Transduction

Increased Insoluble Amyloid-β Induces Negligible Cognitive Deficits in Old AppNL/NL Knock-In Mice. - Salas, Isabel H; Callaerts-Vegh, Zsuzsanna; D'Hooge, Rudi; Saido, Takaomi C; Dotti, Carlos G; De Strooper, Bart (J Alzheimers Dis, 2018)
Commonly used Alzheimer's disease mouse models are based on the ectopic overexpression of the human amyloid precursor protein (APP) gene, together with a mutant presenilin gene. Surprisingly, humanized APP knock-in mouse models carrying a single APP Swedish mutation (AppNL), failed to develop amyloid plaque aggregation or cognitive deficits. Here we characterized the effect of this mutation in more advanced ages. We show that 24-month-old AppNL/NL mice, despite presenting an age dependent increase in insoluble amyloid-β oligomers in the prefrontal cortex, they do not develop amyloid plaque deposition, reactive gliosis, or cognitive deficits.

Increased Prevalence of Obesity/Type 2 Diabetes and Lower Levels of Lithium in Rural Texas Counties May Explain Greater Alzheimer's Disease Risk. - Baranowski, Bradley J; Hayward, Grant C; Fajardo, Val A; MacPherson, Rebecca E K (J Alzheimers Dis, 2018)
BACKGROUND/OBJECTIVE: To compare Alzheimer's disease (AD) mortality rates and coinciding risk factors in rural and urban Texas populations. METHODS: 155 Texas counties were divided into 73 rural and 82 urban areas using the U.S. Census Bureau definition of rurality. Changes in age-adjusted AD mortality across these counties were calculated using a 7-year aggregation model from 2000-2006 and 2009-2015. Data pertaining to gender, race, education, obesity, diabetes, physical inactivity, and lithium concentrations in tap water were also collected from readily available databases. RESULTS: Change in age-adjusted AD mortality was higher in rural counties (9.5±1.4) versus urban (5.9±1.1) over the time period examined. Similarly, obesity (30.2±0.2% ), diabetes (11.0±0.1% ), and physical inactivity (29.4±0.2% ) levels were significantly higher in rural populations compared to urban (29.1±0.2%, 9.7±0.1%, and 26.7±0.3, respectively). In contrast, the percent of population with some college education (40.1±0.7% ) was lower compared to urban (29.4±0.2% and 44.4±0.9%, respectively). Lithium concentrations in tap water was significantly lower in rural counties compared to urban (63.3±8.2 and 33.4±4.7μg/L, respectively). No significant differences were observed among females and however, we did find significant differences in the percent of African American and Hispanics. Correlational analysis uncovered a negative association between education status and AD mortality over time (r = -0.17). Further analysis controlling for physical inactivity, education, and trace lithium concentrations results in a loss of statistical significance. CONCLUSIONS: AD mortality rates are higher in rural counties when compared to urban counties, and this may be linked to greater physical inactivity, obesity, and diabetes, as well as lower trace lithium levels in tap water.

Increased Risk of Dementia in Subjective Cognitive Decline if CT Brain Changes are Present. - Sacuiu, Simona; Eckerström, Marie; Johansson, Lena; Kern, Silke; Sigström, Robert; Xinxin, Guo; Östling, Svante; Skoog, Ingmar (J Alzheimers Dis, 2018)
BACKGROUND: Subjective cognitive decline (SCD) has low predictive value for incident dementia. OBJECTIVES: We examined whether CT detectable brain changes add predictive value to SCD in a population sample with high scores on the Mini-Mental State Examination. METHODS: Subjective reports of memory and executive function were gathered in a non-demented population sample ≥70 years (n = 921). CT-brain was performed at baseline (n = 626). Brain atrophy, infarcts, and white matter lesions (WMLs) were classified using visual ratings. Dementia incidence was evaluated periodically during 12 years. RESULTS: The prevalence of SCD was 32.5% among individuals without dementia. During follow-up, 151 individuals (16.4%) developed dementia. The risk of dementia was increased in SCD, and increased further with WMLs and cortical atrophy present. However, the positive predictive values for incident dementia were low, 25% in SCD and 41% in SCD with WMLs and cortical atrophy. CONCLUSION: Our observations add clinical value to the use of SCD and CT to select relevant populations for interventions against dementia, but more stringent screening methods are necessary to reach individuals at risk.

Increased Serum Acylated Ghrelin Levels in Patients with Mild Cognitive Impairment. - Cao, Xi; Zhu, Min; He, Yan; Chu, Wenzheng; Du, Yifeng; Du, Heng (J Alzheimers Dis, 2018)
Ghrelin is a stomach-derived circulating hormone. In addition to its function as an orexigenic stimulant, the role of ghrelin in the consolidation of learning and memory has been implicated in recent years. However, the status of circulating acylated ghrelin (AG, that is, the functional form of ghrelin) in the symptomatic predementia stage of Alzheimer's disease (AD) has rarely been investigated. In the current study, we examined the serum levels of acylated and total ghrelin in 22 patients with mild cognitive impairment (MCI) and 30 cognitively normal controls. We have found that patients with MCI had significantly increased serum AG levels, which were inversely associated with defected short- and long-term memory as well as language skills. Of note, the levels of total circulating ghrelin were similar between the two groups. Intriguingly, serum AG but not total ghrelin was associated with AD risk factors including the age, hypertension, and hyperlipidemia. Therefore, circulating AG may serve as a potential early systemic biomarker for AD-related cognitive impairments. Nevertheless, the simplest interpretation of the results is that the levels of circulating AG are associated with cognitive impairments in patients with MCI, thereby forming the groundwork for our future studies on the systemic mechanisms of AD pertaining to the ghrelin system.
Keywords: Aged; Alzheimer Disease; Biomarkers; Case-Control Studies; Cognitive Dysfunction; Female; Ghrelin; Humans; Male; Middle Aged; Risk Factors

Increased Vulnerability of the Hippocampus in Transgenic Mice Overexpressing APP and Triple Repeat Tau. - Arner, Andrew; Rockenstein, Edward; Mante, Michael; Florio, Jazmin; Masliah, Deborah; Salehi, Bahar; Adame, Anthony; Overk, Cassia; Masliah, Eliezer; Rissman, Robert A (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is the most common tauopathy, characterized by progressive accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. While pathology associated with the 4-repeat (4R) tau isoform is more abundant in corticobasal degeneration and progressive supranuclear palsy, both 3R and 4R tau isoforms accumulate in AD. Many studies have investigated interactions between Aβ and 4R tau in double transgenic mice, but few, if any, have examined the effects of Aβ with 3R tau. To examine this relationship, we crossed our APP751 mutant line with our recently characterized 3R tau mutant model to create a bigenic line (hAPP-3RTau) to model AD neuropathology. Mice were analyzed at 3 and 6 months of age for pathological and behavioral endpoints. While both the 3RTau and the hAPP-3RTau mice showed neuronal loss, increased tau aggregation, Aβ plaques and exhibited more behavioral deficits compared to the non-tg control, the bigenic mice often displaying relatively worsening levels. We found that even in young animals we found that the presence of APP/Aβ increased the accumulation of 3R tau in the neocortex and hippocampus. This observation was accompanied by activation of GSK3 and neurodegeneration in the neocortex and CA1 region. These results suggest that in addition to 4R tau, APP/Aβ may also enhance accumulation of 3R tau, a process which may be directly relevant to pathogenic pathways in AD. Our results demonstrate that this bigenic model closely parallels the pathological course of AD and may serve as a valuable model for testing new pharmacological interventions.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Female; Glycogen Synthase Kinase 3; Hippocampus; Humans; Male; Mice; Mice, Transgenic; Neocortex; tau Proteins; Tauopathies

Increasing Diagnostic Accuracy of Mild Cognitive Impairment due to Alzheimer's Disease by User-Independent, Web-Based Whole-Brain Volumetry. - Hedderich, Dennis M; Spiro, Judith E; Goldhardt, Oliver; Kaesmacher, Johannes; Wiestler, Benedikt; Yakushev, Igor; Zimmer, Claus; Boeckh-Behrens, Tobias; Grimmer, Timo (J Alzheimers Dis, 2018)
BACKGROUND: Volumetric quantification of structural MRI has been shown to increase the diagnostic accuracy of patients with mild cognitive impairment (MCI); however, its implementation in clinical routine is usually technically difficult and time-consuming. OBJECTIVE: The purpose of this study was to investigate whether volumetric information obtained from the free and easy-to-use online tool volBrain can improve correct identification of MCI patients with Alzheimer's disease (AD) compared to visual reading. METHODS: The study cohort consisted of 27 patients with MCI due to AD (AD positive) as determined by biomarker information and 26 cognitively normal controls (CN). Three blinded readers, 2 radiologists and 1 clinical dementia expert, assessed the patients' MRI regarding brain atrophy and probability of underlying AD two times, without and with supporting volumetric information from volBrain. To assess diagnostic accuracy of volBrain measures alone, a simple sum score based on basic volumetric measures was developed and tested. RESULTS: Correct patient classification by readers 1, 2, and 3 without a volumetric report was 73.6%, 77.4%, and 83.0%. With a volumetric report, correct classification increased for the radiological readers to 77.4% and 81.1%, respectively and decreased to 77.4% for reader 3. Usage of the volumetric report alone yielded the highest diagnostic accuracy of 84.9%. Diagnostic confidence increased significantly for radiological readers. CONCLUSION: Volumetric information from volBrain increases the radiologist's diagnostic performance and confidence in identifying MCI patients with AD. We propose that such tools may be implemented in the routine diagnostic work-up of patients with suspected AD.

INDEL Length and Haplotypes in the β-Synuclein Gene: A Key to Differentiate Dementia with Lewy Bodies? - Gámez-Valero, Ana; Canet-Pons, Julia; Urbizu, Aintzane; Anillo, Ana; Santos, Cristina; Ariza, Aurelio; Beyer, Katrin (J Alzheimers Dis, 2018)
Lewy body diseases (LBD) include Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and together with Alzheimer's disease (AD) they show an important neuropathological and clinical overlap. The human alpha- and beta-synuclein genes (SNCA and SNCB) are key factors for the development of Lewy body diseases. Here, we aimed to analyze the genotype distribution of potentially functional SNPs in SNCA and SNCB, perform haplotype analysis for SNCB, and to identify functional insertion and deletion (INDEL) variations within the regulatory region of SNCB which might be responsible for the drastically diminished beta-synuclein levels reported for pure DLB. Thus, we genotyped brain samples from AD, DLB, PD, and healthy controls for two SNCA and four SNCB SNPs. We also analyzed INDEL variations upstream of SNCB, determined SNCB expression levels, and correlated INDEL lengths with expression levels. Applying Fisher's exact, chi-square, ANOVA tests, and the ΔΔCt method, we found disease-specific genotype distribution of SNCA and SNCB SNPs. Additionally, we identified three INDEL variations upstream of SNCB and showed that the INDEL allele lengths were associated with SNCB expression levels. INDEL alleles associated with low SNCB expression were accumulated in pure DLB. Finally, one major and four minor DLB specific SNCB haplotypes were identified with Haploview and Arlequin. In summary, our study showed that different SNCA and SNCB genotypes are associated with the development of either PD or DLB, and that the frequencies of genotypes associated with low SNCB expression are elevated in DLB.

The Independent Associations of Physical Activity and Sleep with Cognitive Function in Older Adults. - Falck, Ryan S; Best, John R; Davis, Jennifer C; Liu-Ambrose, Teresa (J Alzheimers Dis, 2018)
BACKGROUND: Current evidence suggests physical activity (PA) and sleep are important for cognitive health; however, few studies examining the role of PA and sleep for cognitive health have measured these behaviors objectively. OBJECTIVE: We cross-sectionally examined whether 1) higher PA is associated with better cognitive performance independently of sleep quality; 2) higher sleep quality is associated with better cognitive performance independently of PA; and 3) whether higher PA is associated with better sleep quality. METHODS: We measured PA, subjective sleep quality using the Pittsburgh Sleep Quality Index (PSQI), and objective sleep quality (i.e., fragmentation, efficiency, duration, and latency) using the MotionWatch8© in community-dwelling adults (N = 137; aged 55+). Cognitive function was indexed using the Alzheimer's Disease Assessment Scale-Plus. Correlation analyses were performed to determine relationships between PA, sleep quality, and cognitive function. We then used latent variable modelling to examine the relationships of PA with cognitive function independently of sleep quality, sleep quality with cognitive function independently of PA, and PA with sleep quality. RESULTS: We found greater PA was associated with better cognitive performance independently of 1) PSQI (β= -0.03; p < 0.01); 2) sleep fragmentation (β= -0.02; p < 0.01); 3) sleep duration (β= -0.02; p < 0.01); and 4) sleep latency (β= -0.02; p < 0.01). In addition, better sleep efficiency was associated with better cognitive performance independently of PA (β= -0.01; p = 0.04). We did not find any associations between PA and sleep quality. CONCLUSIONS: PA is associated with better cognitive performance independently of sleep quality, and sleep efficiency is associated with better cognitive performance independently of PA. However, PA is not associated with sleep quality and thus PA and sleep quality may be related to cognitive performance through independent mechanisms.

An Inducible Alpha-Synuclein Expressing Neuronal Cell Line Model for Parkinson's Disease1. - Vasquez, Velmarini; Mitra, Joy; Perry, George; Rao, K S; Hegde, Muralidhar L (J Alzheimers Dis, 2018)
Altered expression of α-synuclein is linked to Parkinson's disease (PD). A major challenge to explore how the increased α-synuclein affect neurotoxicity is the lack of a suitable human neuronal cell model that mimics this scenario. Its expression in neural precursors affects their differentiation process, in addition to the neuronal adaptability and variability in maintaining a constant level of expression across passages. Here, we describe an SH-SY5Y line harboring Tet-ON SNCA cDNA cassette that allows for induction of controlled α-synuclein expression after neuronal differentiation, which can be an important tool for PD research.

Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides. - Cam, Morgane; Durieu, Emilie; Bodin, Marion; Manousopoulou, Antigoni; Koslowski, Svenja; Vasylieva, Natalia; Barnych, Bogdan; Hammock, Bruce D; Bohl, Bettina; Koch, Philipp; Omori, Chiori; Yamamoto, Kazuo; et al. (J Alzheimers Dis, 2018)
Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.

Inflammatory Cytokine, IL-1β, Regulates Glial Glutamate Transporter via microRNA-181a in vitro. - Zumkehr, Joannee; Rodriguez-Ortiz, Carlos J; Medeiros, Rodrigo; Kitazawa, Masashi (J Alzheimers Dis, 2018)
Glutamate overload triggers synaptic and neuronal loss that potentially contributes to neurodegenerative diseases including Alzheimer's disease (AD). Glutamate clearance and regulation at synaptic clefts is primarily mediated by glial glutamate transporter 1 (GLT-1). We determined that inflammatory cytokines significantly upregulated GLT-1 through microRNA-181a-mediated post-transcriptional modifications. Unveiling the key underlying mechanisms modulating GLT-1 helps better understand its physiological and pathological interactions with cytokines. Primary murine astrocyte and neuron co-culture received 20 ng/mL IL-1β, TNF-α, or IL-6 for 48 h. Soluble proteins or total RNA were extracted after treatment for further analyses. Treatment with inflammatory cytokines, IL-1β and TNF-α, but not IL-6, significantly increased GLT-1 steady-state levels (p≤0.05) without affecting mRNA levels, suggesting the cytokine-induced GLT-1 was regulated through post-transcriptional modifications. Among the candidate microRNAs predicted to modulate GLT-1, only microRNA-181a was significantly decreased following the IL-1β treatment (p≤0.05). Co-treatment of microRNA-181a mimic in IL-1β-treated primary astrocytes and neurons effectively blocked the IL-1β-induced upregulation of GLT-1. Lastly, we attempted to determine the link between GLT-1 and microRNA-181a in human AD brains. A significant reduction of GLT-1 was found in AD hippocampus tissues, and the ratio of mature microRNA-181a over primary microRNA-181a had an increasing tendency in AD. MicroRNA-181a controls rapid modifications of GLT-1 levels in astrocytes. Cytokine-induced inhibition of microRNA-181a and subsequent upregulation of GLT-1 may have physiological implications in synaptic plasticity while aberrant maturation of microRNA-181a may be involved in pathological consequences in AD.

Influence of Butyrylcholinesterase in Progression of Mild Cognitive Impairment to Alzheimer's Disease. - Gabriel, António José; Almeida, Maria Rosário; Ribeiro, Maria Helena; Carneiro, Diogo; Valério, Daniela; Pinheiro, Ana Cristina; Pascoal, Rui; Santana, Isabel; Baldeiras, Ines (J Alzheimers Dis, 2018)
BACKGROUND: Several demographic and genetic prognostic factors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) have been recognized so far. The most frequent polymorphism of butyrylcholinesterase (BuChE), the K-variant, has been proposed as a risk factor for AD, but data regarding its influence on early disease progression is still limited. OBJECTIVE: To investigate the influence of the BuChE-K variant in MCI progression to AD. METHODS: 96 MCI patients were included in the study and were genotyped for BuChE-K variant and Apolipoprotein E (ApoE). Cerebrospinal fluid (CSF) BuChE activity, as well as the levels of AD biomarkers amyloid-β 42 (Aβ42), total and hyperphosphorylated tau (t-tau and p-tau) were also determined. RESULTS: No significant differences were found in either BuChE-K variant or BuChE activity between MCI patients that progressed to AD (MCI-AD) and patients that remained stable during clinical follow-up (MCI-St). As expected, baseline CSF levels of Aβ42 were significantly lower and t-Tau, p-Tau, and ApoE ɛ4 allele frequency were significantly higher in MCI-AD patients. An association between the ApoE ɛ4 allele and the BuChE-K variant in MCI-AD, but not in MCI-St patients, was found with patients carrying both alleles presenting the highest incidence of progression and the lowest estimated time of progression to AD. CONCLUSION: Although BuChE-K alone does not seem to play a major role in progression to AD in MCI patients, a synergistic effect with the ApoE ɛ4 allele was found, highlighting the importance of assessing these combined genotypes for evaluating risk progression in MCI patients.
Keywords: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Biomarkers; Butyrylcholinesterase; Cognitive Dysfunction; Disease Progression; Female; Genetic Predisposition to Disease; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Risk Factors; tau Proteins

Influence of Lewy Pathology on Alzheimer's Disease Phenotype: A Retrospective Clinico-Pathological Study. - Roudil, Jennifer; Deramecourt, Vincent; Dufournet, Boris; Dubois, Bruno; Ceccaldi, Mathieu; Duyckaerts, Charles; Pasquier, Florence; Lebouvier, Thibaud (J Alzheimers Dis, 2018)
BACKGROUND: Studies have shown the frequent coexistence of Lewy pathology (LP) in Alzheimer's Disease (AD). OBJECTIVE: The aim of this study was to determine the influence of LP on the clinical and cognitive phenotype in a cohort of patients with a neuropathological diagnosis of AD. METHODS: We reviewed neuropathologically proven AD cases, reaching Braak stages V and VI in the brain banks of Lille and Paris between 1993 and 2016, and classified them according to LP extension (amygdala, brainstem, limbic, or neocortical). We then searched patient files for all available clinical and neuropsychiatric features and neuropsychological data. RESULTS: Thirty-three subjects were selected for this study, among which 16 were devoid of LP and 17 presented AD with concomitant LP. The latter were stratified into two subgroups according to LP distribution: 7 were AD with amygdala LP and 10 were AD with 'classical' (brainstem, limbic or neocortical) LP. When analyzing the incidence of each clinical feature at any point during the disease course, we found no significant difference in symptom frequency between the three groups. However, fluctuations appeared significantly earlier in patients with classical LP (2±3.5 years) than in patients without LP (7±1.7 years) or with amygdala LP (8±2.8 years; p < 0.01). There was no significant difference in cognitive profiles. CONCLUSION: Our findings suggest that the influence of LP on the clinical phenotype of AD is subtle. Core features of dementia with Lewy bodies do not allow clinical diagnosis of a concomitant LP on a patient-to-patient basis.

The Influence of Polypharmacy on the Initiation of Anti-Dementia Therapy in Germany. - Bohlken, Jens; Jacob, Louis; van den Bussche, Hendrik; Kostev, Karel (J Alzheimers Dis, 2018)
The goal of the present retrospective study was to focus on the potential influence of polypharmacy on the initiation of antidementia therapy in patients diagnosed with dementia in general practices in Germany. The current study sample included patients diagnosed with dementia in 1,217 general practices in Germany between 2014 and 2016 (index date). The primary outcome measure was the rate of prescription of anti-dementia drugs within one year following the index date. The explanatory variable was the number of different drugs prescribed at baseline per patient. Independent variables included age, sex, and type of dementia. Logistic regression analyses were conducted to study the impact of the number of different drugs prescribed at baseline per participant on the odds of receiving anti-dementia therapy (in all patients and in patients diagnosed with Alzheimer's disease). The study included 21,888 patients with all-cause dementia. Mean age was 80.2 years (SD = 7.3 years) and 61.4% of the study population were women. Individuals receiving six drugs or more at baseline were significantly less likely to be prescribed anti-dementia treatment when compared to those without any drug at baseline (6- 9 drugs: odds ratio [OR] = 0.75;≥10 drugs: OR = 0.58). In the subgroup of patients with Alzheimer's disease, the odds of being prescribed anti-dementia therapy were lower in individuals with four drugs or more, compared to patients who had not been prescribed any drugs at baseline (4- 5 drugs: OR = 0.60; 6- 9 drugs: OR = 0.49;≥10 drugs: OR = 0.36). There is a negative association between polypharmacy and antidementia therapy initiation in general practices in Germany.

The Influence of the Val66Met Polymorphism of Brain-Derived Neurotrophic Factor on Neurological Function after Traumatic Brain Injury. - Finan, John D; Udani, Shreya V; Patel, Vimal; Bailes, Julian E (J Alzheimers Dis, 2018)
Functional outcomes after traumatic brain injury (TBI) vary widely across patients with apparently similar injuries. This variability hinders prognosis, therapy, and clinical innovation. Recently, single nucleotide polymorphism (SNPs) that influence outcome after TBI have been identified. These discoveries create opportunities to personalize therapy and stratify clinical trials. Both of these changes would propel clinical innovation in the field. This review focuses on one of most well-characterized of these SNPs, the Val66Met SNP in the brain-derived neurotrophic factor (BDNF) gene. This SNP influences neurological function in healthy subjects as well as TBI patients and patients with similar acute insults to the central nervous system. A host of other patient-specific factors including ethnicity, age, gender, injury severity, and post-injury time point modulate this influence. These interactions confound efforts to define a simple relationship between this SNP and TBI outcomes. The opportunities and challenges associated with personalizing TBI therapy around this SNP and other similar SNPs are discussed in light of these results.

Inhibition of Histone Acetylation by ANP32A Induces Memory Deficits. - Chai, Gao-Shang; Feng, Qiong; Ma, Rong-Hong; Qian, Xiao-Hang; Luo, Dan-Ju; Wang, Zhi-Hao; Hu, Yu; Sun, Dong-Sheng; Zhang, Jun-Fei; Li, Xiao; Li, Xiao-Guang; Ke, Dan; et al. (J Alzheimers Dis, 2018)
There is accumulating evidence that decreased histone acetylation is involved in normal aging and neurodegenerative diseases. Recently, we found that ANP32A, a key component of INHAT (inhibitor of acetyltransferases) that suppresses histone acetylation, increased in aged and cognitively impaired C57 mice and expressing wild-type human full length tau (htau) transgenic mice. Downregulating ANP32A restored cognitive function and synaptic plasticity through upregulation of the expressions of synaptic-related proteins via increasing histone acetylation. However, there is no direct evidence that ANP32A can induce neurodegeneration and memory deficits. In the present study, we overexpressed ANP32A in the hippocampal CA3 region of C57 mice and found that ANP32A overexpression induced cognitive abilities and synaptic plasticity deficits, with decreased synaptic-related protein expression and histone acetylation. Combined with our recent studies, our findings reveal that upregulated ANP32A induced-suppressing histone acetylation may underlie the cognitive decline in neurodegenerative disease, and suppression of ANP32A may represent a promising therapeutic approach for neurodegenerative diseases including Alzheimer's disease.

The In-Hospital Length of Stay after Hip Fracture in Octogenarians: Do Delirium and Dementia Shape a New Care Process? - Monacelli, Fiammetta; Pizzonia, Monica; Signori, Alessio; Nencioni, Alessio; Giannotti, Chiara; Minaglia, Cecilia; Granello di Casaleto, Tommaso; Podestà, Silvia; Santolini, Federico; Odetti, Patrizio (J Alzheimers Dis, 2018)
BACKGROUND: Hip fracture is a major health problem and a patient's biological age, comorbidity, and cognitive vulnerability have an impact on its related outcomes. Length of stay (LOS) for these highly vulnerable patients is rather long and the possible causes have not been clearly identified yet. OBJECTIVE: We aimed to assess the main clinical factors associated with protracted LOS, focusing on delirium with or without dementia in older age hip fractured patients. METHODS: 218 subjects (mean age 86.70±6.18 years), admitted to the Orthogeriatric Unit of the Ospedale Policlinico San Martino (Italy), were recruited. All patients received physical and comprehensive geriatric assessment. Days to surgery, days from surgery to rehabilitation, and LOS were recorded. In-hospital and three months' mortality were reported. RESULTS: Prevalent delirium at hospital admission was of 3.1%. 35% of patients developed incident delirium. 56.4% were affected by dementia of Alzheimer-type. In addition, 52% of patients developed delirium superimposed to dementia. Mean LOS was 13.5±4.99 days. Namely, delirium, time to surgery, and complication rate disproportionally affected LOS. The analysis with 3 months mortality, based on cognitive vulnerability profiles, showed how delirium mainly affect short-term mortality in patients with dementia. CONCLUSION: Our exploratory study originally pointed out the high incidence of delirium superimposed to dementia in orthogeriatric wards and how delirium turns to be a moderator of LOS. The results meet the need for additional research by virtue of a deeper understanding of the impact of delirium and dementia on orthogeriatric clinical management and outcomes.

Innovative Biomarkers for Alzheimer's Disease: Focus on the Hidden Disease Biomarkers. - Ghidoni, Roberta; Squitti, Rosanna; Siotto, Mariacristina; Benussi, Luisa (J Alzheimers Dis, 2018)
The criteria for the clinical diagnosis of AD include the analysis of biomarkers of the underlying brain disease pathology; a set of cerebrospinal fluid (CSF) tests, amyloid-β1-42 (Aβ42), total-tau (t-tau), and phosphorylated tau (p-tau), are available and their performance in a clinical setting has been assessed in several studies. Thus, in dementia research, great advances have been made in the discovery of putative biomarkers; however, disappointingly, few of them have been translated into clinically applicable assays. To find biomarkers able to reliably detect AD pathology already at prodromal stages and in blood is even more important. Recent technical breakthroughs have provided ultrasensitive methods that allow the detection of brain-specific proteins in blood. In the present review, we will focus on the usefulness of ultrasensitive technologies for biomarker discovery and trace elements detection; moreover, we will review studies on circulating nano-compartments, a promising novel source of material for molecular diagnostics.

Integrating Sleep and Alzheimer's Disease Pathophysiology: Hints for Sleep Disorders Management. - Proserpio, Paola; Arnaldi, Dario; Nobili, Flavio; Nobili, Lino (J Alzheimers Dis, 2018)
Sleep represents an active phenomenon regulated by a highly integrated network of cortical and subcortical structures. This complex model results in disruptions at various levels during physiological aging and more deeply during neurodegenerative disorders, thus leading to different sleep alterations. In Alzheimer's disease (AD), sleep-wake abnormalities were described to occur even in the preclinical phase, thus suggesting they could be a possible AD biomarker. On the other hand, they also favor the progression of the disease. In this paper, we review current theories regarding sleep regulations and functions to highlight the pathophysiological mechanisms at the basis of the bidirectional relationship between sleep and AD. A better understanding of these complex interactions might also be useful to target both sleep disorder management and AD-related symptoms.

Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer's Disease Development. - Lövheim, Hugo; Olsson, Jan; Weidung, Bodil; Johansson, Anders; Eriksson, Sture; Hallmans, Göran; Elgh, Fredrik (J Alzheimers Dis, 2018)
BACKGROUND: Several environmental factors, including infectious agents, have been suggested to cause Alzheimer's disease (AD). Cytomegalovirus (CMV) has been associated with AD in several recent studies. OBJECTIVE: To investigate whether carriage of CMV, alone or in combination with Herpes simplex virus (HSV), increased the risk of developing AD. METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years), taken an average of 9.6 years before AD diagnosis, and 360 age-, sex-, cohort-, and sampling date matched dementia-free controls were analyzed to detect anti-CMV (immunoglobulin [Ig] G and IgM), group-specific anti-HSV (IgG and IgM), and specific anti-HSV1 and HSV2 IgG antibodies by enzyme-linked immunosorbent assays. AD cases and dementia-free controls were compared using conditional logistic regression analyses. RESULTS: The presence of anti-CMV IgG antibodies did not increase the risk of AD (odds ratio [OR], 0.857; p = 0.497). Among AD cases, an association between CMV and HSV1 carriage was detected (OR 7.145, p < 0.001); in a conditional logistic regression model, the interaction between CMV and HSV1 was associated with AD development (OR 5.662; p = 0.007). CONCLUSION: The present findings do not support a direct relationship between CMV infection and the development of AD; however, an interaction between CMV and HSV1 was found to be associated significantly with AD development. These findings suggest that CMV infection facilitates the development of HSV1-associated AD, possibly via its effects on the immune system.
Keywords: Aged; Alzheimer Disease; Antibodies, Viral; Case-Control Studies; Cytomegalovirus; Cytomegalovirus Infections; Enzyme-Linked Immunosorbent Assay; Female; Herpes Simplex; Herpesvirus 1, Human; Humans; Immunoglobulin G; Immunoglobulin M; Logistic Models; Male; Middle Aged

Interactions between Atrial Fibrillation, Cardiovascular Risk Factors, and ApoE Genotype in Promoting Cognitive Decline in Patients with Alzheimer's Disease: A Prospective Cohort Study. - Falsetti, Lorenzo; Viticchi, Giovanna; Buratti, Laura; Grigioni, Francesco; Capucci, Alessandro; Silvestrini, Mauro (J Alzheimers Dis, 2018)
BACKGROUND: An association between non-valvular atrial fibrillation (NVAF) and cognitive impairment has been hypothesized. OBJECTIVE: We sought to evaluate whether and how permanent NVAF (pNVAF) is associated with progression of cognitive impairment in patients with Alzheimer's disease (AD) in the presence of vascular or genetic risk factors. METHODS: 310 consecutive patients affected by mild-moderate AD were included and followed for a 24-month period. At the end of the follow-up, based on the results of the neuropsychological evaluation patients were classified as stable or deteriorated to severe AD. Clinical history, therapy, time in therapeutic range for anticoagulation, Framingham cardiovascular risk profile (FCRP), CHA2DS2-VASc score, Mini-Mental State Examination (MMSE), ApoE genotype, brain CT-scan, carotid ultrasound, and ECG were collected. Binary logistic and path analysis were adopted to assess relationships between pNVAF, ApoE, and cognitive outcome. RESULTS: Despite anticoagulant therapy, pNVAF was associated with lower entry MMSE, higher mean intima-media thickness (mIMT) and higher FCRP. Among patients carrying ApoE ɛ4 allele and affected by pNVAF, the lowest MMSE (14.90±7.62) and the highest mIMT (1.16±0.17 mm) and FCRP (26.24±3.96) values were detected. In this group, the risk of cognitive deterioration reached the highest probability. pNVAF was associated with an increased cognitive deterioration in subjects with high FCRP, CHA2DS2-VASc, or mIMT. CONCLUSIONS: pNVAF seems to identify AD patients with a significant atherosclerotic burden and reduced cognitive performances. The interaction between pNVAF and ApoE ɛ4 genotype, especially with aggregated risk factors and an advanced stage of vascular damage is associated with higher risk of fast cognitive deterioration.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Atherosclerosis; Atrial Fibrillation; Carotid Intima-Media Thickness; Cognitive Dysfunction; Disease Progression; Female; Humans; Logistic Models; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Prospective Studies; Risk Factors; Tomography, X-Ray Computed

Interactive Effect of Depression and Cognitive Impairment on Olfactory Identification in Elderly People. - Chen, Ben; Zhong, Xiaomei; Mai, Naikeng; Peng, Qi; Zhang, Min; Chen, Xinru; Wu, Zhangying; Zou, Laiquan; Liang, Wanyuan; Ouyang, Cong; Wu, Yujie; Ning, Yuping (J Alzheimers Dis, 2018)
Olfactory identification (OI) deficits have been regarded as an indicator of cognitive impairment in the elderly, but few studies have analyzed the mixed effect of depression on OI. Since depression is common in the elderly and strongly associated with OI, we aimed to explore whether the comorbidity of depression and cognitive impairment may be associated with worse outcomes. In total, 153 elderly patients with depression and 154 normal elderly were recruited. Subjects underwent assessments of depression, cognitive function, and OI. Information on the factors that may affect OI performance was collected (age, sex, smoking history, diabetes, etc.). Correlation analysis showed that several factors had a significant influence on OI performance in the elderly, including severity of depression, cognitive scores, age, sex, and years of education (p < 0.05). Among the different cognitive domains, OI was positively associated with global cognition, memory, language, executive function, and attention performance (p < 0.05). The multiple linear regression analysis indicated that memory scores, age, HAMD scores, and sex were the most relevant factors to OI scores across all elderly participants. The factorial analysis suggested that elderly with comorbidity of depression and cognitive impairment (memory deficits or language deficits) had worse OI impairment, and there was an interactive effect of depression and memory deficits on OI in elderly people. The present study suggested that the coexistence of depressive symptoms and cognitive impairment was associated with worse OI in the elderly. Studies exploring the association between OI and cognitive function should include an assessment of depression and adjust the interactive effects of depression.

Internal Consistency Over Time of Subjective Cognitive Decline: Drawing Preclinical Alzheimer's Disease Trajectories. - Ávila-Villanueva, Marina; Maestú, Fernando; Fernández-Blázquez, Miguel A (J Alzheimers Dis, 2018)
BACKGROUND: Early intervention to prevent, or delay, the transition from healthy cognition to cognitive impairment in older adults is an important goal. In this way, it is critical to find sensitive, reproducible, and early markers to use low cost methods for the detection of that transition. One of those early markers for symptomatic manifestation of AD is subjective cognitive decline (SCD). OBJECTIVE: To examine the internal consistency of the concept of SCD and to evaluate its clinical significance on the progression through the continuum of AD. METHODS: 1,091 cognitively healthy individuals from the Vallecas Project cohort were followed for three years. Cognitive complaints were systematically collected and analyzed along with clinical data. All participants were classified in three groups at every visit based on specific features of their complaints. RESULTS: Concordance analyses showed a good agreement in longitudinal classification of SCD. The Multi-state Markov Model highlighted a unidirectional transition from the status of no cognitive complaints to SCD. Interestingly, a more severe condition of SCD, namely SCD Plus, showed the highest risk of progression to mild cognitive impairment. CONCLUSIONS: The concept of SCD is stable over time when it is operationally defined and consistently assessed. It provides not only a fast identification of individuals at higher risk of future mild cognitive impairment, but also it allows us to track longitudinal trajectories.

Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cells and Brain Samples. - Leskelä, Stina; Takalo, Mari; Marttinen, Mikael; Huber, Nadine; Paananen, Jussi; Mitra, Vikram; Rauramaa, Tuomas; Mäkinen, Petra; Leinonen, Ville; Soininen, Hilkka; Pike, Ian; Remes, Anne M; et al. (J Alzheimers Dis, 2018)
A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-β (Aβ) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-β protein precursor (AβPP) resulted in increased levels of secreted AβPP fragments and Aβ, while levels of AβPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AβPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AβPP fragments or Aβ remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Aβ42 levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AβPP processing, but warrant further studies to clarify the underlying mechanisms.

Intracellular Targeting of Heat Shock Proteins in Differentiated Human Neuronal Cells Following Proteotoxic Stress. - Deane, Catherine A S; Brown, Ian R (J Alzheimers Dis, 2018)
HSPA6 (Hsp70B') is an inducible member of the Hsp70 (HSPA) family of heat shock proteins that is present in the human genome and not found in mouse and rat. Hence it is lacking in current animal models of neurodegenerative diseases. To advance knowledge of the little studied HSPA6, differentiated human neuronal SH-SY5Y cells were treated with the proteotoxic stress-inducing agent MG132. A robust induction of HSPA6 was apparent which localized to the periphery of MG132-induced protein aggregates in the neuronal cytoplasm. Components of the protein disaggregation/refolding machine that co-operate with Hsp70 also targeted the periphery of cytoplasmic protein aggregates, including DNAJB1 (Hsp40-1), HSPH1 (Hsp105α), and HSPB1 (Hsp27). These data suggest that HSPA6 is involved in the response of human neuronal cells to proteotoxic stress that is a feature of neurodegenerative diseases which have been characterized as protein misfolding disorders. Constitutively expressed HSPA8 (Hsc70) also localized tothe periphery of cytoplasmic protein aggregates following the treatment of differentiated human neuronal cells with MG132. HSPA8 could provide a rapid response to proteotoxic stress in neuronal cells, circumventing the time required to upregulate inducible Hsps.

Intracranial Transplantation of Pancreatic Islets Attenuates Cognitive and Peripheral Metabolic Dysfunctions in a Rat Model of Sporadic Alzheimer's Disease. - Bloch, Konstantin; Gil-Ad, Irit; Vanichkin, Alexey; Hornfeld, Shay Henry; Taler, Michal; Dar, Shira; Azarov, Dmitry; Vardi, Pnina; Weizman, Abraham (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is often associated with brain insulin resistance and peripheral metabolic dysfunctions. Recently, we developed a model of sporadic AD associated with obesity-related peripheral metabolic abnormalities in Lewis rats using intracerebroventricular administration of streptozotocin (icv-STZ). OBJECTIVE: We aimed to assess the effect of intracranially grafted pancreatic islets on cognitive and peripheral metabolic dysfunctions in the icv-STZ Lewis rats. METHODS: AD-like dementia associated with obesity was induced in inbred Lewis rats using a single icv-STZ. Two months after icv-STZ, syngeneic islets (100 islets per recipient) were implanted in the cranial subarachnoid cavity of icv-STZ rats. Morris water maze and marble burying tests were used for studying cognitive and behavioral functions. Central and peripheral metabolic alterations were assessed by histological and biochemical assays. RESULTS: The icv-STZ induced increases in food intake, body weight, and blood levels of insulin and leptin without alteration of glucose homeostasis. Grafted islets reduced body weight gain, food consumption, peripheral insulin resistance, and hyperleptinemia. Biochemical and histological analysis of the brain revealed viable grafted islets expressing insulin and glucagon. The grafted islets did not affect expression of brain insulin receptors and peripheral glucose homeostasis. Two months after islet transplantation, cognitive and behavioral functioning in transplanted rats were significantly better than the sham-operated icv-STZ rats. No significant differences in the locomotor activity between transplanted and non-transplanted icv-STZ rats were found. CONCLUSIONS: Intracranial islet transplantation attenuates cognitive decline and peripheral metabolic dysfunctions providing a novel therapeutic approach for sporadic AD associated with peripheral metabolic dysfunctions.

Involvement of Activation of Asparaginyl Endopeptidase in Tau Hyperphosphorylation in Repetitive Mild Traumatic Brain Injury. - Hu, Wen; Tung, Yunn Chyn; Zhang, Yanchong; Liu, Fei; Iqbal, Khalid (J Alzheimers Dis, 2018)
Traumatic brain injury (TBI) is an established risk factor for the development of neurodegeneration and dementia late in life. Repetitive mild TBI (r-mTBI) is directly associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder characterized by focal perivascular to widespread Alzheimer-type neurofibrillary pathology of hyperphosphorylated tau. Studies in animal models have shown hyperphosphorylation of tau after TBI. However, the molecular mechanisms by which TBI leads to tau pathology are not understood. In this study, we employed western blots and immunohistochemistry to test, in triple-transgenic mouse model of Alzheimer's disease (3xTg-AD), the effect of r-mTBI on tau hyperphosphorylation and activation of asparaginyl endopeptidase (AEP), a cysteine proteinase which is known to be involved in tau hyperphosphorylation. We found that the level of active AEP was increased and correlated with the level of tau hyperphosphorylation following r-mTBI, and that fimbria showed increased immunoreactivity to phospho-tau. In addition, inhibitor 2 of protein phosphatase 2A (I2PP2A) was translocated from neuronal nucleus to the cytoplasm and colocalized with hyperphosphorylated tau. These data suggest the involvement of AEP-I2PP2A-PP2A-ptau pathway in tau pathology in TBI.

Involvement of the Cingulate Cortex in Anosognosia: A Multimodal Neuroimaging Study in Alzheimer's Disease Patients. - Guerrier, Laura; Le Men, Johanne; Gane, Anaıs; Planton, Mélanie; Salabert, Anne-Sophie; Payoux, Pierre; Dumas, Hervé; Bonneville, Fabrice; Péran, Patrice; Pariente, Jérémie (J Alzheimers Dis, 2018)
BACKGROUND: Anosognosia is a frequent symptom of Alzheimer's disease (AD), but its neural substrates remain in question. OBJECTIVE: In this study, we combined neuroimaging with a neuropsychological evaluation to assess neural substrates of anosognosia. METHODS: We prospectively recruited 30 patients with probable early-stage AD and matched healthy controls. Participants underwent MRI, FDG-PET, and a neuropsychological evaluation that includes an assessment of anosognosia. In the AD group, correlations between the anosognosia score, neuroimaging modalities, and neuropsychological performance were performed. RESULTS: Atrophy and hypometabolism were correlated with the anosognosia score in the left dorsal anterior cingulate cortex. The anosognosia score was also correlated with atrophy of the cerebellar vermis, the left postcentral gyrus, and the right fusiform gyrus. No relation was found between anosognosia and the neuropsychological assessment. DISCUSSION: Structural and metabolic alteration in the dorsal anterior cingulate cortex seems to be associated with a diminution of awareness in patients with early-stage AD.

Iron and Alzheimer's Disease: An Update on Emerging Mechanisms. - Lane, Darius J R; Ayton, Scott; Bush, Ashley I (J Alzheimers Dis, 2018)
Iron is a crucial transition metal for life and is the most abundant transition metal in the brain. However, iron's biological utility as an effective redox cycling metal also endows it with the potential to catalyze production of noxious free radicals. This "Janus-faced" nature of iron demands a tight regulation of cellular its metabolism. This regulation is crucial in the CNS, where iron plays myriad keystone roles in CNS processes, including mitochondrial energy transduction, enzyme catalysis, mitochondrial function, myelination, neurotransmitter anabolism and catabolism. Aberrations in brain iron homeostasis can elevate levels of this redox-active metal, leading to mislocalization of the metal and catastrophic oxidative damage to sensitive cellular and subcellular structures. Iron dyshomeostasis has been strongly linked to the pathogenesis of Alzheimer's disease (AD), as well as other major neurodegenerative diseases. Despite the growing societal burden of AD, no disease-modifying therapy exists, necessitating continued investment into both drug-development and the fundamental science investigating the disease-causing mechanisms. Targeting iron dyshomeostasis in the brain represents a rational approach to treat the underlying disease. Here we provide an update on known and emerging iron-associated mechanisms involved in AD. We conclude with an overview of evidence suggesting that, in addition to apoptosis, neuronal loss in AD involves "ferroptosis", a newly discovered iron- and lipid-peroxidation-dependent form of regulated necrosis. The ferroptosis field is rapidly progressing and may provide key insights for future drug-development with disease-modifying potential in AD.

Joint Assessment of Quantitative 18F-Florbetapir and 18F-FDG Regional Uptake Using Baseline Data from the ADNI. - Ben Bouallègue, Fayçal; Mariano-Goulart, Denis; Payoux, Pierre (J Alzheimers Dis, 2018)
Joint analysis of amyloid and metabolic PET patterns across healthy, mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects was performed using baseline 18F-florbetapir and 18F-FDG PET of 684 subjects from the ADNI (251 normal, 204 stable MCI, 85 AD converters, and 144 AD). Correlation between regional amyloid and metabolic uptake was measured and predictive value of PET profile regarding AD conversion in cognitively impaired subjects was assessed using survival analysis and support vector machine classification (SVM). The highest correlations were found in the temporal cortex, precuneus, and posterior cingulum. With respect to normal controls, amyloid load increase was diffuse and early in MCI subjects, whereas metabolism decrease occurred later and predominated in temporo-parietal, precuneus, and cingulate cortices. Five-year AD conversion rates in cognitively impaired subjects were 5%, 22%, 42%, and 78% in amyloid-/FDG-, amyloid-/FDG+, amyloid+/FDG-, and amyloid+/FDG+ subjects respectively (mean follow-up 37±14 months). Using SVM, the combination of ADAS-cog score, amyloid PET, and FDG PET yielded better performance in predicting AD conversion (77% accuracy; 58% positive predictive value; 88% negative predictive value) than ADAS-cog (72%; 52%; 86%), amyloid PET (72%; 52%; 87%), and FDG PET (67%; 47%; 84%). This study attests the complementary value of amyloid and FDG PET in MCI assessment and the efficiency of combined cognitive, amyloid, and metabolic scores to predict AD conversion.

Kainic Acid Impairs the Memory Behavior of APP23 Mice by Increasing Brain Amyloid Load through a Tumor Necrosis Factor-α-Dependent Mechanism. - Ruan, Yang; Guo, Shi-Jie; Wang, Xu; Dong, Dong; Shen, Dong-Hui; Zhu, Jie; Zheng, Xiang-Yu (J Alzheimers Dis, 2018)
Kainic acid (KA) was recently identified as an epileptogenic and neuroexcitotoxic agent that is responsible for inducing learning and memory deficits in various neurodegenerative diseases, such as Alzheimer's disease (AD). However, the mechanism by which KA acts upon AD remains unclear. To this end, we presently investigated the roles of KA in processing amyloid-β protein precursor (AβPP) and amyloid-β protein (Aβ) loads during the course of AD development and progression. Specifically, KA treatment clearly caused the upregulation of tumor necrosis factor α (TNF-α) via activation of the PI3-K/AKT, ERK1/2, and p65 pathways in glial cells. TNF-α secreted from glial cells was then found to be responsible for stimulating the expression of BACE-1 and PS1/2, which resulted in the production and deposition of Aβ in neurons. Finally, the accumulation and aggregation of Aβ lead to the cognitive decline of APP23 mice. These results indicate that KA accelerates the progression of AD by inducing the crosstalk between glial cells and neurons.

Ketogenic Medium Chain Triglycerides Increase Brain Energy Metabolism in Alzheimer's Disease. - Croteau, Etienne; Castellano, Christian-Alexandre; Richard, Marie Anne; Fortier, Mélanie; Nugent, Scott; Lepage, Martin; Duchesne, Simon; Whittingstall, Kevin; Turcotte, Éric E; Bocti, Christian; Fülöp, Tamás; Cunnane, Stephen C (J Alzheimers Dis, 2018)
BACKGROUND: In Alzheimer's disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement. OBJECTIVE: To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults. METHODS: Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n = 11), followed by a wash-out and then tricaprylin (95%; n = 6). Brain ketone (11C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention. RESULTS: Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization. CONCLUSION: Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved.

Learning Processes and Brain Connectivity in A Cognitive-Motor Task in Neurodegeneration: Evidence from EEG Network Analysis. - Vecchio, Fabrizio; Miraglia, Francesca; Quaranta, Davide; Lacidogna, Giordano; Marra, Camillo; Rossini, Paolo Maria (J Alzheimers Dis, 2018)
Electroencephalographic (EEG) rhythms are linked to any kind of learning and cognitive performance including motor tasks. The brain is a complex network consisting of spatially distributed networks dedicated to different functions including cognitive domains where dynamic interactions of several brain areas play a pivotal role. Brain connectome could be a useful approach not only to mechanisms underlying brain cognitive functions, but also to those supporting different mental states. This goal was approached via a learning task providing the possibility to predict performance and learning along physiological and pathological brain aging. Eighty-six subjects (22 healthy, 47 amnesic mild cognitive impairment, 17 Alzheimer's disease) were recruited reflecting the whole spectrum of normal and abnormal brain connectivity scenarios. EEG recordings were performed at rest, with closed eyes, both before and after the task (Sensory Motor Learning task consisting of a visual rotation paradigm). Brain network properties were described by Small World index (SW), representing a combination of segregation and integration properties. Correlation analyses showed that alpha 2 SW in pre-task significantly predict learning (r  =  -0.2592, p < 0.0342): lower alpha 2 SW (higher possibility to increase during task and better the learning of this task), higher the learning as measured by the number of reached targets. These results suggest that, by means of an innovative analysis applied to a low-cost and widely available techniques (SW applied to EEG), the functional connectome approach as well as conventional biomarkers would be effective methods for monitoring learning progress during training both in normal and abnormal conditions.

Leisure-Time Physical Activity and the Risk of Incident Dementia: The Mayo Clinic Study of Aging. - Krell-Roesch, Janina; Feder, Nathanael T; Roberts, Rosebud O; Mielke, Michelle M; Christianson, Teresa J; Knopman, David S; Petersen, Ronald C; Geda, Yonas E (J Alzheimers Dis, 2018)
We conducted a prospective cohort study derived from the population-based Mayo Clinic Study of Aging. We investigated if leisure-time physical activity among individuals with mild cognitive impairment (MCI) was associated with a decreased risk of developing dementia. 280 persons aged≥70 years (median 81 years, 165 males) with MCI and available data from neurologic evaluation, neuropsychological testing, and questionnaire-based physical activity assessment, were followed for a median of 3 years to the outcomes of incident dementia or censoring variables. We conducted Cox proportional hazards regression analyses with age as a time scale and adjusted for sex, education, medical comorbidity, depression, and APOE ɛ4 status. Moderate intensity midlife physical activity among MCI participants was significantly associated with a decreased risk of incident dementia (HR = 0.64; 95% CI, 0.41-0.98). There was a non-significant trend for a decreased risk of dementia for light and vigorous intensity midlife physical activity, as well as light and moderate intensity late-life physical activity. In conclusion, we observed that physical activity may be associated with a reduced risk of dementia among individuals with MCI. Furthermore, intensity and timing of physical activity may be important factors when investigating this association.

Lentivirus-Mediated HDAC3 Inhibition Attenuates Oxidative Stress in APPswe/PS1dE9 Mice. - Yu, Linjie; Liu, Yi; Jin, Yuexinzi; Cao, Xiang; Chen, Jian; Jin, Jiali; Gu, Yue; Bao, Xinyu; Ren, Zhuoying; Xu, Yun; Zhu, Xiaolei (J Alzheimers Dis, 2018)
Amyloid-β (Aβ) induces a burst of oxidative stress and plays a critical role in the pathogenesis of Alzheimer's disease (AD). Our previous results have shown that histone deacetylase 3 (HDAC3) inhibition ameliorates spatial memory deficits and decreases the Aβ burden in the brains of 9-month-old APPswe/PS1dE9 (APP/PS1) mice. In this study, we investigated the role of HDAC3 inhibition in oxidative stress in vivo and in vitro models of AD. HDAC3 was detected mainly in the neurons, and HDAC3 inhibition significantly decreased reactive oxygen species generation and improved primary cortical neuron viability. In addition, HDAC3 inhibition attenuated spatial memory dysfunction in 6-month-old APP/PS1 mice, and decreased the apoptotic rate in the hippocampi as demonstrated by TUNEL staining. HDAC3 inhibition also reduced markers of lipid peroxidation, protein oxidation, and DNA/RNA oxidation in the hippocampi of APP/PS1 mice. Moreover, HDAC3 inhibition inactivated the c-Abl/MST1/YAP signaling pathway in the hippocampi of APP/PS1 mice. In conclusion, our data show that HDAC3 inhibition can attenuate spatial memory deficits and inhibit oxidative stress in APP/PS1 mice; these results indicate a potential strategy for AD treatment.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Hippocampus; Histone Deacetylases; Lentivirus; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Oxidative Stress; Plaque, Amyloid; Primary Cell Culture; Reactive Oxygen Species; Spatial Memory; tau Proteins

The Level of Plasma Amyloid-β40 Is Correlated with Peripheral Transport Proteins in Cognitively Normal Adults: A Population-Based Cross-Sectional Study. - Gao, Ling; Jiang, Yu; Wei, Shan; Shang, Suhang; Li, Pei; Chen, Chen; Dang, Liangjun; Wang, Jin; Huo, Kang; Deng, Meiying; Wang, Jingyi; Zhang, Rong; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Transport proteins, soluble low-density lipoprotein receptor-related protein-1 (sLRP1), and soluble receptor of advanced glycation end products (sRAGE), play an important role in the clearance of plasma amyloid-β (Aβ). However, their relationship is not clear. OBJECTIVE: The aim was to explore the relationship between plasma levels of sLRP1, sRAGE, and Aβ in a cross-sectional study. METHODS: A total of 1,185 cognitively normal participants (age above 40) from a village in the suburbs of Xi'an, China were enrolled from October 8, 2014 to March 30, 2015. Plasma Aβ40, Aβ42, sLRP1, and sRAGE were tested using a commercial ELISA. Apolipoprotein E (APOE) genotyping was conducted using PCR and sequencing. The relationship between plasma levels of sLRP1, sRAGE, and Aβ was analyzed using Pearson's correlation analysis and multiple linear regression. RESULTS: In the total population, Log sLRP1 and Log sRAGE were positively correlated with plasma Aβ40 (r= 0.103, p < 0.001; r= 0.064, p = 0.027, respectively), but neither were associated with plasma Aβ42. After multivariable adjustment in the regression model, Log sLRP1 and Log sRAGE were still positively related with plasma Aβ40 (β= 2.969, p < 0.001; β= 1.936, p = 0.017, respectively) but not Aβ42. Furthermore, the positive correlations between transport proteins and plasma Aβ40 remained significant only in APOEɛ4 non-carriers after Pearson's analysis and multiple regression analysis after stratification by gene status. CONCLUSION: The concentrations of plasma sLRP1 and sRAGE had a significant impact on the level of plasma Aβ40 in cognitively normal adults, especially in APOEɛ4 non-carriers. However, the mechanism by which the transport proteins are involved in peripheral Aβ clearance and the relationship between transporters and amyloid burden in the brain needs further validation.

Lifetime Risk Factors for Functional and Cognitive Outcomes in Patients with Alzheimer's Disease. - de Oliveira, Fabricio Ferreira; de Almeida, Sandro Soares; Chen, Elizabeth Suchi; Smith, Marilia Cardoso; Naffah-Mazzacoratti, Maria da Graça; Bertolucci, Paulo Henrique Ferreira (J Alzheimers Dis, 2018)
Lifetime risk factors for cognitive and functional decline in Alzheimer's disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from São Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE ε 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE ε 4/ε 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE ε 4. Exclusively for carriers of APOE ε 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration.

A Link between Subjective Perceptions of Memory and Physical Function: Implications for Subjective Cognitive Decline. - Cosentino, Stephanie; Devanand, Davangere; Gurland, Barry (J Alzheimers Dis, 2018)
Subjective impairment in memory is a frequently defining feature of subjective cognitive decline (SCD), a state hypothesized to precede objectively apparent cognitive symptoms of Alzheimer's disease (AD) and to hold promise as a non-invasive, inexpensive, preclinical indicator of AD. However, a full model of the factors that contribute to subjective memory (SM), and therefore to SCD, has yet to be articulated. While SM impairment is widely known to be associated with negative affect, the extent to which SM functioning may also reflect other factors, particularly subjective beliefs or perceptions about one's health, is not known. To examine the extent to which SM is associated with subjective perceptions of health more broadly, the current study investigated the link between SM and subjective physical functioning (independent of depressive affect, and objective cognitive and physical function) in an ethnically diverse sample of 471 older adults enrolled in the population-based Northern Manhattan Aging Project. 199 (42%) participants endorsed no difficulty on a 5-point SM index while 272 (58%) endorsed some degree of difficulty. As hypothesized, SM correlated with both depression and subjective physical function, but not with age, education, global cognition, or objective physical function. When objective and subjective physical function were entered in two separate, adjusted linear regressions predicting SM, only subjective physical function and depressive affect independently predicted SM. Subjective perceptions of memory appear to reflect individuals' broader health perceptions in part. Articulating the various correlates of SM will improve identification of SCD specific to preclinical AD.
Keywords: Aged; Aged, 80 and over; Cognitive Dysfunction; Executive Function; Female; Humans; Linear Models; Male; Memory; Neuropsychological Tests; New York City; Perception

Linking Atrial Fibrillation with Alzheimer's Disease: Epidemiological, Pathological, and Mechanistic Evidence. - Ihara, Masafumi; Washida, Kazuo (J Alzheimers Dis, 2018)
Many studies have shown a relationship between atrial fibrillation (AF) and vascular dementia. AF is a major risk factor for stroke, and stroke is the greatest risk factor for vascular dementia. However, the relationship between Alzheimer's disease (AD), the leading cause of dementia, and AF remains unclear. At least four epidemiological studies have reported AF significantly raises the risk of AD 1.5- to 2.5-fold. Chronic cerebral hypoperfusion, resulting from persistent AF, could explain the link as hypoperfusion may mechanistically exacerbate amyloid-β (Aβ) neuropathology, such as senile plaques and amyloid angiopathy, by upregulating Aβ-producing enzymes and lowering Aβ clearance efficiency. In addition, hypoperfusion may exacerbate tau pathology directly through upregulation of tau-phosphorylating enzymes and indirectly via the amyloid cascade. However, most neuropathological studies do not support the direct link between AD pathology and AF but rather suggests vascular neuropathology is related to, or coexistent with, AF and lowers the threshold for clinically-evident AD. Vascular neuropathology may thus mediate the link between AD and AF. From a treatment perspective, an observational study has shown that catheter ablation is associated with less incidence of AD in AF patients, suggesting rhythm-control suppresses hypoperfusion-induced AD neuropathology. In addition, rate-control may lower the rate of cognitive decline in cognitively impaired elderly subjects with AF. Further studies are warranted to clarify the mechanisms underlying the linkage between AF and AD. However, anticoagulation and rhythm-/rate-control against AF may hold promise even for AD patients.

Lipid Metabolism and Survival Across the Frontotemporal Dementia-Amyotrophic Lateral Sclerosis Spectrum: Relationships to Eating Behavior and Cognition. - Ahmed, Rebekah M; Highton-Williamson, Elizabeth; Caga, Jashelle; Thornton, Nicolette; Ramsey, Eleanor; Zoing, Margaret; Kim, Woojin Scott; Halliday, Glenda M; Piguet, Olivier; Hodges, John R; Farooqi, I Sadaf; Kiernan, Matthew C (J Alzheimers Dis, 2018)
BACKGROUND: Patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behavior that could potentially affect lipid levels. OBJECTIVE: This study aimed to document changes in lipid metabolism across the ALS-FTD spectrum to identify potential relationships to eating behavior (including fat intake), cognitive change, body mass index (BMI), and effect on survival. METHODS: One hundred and twenty-eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioral change (ALS-Plus), 13 ALS-FTD, 31 behavioral variant FTD, and 32 healthy controls. Fasting total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglyceride levels were measured and correlated to eating behavior (caloric, fat intake), cognitive change, and BMI; effect on survival was examined using cox regression analyses. RESULTS: There was a spectrum of lipid changes from ALS to FTD with increased triglyceride (p < 0.001), total cholesterol/HDL ratio (p < 0.001), and lower HDL levels (p = 0.001) in all patient groups compared to controls. While there was no increase in total cholesterol levels, a higher cholesterol level was found to correlate with 3.25 times improved survival (p = 0.008). Triglyceride and HDL cholesterol levels correlated to fat intake, BMI, and measures of cognition and disease duration. CONCLUSION: A spectrum of changes in lipid metabolism has been identified in ALS-FTD, with total cholesterol levels found to potentially impact on survival. These changes were mediated by changes in fat intake, and BMI, and may also be mediated by the neurodegenerative process, offering the potential to modify these factors to slow disease progression and improve survival.
Keywords: Adult; Aged; Amyotrophic Lateral Sclerosis; Australia; Body Mass Index; Case-Control Studies; Cholesterol; Cholesterol, HDL; Cognition; Energy Intake; Feeding Behavior; Female; Frontotemporal Dementia; Humans; Lipid Metabolism; Male; Middle Aged; Neuropsychological Tests; Survival Analysis

A Long Journey into Aging, Brain Aging, and Alzheimer's Disease Following the Oxidative Stress Tracks. - Mecocci, Patrizia; Boccardi, Virginia; Cecchetti, Roberta; Bastiani, Patrizia; Scamosci, Michela; Ruggiero, Carmelinda; Baroni, Marta (J Alzheimers Dis, 2018)
The Editors of the Journal of Alzheimer's Disease invited Professor Patrizia Mecocci to contribute a review article focused on the importance and implications of her research on aging, brain aging, and senile dementias over the last years. This invitation was based on an assessment that she was one of the journal's top authors and a strong supporter of the concept that oxidative stress is a major contributor to several alterations observed in age-related conditions (sarcopenia, osteoporosis) and, more significantly, in brain aging suggesting a pivotal role in the pathogenesis and progression of one of the most dramatic age-related diseases, Alzheimer's disease (AD). Her first pioneering research was on the discovery of high level of 8-hydroxy-2'-deoxyguanosine (OH8dG), a marker of oxidation in nucleic acids, in mitochondrial DNA isolated from cerebral cortex. This molecule increases progressively with aging and more in AD brain, supporting the hypothesis that oxidative stress, a condition of unbalance between the production of reactive oxygen species and antioxidants, gives a strong contribution to the high incidence of AD in old age subjects. OH8dG also increases in peripheral lymphocyte from AD subjects, suggesting that AD is not only a cerebral but also a systemic disease. The role of antioxidants, particularly vitamin E and zinc, were also studied in longevity and in cognitive decline and dementia. This review shows the main findings from Mecocci's laboratory related to oxidative stress in aging, brain aging, and AD and discusses the importance and implications of some of the major achievements in this field of research.
Keywords: Aging; Alzheimer Disease; Animals; Brain; Humans; Oxidative Stress

Longitudinal Changes in Serum Glucose Levels are Associated with Metabolic Changes in Alzheimer's Disease Related Brain Regions. - Burns, Christine M; Kaszniak, Alfred W; Chen, Kewei; Lee, Wendy; Bandy, Daniel J; Caselli, Richard J; Reiman, Eric M (J Alzheimers Dis, 2018)
BACKGROUND: The association between longitudinal changes in serum glucose level and longitudinal changes in [18F] Fluorodeoxyglucose-PET (FDG PET) measurements of Alzheimer's disease (AD) risk are unknown. OBJECTIVE: To investigate whether variation in serum glucose levels across time are associated with changes in FDG PET measurements of cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer's disease (AD). METHODS: Participants are a subset of a prospective cohort study investigating FDG PET, apolipoprotein E (APOE) ɛ4, and risk for AD which includes data from baseline, interim, and follow up visits over 4.4±1.0-years. An automated brain-mapping algorithm was utilized to characterize and compare associations between longitudinal changes in serum glucose levels and longitudinal changes in rCMRgl. RESULTS: This study included 80 adults aged 61.5±5 years, including 38 carriers and 42 non-carriers of the APOE ɛ4 allele. Longitudinal increases in serum glucose levels were associated with longitudinal CMRgl decline in the vicinity of parietotemporal, precuneus/posterior cingulate, and prefrontal brain regions preferentially affected by AD (p < 0.05, corrected for multiple comparisons). Findings remained significant when controlled for APOE ɛ4 status and baseline and advancing age. CONCLUSIONS: Additional studies are needed to clarify and confirm the relationship between longitudinal changes in peripheral glucose and FDG PET measurements of AD risk. Future findings will set the stage on the use of FDG PET in the evaluation of possible interventions that target risk factors for the development of AD.
Keywords: Aged; Alzheimer Disease; Apolipoprotein E4; Blood Glucose; Brain; Brain Mapping; Female; Fluorodeoxyglucose F18; Heterozygote; Humans; Longitudinal Studies; Male; Middle Aged; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals

Longitudinal Modeling of Functional Decline Associated with Pathologic Alzheimer's Disease in Older Persons without Cognitive Impairment. - Wang, Dai; Schultz, Tim; Novak, Gerald P; Baker, Susan; Bennett, David A; Narayan, Vaibhav A (J Alzheimers Dis, 2018)
BACKGROUND: Therapeutic research on Alzheimer's disease (AD) has moved to intercepting the disease at the preclinical phase. Most drugs in late development have focused on the amyloid hypothesis. OBJECTIVE: To understand the magnitude of amyloid-related functional decline and to identify the functional domains sensitive to decline in a preclinical AD population. METHODS: Data were from the Religious Orders Study and the Rush Memory and Aging Project. Cognitive decline was measured by a modified version of the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite. The trajectories of functional decline, as measured by the instrumental and basic activities of daily living, were longitudinally modeled in 484 participants without cognitive impairment at baseline and having both a final clinical and a postmortem neuropathology assessment of AD. RESULTS: Individuals with different final clinical diagnoses had different trajectories of cognitive and functional decline. Individuals with AD dementia, minor cognitive impairment, and no cognitive impairment had the most, intermediate, and least declines. While individuals with pathologic AD had significantly more cognitive decline over time than those without, the magnitude of difference in functional decline between these two groups was small. Functional domains such as handling finance and handling medications were more sensitive to decline. CONCLUSION: Demonstrating the functional benefit of an amyloid-targeting drug represents a significant challenge as elderly people experience functional decline due to a wide range of reasons with limited manifestation attributable to AD neuropathology. More sensitive functional scales focusing on the functional domains sensitive to decline in preclinical AD are needed.

Longitudinal Neuroimaging Analysis in Mild-Moderate Alzheimer's Disease Patients Treated with Plasma Exchange with 5% Human Albumin. - Cuberas-Borrós, Gemma; Roca, Isabel; Boada, Merce; Tárraga, Lluís; Hernandez, Isabel; Buendia, Mar; Rubio, Lourdes; Torres, Gustavo; Bittini, Ángel; Guzmán-de-Villoria, Juan A; Pujadas, Francesc; Torres, Mireia; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Recently, modifications of Aβ1-42 levels in CSF and plasma associated with improvement in memory and language functions have been observed in patients with mild-moderate Alzheimer's disease (AD) treated with plasma exchange (PE) with albumin replacement. OBJECTIVE: To detect structural and functional brain changes in PE-treated AD patients as part of a Phase II clinical trial. METHODS: Patients received between 3 and 18 PE with albumin (Albutein® 5%, Grifols) or sham-PE (controls) for 21 weeks (divided in one intensive and two maintenance periods) followed by 6-month follow-up. Brain perfusion assessed by SPECT scans using an automated software (NeuroGam®) and brain structural changes assessed by MRI were performed at weeks 0 (baseline), 21, and 44 (with additional SPECT at weeks 9 and 33). Statistical parametric mapping (voxel-based analysis, SPM) and Z-scores calculations were applied to investigate changes to baseline. RESULTS: 42 patients were recruited (39 evaluable; 37 analyzed: 18 PE-treated; 19 controls). There was a trend toward decreasing hippocampi and total intracranial volume for both patient groups during the study (p < 0.05). After six months, PE-treated patients had less cerebral perfusion loss than controls in frontal, temporal, and parietal areas, and perfusion stabilization in Brodmann area BA38-R during the PE-treatment period (p < 0.05). SPM analysis showed stabilization or absence of progression of perfusion loss in PE-treated patients until week 21, not observed in controls. CONCLUSIONS: Mild-moderate AD patients showed decreased brain volume and impairment of brain perfusion as expected for the progression of the disease. PE-treatment with albumin replacement favored the stabilization of perfusion.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Plasma Exchange; Serum Albumin, Human; Time Factors; Tomography, Emission-Computed, Single-Photon; Treatment Outcome

A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment. - Wang, Hua; Stewart, Tessandra; Toledo, Jon B; Ginghina, Carmen; Tang, Lu; Atik, Anzari; Aro, Patrick; Shaw, Leslie M; Trojanowski, John Q; Galasko, Douglas R; Edland, Steven; Jensen, Poul H; et al. (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson's disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ42), tau, and phosphorylated tau (p-tau181)] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer's Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total α-synuclein, pS129, Aβ42, tau, and p-tau181. pS129, but not total α-synuclein, was weakly associated with diagnosis at baseline when t-tau/Aβ42 was included in the statistical model (β= 0.0026, p = 0.041, 95% CI [(0.0001)-(0.005)]). CSF α-synuclein predicted Alzheimer's Disease Assessment Scale-Cognitive (β= -0.59, p = 0.0015, 95% CI [(-0.96)-(-0.23)]), memory (β= 0.4, p = 0.00025, 95% CI [(0.16)-(0.59)]), and executive (0.62,<0.0001, 95% CI [(0.31)-(0.93)]) function composite scores, and progression from MCI to AD (β= 0.019, p = 0.0011, 95% CI [(0.002)-(0.20)]). pS129 was associated with executive function (β= -2.55, p = 0.0085, 95% CI [(-4.45)-(-0.66)]). Lower values in the mismatch between α-synuclein and p-tau181 predicted faster cognitive decline (β= 0.64, p = 0.0012, 95% CI [(0.48)-(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The α-synuclein-p-tau181-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.
Keywords: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Disease Progression; Executive Function; Female; Humans; Linear Models; Longitudinal Studies; Male; Memory Disorders; Multivariate Analysis; Neuropsychological Tests; Phosphorylation; tau Proteins

Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study. - Salloway, Stephen P; Sperling, Reisa; Fox, Nick C; Sabbagh, Marwan N; Honig, Lawrence S; Porsteinsson, Anton P; Rofael, Hany; Ketter, Nzeera; Wang, Daniel; Liu, Enchi; Carr, Stephen; Black, Ronald S; et al. (J Alzheimers Dis, 2018)
BACKGROUND: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized. OBJECTIVES: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. METHODS: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies. RESULTS: A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. CONCLUSIONS: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

Long-Term Severe Mental Disorders Preceding Behavioral Variant Frontotemporal Dementia: Frequency and Clinical Correlates in an Outpatient Sample. - Gambogi, Leandro Boson; Guimarães, Henrique Cerqueira; de Souza, Leonardo Cruz; Caramelli, Paulo (J Alzheimers Dis, 2018)
BACKGROUND: The behavioral variant frontotemporal dementia (bvFTD) shares some clinical features with severe mental disorders, such as bipolar affective disorder (BAD), schizophrenia (SCZ), and schizoaffective disorder (SZA), and at least for a small subgroup of patients, these conditions may share similar pathological genetic mutations. OBJECTIVES: To investigate the frequency of a past medical history satisfying diagnostic criteria for BAD, SCZ, and SZA in a bvFTD outpatient sample, and to compare the clinical profile of patients with and without a positive history. METHODS: Cross-sectional study in which participants were consecutively selected after receiving a diagnosis of probable bvFTD and had a caregiver interviewed with SCID-I. The sample was categorized into two groups: with (bvFTD+) or without (bvFTD-) prior medical history satisfying diagnostic criteria for BAD/SCZ/SZA. Subjects went through cognitive, functional, and neuropsychiatric evaluations. RESULTS: Overall, 46 bvFTD patients were included; bvFTD+ patients accounted for 36.9% of the sample. The main nosology fulfilling criteria was BAD (76.5%). The groups differed in Neuropsychiatric Inventory scores (p = 0.01), use of antipsychotics (p = 0.01), family history of psychosis (p = 0.01), presence of primitive reflexes (p = 0.04), Frontal Assessment Battery performance (p = 0.01), Ekman's facial emotion recognition test (p = 0.03), frequency of apathy (p = 0.03), and stereotyped behavior (p = 0.01). All these parameters were more frequent/worse in the bvFTD+ group. CONCLUSIONS: A prior medical history compatible with BAD/SCZ/SZA was found in more than 1/3 of this sample of bvFTD patients and was associated with subtle distinctive clinical features.

Loss in PKC Epsilon Causes Downregulation of MnSOD and BDNF Expression in Neurons of Alzheimer's Disease Hippocampus. - Sen, Abhik; Nelson, Thomas J; Alkon, Daniel L; Hongpaisan, Jarin (J Alzheimers Dis, 2018)
Oxidative stress and amyloid-β (Aβ) oligomers have been implicated in Alzheimer's disease (AD). The growth and maintenance of neuronal networks are influenced by brain derived neurotrophic factor (BDNF) expression, which is promoted by protein kinase C epsilon (PKCɛ). We investigated the reciprocal interaction among oxidative stress, Aβ, and PKCɛ levels and subsequent PKCɛ-dependent MnSOD and BDNF expression in hippocampal pyramidal neurons. Reduced levels of PKCɛ, MnSOD, and BDNF and an increased level of Aβ were also found in hippocampal neurons from autopsy-confirmed AD patients. In cultured human primary hippocampal neurons, spherical aggregation of Aβ (amylospheroids) decreased PKCɛ and MnSOD. Treatment with t-butyl hydroperoxide (TBHP) increased superoxide, the oxidative DNA/RNA damage marker, 8-OHG, and Aβ levels, but reduced PKCɛ, MnSOD, BDNF, and cultured neuron density. These changes were reversed with the PKCɛ activators, bryostatin and DCPLA-ME. PKCɛ knockdown suppressed PKCɛ, MnSOD, and BDNF but increased Aβ. In cultured neurons, the increase in reactive oxygen species (ROS) associated with reduced PKCɛ during neurodegeneration was inhibited by the SOD mimetic MnTMPyP and the ROS scavenger NAc, indicating that strong oxidative stress suppresses PKCɛ level. Reduction of PKCɛ and MnSOD was prevented with the PKCɛ activator bryostatin in 5-6-month-old Tg2576 AD transgenic mice. In conclusion, oxidative stress and Aβ decrease PKCɛ expression. Reciprocally, a depression of PKCɛ reduces BDNF and MnSOD, resulting in oxidative stress. These changes can be prevented with the PKCɛ-specific activators.

Lost in Translation? Finding Our Way To Effective Alzheimer's Disease Therapies. - Quinn, Joseph F (J Alzheimers Dis, 2018)
Efforts over the past two decades to develop effective disease-modifying treatments for Alzheimer's disease have been disappointing, while parallel efforts in another chronic neurologic disease, multiple sclerosis, have been remarkably productive. In an effort to advance development of therapeutics for Alzheimer's disease, these two fields are contrasted in terms of the utility of animal models, definition of study populations, and utility of biomarkers. Possible solutions are suggested, and the review concludes with description of some active peer-reviewed, publicly funded clinical studies which address some of the identified weaknesses in past clinical trials for age-related dementia.

Low Accuracy of Brief Cognitive Tests in Tracking Longitudinal Cognitive Decline in an Asian Elderly Cohort. - Phua, April Ka Sin; Hiu, Shaun Kuan Wei; Goh, Win King; Ikram, Mohammad Kamran; Venketasubramanian, Narayanaswamy; Tan, Boon Yeow; Chen, Christopher Li-Hsian; Xu, Xin (J Alzheimers Dis, 2018)
BACKGROUND: Researchers have questioned the utility of brief cognitive tests such as the Mini-Mental Status Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in serial administration and suggested that brief cognitive tests may not accurately track changes in Global Cognition. OBJECTIVE: To examine the accuracy of longitudinal changes on brief cognitive tests in reflecting progression in Global Cognition measured using comprehensive neuropsychological assessments. METHODS: Two hundred and seven participants were assessed with the MMSE, MoCA, and a validated comprehensive neuropsychological battery. Global z-scores on the battery were derived and used to assess overall and significant (≥0.5 standard deviation) decline on Global Cognition. Different patterns of decline on MMSE/MoCA were classified. Accuracy was examined using receiver operating characteristic curve, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were reported. RESULTS: The overall ability of MMSE/MoCA change scores to discriminate participants who did and did not decline on Global Cognition was fair-to-moderate (AUC [95% CI] = 0.71 [0.64-0.78] & 0.73 [0.66-0.80] for overall decline; 0.78 [0.70-0.85] & 0.80 [0.73-0.86] for significant decline, respectively). Changes in MMSE/MoCA had low accuracy in identifying significant Global Cognitive Decline (PPV = 0.41 & 0.46, respectively) but high accuracy in ruling out significant decline and identifying cognitively stable participants (NPV = 0.89 & 0.88, respectively). CONCLUSION: There is limited utility in brief cognitive tests for tracking cognitive decline. Instead, they should be used for identifying participants who remain cognitively stable on follow up. These results accentuate the importance of acknowledging the limitations of brief cognitive tests when assessing cognitive change.

Low Cerebrospinal Fluid Aβ42 and Aβ40 are Related to White Matter Lesions in Cognitively Normal Elderly. - Skoog, Ingmar; Kern, Silke; Zetterberg, Henrik; Östling, Svante; Börjesson-Hanson, Anne; Guo, Xinxin; Blennow, Kaj (J Alzheimers Dis, 2018)
BACKGROUND: Low cerebrospinal fluid (CSF) levels of Aβ42 may be the earliest manifestation of Alzheimer's disease (AD). Knowledge on how CSF Aβ interacts with different brain pathologies early in the disease process is limited. We examined how CSF Aβ markers relate to brain atrophy and white matter lesions (WMLs) in octogenarians with and without dementia to explore the earliest pathogenetic pathways of AD in the oldest old. OBJECTIVE: To study CSF amyloid biomarkers in relation to brain atrophy and WMLs in 85-year-olds with and without dementia. METHODS: 53 octogenarians took part in neuropsychiatric examinations and underwent both a lumbar puncture and a brain CT scan. CSF levels of Aβ42 and Aβ40 were examined in relation to cerebral atrophy and WMLs. Dementia was diagnosed. RESULTS: In 85-year-olds without dementia, lower levels of both CSF Aβ42 and CSF Aβ40 were associated with WMLs. CSF Aβ42 also correlated with measures of central atrophy, but not with cortical atrophy. In participants with dementia, lower CSF levels of Aβ42 were related to frontal, temporal, and parietal cortical atrophy but not to WMLs. CONCLUSIONS: Our findings may suggest that there is an interrelationship between Aβ and subcortical WMLs in older persons without dementia. After onset of dementia, low CSF Aβ42, probably representing amyloid deposition in plaques, is associated with cortical atrophy. WMLs may be an earlier manifestation of Aβ deposition than cortical degeneration.

Low Prevalence of Cancer in Patients with Frontotemporal Lobar Degeneration. - Katisko, Kasper; Haapasalo, Annakaisa; Koivisto, Anne; Krüger, Johanna; Hartikainen, Päivi; Korhonen, Ville; Helisalmi, Seppo; Herukka, Sanna-Kaisa; Remes, Anne M; Solje, Eino (J Alzheimers Dis, 2018)
Several studies have reported reduced risk of cancer in patients with Alzheimer's disease (AD) or Parkinson's disease. The relationship between cancer and frontotemporal lobar degeneration (FTLD) has not been previously reported. Here, our aim was to evaluate the occurrence of cancer in Finnish FTLD patients with a high proportion of C9ORF72 repeat expansion carriers in comparison to age- and sex-matched group of AD patients and control subjects classified as not cognitively impaired (NCI). The prevalence of cancer was 9.7% in FTLD, 18.7% in AD, and 17.4% in NCI (FTLD versus AD p = 0.012, FTLD versus NCI p = 0.029) groups. No differences were observed between C9ORF72 repeat expansion carriers and non-carriers inside the FTLD group. To our knowledge, this is the first study showing significantly lower prevalence of cancer in FTLD patients compared to patients with AD or NCI subjects. Our data suggest an inverse association between neurodegeneration and cancer and that FTLD-specific mechanisms may underlie the especially strong inverse association observed in this study.
Keywords: Aged; Alzheimer Disease; C9orf72 Protein; DNA Repeat Expansion; Female; Finland; Frontotemporal Lobar Degeneration; Heterozygote; Humans; Male; Middle Aged; Neoplasms; Prevalence

Lower Serum Antibodies Against Tau Protein and Heavy Neurofilament in Alzheimer's Disease. - Bartos, Ales; Fialová, Lenka; Švarcová, Jana (J Alzheimers Dis, 2018)
BACKGROUND: Unlike antibodies against amyloid-β, little is known about serum antibodies to neuron-specific cytoskeletal proteins in patients with Alzheimer's disease (AD). OBJECTIVE: We aimed to study IgG autoantibodies against tau protein, light (NFL) and heavy subunits (NFH) of neurofilaments in serum of AD patients and elderly controls and to explore the evolution of antineurocytoskeletal antibody levels over time. METHODS: Antibodies against three targets (tau, NFL, and NFH) were measured using ELISA in 100 serum samples from 51 cognitively normal elderly controls and 49 patients with AD. Our primary cross-sectional design was further extended to monitor fluctuations over 1-2 years in a subset of individuals. RESULTS: The AD patients had lower levels of anti-tau antibodies (p = 0.03) and even lower anti-NFH antibodies (p = 0.005) than those in the control group at baseline. On the contrary, anti-NFL antibodies or total IgG concentrations in serum did not differ. All three antibodies remained stable in both groups except for a selective and significant anti-tau decline in AD patients (p = 0.03). CONCLUSIONS: The different responses to these antigens suggest some antibody selectivity in AD. The significant decline was observed for only serum anti-tau antibodies in AD patients over time and it corresponds to lower anti-tau levels in these patients. Our findings indicate a special feature of disease-relevant antigens and humoral autoimmunity in AD.

Mapping the Proxies of Memory and Learning Function in Senior Adults with High-performing, Normal Aging and Neurocognitive Disorders. - Lu, Hanna; Ni, Xi; Fung, Ada W T; Lam, Linda C W (J Alzheimers Dis, 2018)
BACKGROUND: Memory and learning, as the core brain function, shows controversial results across studies focusing on aging and dementia. One of the reasons is because of the multi-faceted nature of memory and learning. However, there is still a dearth of comparable proxies with psychometric and morphometric portrait in clinical and non-clinical populations. OBJECTIVE: We aim to investigate the proxies of memory and learning function with direct and derived measures and examine their associations with morphometric features in senior adults with different cognitive status. METHODS: Based on two modality-driven tests, we assessed the component-specific memory and learning in the individuals with high performing (HP), normal aging, and neurocognitive disorders (NCD) (n = 488). Structural magnetic resonance imaging was used to measure the regional cortical thickness with surface-based morphometry analysis in a subsample (n = 52). METHODS: Compared with HP elderly, the ones with normal aging and minor NCD showed declined recognition memory and working memory, whereas had better learning performance (derived scores). Meanwhile, major NCD patients showed more breakdowns of memory and learning function. The correlation between proxies of memory and learning and cortical thickness exhibited the overlapped and unique neural underpinnings. CONCLUSIONS: The proxies of memory and learning could be characterized by component-specific constructs with psychometric and morphometric bases. Overall, the constructs of memory are more likely related to the pathological changes, and the constructs of learning tend to reflect the cognitive abilities of compensation.

Mechanism of Tau Hyperphosphorylation Involving Lysosomal Enzyme Asparagine Endopeptidase in a Mouse Model of Brain Ischemia. - Basurto-Islas, Gustavo; Gu, Jin-Hua; Tung, Yunn Chyn; Liu, Fei; Iqbal, Khalid (J Alzheimers Dis, 2018)
Dementias including Alzheimer's disease (AD) are multifactorial disorders that involve several different etiopathogenic mechanisms. Cerebral ischemia has been suspected in the altered regulation of protein kinases and phosphatases that leads to hyperphosphorylation of tau and further neurofibrillary pathology, a key hallmark of AD and related neurodegenerative diseases. However, the deregulation of these enzymes and their relationship with ischemia and AD remain unclear. Previously, we reported a mechanism by which the lysosomal enzyme asparagine endopeptidase (AEP) is associated with brain acidosis and AD. In this study, we subjected mice to middle cerebral artery occlusion and found that compared with wild type mice, the ischemia-induced brain injury and motor deficit in AEP-knockout mice are reduced, probably because ischemia activates AEP. AEP cleaves inhibitor 2 of protein phosphatase 2A (I2PP2A), which translocates from the neuronal nucleus to the cytoplasm and produces hyperphosphorylation of tau through inhibition of PP2A. These findings suggest a possible mechanism of tau pathology associated with ischemia.

Medical and Research Consent Decision-Making Capacity in Patients with Alzheimer's Disease: A Systematic Review. - van Duinkerken, Eelco; Farme, Juliana; Landeira-Fernandez, Jesus; Dourado, Marcia C; Laks, Jerson; Mograbi, Daniel C (J Alzheimers Dis, 2018)
The capacity to make decisions is an important feature of daily living, which is closely linked to proper cognitive functioning. In conditions in which cognitive functioning becomes compromised, such as in Alzheimer's disease (AD), decision-making capacity can also get affected. Especially in AD, this has important implications, since over the course of the condition many important clinical decisions have to be made. For caregivers as well as physicians, it is sometimes difficult to determine how and when to intervene in the decision-making process. The aim of this systematic literature review was to identify studies that have evaluated medical and research consent decision-making capacity in patients with AD. Studies consistently show that decision-making capabilities are impaired in patients with AD. The cognitive and neuronal correlates of this process are, however, poorly studied. The few studies that investigated correlations have shown worse cognitive performance, mainly on the MMSE, to be related to poorer decision-making capacity. As most of these correlations have been performed in groups combining patients and controls, it remains unknown if these associations are disease specific. There is a need to study more systematically the decision-making process in relation to cognitive functioning and neural correlates to be able to develop a framework of decision-making capacity in AD, ultimately aiding clinicians and caregivers to understand and evaluate those capabilities in patients.

Medical Comorbidity in Alzheimer's Disease: A Nested Case-Control Study. - Wang, Jen-Hung; Wu, Ya-Ju; Tee, Boon Lead; Lo, Raymond Y (J Alzheimers Dis, 2018)
BACKGROUND: Little is known about the distribution of medical comorbidities in Alzheimer's disease (AD). OBJECTIVE: We aimed to describe the comorbidity pattern of AD in a nested case-control study. METHODS: Incident AD cases were identified by International Classification of Diseases codes in a random sample of 2 million individuals in Taiwan National Health Insurance program during 2001-2011. We further restricted cases to those treated with AD drugs of approved reimbursement. We sampled a set of age- and sex-matched control subjects (2:1 ratio) and employed conditional logistic regression to estimate the associations between pre-specified 14 comorbidities and AD. The clusters of multiple chronic diseases were then identified by exploratory factor analysis. RESULTS: A total of 2,618 AD cases were identified during 2001-2011 with a mean age of 76.1 years and female preponderance (59%). The most common 5 comorbidities in AD were hypertension (55.1%), osteoarthritis (38.2%), depression (32.3%), diabetes mellitus (DM) (25.7%), and cerebrovascular disease (CVD) (22.7%). After adjusting for age and sex, DM, osteoporosis, depression, and CVD were significantly associated with AD. The number of comorbidity was 3-fold greater in the AD group. The cluster of hypertension, DM, and hyperlipidemia was the most common combination in old age, whereas the cluster osteoarthritis and osteoporosis was the only multimorbidity pattern significantly associated with AD. CONCLUSION: Multimorbidity is common in AD. Depression, CVD, osteoporosis, and DM are associated with incident AD, supporting that their co-existence is a typical feature of AD at old age. Comorbidity care should be integrated into current management for patients with AD.

Mediterranean Diet, Its Components, and Amyloid Imaging Biomarkers. - Vassilaki, Maria; Aakre, Jeremiah A; Syrjanen, Jeremy A; Mielke, Michelle M; Geda, Yonas E; Kremers, Walter K; Machulda, Mary M; Alhurani, Rabe E; Staubo, Sara C; Knopman, David S; Petersen, Ronald C; Lowe, Val J; et al. (J Alzheimers Dis, 2018)
BACKGROUND: There is accumulating evidence suggesting that diet may play a role in preventing or delaying cognitive decline and dementia, but the underlying biological mechanisms are not well understood. OBJECTIVES: To examine the cross-sectional associations of the Mediterranean diet (MeDi) and its components with 11C-PiB-PET scan measures of amyloid-β (Aβ) deposition. METHODS: The study consisted of 278 Mayo Clinic Study of Aging participants 70+ years old, who were cognitively unimpaired (CU) at the time of completion of the Food Frequency Questionnaire (FFQ) and when they underwent PET imaging. Adherence to the MeDi was assessed by computing the MeDi score for each participant. All scans were performed after the FFQ completion; median [IQR] time between FFQ and Aβ PET was 3.5 (1.4) years. Z-scores were created for component, macro- and micronutrients measured. Linear and logistic regression models were adjusted for age, sex, education, apolipoprotein E (APOE) ɛ4 allele carrier status, time interval between the FFQ completion and PET scan, and total energy intake. RESULTS: Participants' median age at FFQ was 77.7 years (55.8% men; 26.6% with an APOE ɛ4 allele). Higher MeDi score (linear regression slope (beta):-0.035, p = 0.012; per standard deviation increase), vegetable intake (beta:-0.043, p = 0.002), intake of vitamin A (beta:-0.041, p = 0.003) or β-carotene (beta: -0.039, p = 0.005) from food sources and moderate alcohol consumption (beta: -0.074, p = 0.03) were associated with lower 11C-PiB standardized uptake value ratio. CONCLUSION: Findings are consistent with previous studies suggesting that higher adherence to a MeDi pattern and higher vegetable consumption are associated with better neuroimaging biomarker profile. Prospective studies are needed to validate current findings.

Melatonin in Synaptic Impairments of Alzheimer's Disease. - Shi, Yan; Fang, Ying-Yan; Wei, Yu-Ping; Jiang, Qian; Zeng, Peng; Tang, Na; Lu, Youming; Tian, Qing (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) underlies dementia for millions of people worldwide with no effective treatment. The dementia of AD is thought stem from the impairments of the synapses because of their critical roles in cognition. Melatonin is a neurohormone mainly released by the pineal gland in a circadian manner and it regulates brain functions in various manners. It is reported that both the melatonin deficit and synaptic impairments are present in the very early stage of AD and strongly contribute to the progress of AD. In the mammalian brains, the effects of melatonin are mainly relayed by two of its receptors, melatonin receptor type 1a (MT1) and 1b (MT2). To have a clear idea on the roles of melatonin in synaptic impairments of AD, this review discussed the actions of melatonin and its receptors in the stabilization of synapses, modulation of long-term potentiation, as well as their contributions in the transmissions of glutamatergic, GABAergic and dopaminergic synapses, which are the three main types of synapses relevant to the synaptic strength. The synaptic protective roles of melatonin in AD treatment were also summarized. Regarding its protective roles against amyloid-β neurotoxicity, tau hyperphosphorylation, oxygenation, inflammation as well as synaptic dysfunctions, melatonin may be an ideal therapeutic agent against AD at early stage.

Memantine for the Treatment of Dementia: A Review on its Current and Future Applications. - Folch, Jaume; Busquets, Oriol; Ettcheto, Miren; Sánchez-López, Elena; Castro-Torres, Ruben Dario; Verdaguer, Ester; Garcia, Maria Luisa; Olloquequi, Jordi; Casadesus, Gemma; Beas-Zarate, Carlos; Pelegri, Carme; Vilaplana, Jordi; et al. (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.

Memory Binding Test Predicts Incident Dementia: Results from the Einstein Aging Study. - Mowrey, Wenzhu B; Lipton, Richard B; Katz, Mindy J; Ramratan, Wendy S; Loewenstein, David A; Zimmerman, Molly E; Buschke, Herman (J Alzheimers Dis, 2018)
BACKGROUND: The Memory Binding Test (MBT) demonstrated good cross-sectional discriminative validity and predicted incident aMCI. OBJECTIVE: To assess whether the MBT predicts incident dementia better than a conventional list learning test in a longitudinal community-based study. METHODS: As a sub-study in the Einstein Aging Study, 309 participants age≥70 initially free of dementia were administered the MBT and followed annually for incident dementia for up to 13 years. Based on previous work, poor memory binding was defined using an optimal empirical cut-score of≤17 on the binding measure of the MBT, Total Items in the Paired condition (TIP). Cox proportional hazards models were used to assess predictive validity adjusting for covariates. We compared the predictive validity of MBT TIP to that of the free and cued selective reminding test free recall score (FCSRT-FR; cut-score:≤24) and the single list recall measure of the MBT, Cued Recalled from List 1 (CR-L1; cut-score:≤12). RESULTS: Thirty-five of 309 participants developed incident dementia. When assessing each test alone, the hazard ratio (HR) for dementia was significant for MBT TIP (HR = 8.58, 95% CI: (3.58, 20.58), p < 0.0001), FCSRT-FR (HR = 4.19, 95% CI: (1.94, 9.04), p = 0.0003) and MBT CR-L1 (HR = 2.91, 95% CI: (1.37, 6.18), p = 0.006). MBT TIP remained a significant predictor of dementia (p = 0.0002) when adjusting for FCSRT-FR or CR-L1. CONCLUSIONS: Older adults with poor memory binding as measured by the MBT TIP were at increased risk for incident dementia. This measure outperforms conventional episodic memory measures of free and cued recall, supporting the memory binding hypothesis.

Memory Loss and the Onset of Alzheimer's Disease Could Be Under the Control of Extracellular Heat Shock Proteins. - Arispe, Nelson; De Maio, Antonio (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a major contemporary and escalating malady in which amyloid-β (Aβ) peptides are the most likely causative agent. Aβ peptides spontaneously tend to aggregate in extracellular fluids following a progression from a monomeric state, through intermediate forms, ending in amyloid fibers and plaques. It is generally accepted now that the neurotoxic agents leading to cellular death, memory loss, and other AD characteristics are the Aβ intermediate aggregated states. However, Aβ peptides are continuously produced, released into the extracellular space, and rapidly cleared from healthy brains. Coincidentally, members of the heat shock proteins (hsp) family are present in the extracellular medium of healthy cells and body fluids, opening the possibility that hsps and Aβ could meet and interact in the extracellular milieu of the brain. In this perspective and reflection article, we place our investigation showing that the presence of Hsp70s mitigate the formation of low molecular weight Aβ peptide oligomers resulting in a reduction of cellular toxicity, in context of the current understanding of the disease. We propose that it may be an inverse relationship between the presence of Hsp70, the stage of Aβ oligomers, neurotoxicity, and the incidence of AD, particularly since the expression and circulating levels of hsp decrease with aging. Combining these observations, we propose that changes in the dynamics of Hsp70s and Aβ concentrations in the circulating brain fluids during aging defines the control of the formation of Aβ toxic aggregates, thus determining the conditions for neuron degeneration and the incidence of AD.

Mental States in Moving Shapes: Distinct Cortical and Subcortical Contributions to Theory of Mind Impairments in Dementia. - Synn, Artemis; Mothakunnel, Annu; Kumfor, Fiona; Chen, Yu; Piguet, Olivier; Hodges, John R; Irish, Muireann (J Alzheimers Dis, 2018)
Impaired capacity for Theory of Mind (ToM) represents one of the hallmark features of the behavioral variant of frontotemporal dementia (bvFTD) and is suggested to underpin an array of socioemotional disturbances characteristic of this disorder. In contrast, while social processing typically remains intact in Alzheimer's disease (AD), the cognitive loading of socioemotional tasks may adversely impact mentalizing performance in AD. Here, we employed the Frith-Happé animations as a dynamic on-line assessment of mentalizing capacity with reduced incidental task demands in 18 bvFTD, 18 AD, and 25 age-matched Controls. Participants viewed silent animations in which geometric shapes interact in Random, Goal-Directed, and ToM conditions. An exclusive deficit in ToM classification was observed in bvFTD relative to Controls, while AD patients were impaired in the accurate classification of both Random and ToM trials. Correlation analyses revealed robust associations between ToM deficits and carer ratings of affective empathy disruption in bvFTD, and with episodic memory dysfunction in AD. Voxel-based morphometry analyses further identified dissociable neural correlates contingent on patient group. A distributed network of medial prefrontal, frontoinsular, striatal, lateral temporal, and parietal regions were implicated in the bvFTD group, whereas the right hippocampus correlated with task performance in AD. Notably, subregions of the cerebellum, including lobules I-IV and V, bilaterally were implicated in task performance irrespective of patient group. Our findings reveal new insights into the mechanisms potentially mediating ToM disruption in dementia syndromes, and suggest that the cerebellum may play a more prominent role in social cognition than previously appreciated.
Keywords: Aged; Alzheimer Disease; Brain; Case-Control Studies; Female; Frontotemporal Dementia; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Memory, Episodic; Mentalization; Middle Aged; Neuropsychological Tests; Task Performance and Analysis; Theory of Mind

Mesenchymal Stem Cell-Derived Extracellular Vesicles Suppresses iNOS Expression and Ameliorates Neural Impairment in Alzheimer's Disease Mice. - Wang, Shan-Shan; Jia, Jianjun; Wang, Zhenfu (J Alzheimers Dis, 2018)
BACKGROUND: Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been reported to exhibit therapeutic effects in various animal models of neurological diseases, such as stroke and hypoxic-ischemic brain injury. OBJECTIVE: The present study investigated the potential beneficial effect of MSC-derived EVs in an animal model of Alzheimer's disease (AD). METHODS: APP/PS1 mice and their non-transgenic littermates (WT) received intracerebroventricle injection of MSC-derived EVs once per two days for two weeks. Then novel object recognition and water maze tasks were carried out to measure the cognitive behaviors. Electrophysiological tests were carried out to measure hippocampal synaptic plasticity. Inducible nitric oxide synthase (iNOS) mRNA and protein levels were measured by qRT-PCR and western blotting in primary cultured neurons treated with amyloid-β peptide (Aβ) or prepared from APP/PS1 mice. RESULTS: Treatment with MSC-derived EVs alleviates exogenous Aβ-induced iNOS mRNA and protein expression. In cultured primary neurons prepared from APP/PS1 pups, iNOS mRNA and protein levels were significantly reduced when treated with MSC-derived EVs. MSC-derived EVs improved cognitive behavior, rescued impairment of CA1 synaptic transmission, and long-term potentiation in APP/PS1 mice. CONCLUSION: MSC-derived EVs possessed beneficial effects in a mouse model of AD, probably by suppressing Aβ induced iNOS expression.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cells, Cultured; Disease Models, Animal; Extracellular Vesicles; Humans; Male; Mesenchymal Stem Cells; Mice; Mice, Transgenic; Neuronal Plasticity; Neurons; Nitric Oxide Synthase Type II; Synaptic Transmission

Meta-Analysis of Personality Traits in Alzheimer's Disease: A Comparison with Healthy Subjects. - D'Iorio, Alfonsina; Garramone, Federica; Piscopo, Fausta; Baiano, Chiara; Raimo, Simona; Santangelo, Gabriella (J Alzheimers Dis, 2018)
BACKGROUND: The role of specific personality traits as factor risks of Alzheimer's disease (AD) has been consistently found, whereas personality traits specifically related to AD (after the diagnosis) have not been outlined yet. OBJECTIVE: A meta-analysis of published studies was performed to determine whether AD patients have a distinctive personality trait profile compared to healthy subjects (HC), similar to or different from a premorbid personality profile consistently reported in previous studies. METHODS: A systematic literature search was performed using PsycInfo (PROQUEST), PubMed, and Scopus. The meta-analysis pooled results from primary studies using Hedges' g unbiased approach. RESULTS: The meta-analysis included 10 primary studies and revealed that, when the personality was evaluated by informant-rated measures, AD patients had significantly higher levels of Neuroticism, lower levels of Openness, Agreeableness, Conscientiousness, and Extraversion than HCs. When the personality was evaluated by self-rated measures, the results obtained from informants were confirmed for Neuroticism, Openness, and Extraversion but not for Agreeableness and Conscientiousness where AD patients and HCs achieved similar scores. CONCLUSIONS: The meta-analysis revealed that high Neuroticism and low Openness and Extraversion are distinctive personality traits significantly associated with a diagnosis of AD when evaluated both self-rated and informant-rated measures. This personality trait profile is similar to premorbid one, which contributes to development of AD over time. Therefore, our findings indirectly support the idea of specific premorbid personality traits as harbingers of AD.
Keywords: Alzheimer Disease; Case-Control Studies; Humans; Personality; Personality Inventory

Meta-Analysis of the Association between Variants in ABCA7 and Alzheimer's Disease. - Ma, Fang-Chen; Wang, Hui-Fu; Cao, Xi-Peng; Tan, Chen-Chen; Tan, Lan; Yu, Jin-Tai (J Alzheimers Dis, 2018)
The ATP-binding cassette transporter A7 (ABCA7) was identified as a known risk factor for Alzheimer's disease (AD). However, the relation between ABCA7 and AD was still inconsistent across these studies. Here, our meta-analysis aimed at confirming the association of ABCA7 with AD. Finally, 16 case-control studies (63747 versus 85833) were retrieved from PubMed and other databases. Three common loci were confirmed to increase the risk of AD (rs3764650: OR = 1.20, 95% CI = 1.16-1.24; rs3752246: OR = 1.13,95% CI = 1.08-1.19; rs4147929: OR = 1.17, 95% CI = 1.10-1.24), but the associations varied among the different races. Furthermore, ABCA7 loss-of-function (LOF) mutations conferred a higher risk for AD than did the above variants (LOF: OR = 1.78, 95%  = 1.43-2.22). In conclusion, ABCA7 genetic variants, especially the LOF mutations, were significantly associated with the risk of AD.

Metabolic Dysfunction in Alzheimer's Disease: From Basic Neurobiology to Clinical Approaches. - Clarke, Julia R; Ribeiro, Felipe C; Frozza, Rudimar L; De Felice, Fernanda G; Lourenco, Mychael V (J Alzheimers Dis, 2018)
Clinical trials have extensively failed to find effective treatments for Alzheimer's disease (AD) so far. Even after decades of AD research, there are still limited options for treating dementia. Mounting evidence has indicated that AD patients develop central and peripheral metabolic dysfunction, and the underpinnings of such events have recently begun to emerge. Basic and preclinical studies have unveiled key pathophysiological mechanisms that include aberrant brain stress signaling, inflammation, and impaired insulin sensitivity. These findings are in accordance with clinical and neuropathological data suggesting that AD patients undergo central and peripheral metabolic deregulation. Here, we review recent basic and clinical findings indicating that metabolic defects are central to AD pathophysiology. We further propose a view for future therapeutics that incorporates metabolic defects as a core feature of AD pathogenesis. This approach could improve disease understanding and therapy development through drug repurposing and/or identification of novel metabolic targets.

Metabolic Syndrome and Amyloid Accumulation in the Aging Brain. - Gomez, Gabriela; Beason-Held, Lori L; Bilgel, Murat; An, Yang; Wong, Dean; Studenski, Stephanie; Ferrucci, Luigi; Resnick, Susan M (J Alzheimers Dis, 2018)
BACKGROUND: Recent studies show links between metabolic syndrome and Alzheimer's disease (AD) neuropathology. Understanding the link between vascular-related health conditions and dementia will help target at risk populations and inform clinical strategies for early detection and prevention of AD. OBJECTIVE: To determine whether metabolic syndrome is associated with global cerebral amyloid-β (Aβ) positivity and longitudinal Aβ accumulation. METHODS: Prospective study of 165 participants who underwent (11)C-Pittsburgh compound B (PiB) PET neuroimaging to measure Aβ, from June 2005 to May 2016. Metabolic syndrome was defined using the revised Third Adults Treatment Panel of the National Cholesterol Education Program criteria. Participants were classified as PiB+/- . Linear mixed effects models assessed the relationships between baseline metabolic syndrome and PiB status and regional Aβ change over time. RESULTS: A total of 165 cognitively normal participants of the Baltimore Longitudinal Study of Aging (BLSA) Neuroimaging substudy, aged 55-92 years (mean baseline age = 76.4 years, 85 participants were male), received an average of 2.5 PET-PiB scans over an average interval of 2.6 (3.08 SD) years between first and last visits. Metabolic syndrome was not associated with baseline PiB positivity or concurrent regional Aβ. Metabolic syndrome was associated with increased rates of Aβ accumulation in superior parietal and precuneus regions over time in the PiB+ group. Elevated fasting glucose and blood pressure showed individual associations with accelerated Aβ accumulation. CONCLUSION: Metabolic syndrome was associated with accelerated Aβ accumulation in PiB+ individuals and may be an important factor in the progression of AD pathology.

Metabolic Syndrome, Brain Insulin Resistance, and Alzheimer's Disease: Thioredoxin Interacting Protein (TXNIP) and Inflammasome as Core Amplifiers. - Nasoohi, Sanaz; Parveen, Kehkashan; Ishrat, Tauheed (J Alzheimers Dis, 2018)
Empirical evidence indicates a strong association between insulin resistance and pathological alterations related to Alzheimer's disease (AD) in different cerebral regions. While cerebral insulin resistance is not essentially parallel with systemic metabolic derangements, type 2 diabetes mellitus (T2DM) has been established as a risk factor for AD. The circulating "toxic metabolites" emerging in metabolic syndrome may engage several biochemical pathways to promote oxidative stress and neuroinflammation leading to impair insulin function in the brain or "type 3 diabetes". Thioredoxin-interacting protein (TXNIP) as an intracellular amplifier of oxidative stress and inflammasome activation may presumably mediate central insulin resistance. Emerging data including those from our recent studies has demonstrated a sharp TXNIP upregulation in stroke, aging and AD and well underlining the significance of this hypothesis. With the main interest to illustrate TXNIP place in type 3 diabetes, the present review primarily briefs the potential mechanisms contributing to cerebral insulin resistance in a metabolically deranged environment. Then with a particular focus on plausible TXNIP functions to drive and associate with AD pathology, we present the most recent evidence supporting TXNIP as a promising therapeutic target in AD as an age-associated dementia.

Metabolomics Analyses of Saliva Detect Novel Biomarkers of Alzheimer's Disease. - Huan, Tao; Tran, Tran; Zheng, Jiamin; Sapkota, Shraddha; MacDonald, Stuart W; Camicioli, Richard; Dixon, Roger A; Li, Liang (J Alzheimers Dis, 2018)
Using a non-invasive biofluid (saliva), we apply a powerful metabolomics workflow for unbiased biomarker discovery in Alzheimer's disease (AD). We profile and differentiate Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD groups. The workflow involves differential chemical isotope labeling liquid chromatography mass spectrometry using dansylation derivatization for in-depth profiling of the amine/phenol submetabolome. The total sample (N = 109) was divided in to the Discovery Phase (DP) (n = 82; 35 CN, 25 MCI, 22 AD) and a provisional Validation Phase (VP) (n = 27; 10 CN, 10 MCI, 7 AD). In DP we detected 6,230 metabolites. Pairwise analyses confirmed biomarkers for AD versus CN (63), AD versus MCI (47), and MCI versus CN (2). We then determined the top discriminating biomarkers and diagnostic panels. A 3-metabolite panel distinguished AD from CN and MCI (DP and VP: Area Under the Curve [AUC] = 1.000). The MCI and CN groups were best discriminated with a 2-metabolite panel (DP: AUC = 0.779; VP: AUC = 0.889). In addition, using positively confirmed metabolites, we were able to distinguish AD from CN and MCI with good diagnostic performance (AUC > 0.8). Saliva is a promising biofluid for both unbiased and targeted AD biomarker discovery and mechanism detection. Given its wide availability and convenient accessibility, saliva is a biofluid that can promote diversification of global AD biomarker research.

Metals and Alzheimer's Disease: How Far Have We Come in the Clinic? - Adlard, Paul A; Bush, Ashley I (J Alzheimers Dis, 2018)
It is estimated that by the year 2050 there will be more than 1.5 billion people globally over the age of 65 years. Aging is associated with changes to a number of different cellular processes which are driven by a variety of factors that contribute to the characteristic decline in function that is seen across multiple physiological domains/tissues in the elderly (including the brain). Importantly, aging is also the primary risk factor for the development of neurodegenerative disorders such as Alzheimer's disease. As such, there is an urgent need to provide a greater understanding of both the pathogenesis and treatment of these devastating neurodegenerative disorders. One of the key cellular processes that becomes dysregulated with age and participates both directly and indirectly in age-related dysfunction, is metal homeostasis and the neurochemistry of metalloproteins, the basic science of which has been extensively reviewed in the past. In this review, we will focus on the human clinical intervention trials that have been conducted over approximately the last four decades that have attempted to establish the efficacy of targeting metal ions in the treatment of AD.

Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis. - Campbell, Jared M; Stephenson, Matthew D; de Courten, Barbora; Chapman, Ian; Bellman, Susan M; Aromataris, Edoardo (J Alzheimers Dis, 2018)
BACKGROUND: Metformin, a first line antihyperglycemic medication, is an AMPK activator and has been hypothesized to act as a geroprotective agent. Studies on its association with various classifications of age-related cognitive decline have shown mixed results with positive and negative findings. OBJECTIVE: To synthesize the best available evidence on the association of metformin-use with risk, progression, and severity of dementia. METHOD: Eligible research investigated the effect of metformin on dementia, Alzheimer's disease, or any measure of cognitive impairment compared to any control group who were not receiving metformin. The initial search resulted in 862 citations from which 14 studies (seven cohort, four cross-sectional, two RCTs, and one case control) were included. RESULTS: Meta-analysis of three studies showed that cognitive impairment was significantly less prevalent in diabetic metformin (Odds ratio = 0.55, 95% CI 0.38 to 0.78), while six studies showed that dementia incidence was also significantly reduced (Hazard ratio = 0.76, 95% CI 0.39 to 0.88). Mini-Mental State Examination scores were not significantly affected by metformin-use, although both RCTs showed that metformin had a neuroprotective effect compared to placebo. Some studies found negative or neutral effects for metformin use by people with diabetes; the potential mechanism of metformin-induced vitamin B12 deficiency is discussed. CONCLUSIONS: Metformin should continue to be used as a first line therapy for diabetes in patients at risk of developing dementia or Alzheimer's disease. The use of metformin by individuals without diabetes for the prevention of dementia is not supported by the available evidence.

Methylenetetrahydrofolate Reductase Deficiency Deregulates Regional Brain Amyloid-β Protein Precursor Expression and Phosphorylation Levels. - Hoffman, Alexander; Taleski, Goce; Qian, Helena; Wasek, Brandi; Arning, Erland; Bottiglieri, Teodoro; Sontag, Jean-Marie; Sontag, Estelle (J Alzheimers Dis, 2018)
Deregulation of the amyloid-β protein precursor (AβPP) plays a critical role in the neurodegenerative cascade of Alzheimer's disease (AD). Significantly, common functional polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene are a risk factor for the development of late-onset AD. Reduced MTHFR activity is associated with alterations in folate and homocysteine metabolism. Here, we first show that in young MTHFR knockout mice, mild and severe MTHFR deficiency markedly increase cortical and hippocampal AβPP phosphorylation at the regulatory Thr668 site. However, the hippocampus is especially vulnerable to the effects of aging and mild MTHFR deficiency. Notably, the effects of severe MTHFR deficiency in young mice are recapitulated by prolonged dietary folate deficiency in old mice, which leads to regional brain accumulation of cystathionine due to impaired methylation of homocysteine. The incremental AβPP phosphorylation at Thr668 mediated by severe genetic-or diet-induced impairment of the folate cycle correlates with enhanced accumulation of demethylated protein phosphatase 2A (PP2A), and activation of glycogen synthase kinase-3β (GSK-3β). Lastly, we show that severe disturbances in folate metabolism can also affect AβPP expression levels in a brain region specific manner. Together our findings identify a novel link between genetic MTHFR deficiency, activation of GSK-3β, demethylation of PP2A, and enhanced phosphorylation of AβPP at Thr668, which is known to critically influence neuronal AβPP function and pathological amyloidogenic processing. Deregulation of AβPP provides a novel mechanism by which common human MTHFR polymorphisms may interact with dietary folate deficiency to alter neuronal homeostasis and increase the risk for sporadic AD.

Microglia CREB-Phosphorylation Mediates Amyloid-β-Induced Neuronal Toxicity. - Gao, Yuan; Liu, En-Jie; Wang, Wei-Jin; Wang, Ya-Li; Li, Xiao-Guang; Wang, Xin; Li, Shi-Hong; Zhang, Shu-Juan; Li, Meng-Zhu; Zhou, Qiu-Zhi; Long, Xiao-Bing; Zhang, Hua-Qiu; et al. (J Alzheimers Dis, 2018)
Extracellular accumulation of amyloid-β (Aβ) forming senile plaques is one of the hallmark pathologies in Alzheimer's disease (AD), while the mechanisms underlying the neuronal toxic effect of Aβ are not fully understood. Here, we found that intracerebroventricular infusion of the aged Aβ42 in mice only induces memory deficit at 24 h but not at 7 days. Interestingly, a remarkably increased CREB (cAMP response element-binding protein) Ser133-phosphorylation (pS133-CREB) with microglial activation was detected at 24 h but not at 7 days after Aβ infusion. Aβ treatment for 24 h increased pS133-CREB level in microglia of the hippocampal non-granular cell layers with remarkably decreased pS133-CREB immunoreactivity in neurons of the hippocampal granular cell layers, including CA1, CA3, and DG subsets. Inhibition of microglia activation by minocycline or CREB phosphorylation by H89, an inhibitor of protein kinase A (PKA), abolished Aβ-induced microglia CREB hyperphosphorylation with restoration of neuronal function and attenuation of inflammatory response, i.e., reduced levels of interleukin-6 (IL6) and pCREB binding of matrix metalloproteinase-9 (MMP9) DNA. Finally, treatment of the primary hippocampal neurons with Aβ-potentiated microglia media decreased neuronal GluN1 and GluA2 levels, while simultaneous inhibition of PKA restored the levels. These novel findings reveal that intracerebroventricular infusion of Aβ only induces transient memory deficit in mice and the molecular mechanisms involve a stimulated microglial CREB phosphorylation.

Microglial Activation During Pathogenesis of Tauopathy in rTg4510 Mice: Implications for the Early Diagnosis of Tauopathy. - Sahara, Naruhiko; Maeda, Jun; Ishikawa, Ai; Tokunaga, Masaki; Suhara, Tetsuya; Higuchi, Makoto (J Alzheimers Dis, 2018)
Tauopathy is characterized by the fibrillar tau accumulation in neurons and glial cells. In order to advance our understanding of the causative mechanisms of tauopathy, neuroinflammation, which has been suggested to play important roles in disease progression, will require particular attention. Neuroinflammation is characterized predominantly by microglial activation. At present, it is still under debate whether microglial activation is a cause or a result of neurodegeneration. To search for a temporal relationship between neurodegeneration and neuroinflammation, our group demonstrated that in vivo imaging (e.g., tau-PET, TSPO-PET, and volumetric MRI) of tauopathy mice strongly supports the evidence of microglial activation along with both pathological tau accumulation and brain atrophy. Both in vivo imaging and histochemical analysis confirmed that microglial TSPO accumulation was the late event during the pathogenesis of tauopathy. On the other hand, it is known that purinergic receptor P2Y12 as a marker of homeostatic microglia cells was reduced at an early stage of disease progression. In this review, we will introduce a phenotypic change of microglia in a mouse model of tauopathy and propose novel approaches to the establishment of imaging biomarkers, thereby targeting the early diagnosis of tauopathy.

microRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer's Disease. - Manzine, Patricia R; Pelucchi, Silvia; Horst, Maria A; Vale, Francisco A C; Pavarini, Sofia C I; Audano, Matteo; Mitro, Nico; Di Luca, Monica; Marcello, Elena; Cominetti, Márcia R (J Alzheimers Dis, 2018)
ADAM10 is the α-secretase that cleaves amyloid-β protein precursor in the non-amyloidogenic pathway in Alzheimer's disease (AD) and is known to be regulated by different microRNAs (miRNAs), which are post-transcriptional regulators related to several biological and pathological processes, including AD. Here we proposed to explore and validate miRNAs that have direct or indirect relations to the AD pathophysiology and ADAM10 gene. Approximately 700 miRNAs were analyzed and 21 differentially expressed miRNAs were validated in a sample of 21 AD subjects and 17 cognitively healthy matched controls. SH-SY5Y cells were transfected with miR-144-5p, miR-221, and miR-374 mimics and inhibitors, and ADAM10 protein levels were evaluated. miR-144-5p, miR-221, and miR-374 were downregulated in AD. The overexpression of miR-221 in SH-SY5Y cells resulted in ADAM10 reduction and its inhibition in ADAM10 increased. These findings show that miR-221 can be a new potential therapeutic target for increasing ADAM10 levels in AD. In addition, these results can contribute to the better understanding of ADAM10 post-transcriptional regulation.
Keywords: ADAM10 Protein; Aged; Aged, 80 and over; Alzheimer Disease; Cell Line, Tumor; Cohort Studies; Down-Regulation; Female; Humans; Male; MicroRNAs; Middle Aged; Neuroblastoma; Psychiatric Status Rating Scales; RNA, Messenger; ROC Curve; Transfection

Midlife Physical Activity, Psychological Distress, and Dementia Risk: The HUNT Study. - Zotcheva, Ekaterina; Bergh, Sverre; Selbæk, Geir; Krokstad, Steinar; Håberg, Asta Kristine; Strand, Bjørn Heine; Ernstsen, Linda (J Alzheimers Dis, 2018)
BACKGROUND: Physical activity (PA) is associated with a decreased dementia risk, whereas psychological distress (distress) is linked to an increased dementia risk. OBJECTIVE: We investigated independent and joint associations of midlife moderate-to-vigorous PA (MVPA) and distress with incident dementia. METHODS: Our study comprised 28,916 participants aged 30-60 years from the Nord-Trøndelag Health Study (HUNT1, 1984-1986). Data on MVPA and distress from HUNT1 was linked to the Health and Memory Study in Nord-Trøndelag for dementia case identification. Participants were followed from 1995 until 2011. We used adjusted Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI). RESULTS: In fully adjusted analyses, MVPA was associated with a reduced dementia risk (HR 0.81, 95% CI 0.62-1.06), compared to no MVPA. Distress was associated with an increased dementia risk (HR 1.30, 95% CI 0.99-1.70). Compared to distressed participants not taking part in MVPA, non-distressed no-MVPA participants had a reduced dementia risk (HR 0.72, 95% CI 0.54-0.96). The same applied to distressed MVPA participants (HR 0.50, 95% CI 0.22-1.14), and non-distressed MVPA participants (HR 0.63, 95% CI 0.44-0.90). Our results indicated an additive interaction between MVPA and distress on dementia risk. CONCLUSION: Our results suggest that midlife MVPA reduces risk of incident dementia among both distressed and non-distressed individuals.

Minor Hallucinations in Alzheimer's Disease. - Ruiz, Maria; Arias, Alfonso; Sánchez-Llanos, Ernesto; Gil, Maria Pilar; López-Ortega, Ricard; Dakterzada, Faridé; Purroy, Francisco; Piñol-Ripoll, Gerard (J Alzheimers Dis, 2018)
BACKGROUND: Hallucinations may have a broad spectrum and include so-called minor hallucinations (MHs). MHs include passage hallucinations (PHs), visual illusions, and presence hallucinations (PrHs). OBJECTIVE: To determine the prevalence and characteristics of MHs in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) patients, and to describe their potential relationship with cognition, behavioral symptoms, and use of psychoactive drugs. METHODS: We have recruited prospectively and consecutively 268 subjects (90 AD mild-moderate drug-naïve patients, 78 aMCI, and 100 controls). All patients responded to a semi-structured questionnaire in order to rate psychotic phenomena. Clinical, neuropsychological, and demographic data of patients with and without MH were compared with those of age, sex, and education-matched controls. RESULTS: The prevalence of MHs was 21.1% (19) in AD, 12.8% (10) in aMCI, and 3% (3) in controls (p < 0.01). The most frequent MH was PrH (9.3%), followed by PH (4.9%) and illusion (0.7%). Eight (27.8%) patients had more than one MH. After adjusting for age and gender, there was a negative correlation between the presence of MHs and MMSE score (r = -0.261; p < 0.01) and a positive correlation between MHs and Neuropsychiatric Inventory score (r = 0.237; p < 0.01). We did not observe a significant relationship between presence of MHs and the consumption of psychoactive drugs (p > 0.05). CONCLUSION: We have shown that the presence of MHs in patients with newly diagnosed, untreated AD and aMCI is more than controls. MHs were correlated with other behavioral symptoms and a worse cognitive performance. We suggest the specific interrogation for MHs as a clinical feature for this population.

miRNA 933 Expression by Endothelial Cells is Increased by 27-Hydroxycholesterol and is More Prevalent in Plasma from Dementia Patients. - Dias, Irundika H K; Brown, Caroline L; Shabir, Kiran; Polidori, M Cristina; Griffiths, Helen R (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) etiology is complex; gene and environmental risk factors may interact to predispose to disease. From single nucleotide polymorphism analyses and genome-wide association studies, a number of candidate risk genes for the onset of AD have been identified and cluster around lipid metabolism and inflammation. We hypothesized that endothelial cells which line the blood-brain barrier are likely to be critical mediators of systemic metabolism within the brain. Therefore, we have studied the effect of 27 hydroxycholesterol (27-OHC) on microvascular endothelial cell (HMVEC) redox state, inflammatory cytokine secretion, and microRNA (miR) expression. Using a transwell method, we have studied directional secretion profiles for the proinflammatory cytokines TNFα and IL-6 and confirmed that 27-OHC induces discrete and directional inflammatory molecular signatures from HMVEC. The lipids caused depletion of cellular glutathione and cytokine secretion is HMVEC-redox state-dependent. Discovery miR expression change in HMVEC with and without 27-OHC treatment was undertaken. We selected three genes for further analysis by qPCR; miR-144 and 146 expression, which are anti-inflammatory and redox regulating modulators, were not affected significantly by 27-OHC. However, increased expression of a putative neurotrophic regulatory factor miR933 in HMVEC with 27-OHC was confirmed by qPCR. In plasma from patients with dementia, all three miR were found at significantly elevated levels compared to healthy older adults. These data highlight that 27-OHC has an important regulatory effect on endothelial microvascular cells to increase expression of a miR (-933) and secretion of inflammatory cytokines that are elevated in plasma from dementia patients.

Mitochondria and Mitochondrial Cascades in Alzheimer's Disease. - Swerdlow, Russell H (J Alzheimers Dis, 2018)
Decades of research indicate mitochondria from Alzheimer's disease (AD) patients differ from those of non-AD individuals. Initial studies revealed structural differences, and subsequent studies showed functional deficits. Observations of structure and function changes prompted investigators to consider the consequences, significance, and causes of AD-related mitochondrial dysfunction. Currently, extensive research argues mitochondria may mediate, drive, or contribute to a variety of AD pathologies. The perceived significance of these mitochondrial changes continues to grow, and many currently believe AD mitochondrial dysfunction represents a reasonable therapeutic target. Debate continues over the origin of AD mitochondrial changes. Some argue amyloid-β (Aβ) induces AD mitochondrial dysfunction, a view that does not challenge the amyloid cascade hypothesis and that may in fact help explain that hypothesis. Alternatively, data indicate mitochondrial dysfunction exists independent of Aβ, potentially lies upstream of Aβ deposition, and suggest a primary mitochondrial cascade hypothesis that assumes mitochondrial pathology hierarchically supersedes Aβ pathology. Mitochondria, therefore, appear at least to mediate or possibly even initiate pathologic molecular cascades in AD. This review considers studies and data that inform this area of AD research.

Mitochondrial Dysfunction as a Predictor and Driver of Alzheimer's Disease-Like Pathology in OXYS Rats. - Tyumentsev, Mikhail A; Stefanova, Natalia A; Muraleva, Natalia A; Rumyantseva, Yulia V; Kiseleva, Elena; Vavilin, Valentin A; Kolosova, Nataliya G (J Alzheimers Dis, 2018)
Growing evidence suggests that mitochondrial dysfunction is an early event in sporadic Alzheimer's disease (AD), but the impact of mitochondrial dysfunction on the transition from healthy aging to AD remains elusive. Here we estimated the influence of mitochondrial dysfunction on the initiation of AD signs in OXYS rats, which simulate key characteristics of sporadic AD. We assessed the mitochondrial ultrastructure of pyramidal neurons of the hippocampus at the age preceding the development (age 20 days), during manifestation (4-5 months), and at the well-pronounced stages (18-24 months) of the AD-like pathology in OXYS rats. Ultrastructural alterations were collated with the amounts of proteins mediating mitochondrial dynamics [mitofusins (MFN1 and MFN2) and dynamin-1-like protein (DRP1)]; with activity of respiratory chain complexes I, IV, and V in the hippocampal mitochondria; with reactive oxygen species (ROS) production; and with expression of uncoupling protein 2 (UCP2) regulating ROS production. Already at the preclinical stage, OXYS rats showed some characteristic changes in hippocampal mitochondria, which increased in size with the manifestation and progression of AD-like pathology, including decreased activity of respiratory complexes against the background of greater fusion and formation of larger mitochondria. Signs of AD developed simultaneously with increasing dysfunction of mitochondria, with a dramatic decrease in their number, and with increased fission but without upregulation of ROS production (observed only in 20-day-old OXYS rats). Summarizing the data from our present and previous studies, we conclude that mitochondrial dysfunction appears to mediate or possibly even initiate pathological molecular cascades of AD-like pathology in OXYS rats and can be considered a predictor of the early development of the late-onset form of AD in humans.

Mitochondrial Function, Dynamics, and Permeability Transition: A Complex Love Triangle as A Possible Target for the Treatment of Brain Aging and Alzheimer's Disease. - Stockburger, Carola; Eckert, Schamim; Eckert, Gunter P; Friedland, Kristina; Müller, Walter E (J Alzheimers Dis, 2018)
Because of the failure of all amyloid-β directed treatment strategies for Alzheimer's disease (AD), the concept of mitochondrial dysfunction as a major pathomechanism of the cognitive decline in aging and AD has received substantial support. Accordingly, improving mitochondrial function as an alternative strategy for new drug development became of increasing interest and many different compounds have been identified which improve mitochondrial function in preclinical in vitro and in vivo experiments. However, very few if any have been investigated in clinical trials, representing a major drawback of the mitochondria directed drug development. To overcome these problems, we used a top-down approach by investigating several older antidementia drugs with clinical evidence of therapeutic efficacy. These include EGb761® (standardized ginkgo biloba extract), piracetam, and Dimebon. All improve experimentally many aspects of mitochondrial dysfunction including mitochondrial dynamics and also improve cognition and impaired neuronal plasticity, the functionally most relevant consequences of mitochondrial dysfunction. All partially inhibit opening events of the mitochondrial permeability transition pore (mPTP) which previously has mainly been discussed as a mechanism relevant for the induction of apoptosis. However, as more recent work suggests the mPTP as a master regulator of many mitochondrial functions, our data suggest the mPTP as a possible relevant drug target within the love triangle between mPTP regulation, mitochondrial dynamics, and mitochondrial function including regulation of neuronal plasticity. Drugs interfering with mPTP function will improve not only mitochondrial impairment in aging and AD but also will have beneficial effects on impaired neuronal plasticity, the pathomechanism which correlates best with functional deficits (cognition, behavior) in aging and AD.

Mitochondrial Translocase of the Outer Membrane Alterations May Underlie Dysfunctional Oxidative Phosphorylation in Alzheimer's Disease. - Chai, Yuek Ling; Xing, Huayang; Chong, Joyce R; Francis, Paul T; Ballard, Clive G; Chen, Christopher P; Lai, Mitchell K P (J Alzheimers Dis, 2018)
BACKGROUND: The translocase of the outer membrane (TOM) is a vital mitochondrial transport system facilitating the importation of nuclear encoded proteins into the organelle. While mitochondrial dysfunction, including perturbation of oxidative phosphorylation (OXPHOS) complex, is evident in Alzheimer's disease (AD), it remains unclear whether the observed OXPHOS deficits may be associated with TOM alterations. OBJECTIVES: To correlate TOM subunits with OXPHOS complex proteins in AD. METHODS: Postmortem neocortex (BA40) from AD and age-matched controls were processed to obtain mitochondrial enriched homogenates for the measurement of Tom20, Tom22, Tom40, and Tom70 as well as components of OXPHOS complex I-V by immunoblotting. RESULTS: Tom20 and Tom70 immunoreactivities were significantly reduced in AD, as were components of OXPHOS complex I and III. Both Tom20 and Tom70 positively correlated with complex III and V, while Tom20 also correlated withcomplex IV. CONCLUSION: Reductions in certain TOM subunits and their correlations with specific OXPHOS complex proteins suggest that an impaired mitochondrial transportation system may contribute to previously observed oxidative phosphorylation deficits in AD. Follow-up studies are needed to corroborate the present correlative study.
Keywords: Aged, 80 and over; Alzheimer Disease; Autopsy; Brain; Female; Humans; Male; Mitochondria; Mitochondrial Membrane Transport Proteins; Multivariate Analysis; Oxidative Phosphorylation

Modeling Prion-Like Processing of Tau Protein in Alzheimer's Disease for Pharmaceutical Development. - Wischik, Claude M; Schelter, Björn O; Wischik, Damon J; Storey, John M D; Harrington, Charles R (J Alzheimers Dis, 2018)
Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer's disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro, or "prion-like processing", that has now been demonstrated for several neurodegenerative disorders. Here we review the findings that led to the first clinical trials to test tau aggregation inhibitor therapy in AD as a way to block this cascade. Although further trials are still needed, the results to date suggest that a treatment targeting the prion-like processing of tau protein may have a role in both prevention and treatment of AD.

The Montreal Cognitive Assessment: Normative Data from a German-Speaking Cohort and Comparison with International Normative Samples. - Thomann, Alessandra E; Goettel, Nicolai; Monsch, Raphael J; Berres, Manfred; Jahn, Thomas; Steiner, Luzius A; Monsch, Andreas U (J Alzheimers Dis, 2018)
BACKGROUND: The Montreal Cognitive Assessment (MoCA) is used to evaluate multiple cognitive domains in elderly individuals. However, it is influenced by demographic characteristics that have yet to be adequately considered. OBJECTIVE: The aim of our study was to investigate the effects of age, education, and sex on the MoCA total score and to provide demographically adjusted normative values for a German-speaking population. METHODS: Subjects were recruited from a registry of healthy volunteers. Cognitive health was defined using the Mini-Mental State Examination (score ≥27/30 points) and the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (total score ≥85.9 points). Participants were assessed with the German version of the MoCA. Normative values were developed based on regression analysis. Covariates were chosen using the Predicted Residual Sums of Squares approach. RESULTS: The final sample consisted of 283 participants (155 women, 128 men; mean (SD) age = 73.8 (5.2) years; education = 13.6 (2.9) years). Thirty-one percent of participants scored below the original cut-off (<26/30 points). The MoCA total score was best predicted by a regression model with age, education, and sex as covariates. Older age, lower education, and male sex were associated with a lower MoCA total score (p < 0.001). CONCLUSION: We developed a formula to provide demographically adjusted standard scores for the MoCA in a German-speaking population. A comparison with other MoCA normative studies revealed considerable differences with respect to selection of volunteers and methods used to establish normative data.

Moringa Oleifera Alleviates Homocysteine-Induced Alzheimer's Disease-Like Pathology and Cognitive Impairments. - Mahaman, Yacoubou Abdoul Razak; Huang, Fang; Wu, Mengjuan; Wang, Yuman; Wei, Zhen; Bao, Jian; Salissou, Maibouge Tanko Mahamane; Ke, Dan; Wang, Qun; Liu, Rong; Wang, Jian-Zhi; Zhang, Bin; et al. (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is multifactorial with unclear etiopathology. Due to the complexity of AD, many attempted single therapy treatments, like Aβ immunization, have generally failed. Therefore, there is a need for drugs with multiple benefits. Naturally occurring phytochemicals with neuroprotective, anti-amyloidogenic, antioxidative, and anti-inflammatory properties could be a possible way out. In this study, the effect of Moringa oleifera (MO), a naturally occurring plant with high antioxidative, anti-inflammatory, and neuroprotective effects, was evaluated on hyperhomocysteinemia (HHcy) induced AD-like pathology in rats. Homocysteine (Hcy) injection for 14 days was used to induce AD-like pathology. Simultaneous MO extract gavage followed the injection as a preventive treatment or, after injection completion, MO gavage was performed for another 14 days as a curative treatment. MO was found to not only prevent but also rescue the oxidative stress and cognitive impairments induced by Hcy treatment. Moreover, MO recovered the decreased synaptic proteins PSD93, PSD95, Synapsin 1 and Synaptophysin, and improved neurodegeneration. Interestingly, MO decreased the Hyc-induced tau hyperphosphorylation at different sites including S-199, T-231, S-396, and S-404, and at the same time decreased Aβ production through downregulation of BACE1. These effects in HHcy rats were accompanied by a decrease in calpain activity under MO treatment, supporting that calpain activation might be involved in AD pathogenesis in HHcy rats. Taken together, our data, for the first time, provided evidence that MO alleviates tau hyperphosphorylation and Aβ pathology in a HHcy AD rat model. This and previous other studies support MO as a good candidate for, and could provide new insights into, the treatment of AD and other tauopathies.

Morphological and Pathological Characteristics of Brain in Diabetic Encephalopathy. - Chen, Rui; Shi, Jiangwei; Yin, Qingsheng; Li, Xiaojin; Sheng, Yanyuan; Han, Juan; Zhuang, Pengwei; Zhang, Yanjun (J Alzheimers Dis, 2018)
Diabetes mellitus is a metabolic disease often accompanied by a series of complications, such as diabetic nephropathy, retinopathy, and diabetic foot. The survival time of diabetics has been significantly prolonged due to advancements in medicine. However, the prolonged survival time for diabetics can increase the prevalence of diabetic central nervous system disease. Diabetic encephalopathy (DE) has become one of the main complications of the disease, and the main clinical manifestation of DE is cognitive dysfunction. However, the typical morphological and pathological characteristics of the brain in DE are rarely systematically reported. Thus, this phenomenon severely restricts the diagnosis and treatment of DE. This article presents a description of the pathology characteristics of DE, including atrophy of the brain (gray matter, white matter, and hippocampus), changes in cerebrovascular morphology and function, impairment of synaptic plasticity, and dysfunction of neuroglia. In addition, abnormalities in the glymphatic clearance system of the brain are closely related to the progression of DE. A review of typical brain morphological and pathological characteristics would aid in the diagnosis and treatment of DE.

MRI-Based Screening of Preclinical Alzheimer's Disease for Prevention Clinical Trials. - Casamitjana, Adrià; Petrone, Paula; Tucholka, Alan; Falcon, Carles; Skouras, Stavros; Molinuevo, José Luis; Vilaplana, Verónica; Gispert, Juan Domingo (J Alzheimers Dis, 2018)
The identification of healthy individuals harboring amyloid pathology represents one important challenge for secondary prevention clinical trials in Alzheimer's disease (AD). Consequently, noninvasive and cost-efficient techniques to detect preclinical AD constitute an unmet need of critical importance. In this manuscript, we apply machine learning to structural MRI (T1 and DTI) of 96 cognitively normal subjects to identify amyloid-positive ones. Models were trained on public ADNI data and validated on an independent local cohort. Used for subject classification in a simulated clinical trial setting, the proposed method is able to save 60% of unnecessary CSF/PET tests and to reduce 47% of the cost of recruitment. This recruitment strategy capitalizes on available MR scans to reduce the overall amount of invasive PET/CSF tests in prevention trials, demonstrating a potential value as a tool for preclinical AD screening. This protocol could foster the development of secondary prevention strategies for AD.

Multicenter Resting State Functional Connectivity in Prodromal and Dementia Stages of Alzheimer's Disease. - Teipel, Stefan J; Metzger, Coraline D; Brosseron, Frederic; Buerger, Katharina; Brueggen, Katharina; Catak, Cihan; Diesing, Dominik; Dobisch, Laura; Fliebach, Klaus; Franke, Christiana; Heneka, Michael T; Kilimann, Ingo; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer's disease (AD). OBJECTIVE: To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD. METHODS: We determined rs-fMRI functional connectivity based on Pearson's correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. We determined cross-validated discrimination accuracy based on penalized logistic regression to account for multicollinearity of predictors. RESULTS: Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume. CONCLUSION: Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD.

A Multi-Center Study on Human Brain Glutathione Conformation using Magnetic Resonance Spectroscopy. - Shukla, Deepika; Mandal, Pravat K; Ersland, Lars; Grüner, Eli Renate; Tripathi, Manjari; Raghunathan, Partha; Sharma, Ankita; Chaithya, G R; Punjabi, Khushboo; Splaine, Christopher (J Alzheimers Dis, 2018)
Molecular dynamics simulation and in vitro nuclear magnetic resonance (NMR) studies on glutathione (GSH) indicated existence of closed and extended conformations. The present work in a multi-center research setting reports in-depth analysis of GSH conformers in vivo using a common magnetic resonance spectroscopy (MRS) protocol and signal processing scheme. MEGA-PRESS pulse sequence was applied on healthy subjects using 3T Philips MRI scanner (India) and 3T GE MRI scanner (Norway) using the same experimental parameters (echo time, repetition time, and selective 180° refocusing ON-pulse at 4.40 ppm and 4.56 ppm). All MRS data were processed at one site National Brain Research Center (NBRC) using in-house MRS processing toolbox (KALPANA) for consistency. We have found that both the closed and extended GSH conformations are present in human brain and the relative proportion of individual conformer peak depends on the specific selection of refocusing ON-pulse position in MEGA-PRESS pulse sequence. It is important to emphasize that in vivo experiments with different refocusing and inversion pulse positions, echo time, and voxel size, clearly evidence the presence of both the GSH conformations. The GSH conformer peak positions for the closed GSH (Cys-Hβ) peak at ∼2.80 ppm and extended GSH (Cys-Hβ) peak at ∼2.95 ppm remain consistent irrespective of the selective refocusing OFF-pulse positions. This is the first in vivo study where both extended and closed GSH conformers are detected using the MEGA-PRESS sequence employing the parameters derived from the high resolution in vitro NMR studies on GSH.

Multi-Faceted Role of Melatonin in Neuroprotection and Amelioration of Tau Aggregates in Alzheimer's Disease. - Balmik, Abhishek Ankur; Chinnathambi, Subashchandrabose (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is one of the major age related neurodegenerative diseases whose pathology arises due to the presence of two distinct protein aggregates, viz., amyloid-β plaques in extracellular matrix and tau neurofibrillary tangles in neurons. Multiple factors play a role in AD pathology, which includes familial mutations, oxidative stress, and post-translational modifications. Melatonin is an endocrine hormone, secreted during darkness, derived from tryptophan, and produced mainly by the pineal gland. It is an amphipathic molecule, which makes it suitable to cross not only blood-brain barrier, but also to enter several other subcellular compartments like mitochondria and endoplasmic reticulum. In this context, the neuroprotective effect of melatonin may be attributed to its role as an antioxidant. Melatonin's pleiotropic function as an antioxidant and neuroprotective agent has been widely studied. However, its direct effect on the aggregation of tau and amyloid-β needs to be explored. Furthermore, an important aspect of its function is its ability to regulate the process of phosphorylation of tau by affecting the function of kinases and phosphatases. In this review, we are focusing on the pleiotropic function of melatonin on the aspect of its neuroprotective function in tau pathology, which includes antioxidant function, regulation of enzymes, including kinases and enzymes involved in free radical scavenging and mitochondrial protection.

Multimodal Neuroimaging in Alzheimer's Disease: Early Diagnosis, Physiopathological Mechanisms, and Impact of Lifestyle. - Chételat, Gaël (J Alzheimers Dis, 2018)
Over the last ten years, we have conducted research in Alzheimer's disease (AD) using multimodal neuroimaging techniques to improve diagnosis, further our understanding of the pathological mechanisms underlying the disease, and support the development of innovative non-pharmacological preventive strategies. Our works emphasized the interest of hippocampal subfield volumetry in early diagnosis and the need for further development in this field including optimization, standardization, and automatization of the techniques. Also, we conducted several studies in cognitively intact at-risk elderly (e.g., subjective cognitive decline patients and APOE4 carriers) to better identify biomarkers associated with increased risk of developing AD. Regarding the physiopathological mechanisms, specific multimodal neuroimaging techniques allowed us to highlight the relevance of diaschisis, the mismatch between neurodegeneration and local Aβ deposition and the regional variation in the mechanisms underlying structural or functional alterations. Further works integrating other biomarkers known to play a role in the physiopathology of AD (tau, TDP-43, inflammation, etc.) in a longitudinal design would be useful to get a comprehensive understanding of their relative role, sequence, and causal relationships. Our works also highlighted the relevance of functional connectivity in further understanding the specificity of cognitive deficits in AD and how connectivity differentially influences the propagation of the different AD biomarkers. Finally, we conducted several studies on the links between lifestyle factors and neuroimaging biomarkers to unravel mechanisms of reserve. Further efforts are needed to better understand which lifestyle factor, or combination of factors, impact on AD pathology, and when, to help translating our knowledge to training programs that might prevent or delay brain and cognitive changes leading to AD dementia.

Multi-Modality Sparse Representation for Alzheimer's Disease Classification. - Kwak, Kichang; Yun, Hyuk Jin; Park, Gilsoon; Lee, Jong-Min (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are age-related neurodegenerative diseases characterized by progressive loss of memory and irreversible cognitive functions. The hippocampus, a brain area critical for learning and memory processes, is especially susceptible to damage at early stages of AD. OBJECTIVE: We aimed to develop prediction model using a multi-modality sparse representation approach. METHODS: We proposed a sparse representation approach to the hippocampus using structural T1-weighted magnetic resonance imaging (MRI) and 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) to distinguish AD/MCI from healthy control subjects (HCs). We considered structural and function information for the hippocampus and applied a sparse patch-based approach to effectively reduce the dimensions of neuroimaging biomarkers. RESULTS: In experiments using Alzheimer's Disease Neuroimaging Initiative data, our proposed method demonstrated more reliable than previous classification studies. The effects of different parameters on segmentation accuracy were also evaluated. The mean classification accuracy obtained with our proposed method was 0.94 for AD/HCs, 0.82 for MCI/HCs, and 0.86 for AD/MCI. CONCLUSION: We extracted multi-modal features from automatically defined hippocampal regions of training subjects and found this method to be discriminative and robust for AD and MCI classification. The extraction of features in T1 and FDG-PET images is expected to improve classification performance due to the relationship between brain structure and function.

Multi-Parametric Classification of Vascular Cognitive Impairment and Dementia: The Impact of Diverse Cerebrovascular Injury Biomarkers. - Lang, Brittany; Kindy, Mark S; Kozel, F Andrew; Schultz, Susan K; Taheri, Saeid (J Alzheimers Dis, 2018)
Vascular cognitive impairment and dementia (VCID) is a diagnostic term applied to cognitively impaired individuals with heterogeneous cerebrovascular conditions affecting large and/or small vessels. Individual biomarkers have been identified as instrumental in relating VCID to specific underlying pathologies to better characterize this syndrome. Emerging research to refine panels of biomarkers will increase classification sensitivity and specificity. Refined VCID clustering based on the severity and pathology of vascular injury will permit the development of optimal prevention and treatment strategies. Here, we review recently reported data concerning the diversity of VCID-related pathology and attempts for VCID clustering based on biomarkers obtained from different sets of measurements. We discuss three major sets of biomarkers: 1) neuroimaging biomarkers, 2) neuropsychological performance measures, and 3) biochemical markers in current VCID clustering. Finally, we highlight the effect of blood-brain barrier health on cerebrovascular disease trajectory.

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1. - Jellinger, Kurt A (J Alzheimers Dis, 2018)
Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein in both glia (mainly oligodendroglia) and neurons forming glial and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded α-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed.

Multisensory Stimulation and Individualized Music Sessions on Older Adults with Severe Dementia: Effects on Mood, Behavior, and Biomedical Parameters. - Maseda, Ana; Cibeira, Nuria; Lorenzo-López, Laura; González-Abraldes, Isabel; Buján, Ana; de Labra, Carmen; Millán-Calenti, José Carlos (J Alzheimers Dis, 2018)
BACKGROUND: Multisensory stimulation and individualized music have shown to be good in handling the psychological and behavioral symptoms in people with severe dementia. OBJECTIVE: Explore the effects of two nonpharmacological interventions, multisensory stimulation environment (MSSE) in a Snoezelen room and individualized music sessions, on mood, behavior, and biomedical parameters of institutionalized elderly patients with severe dementia. METHODS: Randomized trial of 21 patients aged ≥65 years randomly assigned to two groups (MSSE and individualized music). Interventions administered in two-weekly sessions lasted 30 minutes for a period of 12 weeks. Main outcomes were recorded before, during, and at the end of the intervention. RESULTS: Both groups had immediate positive effects on mood and behavior. Participants were more happy/more content (p < 0.001), talked more spontaneously (p = 0.009), related to people better (p = 0.002), were more attentive to/focused on their environment (p < 0.001), enjoyed themselves (p = 0.003), were less bored/inactive (p = 0.004), and more relaxed/content (p = 0.003). The MSSE group performed a better visual follow-up of the stimuli (p = 0.044), and the music group were more relaxed and happy (p = 0.003). A decrease in heart rate (p = 0.013) and an increase in oxygen saturation (p = 0.011) were observed from before to after interventions in both groups, with no significant differences between them. CONCLUSIONS: Both interventions seem to be effective at managing mood and behavioral disturbances in the short term and at improving physiological rates, highlighting the efficacy of nonpharmacological treatments in patients with severe dementia.

Multivariate Approach for Alzheimer's Disease Detection Using Stationary Wavelet Entropy and Predator-Prey Particle Swarm Optimization. - Zhang, Yudong; Wang, Shuihua; Sui, Yuxiu; Yang, Ming; Liu, Bin; Cheng, Hong; Sun, Junding; Jia, Wenjuan; Phillips, Preetha; Górriz, Juan Manuel (J Alzheimers Dis, 2018)
BACKGROUND: The number of patients with Alzheimer's disease is increasing rapidly every year. Scholars often use computer vision and machine learning methods to develop an automatic diagnosis system. OBJECTIVE: In this study, we developed a novel machine learning system that can make diagnoses automatically from brain magnetic resonance images. METHODS: First, the brain imaging was processed, including skull stripping and spatial normalization. Second, one axial slice was selected from the volumetric image, and stationary wavelet entropy (SWE) was done to extract the texture features. Third, a single-hidden-layer neural network was used as the classifier. Finally, a predator-prey particle swarm optimization was proposed to train the weights and biases of the classifier. RESULTS: Our method used 4-level decomposition and yielded 13 SWE features. The classification yielded an overall accuracy of 92.73±1.03%, a sensitivity of 92.69±1.29%, and a specificity of 92.78±1.51%. The area under the curve is 0.95±0.02. Additionally, this method only cost 0.88 s to identify a subject in online stage, after its volumetric image is preprocessed. CONCLUSION: In terms of classification performance, our method performs better than 10 state-of-the-art approaches and the performance of human observers. Therefore, this proposed method is effective in the detection of Alzheimer's disease.

Music and Dementia: Individual Differences in Response to Personalized Playlists. - Garrido, Sandra; Stevens, Catherine J; Chang, Esther; Dunne, Laura; Perz, Janette (J Alzheimers Dis, 2018)
Personalized music playlists are increasingly being used in health-care contexts to address the psychological and behavioral symptoms in people with dementia. However, there is little understanding of how people with different mental health histories and symptoms respond differently to music. A factorial experiment was conducted to investigate the influence of depression, anxiety, apathy, and cognitive decline on affective response to music. Ninety-nine people with dementia listened to three music playlists based on personal preferences. Activation of facial action units was measured, and behavioural responses continuously observed. Results demonstrated that people with high levels of depression and with symptoms of Alzheimer's type dementia demonstrated increased levels of sadness when listening to music. People with low depression but high levels of apathy demonstrated the highest behavioral evidence of pleasure during music listening, although behavioral evidence declined with severity of cognitive impairment. It is concluded that as well as accounting for personal preferences, music interventions for people with dementia need to take mental health history and symptoms into account.

Mutation Screening of the CHCHD2 Gene for Alzheimer's Disease and Frontotemporal Dementia in Chinese Mainland Population. - Che, Xiang-Qian; Zhao, Qian-Hua; Huang, Yue; Li, Xia; Ren, Ru-Jing; Chen, Sheng-Di; Guo, Qi-Hao; Wang, Gang (J Alzheimers Dis, 2018)
As an important multifunctional protein involved in regulation of mitochondrial metabolism, CHCHD2 was identified as a causative gene for Parkinson's disease (PD), yet the relationship between CHCHD2 and neurodegenerative dementia is not well understood. We directly sequenced the entire coding region of CHCHD2 gene in 150 AD patients, 84 FTD patients, and 417 controls. Four rare putative pathogenic variants of CHCHD2, including rs142444896 (c.5C>T, p.P2L), rs752705344 (c.15C>G, p.S5R), rs145190179 (c.94G>A, p.A32T), and rs182992574 (c.255T>A, p.S85R) were identified from a cohort composed of 150 AD and 84 FTD patients. These results suggest that CH CHD2 gene play an important role in other neurodegenerative disorders from our dementia study in China.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Asian Continental Ancestry Group; Case-Control Studies; China; Female; Frontotemporal Dementia; Genetic Association Studies; Humans; Male; Middle Aged; Mitochondrial Proteins; Mutation; Transcription Factors

Nailfold Capillary Morphology in Alzheimer's Disease Dementia. - Cousins, Clara C; Alosco, Michael L; Cousins, Henry C; Chua, Alicia; Steinberg, Eric G; Chapman, Kimberly R; Bing-Canar, Hanaan; Tripodis, Yorghos; Knepper, Paul A; Stern, Robert A; Pasquale, Louis R (J Alzheimers Dis, 2018)
BACKGROUND: Cerebrovascular disease (CVD) is highly comorbid with Alzheimer's disease (AD), yet its role is not entirely understood. Nailfold video capillaroscopy (NVC) is a noninvasive method of live imaging the capillaries near the fingernail's cuticle and may help to describe further vascular contributions to AD. OBJECTIVE: To examine finger nailfold capillary morphology using NVC in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition (NC). METHODS: We evaluated nailfold capillary hemorrhages, avascular zones ≥100 microns, and degree of tortuosity in 28 NC, 15 MCI, and 18 AD dementia subjects using NVC. Tortuosity was measured with a semi-quantitative rating scale. To assess the relation between nailfold capillary morphological features and diagnostic grouping, univariate and multivariable logistic regression models were fit to the data. RESULTS: 56% of subjects with AD dementia compared to 14% with NC and 13% with MCI displayed moderate to severe tortuosity. Greater severity of tortuosity was associated with 10.6-fold (95% confidence interval [CI]: 2.4, 46.2; p = 0.0018) and 7.4-fold (95% CI: 1.3, 41.3; p = 0.023) increased odds of AD dementia relative to NC and MCI, respectively, after adjusting for multiple covariates. CONCLUSION: Greater nailfold capillary tortuosity was found in participants with AD dementia compared to those with MCI or NC. These data provide preliminary evidence of a systemic microvasculopathy in AD that may be noninvasively and inexpensively evaluated through NVC.

A Natural Benzofuran from the Patagonic Aleurodiscus vitellinus Fungus has Potent Neuroprotective Properties on a Cellular Model of Amyloid-β Peptide Toxicity. - González-Ramírez, Mariela; Gavilán, Javiera; Silva-Grecchi, Tiare; Cajas-Madriaga, Daniel; Triviño, Sergio; Becerra, José; Saez-Orellana, Francisco; Pérez, Claudia; Fuentealba, Jorge (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is characterized by amyloid plaques that form due to an increase in amyloid-β peptide (Aβ) aggregation. One strategy in the search of new treatments for AD focuses on compounds that decrease Aβ accumulation. Compounds containing a benzofuran ring have been described to play an important role in decreasing Aβ-induced toxicity; however, only synthetic benzofurans have been tested thus far. The aim of the present study was to examine the in vitro neuroprotective properties of fomannoxin (Fx), a natural benzofuran isolated from cultures of the Andean-Patagonian fungi Aleurodiscus vitellinus, and evaluate its effect on Aβ peptide. We tested the effect of Fx at a wide concentration range (10-11-10-4 M) in PC-12 cells, and found the compound did not alter cellular viability. Fx also showed a concentration-dependent effect on the Aβ-induced toxicity in PC12 cells, showing viability above 100% at 10-6 M. We then measured the effect of Fx (10-7-10-5 M) on the frequency of cytosolic Ca2+ transients in rat hippocampal neurons at both acute and chronic (24 h) times. Acute incubation with Fx increased the frequency of cytosolic Ca2+ transients to values around 200%, whereas chronic incubation with Fx increased the frequency of Ca2+ transients. Finally, the Aβ-induced decrease in intracellular Ca2+ transients was prevented when Fx (10-6 M) was co-incubated with Aβ (5×10-6 M). The results suggest a potent neuroprotective effect of this naturally occurring benzofuran against Aβ peptide toxicity that could be mediated by an interference with it binding to plasma membrane, and lead Fx as new chemical entity to develop pharmacological tools against Aβ peptide neurotoxicity.
Keywords: Alzheimer Disease; Amyloid beta-Peptides; Animals; Basidiomycota; Benzofurans; Cell Survival; Hippocampus; Neurons; Neuroprotective Agents; PC12 Cells; Plaque, Amyloid; Rats

Naturalistic Driving Study Investigating Self-Regulation Behavior in Early Alzheimer's Disease: A Pilot Study. - Paire-Ficout, Laurence; Lafont, Sylviane; Conte, Fanny; Coquillat, Amandine; Fabrigoule, Colette; Ankri, Joël; Blanc, Frédéric; Gabel, Cécilia; Novella, Jean-Luc; Morrone, Isabella; Mahmoudi, Rachid (J Alzheimers Dis, 2018)
BACKGROUND: Because cognitive processes decline in the earliest stages of Alzheimer's disease (AD), the driving abilities are often affected. The naturalistic driving approach is relevant to study the driving habits and behaviors in normal or critical situations in a familiar environment of participants. OBJECTIVE: This pilot study analyzed in-car video recordings of naturalistic driving in patients with early-stage AD and in healthy controls, with a special focus on tactical self-regulation behavior. METHODS: Twenty patients with early-stage AD (Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), and 21 healthy older adults were included in the study. Data collection equipment was installed in their personal vehicles. Two expert psychologists assessed driving performance using a specially designed Naturalistic Driving Assessment Scale (NaDAS), paying particular attention to tactical self-regulation behavior, and they recorded all critical safety events. RESULTS: Poorer driving performance was observed among AD drivers: their tactical self-regulation behavior was of lower quality. AD patients had also twice as many critical events as healthy drivers and three times more "unaware" critical events. CONCLUSION: This pilot study used a naturalistic approach to accurately show that AD drivers have poorer tactical self-regulation behavior than healthy older drivers. Future deployment of assistance systems in vehicles should specifically target tactical self-regulation components.

Nature of Tau-Associated Neurodegeneration and the Molecular Mechanisms. - Yang, Ying; Wang, Jian-Zhi (J Alzheimers Dis, 2018)
Neurodegeneration is defined as the progressive loss of structure or function of the neurons. As the nature of degenerative cell loss is currently not clear, there is no specific molecular marker to measure neurodegeneration. Therefore, researchers have been using apoptotic markers to measure neurodegeneration. However, neurodegeneration is completely different from apoptosis by morphology and time course. Lacking specific molecular marker has been the major hindrance in research of neurodegenerative disorders. Alzheimer's disease (AD) is the most common neurodegenerative disorder, and tau accumulation forming neurofibrillary tangles is a hallmark pathology in the AD brains, suggesting that tau must play a critical role in AD neurodegeneration. Here we review part of our published papers on tau-related studies, and share our thoughts on the nature of tau-associated neurodegeneration in AD.

The Need to Separate Chronic Traumatic Encephalopathy Neuropathology from Clinical Features. - Iverson, Grant L; Keene, C Dirk; Perry, George; Castellani, Rudolph J (J Alzheimers Dis, 2018)
There is tremendous recent interest in chronic traumatic encephalopathy (CTE) in former collision sport athletes, civilians, and military veterans. This critical review places important recent research results into a historical context. In 2015, preliminary consensus criteria were developed for defining the neuropathology of CTE, which substantially narrowed the pathology previously reported to be characteristic. There are no agreed upon clinical criteria for diagnosis, although sets of criteria have been proposed for research purposes. A prevailing theory is that CTE is an inexorably progressive neurodegenerative disease within the molecular classification of the tauopathies. However, historical and recent evidence suggests that CTE, as it is presented in the literature, might not be pathologically or clinically progressive in a substantial percentage of people. At present, it is not known whether the emergence, course, or severity of clinical symptoms can be predicted by specific combinations of neuropathologies, thresholds for accumulation of pathology, or regional distributions of pathologies. More research is needed to determine the extent to which the neuropathology ascribed to long-term effects of neurotrauma is static, progressive, or both. Disambiguating the pathology from the broad array of clinical features that have been reported in recent studies might facilitate and accelerate research- and improve understanding of CTE.
Keywords: Chronic Traumatic Encephalopathy; Cognition Disorders; Disease Progression; Gait Disorders, Neurologic; Humans; Neurodegenerative Diseases; Neuropathology; Tremor

Negative 11C-PIB PET Predicts Lack of Alzheimer's Disease Pathology in Postmortem Examination. - Scheinin, Noora M; Gardberg, Maria; Röyttä, Matias; Rinne, Juha O (J Alzheimers Dis, 2018)
Our aim was to assess whether in vivo11C-PIB negative memory-impaired subjects may nonetheless exhibit brain Alzheimer's disease (AD) pathology. We re-evaluated the PET images and systematically characterized the postmortem neuropathology of six individuals who had undergone clinically indicated amyloid PET. The single case with negligible amyloid-β (Aβ) pathology had Lewy body disease, where concomitant AD changes are often seen. Further, the subject's plaques were predominantly diffuse. The predictive value of a negative 11C-PIB scan appears to be good, even in memory-impaired populations. Our results suggest that considerable neuritic Aβ plaque pathology in the absence of specific/cortical 11C-PIB binding upon PET is unlikely.

Negative Prospective Memory in Alzheimer's Disease: "Do Not Perform That Action". - El Haj, Mohamad; Coello, Yann; Kapogiannis, Dimitrios; Gallouj, Karim; Antoine, Pascal (J Alzheimers Dis, 2018)
Relatively to "standard" prospective memory, i.e., remembering to perform a future action, little is known about negative prospective memory, i.e., remembering not to perform a future action. This study investigated the latter ability in Alzheimer's disease (AD). AD participants and healthy older adults were asked to click on the keyboard or not to click on it when a cue word was encountered. Results showed more omissions (i.e., forgetting to click the keyboard when the instruction was to do so) in AD participants than in healthy older adults, suggesting a prospective memory deficit. Interestingly, more commissions (i.e., clicking the keyboard when the instruction was not to do so) were also observed in AD participants than in healthy older adults. Similar levels of commissions and omissions were observed in AD participants and in healthy older adults. Also, commissions and omissions were correlated with performance on an inhibition assessment task. Our findings reveal that AD is characterized by not only difficulty in the retrieval of recent information, but also difficulty to inhibit no-longer appropriate stimulus-response associations previously learned, suggesting a specific deficit of negative prospective memory in AD.
Keywords: Aged; Alzheimer Disease; Case-Control Studies; Female; Humans; Inhibition (Psychology); Male; Memory Disorders; Memory, Episodic; Mental Recall; Neuropsychological Tests

A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer's Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOEɛ4 Carriers. - Sapkota, Shraddha; Dixon, Roger A (J Alzheimers Dis, 2018)
BACKGROUND: Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk. OBJECTIVE: We organize three possible combinations into a "network" of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer's disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive trajectories: 1) Apolipoprotein E (APOE), 2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and 3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1 + Phosphatidylinositol-binding clathrin assembly protein). METHOD: We use an accelerated longitudinal design (n = 634; age range = 55-95 years) to test whether AD-GRS (low versus high) moderates the effect of increasing CA-GRS risk on executive function (EF) performance and change as stratified by APOE status (ɛ4+ versus ɛ4-). RESULTS: APOEɛ4 carriers with high AD-GRS had poorer EF performance at the centering age (75 years) and steeper 9-year decline with increasing CA-GRS but this association was not present in APOEɛ4 carriers with low AD-GRS. CONCLUSIONS: APOEɛ4 carriers with high AD-GRS are at elevated risk of cognitive decline when they also possess higher CA-GRS risk. Genetic risk from both common cognitive aging and AD-related indices may interact in intensification networks to differentially predict (1) level and trajectories of EF decline and (2) potential selective vulnerability for transitions into impairment and dementia.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Brain-Derived Neurotrophic Factor; Canada; Catechol O-Methyltransferase; Clusterin; Cognitive Aging; Cognitive Dysfunction; Executive Function; Female; Genetic Predisposition to Disease; Heterozygote; Humans; Longitudinal Studies; Male; Middle Aged; Monomeric Clathrin Assembly Proteins; Neuropsychological Tests; Receptors, Complement 3b

Neural Correlates of Sleep Disturbance in Alzheimer's Disease: Role of the Precuneus in Sleep Disturbance. - Matsuoka, Teruyuki; Imai, Ayu; Fujimoto, Hiroshi; Kato, Yuka; Shibata, Keisuke; Nakamura, Kaeko; Yokota, Hajime; Yamada, Kei; Narumoto, Jin (J Alzheimers Dis, 2018)
BACKGROUND: Sleep disturbance may affect the development of Alzheimer's disease (AD), but the neural correlates of sleep disturbance in AD have not been fully clarified. OBJECTIVE: To examine the factors associated with sleep disturbance in AD. METHODS: A retrospective study was performed in 63 patients with AD. None of the patients had been prescribed antidementia or psychoactive drugs, and all underwent brain magnetic resonance imaging (MRI) before medication. Sleep disturbance was defined as a score of at least 1 point on the sleep disturbance subscale of the Neuropsychiatric Inventory (NPI). Whole brain image analysis was performed using SPM8 and VBM8. A two-sample t-test was used to compare patients with AD with (n = 19) and without (n = 44) sleep disturbance, with age and gender included as covariates. The statistical thresholds were set to an uncorrected p-value of 0.001 at the voxel level and a corrected p-value of 0.05 at the cluster level. In addition, pineal gland volume (PGV) measured using MRI, and white matter hyperintensity (WMH) assessed with the modified Fazekas scale were compared between patients with AD with and without sleep disturbance using independent group t-tests. RESULTS: In whole brain analysis, the precuneus volume in patients with AD with sleep disturbance was significantly smaller than those without sleep disturbance. There were no significant differences in PGV and WMH between the two groups. CONCLUSION: Sleep disturbance in AD was associated with reduction of precuneus volume. This suggests that the precuneus might be an important region in sleep disturbance in AD.

Neuroanatomical Comparison of the "Word" and "Picture" Versions of the Free and Cued Selective Reminding Test in Alzheimer's Disease. - Slachevsky, Andrea; Barraza, Paulo; Hornberger, Michael; Muñoz-Neira, Carlos; Flanagan, Emma; Henriquez, Fernando; Bravo, Eduardo; Farías, Mauricio; Delgado, Carolina (J Alzheimers Dis, 2018)
Episodic memory tests with cued recall, such as the Free and Cued Selective Reminding Test (FCSRT), allow for the delineation of hippocampal and prefrontal atrophy contributions to memory performance in Alzheimer's disease (AD). Both Word and Picture versions of the test exist but show different profiles, with the Picture version usually scoring higher across different cohorts. One possible explanation for this divergent performance between the different modality versions of the test might be that they rely on different sets of neural correlates. The current study explores this by contrasting the neural correlates of the Word and Picture versions of the FCSRT with voxel-based morphometry (VBM) in AD and healthy subjects. We predicted that the Picture version would be associated with different cortical regions than the Word version, which might be more hippocampal-centric. When comparing 35 AD patients and 34 controls, AD patients exhibited impairments on both versions of the FCSRT and both groups performed higher in the Picture version. A region of interest analysis based on prior work revealed significant correlations between free recall of either version with atrophy of the temporal pole and hippocampal regions. Thus, contrary to expectations, performance on both the Word and the Picture version of the FCSRT is associated with largely overlapping networks. Free recall is associated with hippocampal volume and might be properly considered as an indicator of hippocampal structural integrity.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Case-Control Studies; Cues; Female; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Memory, Episodic; Mental Recall; Middle Aged; Neuropsychological Tests; Photic Stimulation

Neuroepigenetics and Alzheimer's Disease: An Update. - Zusso, Morena; Barbierato, Massimo; Facci, Laura; Skaper, Stephen D; Giusti, Pietro (J Alzheimers Dis, 2018)
Epigenetics is the study of changes in gene expression which may be triggered by both genetic and environmental factors, and independent from changes to the underlying DNA sequence-a change in phenotype without a change in genotype-which in turn affects how cells read genes. Epigenetic changes represent a regular and natural occurrence but can be influenced also by factors such as age, environment, and disease state. Epigenetic modifications can manifest themselves not only as the manner in which cells terminally differentiate, but can have also deleterious effects, resulting in diseases such as cancer. At least three systems including DNA methylation, histone modification, and non-coding RNA (ncRNA)-associated gene silencing are thought to initiate and sustain epigenetic change. For example, in Alzheimer's disease (AD), both genetic and non-genetic factors contribute to disease etiopathology. While over 250 gene mutations have been related to familial AD, less than 5% of AD cases are explained by known disease genes. More than likely, non-genetic factors, probably triggered by environmental factors, are causative factors of late-onset AD. AD is associated with dysregulation of DNA methylation, histone modifications, and ncRNAs. Among the classes of ncRNA, microRNAs (miRNAs) have a well-established regulatory relevance. MicroRNAs are highly expressed in CNS neurons, where they play a major role in neuron differentiation, synaptogenesis, and plasticity. MicroRNAs impact higher cognitive functions, as their functional impairment is involved in the etiology of neurological diseases, including AD. Alterations in the miRNA network contribute to AD disease processes, e.g., in the regulation of amyloid peptides, tau, lipid metabolism, and neuroinflammation. MicroRNAs, both as biomarkers for AD and therapeutic targets, are in the early stages of exploration. In addition, emerging data suggest that altered transcription of long ncRNAs, endogenous, ncRNAs longer than 200 nucleotides, may be involved in an elevated risk for AD.

NeuroEPO Preserves Neurons from Glutamate-Induced Excitotoxicity. - Garzón, Fernando; Coimbra, Débora; Parcerisas, Antoni; Rodriguez, Yamila; García, Julio Cesar; Soriano, Eduardo; Rama, Ramón (J Alzheimers Dis, 2018)
Many experimental studies show that erythropoietin (EPO) has a neuroprotective action in the brain. EPO in acute and chronic neurological disorders, particularly in stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, has neuroprotective effects. We previously reported the neuroprotective effect of NeuroEPO, a low sialic form of EPO, against oxidative stress induced by glutamate excitotoxicity. In this paper, we analyze the effect of NeuroEPO against apoptosis induced by glutamate excitotoxicity in primary neuronal cultures obtained from the forebrains of Wistar rat embryos after 17 days of gestation. Excitotoxicity was induced after nine days of in vitro culture by treatment with a culture medium containing 100μM glutamate for 15 min. To withdraw glutamate, a new medium containing 100 ng NeuroEPO/mL was added. Apoptosis was analyzed after 24 h. Images obtained by phase contrast microscopy show that neurons treated with glutamate exhibit cell body shrinkage, loss of dendrites that do not make contact with neighboring cells, and that NeuroEPO was able to preserve the morphological characteristics of the control. Immunocytochemistry images show that the culture is essentially pure in neurons; that glutamate causes cell mortality, and that this is partially avoided when the culture medium is supplemented with NeuroEPO. Activation of intrinsic apoptotic pathways was analyzed. The decreases in Bcl-2/Bax ratio, increase in the release of cytochrome c, and in the expression and activity of caspase-3 observed in cells treated with glutamate, were restored by NeuroEPO. The results from this study show that NeuroEPO protects cortical neurons from glutamate-induced apoptosis via upregulation of Bcl-2 and inhibit glutamate-induced activation of caspase-3.

Neuro-Immuno-Gene- and Genome-Editing-Therapy for Alzheimer's Disease: Are We There Yet? - Raikwar, Sudhanshu P; Thangavel, Ramasamy; Dubova, Iuliia; Ahmed, Mohammad Ejaz; Selvakumar, Pushpavathi Govindhasamy; Kempuraj, Duraisamy; Zaheer, Smita; Iyer, Shankar; Zaheer, Asgar (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a highly complex neurodegenerative disorder and the current treatment strategies are largely ineffective thereby leading to irreversible and progressive cognitive decline in AD patients. AD continues to defy successful treatment despite significant advancements in the field of molecular medicine. Repeatedly, early promising preclinical and clinical results have catapulted into devastating setbacks leading to multi-billion dollar losses not only to the top pharmaceutical companies but also to the AD patients and their families. Thus, it is very timely to review the progress in the emerging fields of gene therapy and stem cell-based precision medicine. Here, we have made sincere efforts to feature the ongoing progress especially in the field of AD gene therapy and stem cell-based regenerative medicine. Further, we also provide highlights in elucidating the molecular mechanisms underlying AD pathogenesis and describe novel AD therapeutic targets and strategies for the new drug discovery. We hope that the quantum leap in the scientific advancements and improved funding will bolster novel concepts that will propel the momentum toward a trajectory leading to a robust AD patient-specific next generation precision medicine with improved cognitive function and excellent life quality.

Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer's Disease. - Ehrenberg, Alexander J; Suemoto, Claudia K; França Resende, Elisa de Paula; Petersen, Cathrine; Leite, Renata Elaine Paraizo; Rodriguez, Roberta Diehl; Ferretti-Rebustini, Renata Eloah de Lucena; You, Michelle; Oh, Jun; Nitrini, Ricardo; Pasqualucci, Carlos Augusto; Jacob-Filho, Wilson; et al. (J Alzheimers Dis, 2018)
Clarifying the relationships between neuropsychiatric symptoms and Alzheimer's disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

Neuroprotective Effects of Amylin Analogues on Alzheimer's Disease Pathogenesis and Cognition. - Grizzanti, John; Corrigan, Rachel; Casadesus, Gemma (J Alzheimers Dis, 2018)
Type II diabetes (T2D) has been identified as a major risk factor for the development of Alzheimer's disease (AD). Interestingly, both AD and T2D have similar characteristics including amyloid peptide aggregation, decreased metabolism, and increased oxidative stress and inflammation. Despite their prevalence, therapies for these diseases are limited. To date, most therapies for AD have targeted amyloid-β or tau. Unfortunately, most of these clinical trials have been largely unsuccessful, creating a crucial need for novel therapies. A number of studies have shown that metabolic hormone therapies are effective at ameliorating high blood glucose levels in diabetics as well as improving cognitive function in AD and mild cognitive impairment patients. Pramlintide, a synthetic analogue of the pancreatic hormone amylin, has been developed and used for years now as a treatment for both type I diabetes and T2D due to the loss of β-islet cells responsible for producing amylin. Importantly, recent data demonstrates its potential therapeutic role for AD as well. This review aims at addressing parallels between T2D and AD at a pathological and functional level, focusing on amylin signaling as a key, overlapping mediator in both diseases. The potential therapeutic use of this hormone to treat AD will also be explored from a mechanistic viewpoint.

Neuroprotective Effects of Ferruginol, Jatrophone, and Junicedric Acid Against Amyloid-β Injury in Hippocampal Neurons. - Zolezzi, Juan M; Lindsay, Carolina B; Serrano, Felipe G; Ureta, Roxana C; Theoduloz, Cristina; Schmeda-Hirschmann, Guillermo; Inestrosa, Nibaldo C (J Alzheimers Dis, 2018)
Soluble amyloid-β (Aβ) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aβ oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aβ peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aβ oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aβ oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aβ oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD.

Neuroprotective Effects of Ginsenoside Rf on Amyloid-β-Induced Neurotoxicity in vitro and in vivo. - Du, Yehong; Fu, Min; Wang, Yu Tian; Dong, Zhifang (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is a neurodegenerative disease characterized by the deposition of amyloid-β peptides (Aβ). Aβ accumulation leads to the formation of neurofibrillary tangles, inflammation, axonal injury, synapse loss, and neuronal apoptosis. Thus, reducing Aβ levels should exert a neuroprotective effect against AD. Ginsenoside Rf, an extract from Panax notoginseng, has potent anti-fatigue, anti-nociception, anti-oxidation, and anti-inflammation properties. However, it is unclear whether ginsenoside Rf is effective in the treatment of AD. Here, we reported that ginsenoside Rf could significantly attenuate Aβ-induced apoptosis in N2A cells, as reflected by a dramatic increase in mitochondrial membrane potential and decrease in Ca2 + concentration, reactive oxygen species, and active caspase-3 expression. Meanwhile, ginsenoside Rf could alleviate the Aβ-induced inflammation reaction, such as the decrease of interferon-gamma (IFN-γ) and active caspase-1 expression and the increase of interleukin-13. Furthermore, we also found that Rf is able to accelerate Aβ clearance and subsequently reduces Aβ level in N2A cells stably transfected with human Swedish mutant APP695 (N2A-APP). More importantly, daily Rf treatment (20 mg/kg, i.p.) throughout the experiment dramatically improved spatial learning and memory in Aβ42-induced mouse model of AD. Taken together, these results indicate that ginsenoside Rf may decrease Aβ-induced neurotoxicity and memory decline via anti-inflammatory response during AD development, suggesting that Rf may be a potential therapeutic agent for treating AD.

Neuropsychiatric and Cognitive Subtypes among Community-Dwelling Older Persons and the Association with DSM-5 Mild Neurocognitive Disorder: Latent Class Analysis. - Liew, Tau Ming; Yu, Junhong; Mahendran, Rathi; Ng, Tze-Pin; Kua, Ee-Heok; Feng, Lei (J Alzheimers Dis, 2018)
BACKGROUND: Neuropsychiatric symptoms (NPS) have been shown to increase the risk of neurocognitive disorders (NCD), leading to the recently-published criteria of mild behavioral impairment (MBI) to identify pre-dementia using NPS alone. However, MBI drew concerns about over-diagnosing subclinical psychiatric disorders. OBJECTIVE: We hypothesized that the specificity of NPS in predicting NCD may be improved by considering NPS together with various domains of cognitive deficits. We tested this hypothesis by identifying subtypes based on the combination of NPS and cognitive deficits among community-dwelling older persons, and evaluating how the identified subtypes were associated with mild NCD. METHODS: Our participants were from a community-based cohort study. They completed assessments such as Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), and Montreal Cognitive Assessment (MoCA). Those with possible cognitive impairment underwent further evaluations for mild NCD. Latent class analysis was conducted using GDS, GAI, and MoCA domains. Logistic regression was performed to investigate the association between the latent-classes and mild NCD. RESULTS: We included 825 participants, and identified four distinct subtypes: Subtype 1 (no NPS or cognitive deficits), Subtype 2 (NPS alone), Subtype 3 (cognitive deficits alone), and Subtype 4 (both NPS and cognitive deficits). Subtype 1 and 2 had low risk of prevalent mild NCD (OR 0.92- 1.00), while Subtype 3 conferred a moderate risk (OR 4.47- 4.85) and Subtype 4 had the highest risk (OR 7.95- 8.63). CONCLUSION: We demonstrated the benefits of combining NPS and cognitive deficits to predict those at highest risk of prevalent mild NCD. Our findings highlighted the relevance of subclinical psychiatric symptoms in predicting NCD, and indirectly supported the need for longer durations of NPS to improve its specificity.
Keywords: Aged; Cognition; Cognitive Dysfunction; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Latent Class Analysis; Logistic Models; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Sensitivity and Specificity

Neuropsychiatric Symptoms and the Diagnostic Stability of Mild Cognitive Impairment. - Sugarman, Michael A; Alosco, Michael L; Tripodis, Yorghos; Steinberg, Eric G; Stern, Robert A (J Alzheimers Dis, 2018)
BACKGROUND: Mild cognitive impairment (MCI) is an intermediate diagnosis between normal cognition (NC) and dementia, including Alzheimer's disease (AD) dementia. However, MCI is heterogeneous; many individuals subsequently revert to NC while others remain stable at MCI for several years. Identifying factors associated with this diagnostic instability could assist in defining clinical populations and determining cognitive prognoses. OBJECTIVE: The current study examined whether neuropsychiatric symptoms could partially account for the temporal instability in cognitive diagnoses. METHOD: The sample included 6,763 participants from the National Alzheimer's Coordinating Center Uniform Data Set. All participants had NC at baseline, completed at least two follow-up visits (mean duration: 5.5 years), and had no recent neurological conditions. Generalized linear models estimated by generalized estimating equations examined associations between changes in cognitive diagnoses and symptoms on the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS-15). RESULTS: 1,121 participants converted from NC to MCI; 324 reverted back to NC and 242 progressed to AD dementia. Higher symptoms on the GDS-15 and circumscribed symptom domains on the NPI-Q were associated with conversion from NC to MCI and a decreased likelihood of reversion from MCI to NC. Individuals with higher symptoms on NPI-Q Hyperactivity and Mood items were more likely to progress to AD dementia. DISCUSSION: The temporal instability of MCI can be partially explained by neuropsychiatric symptoms. Individuals with higher levels of specific symptoms are more likely to progress to AD dementia and less likely to revert to NC. Identification and treatment of these symptoms might support cognitive functioning in older adults.

Neuropsychiatric Symptoms Complicating the Diagnosis of Alzheimer's Disease: A Case Report. - Eikelboom, Willem S; van Rooij, Jeroen G J; van den Berg, Esther; Coesmans, Michiel; Jiskoot, Lize C; Singleton, Ellen; Ossenkoppele, Rik; van Swieten, John C; Seelaar, Harro; Papma, Janne M (J Alzheimers Dis, 2018)
Neuropsychiatric symptoms (NPS) are increasingly recognized as a core element of Alzheimer's disease (AD); however, clinicians still consider AD primarily as a cognitive disorder. We describe a case in which the underrecognition of NPS as part of AD resulted in substantial delay of an AD diagnosis, a wrong psychiatric diagnosis, and the organization of inappropriate care. The aim of this paper is to acknowledge NPS as an (early) manifestation of AD and to suggest features that may point toward underlying AD in older adults with late-life behavioral changes.

Neuropsychological Predictors of Long-Term (10 Years) Mild Cognitive Impairment Stability. - Alves, Luísa; Cardoso, Sandra; Maroco, João; de Mendonça, Alexandre; Guerreiro, Manuela; Silva, Dina (J Alzheimers Dis, 2018)
BACKGROUND: Although the diagnosis of mild cognitive impairment (MCI) corresponds to a condition likely to progress to dementia, essentially Alzheimer's disease, longitudinal studies have shown that some patients may not convert to dementia and maintain the diagnosis of MCI even after many years. OBJECTIVES: To determine whether patients that maintain the diagnosis of MCI in the long term (10 years) are really stable or just declining slowly, and to identify clinical and neuropsychological characteristics associated with long-term stability. METHODS: The Cognitive Complaints Cohort (CCC) was searched for MCI cases who maintained that diagnosis for at least 10 years. For each long-term-stable MCI patient, two MCI patients that converted to dementia during follow-up, matched for age and education, were selected from the same database. The baseline and last neuropsychological evaluations for long-term-stable MCI and converter MCI were compared. Baseline neuropsychological predictors of long-term stability were searched for. RESULTS: Long-term-stable MCI (n = 22) and converter MCI (n = 44) patients did not differ in terms of gender distribution, education, age at first assessment and time between symptom onset and first evaluation. Time of follow-up was on average 11 years for long-term-stable MCI and 3 years for converter MCI. The baseline and follow-up neuropsychological tests were not significantly different in long-term-stable MCI patients, whereas a general decline was observed in converter MCI patients. Higher scores on one memory test, the Word Delayed Total Recall, and on the non-verbal abstraction test, Raven's Progressive Matrices, at the baseline predicted long-term (10 years) clinical stability. CONCLUSIONS: Some patients with MCI remain clinically and neuropsychologically stable for a decade. Better performances at baseline in memory and non-verbal abstraction tests predict long-term stability.

Neurotoxic Effects of Aβ6-42 Peptides Mimicking Putative Products Formed by the Angiotensin Converting Enzyme. - Medvedev, Alexei E; Radko, Sergey P; Yurinskaya, Marina M; Vinokurov, Maxim G; Buneeva, Olga A; Kopylov, Arthur T; Kozin, Sergey A; Mitkevich, Vladimir A; Makarov, Alexander A (J Alzheimers Dis, 2018)
Angiotensin converting enzyme (ACE) is involved in proteolytic processing of the amyloid-β(Aβ) peptide implicated in the development of Alzheimer's disease (AD) and known products of ACE-based processing of Aβ42 are characterized by reduced aggregability and cytotoxicity. Recently it has been demonstrated that ACE can act as an arginine specific endopeptidase cleaving the N-terminal pentapeptide (Aβ1-5) from synthetic Aβ peptide analogues. In the context of proteolytic processing of full length Aβ42, this suggests possible formation of Aβ6-42 species. The aim of this study was to test a hypothesis that some N-terminally truncated Aβ peptide(s) could retain aggregability and neurotoxic properties typical for Aβ42. We have investigated aggregability of two amyloid-β peptides, Aβ6-42 and isoD7-Aβ6-42, mimicking potential proteolytic products of Aβ42 and isoD7-Aβ42, and evaluated their effects on the repertoire of brain Aβ binding proteins, and cytotoxicity towards neuroblastoma SH-SY5Y cells. Aggregability of isoD7-Aβ6-42 and Aβ6-42 was higher than that of full-length peptides Aβ42 and isoD7-Aβ42, while the repertoire of mouse brain Aβ binding proteins dramatically decreased. Aβ6-42 and isoD7-Aβ6-42 exhibited higher neurotoxicity towards SH-SY5Y cells than Aβ42 and isoD7-Aβ42, respectively. They effectively stimulated production of ROS and NO, and also TNFα secretion by cells. Thus, our results suggest that ACE-dependent processing of full-length Aβs could result in formation of more pathogenic peptides.

New Beginnings in Alzheimer's Disease: The Most Prevalent Tauopathy. - Hernández, Félix; Llorens-Martín, María; Bolós, Marta; Pérez, Mar; Cuadros, Raquel; Pallas-Bazarra, Noemí; Zabala, Juan C; Avila, Jesús (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is characterized by the presence of two aberrant structures: namely senile plaques, composed of amyloid-β peptide (Aβ), and neurofibrillary tangles, composed of tau protein. In this regard, Aβ and tau protein have been widely studied in research efforts aiming to find a therapy for AD. Aβ and tau pathologies do not always overlap. The precursor of Aβ is expressed in peripheral tissues and in the central nervous system (CNS), whereas tau is mainly a neuronal protein. Since AD is a disease of the CNS, it has been proposed that Aβ may initiate the disease process, with tau being the executor. In this review, we will focus on future studies of tau pathology, although we will comment on new beginnings for AD, as other molecules other than Aβ and tau may be involved in the onset of dementia.

New Insights into the Spontaneous Human Alzheimer's Disease-Like Model Octodon degus: Unraveling Amyloid-β Peptide Aggregation and Age-Related Amyloid Pathology. - Cisternas, Pedro; Zolezzi, Juan M; Lindsay, Carolina; Rivera, Daniela S; Martinez, Alexis; Bozinovic, Francisco; Inestrosa, Nibaldo C (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite advances in our understanding of the molecular milieu driving AD pathophysiology, no effective therapy is currently available. Moreover, various clinical trials have continued to fail, suggesting that our approach to AD must be revised. Accordingly, the development and validation of new models are highly desirable. Over the last decade, we have been working with Octodon degus (degu), a Chilean rodent, which spontaneously develops AD-like neuropathology, including increased amyloid-β (Aβ) aggregates, tau hyperphosphorylation, and postsynaptic dysfunction. However, for proper validation of degu as an AD model, the aggregation properties of its Aβ peptide must be analyzed. Thus, in this study, we examined the capacity of the degu Aβ peptide to aggregate in vitro. Then, we analyzed the age-dependent variation in soluble Aβ levels in the hippocampus and cortex of third- to fifth-generation captive-born degu. We also assessed the appearance and spatial distribution of amyloid plaques in O. degus and compared them with the plaques in two AD transgenic mouse models. In agreement with our previous studies, degu Aβ was able to aggregate, forming fibrillar species in vitro. Furthermore, amyloid plaques appeared in the anterior brain structures of O. degus at approximately 32 months of age and in the whole brain at 56 months, along with concomitant increases in Aβ levels and the Aβ42/Aβ40 ratio, indicating that O. degus spontaneously develops AD-like pathology earlier than other spontaneous models. Based on these results, we can confirm that O. degus constitutes a valuable model to improve AD research.

A New Perspective in Utilizing MMP-9 as a Therapeutic Target for Alzheimer's Disease and Type 2 Diabetes Mellitus. - Kaminari, Archontia; Tsilibary, Effie C; Tzinia, Athina (J Alzheimers Dis, 2018)
Matrix metalloprotease 9 (MMP-9) is a 92 kDa type IV collagenase and a member of the family of endopeptidases. MMP-9 is involved in the degradation of extracellular matrix components, tissue remodeling, cellular receptor stripping, and processing of various signaling molecules. In the CNS, the effects of MMP-9 are quite complex, since it exerts beneficial effects including neurogenesis, angiogenesis, myelogenesis, axonal growth, and inhibition of apoptosis, or destructive effects including apoptosis, blood-brain barrier disorder, and demyelination. Likewise, in the periphery, physiological events, as the involvement of MMP-9 in angiogenesis, for instance in wound healing, can be turned into pathological, such as in tumor metastasis, depending on the state of the organism. Alzheimer's disease is a neurodegenerative disorder, characterized by amyloid accumulation and deposition in the brain. Amyloidogenesis, however, also occurs in diseases of the periphery, such as type II diabetes mellitus, where an analogous type of amyloid, is deposited in the pancreas. Interestingly, both diseases exhibit similar pathology and disease progression, with insulin resistance being a major common denominator. Hence, combinatorial strategies searching new or existing molecules to apply for therapeutic use for both diseases are gaining momentum. MMP-9 is extensively studied due to its association with a variety of physiological and pathological processes. Consequently, meticulous design could render MMP-9 into a potential therapeutic target for Alzheimer's disease and type 2 diabetes mellitus; two seemingly unrelated diseases.

No Effects of Black Tea on Cognitive Decline Among Older US Men: A Prospective Cohort Study. - Feng, Lei; Langsetmo, Lisa; Yaffe, Kristine; Sun, Ye; Fink, Howard A; Shikany, James M; Leung, P C; Lane, Nancy E; Cauley, Jane A (J Alzheimers Dis, 2018)
BACKGROUND: Accumulating evidence supports the neuroprotective effects of bioactive compounds from tea leaves. There are limited data from black tea consumption populations. OBJECTIVE: To determine whether black tea consumption is associated with cognitive decline among older men. METHODS: We chose to study the association between black tea consumption and cognition using data from the Osteoporotic Fractures in Men (MrOS) cohort, which collected information on tea consumption at baseline and has repeatedly assessed cognitive function in 3,844 men aged 65+ years (mean = 72.4 years). We defined tea drinkers as those who drank black tea at least once per week and further grouped them into weekly drinkers and daily drinkers. Cognitive function was assessed at baseline and approximately 7 years later using the Modified Mini-Mental State Examination (3MSE). Multivariable logistic regression and linear regression models were constructed to assess the association between black tea consumption and risk of fast cognitive decline as a binary variable and change in 3MSE scores as continuous variable. Fast cognitive decline was defined as decline in 3MSE >1.5 standard deviation of mean change score. Models were adjusted for age, education level, and baseline cognitive scores. RESULTS: Weekly and daily black tea drinkers were 24.8% and 12.4% of the study cohort, respectively. Fast cognitive decline occurred in 243 (6.3%) participants. Tea consumption was not associated with risk of cognitive decline, nor was tea associated with cognitive decline measured by absolute change in 3MSE scores. CONCLUSIONS: There was no association of black tea consumption and cognitive decline among older men in the US.

NO-Dependent Akt Inactivation by S-Nitrosylation as a Possible Mechanism of STZ-Induced Neuronal Insulin Resistance. - Crunfli, Fernanda; Mazucanti, Caio Henrique; de Moraes, Ruan Carlos Macêdo; Costa, Andressa Pereira; Rodrigues, Alice Cristina; Scavone, Cristoforo; Torrão, Andréa da Silva (J Alzheimers Dis, 2018)
Sporadic Alzheimer's disease (sAD) is associated with energy metabolism deficiency and impairment of insulin receptor (IR) signaling in the brain. In this context, low doses of intracerebroventricular (icv) injection of streptozotocin (STZ) in rodents has been used as an experimental model of sAD which leads to an insulin-resistant brain state and neurodegeneration. However, the STZ effects on brain insulin signaling-related proteins it is not appropriately elucidated. The aim of this study was to evaluate the beginning and progression of alterations in the brain IR pathway of rats after 1, 3, 5, and 7 days of STZ injection and investigate intracellular signaling involved on STZ induced insulin resistance. We observed that STZ injection causes cognitive impairment in the animals, a temporal variation of the insulin signaling-related proteins and apoptosis cell death in the hippocampus. We also have shown that STZ causes insulin resistance and impairment on phosphoinositide 3-kinase (PI3K) activity in the Neuro-2a cells through protein kinase B (Akt) inactivation by S-nitrosylation, which could upregulate GSK3-β activity. STZ ability to cause an insulin-resistant neuron state involves NO production and ROS production which may play an important role in the mechanism linked to STZ-induced neurotoxicity. The icv injection of STZ model and STZ exposed Neuro-2a cells may be potential experimental models for assessing molecules related to the pathogenesis of sAD.

A Nomogram for Predicting Amyloid PET Positivity in Amnestic Mild Cognitive Impairment. - Kim, Si Eun; Woo, Sookyoung; Kim, Seon Woo; Chin, Juhee; Kim, Hee Jin; Lee, Byung In; Park, Jinse; Park, Kyung Won; Kang, Do-Young; Noh, Young; Ye, Byoung Seok; Yoo, Han Soo; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Most clinical trials focus on amyloid-β positive (Aβ+) amnestic mild cognitive impairment (aMCI), but screening failures are high because only a half of patients with aMCI are positive on Aβ PET. Therefore, it becomes necessary for clinicians to predict which patients will have Aβ biomarker. OBJECTIVE: We aimed to compare clinical factors, neuropsychological (NP) profiles, and apolipoprotein E (APOE) genotype between Aβ+ aMCI and Aβ-aMCI and to develop a clinically useful prediction model of Aβ positivity on PET (PET-Aβ+) in aMCI using a nomogram. METHODS: We recruited 523 aMCI patients who underwent Aβ PET imaging in a nation-wide multicenter cohort. The results of NP measures were divided into following subgroups: 1) Stage (Early and Late-stage), 2) Modality (Visual, Verbal, and Both), 3) Recognition failure, and 4) Multiplicity (Single and Multiple). A nomogram for PET-Aβ+ in aMCI patients was constructed using a logistic regression model. RESULTS: PET-Aβ+ had significant associations with NP profiles for several items, including high Clinical Dementia Rating Scale Sum of Boxes score (OR 1.47, p = 0.013) and impaired memory modality (impaired both visual and verbal memories compared with visual only, OR 3.25, p = 0.001). Also, presence of APOEɛ4 (OR 4.14, p < 0.001) was associated with PET-Aβ+. These predictors were applied to develop the nomogram, which showed good prediction performance (C-statistics = 0.79). Its prediction performances were 0.77/0.74 in internal/external validation. CONCLUSIONS: The nomogram consisting of NP profiles, especially memory domain, and APOEɛ4 genotype may provide a useful predictive model of PET-Aβ+ in patients with aMCI.

Non-Ashkenazi Jewish Origin is Associated with Early Onset Alzheimer's Disease. - Keret, Ophir; Shochat, Tzippy; Steiner, Israel; Glik, Amir (J Alzheimers Dis, 2018)
Early-onset Alzheimer's disease (EOAD) accounts for 1-5% of Alzheimer's disease cases and is associated with specific ethnicities. It has been our impression that non-Ashkenazi Jews have a higher rate of EOAD and we therefore explored this hypothesis. We performed a retrospective case control study of EOAD cases referred to our cognitive neurology clinic between January 1999 and December 2016. Patients (n = 129) were compared to age- and geographically-matched controls generated from the Second Israeli National Health Survey (n = 1,811). Data on country of origin, education, dementia family history, depression, and vascular risk factors were compared between the groups. The association of non-Ashkenazi Jewish heritage and country of origin with EOAD was calculated using a logistic multivariate regression model. The EOAD group's mean age was 59.6±4.1 years, with a female predominance (64.3%). The EOAD group had a higher percentage of individuals of non-Ashkenazi Jewish origin (64.3% versus 51.4%, p = 0.003) and of Yemenite descent in particular (16.28% versus 6.24%, p < 0.001). On multiple logistic regression analysis, Yemenite Jewish origin was an independently associated with EOAD (OR 2.54, 95% CI 1.4-4.8). There were no significant differences in parameters between non-Ashkenazi and Ashkenazi Jews. Only 4.6% of EOAD cases had a positive EOAD family history. In conclusion, EOAD is over-represented among non-Ashkenazi Jews. Yemenite origin is independently associated with EOAD and the majority of patients with EOAD have no family history of Alzheimer's disease. Further evaluation with genetic studies is warranted.

Non-Genetic Risk Factors for Degenerative and Vascular Young Onset Dementia: Results from the INSPIRED and KGOW Studies. - Cations, Monica; Draper, Brian; Low, Lee-Fay; Radford, Kylie; Trollor, Julian; Brodaty, Henry; Sachdev, Perminder; Gonski, Peter; Broe, Gerald Anthony; Withall, Adrienne (J Alzheimers Dis, 2018)
BACKGROUND: Several brain reserve, vascular risk, and other modifiable factors have been associated with late-onset dementia, but their association with young onset dementia (YOD) has not been adequately explored. OBJECTIVE: To examine the association of cognitive reserve enhancing factors, cardiovascular risk factors (including smoking), depression, alcohol use, and traumatic brain injury (TBI) with non-autosomal dominant degenerative and/or vascular YOD. METHODS: Data for this matched case-control study were taken from two larger studies conducted in NSW, Australia. One comprised all people with YOD within a geographical region, while the other exclusively included Aboriginal and Torres Strait Islander participants. Dementia diagnosis was confirmed by clinical consensus, and risk exposure was retrospectively self- and/or informant-reported. RESULTS: Participants were 96 people with YOD (58.4% with probable Alzheimer's disease) and 175 age-group, sex, and sample matched control participants. Poor educational attainment, low participation in cognitive leisure activity, stroke, transient ischemic attack, and self-reported very heavy alcohol use were related to the risk of primary degenerative and/or vascular YOD. The effect of hypertension and depression varied depending on when they occurred relative to dementia onset. Current smoking was significantly associated with risk in univariate analyses but did not retain significance in multivariate modelling. There was no association with hypercholesterolemia, diabetes, or TBI of any kind. Some compensation for low educational attainment was possible via a complex occupation later in life. CONCLUSION: Non-genetic factors have a role in YOD, though the relative importance of each factor may be different to late onset dementia. The timing and severity of exposure, as well as the potential for compensation with later protective exposures, are important considerations for potential prevention strategies.

Non-Phosphorylated Tau in Cerebrospinal Fluid is a Marker of Alzheimer's Disease Continuum in Young Urbanites Exposed to Air Pollution. - Calderón-Garcidueñas, Lilian; Mukherjee, Partha S; Waniek, Katharina; Holzer, Max; Chao, Chih-Kai; Thompson, Charles; Ruiz-Ramos, Rubén; Calderón-Garcidueñas, Ana; Franco-Lira, Maricela; Reynoso-Robles, Rafael; González-Maciel, Angelica; Lachmann, Ingolf (J Alzheimers Dis, 2018)
Long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards is associated with Alzheimer's disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82±6.73 y), a high affinity monoclonal non-phosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid-β1-42, BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25±3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p = 0.0055). Aβ1 - 42 and BDNF concentrations were lower in MMC children (p = 0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p = <0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life.

A Novel Antibody Targeting Tau Phosphorylated at Serine 235 Detects Neurofibrillary Tangles. - Brici, David; Götz, Jürgen; Nisbet, Rebecca M (J Alzheimers Dis, 2018)
Alzheimer's disease is characterized by two main pathological hallmarks in the human brain: the extracellular deposition of amyloid-β as plaques and the intracellular accumulation of the hyperphosphorylated protein tau as neurofibrillary tangles (NFTs). Phosphorylated tau (p-tau) specific-antibodies and silver staining have been used to reveal three morphological stages of NFT formation: pre-NFTs, intraneuronal NFTs (iNFTs), and extraneuronal NFTs (eNFTs). Here we characterize a novel monoclonal antibody, RN235, which is specific for tau phosphorylated at serine 235, and detects iNFTs and eNFTs in brain tissue, suggesting that phosphorylation at this site is indicative of late stage changes in tau.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Animals; Antibodies, Monoclonal; Antibody Specificity; Brain; Disease Models, Animal; Humans; Mice; Neurofibrillary Tangles; Phosphorylation; Plaque, Amyloid; tau Proteins

The Novel DA-CH3 Dual Incretin Restores Endoplasmic Reticulum Stress and Autophagy Impairments to Attenuate Alzheimer-Like Pathology and Cognitive Decrements in the APPSWE/PS1ΔE9 Mouse Model. - Panagaki, Theodora; Gengler, Simon; Holscher, Christian (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) afflicts more than 46.8 million people worldwide, with a newly diagnosed case every 3 seconds and no remission in the disease progression. The discovery of disease-modifying drugs is now on the summit of the neuropharmacological research priorities. The long-lasting derivatives of the insulinotropic incretin hormones-glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)-have repeatedly been shown to cross the blood-brain barrier and counteract an array of deleterious effects across a range of experimental models of neuronal degeneration. Clinical trials for the efficacy of GLP-1 agonists in Alzheimer's and Parkinson's diseases have revealed beneficial effects of these anti-diabetic agents in halting neuronal degeneration progression. Herein, we examine whether the chronic treatment with the novel dual GLP-1/GIP receptor agonist DA-CH3 can restore the cognitive decline and AD-like cerebral pathology of the APPSWE/PS1ΔE9 mouse model at the age of 10 months old. We report that once-a-daily, eight-week intraperitoneal administration of 25 nmol/kg of the novel DA-CH3 dual-incretin analog rescues the spatial acquisition and memory impairments of this murine model that corresponds to the attenuation of the excessive plaque deposition, gliosis and synaptic damage in the APPSWE/PS1ΔE9 brain. The amelioration of the AD-related pathology reflects the resolution of the endoplasmic-reticulum stress and derailed autophagy that both lay downstream of the rectified Akt signaling. Collectively, our findings endorse the beneficial effects of the incretin-based therapeutic approaches for the neurotrophic support of the AD brain and for the first time associate the incretin-induced neuroprotection with the proteostasis machinery in vivo.

Novel GRN Mutations in Alzheimer's Disease and Frontotemporal Lobar Degeneration. - Piaceri, Irene; Imperiale, Daniele; Ghidoni, Enrico; Atzori, Cristiana; Bagnoli, Silvia; Ferrari, Camilla; Ungari, Silvana; Ambrogio, Luca; Sorbi, Sandro; Nacmias, Benedetta (J Alzheimers Dis, 2018)
BACKGROUND: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer's disease or psychiatric disorders, jeopardizing care and research. OBJECTIVE: To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer's disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein). METHODS: The genetic screening was performed on 63 probands diagnosed as FAD before the early 2000s. RESULTS: Four patients out of the 63 studied (4/63, 6.3%) resulted as carrying four different GRN genetic variations: p.T272SfsX10, p.R110X, p.C149LfsX10, and p.W304C. The first two mutations (p.T272SfsX10, p.R110X) are the most frequent ones in Italy in FTD patients; the latter two (p.C149LfsX10 and p.W304C) are not described in the scientific literature. CONCLUSION: Our data suggest that it can be important to re-examine FAD patients diagnosed when the FTD spectrum was not well recognized and the causative FTD genes had not yet been identified. Moreover, we propose initially analyzing genes associated with the first form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia.

Novel Key Players in the Development of Tau Neuropathology: Focus on the 5-Lipoxygenase. - Lauretti, Elisabetta; Praticò, Domenico (J Alzheimers Dis, 2018)
Tauopathies belong to a large group of neurodegenerative diseases characterized by progressive accumulation of hyperphosphorylated tau. Tau is a microtubule binding protein which is necessary for their assembly and stability. However, tau affinity for microtubules mainly depends on its phosphorylation status, which is the result of a delicate balance between kinases and phosphatases activity. Any significant changes in this equilibrium can promote tau fibrillation, aggregation, neuronal dysfunction, and ultimately neuronal loss. Despite intensive research, the molecular mechanism(s) leading to tau hyperphosphorylation are still unknown and there is no cure for these diseases. Development of an effective strategy that successfully prevents tau excessive phosphorylation and/or tau aggregation may offer a real therapeutic opportunity for these less investigated neurodegenerative conditions. Beside tau, chronic brain inflammation is a common feature of all tauopathies and 5-lipoxygenase, an inflammatory enzyme, is upregulated in brain regions affected by tau pathology. Recently, in vitro studies and preclinical investigations with animal models of tauopathy have implicated 5-lipoxygenase in the regulation of tau phosphorylation through activation of the cyclin-dependent kinase 5 pathway, supporting the novel hypothesis that this protein is a promising therapeutic target for the treatment of tauopathies. In this article, we will discuss the contribution of the 5-lipoxygenase signaling pathway in the development of tau neuropathology, and the promising potential that drugs targeting this enzyme activation hold as a novel disease-modifying therapeutic approach for tauopathies.

Novel Lipidized Analog of Prolactin-Releasing Peptide Improves Memory Impairment and Attenuates Hyperphosphorylation of Tau Protein in a Mouse Model of Tauopathy. - Popelová, Andrea; Pražienková, Veronika; Neprašová, Barbora; Kasperová, Barbora Judita; Hrubá, Lucie; Holubová, Martina; Zemenová, Jana; Blum, David; Železná, Blanka; Galas, Marie-Christine; Kuneš, Jaroslav; Maletínská, Lenka (J Alzheimers Dis, 2018)
Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated.

A Novel Therapeutic Approach to Treat Alzheimer's Disease by Neurotrophic Support During the Period of Synaptic Compensation. - Baazaoui, Narjes; Iqbal, Khalid (J Alzheimers Dis, 2018)
Alzheimer's disease (AD), at present, is considered an incurable disease and a major dilemma with no drug to stop or slow down its progression. Drugs that are currently available in the market are able to only transiently improve the clinical symptoms. The repeated failures in developing an effective drug has led to the suggestion that the medical intervention was probably too late to be effective since the pathology starts many years before the appearance of the clinical symptoms. Probably, at the time of the appearance of clinical symptoms the brain has undergone major neuronal and synaptic loss. Because of the uncertainty on when to use a prevention therapy, especially targeting amyloid-β (Aβ) and tau pathologies, interventions that rely on the regenerative capacity of the brain such as the modulation of the inherent neurogenesis and neuronal plasticity represent a promising therapeutic strategy. Such an approach can act both at early as well as late stages of the disease and remove the barrier of the time of intervention. In this article, we review studies mainly from our laboratory that show the merit of early intervention during the synaptic and neuronal compensation period where the brain still has the capacity to self-repair by offering neurotrophic support in reversing cognitive impairment, neuronal and synaptic deficits, Aβ, and tau pathologies and decreasing mortality in a transgenic mouse model of AD.

Nutrition: Review on the Possible Treatment for Alzheimer's Disease. - Botchway, Benson O A; Moore, Masania K; Akinleye, Faith O; Iyer, Ishwari C; Fang, Marong (J Alzheimers Dis, 2018)
Since its discovery some hundred years ago, Alzheimer's disease (AD), a neurodegenerative disease and an eminent cause of most dementia, continues to pose problems for affected families and society, especially in developed countries. With the approved medications by the Food and Drugs Administration in the United States, effectual treatment of AD apropos to the complete eradication of the disease continues to be elusive due to complexities relating to the pathophysiology of the disease. Nutrition has and continues to play a salient role in the survival of living organisms with no exception for human beings. Herein, we report the connection between nutrition and AD with particular attention to vitamins, curcumin, and the Mediterranean diet.
Keywords: Alzheimer Disease; Curcumin; Diet, Mediterranean; Dietary Supplements; Humans; Nutritional Status; Risk Factors; Vitamins

Nutritional Intervention as a Preventive Approach for Cognitive-Related Outcomes in Cognitively Healthy Older Adults: A Systematic Review. - Solfrizzi, Vincenzo; Agosti, Pasquale; Lozupone, Madia; Custodero, Carlo; Schilardi, Andrea; Valiani, Vincenzo; Sardone, Rodolfo; Dibello, Vittorio; Di Lena, Luca; Lamanna, Angela; Stallone, Roberta; Bellomo, Antonello; et al. (J Alzheimers Dis, 2018)
The link diet-cognitive function/dementia has been largely investigated in observational studies; however, there was a lack of evidence from randomized clinical trials (RCTs) on the prevention of late-life cognitive disorders though dietary intervention in cognitively healthy older adults. In the present article, we systematically reviewed RCTs published in the last four years (2014-2017) exploring nutritional intervention efficacy in preventing the onset of late-life cognitive disorders and dementia in cognitively healthy subjects aged 60 years and older using different levels of investigation (i.e., dietary pattern changes/medical food/nutraceutical supplementation/multidomain approach and dietary macro- and micronutrient approaches) as well as possible underlying mechanisms of nutritional prevention. From the 35 included RCTs, there was moderate evidence that intervention through dietary pattern changes, medical food/nutraceutical supplementation, and multidomain approach improved specific cognitive domains or cognitive-related blood biomarkers. There was high evidence that protein supplementation improved specific cognitive domains or functional status in prefrail older adults without effect.

Nutritional Intervention to Prevent Alzheimer's Disease: Potential Benefits of Xanthophyll Carotenoids and Omega-3 Fatty Acids Combined. - Nolan, John M; Mulcahy, Riona; Power, Rebecca; Moran, Rachel; Howard, Alan N (J Alzheimers Dis, 2018)
BACKGROUND: A growing body of scientific evidence suggests that enrichment of certain nutritional compounds in the brain may reduce the risk of Alzheimer's disease (AD). OBJECTIVE: To investigate the impact of supplemental xanthophyll carotenoids plus omega-3 fatty acids on disease progression in patients with AD. METHODS: Three trial experiments were performed. In Trials 1 and 2 (performed on patients with AD over an 18-month period), 12 patients (AD status at baseline: 4 mild and 8 moderate) were supplemented with a xanthophyll carotenoid only formulation (Formulation 1; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day) and 13 patients (AD status at baseline: 2 mild, 10 moderate, and 1 severe) were supplemented with a xanthophyll carotenoid and fish oil combination (Formulation 2; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day plus 1 g/day of fish oil containing 430 mg docohexaenoic acid [DHA] and 90 mg eicopentaenoic acid [EPA]), respectively. In Trial 3, 15 subjects free of AD (the control group) were supplemented for 6 months with Formulation 1. Blood xanthophyll carotenoid response was measured in all trials by HPLC. Omega-3 fatty acids were profiled by direct infusion mass spectrometry. RESULTS: Xanthophyll carotenoid concentration increases were significantly greater for Formulation 2 compared to Formulation 1 (p < 0.05), and progression of AD was less for this group (p = 0.003), with carers reporting functional benefits in memory, sight, and mood. CONCLUSION: This preliminary report suggests positive outcomes for patients with AD who consumed a combination of xanthophyll carotenoids plus fish oil, but further study is required to confirm this important observation.

An Objective Method to Accurately Measure Cardiorespiratory Fitness in Older Adults Who Cannot Satisfy Widely Used Oxygen Consumption Criteria. - Dougherty, Ryan J; Lindheimer, Jacob B; Stegner, Aaron J; Van Riper, Stephanie; Okonkwo, Ozioma C; Cook, Dane B (J Alzheimers Dis, 2018)
Cardiorespiratory fitness (CRF) is routinely investigated in older adults; however, the most appropriate CRF measure to use for this population has received inadequate attention. This study aimed to 1) evaluate the reliability and validity of the oxygen uptake efficiency slope (OUES) as a sub-maximal measurement of CRF; 2) examine demographic, risk-factor, and exercise testing differences in older adults who satisfied standardized criteria for a peak oxygen consumption (V̇O2peak) test compared to those who did not; and 3) determine the difference between directly measured V̇O2peak values and OUES-predicted V̇O2peak values. One hundred ten enrollees from the Wisconsin Registry for Alzheimer's Prevention participated in this study. Participants performed a graded maximal exercise test and wore an accelerometer for 7 days. For each participant, the OUES was calculated at 75%, 90%, and 100% of exercise duration. V̇O2peak was recorded at peak effort, and one week of physical activity behavior was measured. OUES values calculated at separate relative exercise durations displayed excellent reliability (ICC = 0.995; p < 0.001), and were strongly correlated with V̇O2peak (rrange = 0.801-0.909; p < 0.001). As hypothesized, participants who did not satisfy V̇O2peak criteria were significantly older than those who satisfied criteria (p = 0.049) and attained a directly measured V̇O2peak that was 2.31 mL·kg·min-1 less than the value that was predicted by OUES V̇O2peak (p = 0.003). Older adults are less likely to satisfy V̇O2peak criteria, which results in an underestimation of their CRF. Without adhering to standardized criteria, V̇O2peak measurement error may lead to misinterpretation of CRF and age-related associations. Here, we conclude that OUES is a reliable, valid measurement of CRF which does not require achievement of standardized criteria.
Keywords: Aged; Cardiorespiratory Fitness; Exercise Test; Female; Humans; Male; Middle Aged; Oxygen Consumption; Reproducibility of Results; Wisconsin

Observational Study of Clinical and Functional Progression Based on Initial Brain MRI Characteristics in Patients with Alzheimer's Disease. - Choi, Hojin; Yang, YoungSoon; Han, Hyun Jeong; Jeong, Jee Hyang; Park, Mee Young; Kim, Yong Bum; Jo, Kwang Deog; Choi, Jin-Yong; Kang, Kyung-Hun; Kang, Heeyoung; Kwon, Do-Young; Yoo, Bong-Goo; et al. (J Alzheimers Dis, 2018)
BACKGROUND: Magnetic resonance imaging (MRI) is a useful tool to predict the diagnosis and progression of Alzheimer's disease (AD), especially for primary physicians. However, the correlation between baseline MRI findings and AD progression has not been fully established. OBJECTIVE: To investigate the correlation between hippocampal atrophy (HA) and white matter hyperintensities (WMH) on initial brain MRI images and the degree of cognitive decline and functional changes over 1 year. METHODS: In this prospective, 12-month observational study, dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments of HA and WMH on baseline brain MRI were derived as well as cognitive function, dementia severity, activities of daily living, and acetylcholinesterase inhibitor (AChEI) use. Follow-up assessments were conducted at 6 and 12 months. RESULTS: Among 899 enrolled dementia patients, 748 were diagnosed with AD of whom 654 (87%) were taking AChEIs. Baseline WMH showed significant correlations with age, current alcohol consumption, and Clinical Dementia Rating score; baseline HA was correlated with age, family history, physical exercise, and the results of cognitive assessments. Among the AChEI group, changes in the Korean version of the Instrumental Activities of Daily Living (K-IADL) were correlated with the severity of HA on baseline brain MRI, but not with the baseline severity of WMH. In the no AChEI group, changes in K-IADL were correlated with the severity of WMH and HA at baseline. CONCLUSION: Baseline MRI findings could be a useful tool for predicting future clinical outcomes by primary physicians, especially in relation to patients' functional status.

Odor Identification Ability Predicts PET Amyloid Status and Memory Decline in Older Adults. - Kreisl, William Charles; Jin, Peng; Lee, Seonjoo; Dayan, Ezra R; Vallabhajosula, Shankar; Pelton, Gregory; Luchsinger, Jose A; Pradhaban, Gnanavalli; Devanand, D P (J Alzheimers Dis, 2018)
BACKGROUND: Odor identification deficits occur in Alzheimer's disease (AD), as measured by the 40-item University of Pennsylvania Smell Identification Test (UPSIT). OBJECTIVE: To determine if UPSIT scores predict amyloid-β (Aβ) status, determined by 11C-Pittsburgh Compound B PET. We also compared UPSIT scores to Aβ status in predicting future memory decline. METHODS: Subjects were recruited into a longitudinal clinical prediction study. We analyzed data from those who had UPSIT, cognitive testing, PIB PET, and at least 12 months' clinical follow-up. Forty-six amnestic mild cognitive impairment patients and 25 cognitively normal controls were included. Amyloid-positivity was defined as composite PIB standardized uptake value ratio >1.5. Logistic regression and Receiver Operating Characteristic Curve analyses tested the predictive utility of impaired olfaction (defined as UPSIT score <35) and amyloid-positivity for memory decline. RESULTS: High UPSIT scores predicted absence of amyloidosis on PET, with negative predictive value of 100%. Positive predictive value of low UPSIT scores on positive Aβ status was only 41%. Both low UPSIT score (OR = 4.301, 95% CI = 1.248, 14.821, p = 0.021) and positive PET scan (OR = 20.898, 95% CI = 2.222, 196.581, p = 0.008) predicted memory decline. CONCLUSION: Individuals with high UPSIT scores are less likely to have cerebral amyloidosis or experience memory decline. Therefore, UPSIT has potential as a screening tool to determine utility of Aβ PET in clinical practice or enrollment in clinical trials. Low UPSIT score is a non-specific marker of neurodegeneration that could indicate further workup in patients with memory complaints.

Olfactory Function is Associated with Cognitive Performance: Results of the Heinz Nixdorf Recall Study. - Tebrügge, Sarah; Winkler, Angela; Gerards, Diana; Weimar, Christian; Moebus, Susanne; Jöckel, Karl-Heinz; Erbel, Raimund; Jokisch, Martha (J Alzheimers Dis, 2018)
BACKGROUND: There is strong evidence for an association of olfactory dysfunction and neurodegenerative diseases. Studies on the association of olfaction and cognition in the general population are rare. OBJECTIVE: To evaluate gender- and age-specific associations of olfactory function and cognitive performance in a well characterized population-based study sample. METHODS: At the third examination of the Heinz Nixdorf Recall study (n = 3,087), 2,640 participants (48% men; 68.2±7.2 years) underwent Sniffin' Sticks Screening Test measuring olfactory function on a scale of 0-12 points. Olfactory function was rated as anosmic, hyposmic, or normosmic (≤6, 7-10 or ≥11 points, respectively). All participants performed eight validated cognitive subtests. Age- (55-64 years, 65-74 years, 75-86 years) and gender-stratified multivariate analysis of covariance was used to evaluate group differences in cognitive performance. RESULTS: Women showed better olfactory function than men (p < 0.001). For middle-aged participants, olfactory groups differed in almost all cognitive subtests. The analyses revealed no gender effects, although associations were slightly greater for women than for men. Anosmics showed the worst cognitive performance and normosmics showed the best cognitive performance. In the young- and old-aged groups, a quantitative association was found for anosmics in all subtests and for normosmics and hyposmics in almost all subtests. CONCLUSION: This is the first study reporting on age-specific associations of olfactory function and cognitive performance in the general population. The association found in middle-aged participants (65-74 years) may serve as a marker to improve identification of persons at high risk for cognitive decline and dementia.

Optical Depolarization of DCX-Expressing Cells Promoted Cognitive Recovery and Maturation of Newborn Neurons via the Wnt/β-Catenin Pathway. - Zhao, Ming-Liang; Chen, Shi-Jin; Li, Xiao-Hong; Wang, Li-Na; Chen, Feng; Zhong, Shi-Jiang; Yang, Cheng; Sun, Sheng-Kai; Li, Jian-Jun; Dong, Hua-Jiang; Dong, Yue-Qing; Wang, Yi; et al. (J Alzheimers Dis, 2018)
Electrical excitability by membrane depolarization is crucial for survival and maturation of newborn cells in the dentate gyrus of the hippocampus. However, traditional technology for membrane depolarization lacks temporal and spatial precision. Optogenetics can be used to activate channelrhodopsin-2 (ChR2), allowing cationic current to depolarize genetically targeted cells. In this study, we used ChR2-EGFP driven by doublecortin (DCX) to promote survival and maturation of newborn cells in the dentate gyrus after traumatic brain injury (TBI). C57BL/6 mice underwent lateral fluid percussion TBI. TBI mice were transfected with a lentivirus carrying the DCX-ChR2-EGFP gene. We observed that not only immature neurons but also type-2b intermediate progenitor (IPs) and neuroblasts expressed DCX-EGFP, indicating that DCX-expressing newborn cells could provide a long time window for electrical activity regulation. Quantitative results showed that the number of EGFP-expressing cells began to rise at 3 days after TBI and peaked at 9 days after TBI. By optical depolarization of DCX-EGFP-expressing cells between 3 and 12 days, we observed significantly improved cognitive deficits after TBI with enhanced survival and maturation of newborn cells in the dentate gyrus. We also investigated the role of optical depolarization in neural stem cells transfected with a lentivirus carrying the ChR2-DCX-EGFP gene in vitro. By administrating verapamil to block L-type calcium channels, we verified that the up-regulation of MAP2, NeuN, Neurog2, NeuroD1 and GluR2 in newborn cells was mediated by ChR2-elicted depolarization. By using β-catenin inhibitor Dkk1, we demonstrated that optical depolarization of DCX-EGFP-expressing cells facilitated survival and maturation probably through the Wnt/β-catenin signaling cascade.

Our Tau Tales from Normal to Pathological Behavior. - Alonso, Alejandra D; Cohen, Leah S (J Alzheimers Dis, 2018)
The microtubule associated protein tau in a hyperphosphorylated form was identified as the building block of the filamentous aggregates found in the neurons of Alzheimer's disease (AD) patients. In the abnormal state, hyperphosphorylated tau from AD brains (AD P-tau) was unable to promote microtubule assembly and more importantly, it could inhibit the normal activity of tau and other MAPs. AD P-tau was able to disrupt preformed microtubules and, by binding to normal tau, turn the latter into an AD P-tau like molecule. AD P-tau toxic behavior was prevalent in the soluble form and it was lost upon dephosphorylation. Mutations on tau associated with disease, e.g., R406W in frontotemporal dementia with Parkinsonism linked to chromosome 17, altered its conformation to make it a better substrate for kinases. Using phospho-mimetics, it was found that the minimum phospho-sites necessary to acquire such a toxic behavior of tau were at 199, 212, 231 and 262, and tau pseudophosphorylated at those sites in combination with R406W was named Pathological Human Tau (PH-Tau). PH-Tau expressed in cells had similar behavior to AD P-tau: disruption of the microtubule system, change in the normal subcellular localization, and gain of toxic function for cells. In animal models expressing PH-Tau, it was found that two putative mechanisms of neurodegeneration exist depending on the concentration of the toxic protein, both involving cognitive decline, due to synaptic dysfunction at lower concentration and neuronal death at higher. Studies investigating the mechanism of tau pathology and its transmission from neuron to neuron are currently ongoing.

Our Working Point of View of Tau Protein. - Avila, Jesús (J Alzheimers Dis, 2018)
Tau protein, which was discovered in Prof. Kirschner's laboratory in 1975, has been the focus of my research over the last 40 years. In this issue of the Journal of Alzheimer's Disease commemorating its 20th year of publication, I will provide a short review of some of the features of my relationship with tau.

Outcomes for Hospitalized Older Adults with Down Syndrome in the United States. - Mendiratta, Priya; Wei, Jeanne Y; Dayama, Neeraj; Li, Xiaocong (J Alzheimers Dis, 2018)
BACKGROUND: Patients with Down syndrome (DS) often survive into adulthood. Relatively little information is currently available regarding hospitalization outcomes among mature, older adults with DS. OBJECTIVE: To identify risk factors associated with hospital mortality rates and increased costs for hospitalized older adults with DS. METHODS: Data on hospitalized older adults with DS (≥65 years) were identified from the Nationwide Inpatient Sample database (6) from 2002 through 2012. Multivariate analyses were performed to evaluate risk factors associated with hospital mortality and hospitalization cost in these patients. RESULTS: A total of 2,134 older adults with DS were identified. A temporal increase over the 11-year period was observed in the number of older adults with DS who were hospitalized (trend p < 0.0001). However, the hospital mortality rate and post-hospital discharge to skilled nursing facilities have decreased during the same time period. Risk factors associated with increased hospital mortality included advanced age (70-79 years), female gender, admissions in the western United States, and presence of comorbid conditions (ischemic heart disease, Alzheimer's disease, and cerebrovascular accident). The mean cost was $18,241 (SD $56,105) over the 11-year period. However, no significant temporal changes in costs were noted (trend p = 0.14). CONCLUSIONS: The number of hospitalized elderly Americans with DS has increased over the 11-year period. However, hospital mortality and discharge to skilled nursing facilities have decreased during the same time period. Several demographic and co-morbid factors are associated with increased mortality. No significant differences in temporal trends in costs were noted.

Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer's Disease. - Wezyk, Michalina; Szybinska, Aleksandra; Wojsiat, Joanna; Szczerba, Marcelina; Day, Kelly; Ronnholm, Harriet; Kele, Malin; Berdynski, Mariusz; Peplonska, Beata; Fichna, Jakub Piotr; Ilkowski, Jan; Styczyńska, Maria; et al. (J Alzheimers Dis, 2018)
The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-β. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-β pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.

Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer's Disease. - Butterfield, D Allan; Boyd-Kimball, Debra (J Alzheimers Dis, 2018)
Oxidative stress is implicated in the pathogenesis and progression of Alzheimer's disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-β peptide, Aβ1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aβ1-42, but not in Aβ1-42-poor regions, and was among the first to demonstrate Aβ peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. Identification of oxidatively modified brain proteins by the methods of redox proteomics was pioneered in the Butterfield laboratory. Four recurring altered pathways secondary to oxidative damage in brain from persons with AD, aMCI, or Down syndrome with AD are interrelated and contribute to neuronal death. This "Quadrilateral of Neuronal Death" includes altered: glucose metabolism, mTOR activation, proteostasis network, and protein phosphorylation. Some of these pathways are altered even in brains of persons with preclinical AD. We opine that targeting these pathways pharmacologically and with lifestyle changes potentially may provide strategies to slow or perhaps one day, prevent, progression or development of this devastating dementing disorder. This invited review outlines both in vitro and in vivo studies from the Butterfield laboratory related to Aβ1-42 and AD and discusses the importance and implications of some of the major achievements of the Butterfield laboratory in AD research.

Oxidative Stress in Elderly with Different Cognitive Status: My Mind Project. - Fattoretti, Patrizia; Malavolta, Marco; Fabbietti, Paolo; Papa, Roberta; Giacconi, Robertina; Costarelli, Laura; Galeazzi, Roberta; Paoloni, Cristina; Postacchini, Demetrio; Lattanzio, Fabrizia; Giuli, Cinzia (J Alzheimers Dis, 2018)
BACKGROUND: Biomarkers of oxidative stress have been associated with cognitive status in humans and have been proposed to guide prognosis/treatment in Alzheimer's disease (AD) and mild cognitive impairment (MCI). OBJECTIVE: The aim of this study was to compare oxidative stress status in the plasma of mild-moderate AD, MCI, and healthy elderly with normal cognition (HE) undergoing a non-pharmacological intervention including multi-modal cognitive training ("My Mind Project"). METHODS: A prospective randomized trial involving 321 elderly people enrolled in Marche Region, Italy. Each subject was randomly assigned to an experimental (cognitive training) or to a control group. Cognitive performances and biomarkers have been analyzed before intervention (baseline), immediately after termination (follow-up 1), after 6 months (follow-up 2), and after 2 years (follow-up 3). The biological antioxidant potential (BAP) to Diacron reactive oxygen metabolites (d-ROM) ratio has been used as an indicator of oxidative stress status and as outcome variable. RESULTS: We have found no differences in the oxidative status among AD, MCI, and HE. Neither did we find a significant effect of the intervention within experimental groups. Gender was the sole factor with a strong significant effect on BAP/d-ROM. CONCLUSIONS: Based on these results, the utility of biomarkers of oxidative stress to guide prognosis/treatment in AD or MCI seems to be limited by lack of specificity, large interindividual variability, and gender bias.

Ozone Atmospheric Pollution and Alzheimer's Disease: From Epidemiological Facts to Molecular Mechanisms. - Croze, Marine L; Zimmer, Luc (J Alzheimers Dis, 2018)
Atmospheric pollution is a well-known environmental hazard, especially in developing countries where millions of people are exposed to airborne pollutant levels above safety standards. Accordingly, several epidemiological and animal studies confirmed its role in respiratory and cardiovascular pathologies and identified a strong link between ambient air pollution exposure and adverse health outcomes such as hospitalization and mortality. More recently, the potential deleterious effect of air pollution inhalation on the central nervous system was also investigated and mounting evidence supports a link between air pollution exposure and neurodegenerative pathologies, especially Alzheimer's disease (AD). The focus of this review is to highlight the possible link between ozone air pollution exposure and AD incidence. This review's approach will go from observational and epidemiological facts to the proposal of molecular mechanisms. First, epidemiological and postmortem human study data concerning residents of ozone-severely polluted megacities will be presented and discussed. Then, the more particular role of ozone air pollution in AD pathology will be described and evidenced by toxicological studies in rat or mouse with ozone pollution exposure only. The experimental paradigms used to reproduce in rodent the human exposure to ozone air pollution will be described. Finally, current insights into the molecular mechanisms through which ozone inhalation can affect the brain and play a role in AD development or progression will be recapitulated.
Keywords: Air Pollution; Alzheimer Disease; Animals; Central Nervous System; Humans; Incidence; Inhalation Exposure; Ozone; Particulate Matter

Palmitoylethanolamide Blunts Amyloid-β42-Induced Astrocyte Activation and Improves Neuronal Survival in Primary Mouse Cortical Astrocyte-Neuron Co-Cultures. - Beggiato, Sarah; Borelli, Andrea Celeste; Ferraro, Luca; Tanganelli, Sergio; Antonelli, Tiziana; Tomasini, Maria Cristina (J Alzheimers Dis, 2018)
BACKGROUND: Based on the pivotal role of astrocytes in brain homeostasis and the strong metabolic cooperation existing between neurons and astrocytes, it has been suggested that astrocytic dysfunctions might cause and/or contribute to neuroinflammation and neurodegenerative processes. Therapeutic approaches aimed at both neuroprotection and neuroinflammation reduction may prove particularly effective in slowing the progression of these diseases. The endogenous lipid mediator palmitoylethanolamide (PEA) displayed neuroprotective and anti(neuro)inflammatory properties, and demonstrated interesting potential as a novel treatment for Alzheimer's disease. OBJECTIVE AND METHODS: We firstly evaluated whether astrocytes could participate in regulating the Aβ42-induced neuronal damage, by using primary mouse astrocytes cell cultures and mixed astrocytes-neurons cultures. Furthermore, the possible protective effects of PEA against Aβ42-induced neuronal toxicity have also been investigated by evaluating neuronal viability, apoptosis, and morphometric parameters. RESULTS: The presence of astrocytes pre-exposed to Aβ42 (0.5μM; 24 h) induced a reduction of neuronal viability in primary mouse astrocytes-neurons co-cultures. Furthermore, under these experimental conditions, an increase in the number of neuronal apoptotic nuclei and a decrease in the number of MAP-2 positive neurons were observed. Finally, astrocytic Aβ42 pre-exposure induced an increase in the number of neurite aggregations/100μm as compared to control (i.e., untreated) astrocytes-neurons co-cultures. These effects were not observed in neurons cultured in the presence of astrocytes pre-exposed to PEA (0.1μM), applied 1 h before and maintained during Aβ42 treatment. CONCLUSION: Astrocytes contribute to Aβ42-induced neurotoxicity and PEA, by blunting Aβ42-induced astrocyte activation, improved neuronal survival in mouse astrocyte-neuron co-cultures.
Keywords: Amyloid beta-Peptides; Analysis of Variance; Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Astrocytes; Cell Survival; Cells, Cultured; Cerebral Cortex; Coculture Techniques; Ethanolamines; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Neurons; Palmitic Acids; Peptide Fragments; Time Factors

Parietal Involvement in the Semantic Variant of Primary Progressive Aphasia with Alzheimer's Disease Cerebrospinal Fluid Profile. - Bera, Géraldine; Migliaccio, Raffaella; Michelin, Thibaut; Lamari, Foudil; Ferrieux, Sophie; Nogues, Marie; Bertin, Hugo; Habert, Marie Odile; Dubois, Bruno; Teichmann, Marc; Kas, Aurélie (J Alzheimers Dis, 2018)
Semantic variant of primary progressive aphasia (svPPA) is typically associated with non-Alzheimer's disease (AD) pathology. However, some anatomopathological studies have found AD lesions in those patients. We compared brain perfusion SPECT of 18 svPPA patients with cerebrospinal fluid (CSF) biomarkers indicative of non-AD pathology (svPPA-nonAD) and three svPPA patients with CSF biomarkers indicative of underlying AD (svPPA-AD). All svPPA patients had severe left temporopolar hypoperfusion. SvPPA-nonAD had additional anterior cingulate and mediofrontal hypoperfusion, whereas svPPA-AD had greater left parietal and posterior cingulate involvement. Parietal damage in svPPA constitutes a biomarker for underlying Alzheimer pathology thus refining the classification of this PPA variant.

Parkinsonism is a Phenotypical Signature of Amyloidopathy in Patients with Gait Disorders. - Allali, Gilles; Kern, Ilse; Laidet, Magali; Armand, Stéphane; Assal, Frèdèric (J Alzheimers Dis, 2018)
BACKGROUND: Central neurological gait abnormalities (CNGA) are frequently associated with parkinsonism in older adults. However, the neuropathological substrates and the clinical impact of parkinsonism have been not described in CNGA. OBJECTIVE: This cross-sectional study aims to compare the CSF total tau, Aβ1-42, and phosphorylated tau levels in non-Parkinson's disease (PD) patients with CNGA with and without parkinsonism and to study the clinical impact of parkinsonism on gait and cognition. METHODS: CSF biomarkers were measured by ELISA in 49 non-PD patients with CNGA (77.7±6.6 years; 32.7% women). Gait was quantified with an optoelectronic system and cognition with a comprehensive neuropsychological assessment. Parkinsonism was defined by presence of bradykinesia and at least one of the following signs among muscular rigidity, rest tremor, or postural instability. RESULTS: Parkinsonism was identified in 14 CNGA patients (28.6% ). CSF Aβ1-42 level was decreased in CNGA patients with parkinsonism (β: - 189.4; 95% CI [- 352.3; - 26.6]; p = 0.024) even after adjusting for age, gender, comorbidities, and total white matter burden; while CSF total tau and phosphorylated tau levels were similar between CNGA patients with and without parkinsonism. CNGA patients with parkinsonism presented decreased attentional and executive performances but similar gait parameters than those without parkinsonism. CONCLUSION: Parkinsonism represents a phenotype related with amyloidopathy-decreased CSF Aβ1-42 level-in non-PD patients with CNGA. This phenotype is clinically associated with impaired cognition, but similar quantitative gait parameters in comparison to CNGA patients without parkinsonism.

The Past and the Future of Alzheimer's Disease Fluid Biomarkers. - Blennow, Kaj; Zetterberg, Henrik (J Alzheimers Dis, 2018)
Following the development of the first methods to measure the core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of amyloid-β (Aβ42), there has been an enormous expansion of this scientific research area. Today, it is generally acknowledged that these biochemical tests reflect several central pathophysiological features of AD and contribute diagnostically relevant information, also for prodromal AD. In this article in the 20th anniversary issue of the Journal of Alzheimer's Disease, we review the AD biomarkers, from early assay development to their entrance into diagnostic criteria. We also summarize the long journey of standardization and the development of assays on fully automated instruments, where we now have high precision and stable assays that will serve as the basis for common cut-off levels and a more general introduction of these diagnostic tests in clinical routine practice. We also discuss the latest expansion of the AD CSF biomarker toolbox that now also contains synaptic proteins such as neurogranin, which seemingly is specific for AD and predicts rate of future cognitive deterioration. Last, we are at the brink of having blood biomarkers that may be implemented as screening tools in the early clinical management of patients with cognitive problems and suspected AD. Whether this will become true, and whether it will be plasma Aβ42, the Aβ42/40 ratio, or neurofilament light, or a combination of these, remains to be established in future clinical neurochemical studies.
Keywords: Alzheimer Disease; Animals; Biomarkers; Humans

Past to Future: What Animal Models Have Taught Us About Alzheimer's Disease. - Martini, Alessandra C; Forner, Stefania; Trujillo-Estrada, Laura; Baglietto-Vargas, David; LaFerla, Frank M (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) impairs memory and causes significant cognitive deficits. The disease course is prolonged, with a poor prognosis, and thus exacts an enormous economic and social burden. Over the past two decades, genetically engineered mouse models have proven indispensable for understanding AD pathogenesis, as well as for discovering new therapeutic targets. Here we highlight significant studies from our laboratory that have helped advance the AD field by elucidating key pathogenic processes operative in AD and exploring a variety of aspects of the disease which may yield novel therapeutic strategies for combatting this burdensome disease.

Pathological Correlates of Cognitive Impairment in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. - Robinson, Andrew C; Davidson, Yvonne S; Horan, Michael A; Pendleton, Neil; Mann, David M A (J Alzheimers Dis, 2018)
The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III- VI. Cerebral amyloid angiopathy(CAA), α-synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOEɛ4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOEɛ2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity.

Pathologically Confirmed Alzheimer's Disease in APOE ɛ2 Homozygotes is Rare but Does Occur. - Stipho, Faissal; Jackson, Robert; Sabbagh, Marwan N (J Alzheimers Dis, 2018)
BACKGROUND: Homozygous APOEɛ4 status is a well-known risk factor in the development of Alzheimer's disease (AD). However, other genotypes of APOE have not yet been found to have equal clinical significance. There is a paucity of reports regarding clinically or pathologically described AD in APOEɛ2 homozygotes compared to the other alleles. OBJECTIVE: To notify clinicians that patients with homozygous APOEɛ2 are also at risk of developing AD based on results from the largest prospectively gathered registry of brain samples to date. METHODS: We queried the National Alzheimer's Coordinating Center (NACC) database for autopsy-confirmed AD cases. Of the Uniform Data Set (UDS) participants who are deceased, 5,779 were diagnosed with dementia at their last UDS visit prior to death, and autopsy data is available for 3,518. RESULTS: Of the brains in the NACC database with pathologically confirmed dementia, seven were found to be homozygous for APOEɛ2, which represents only 0.2% of the autopsy-confirmed sample. Furthermore, pathology-confirmed AD represents 29% (2/7) of the APOEɛ2/ɛ2 patients diagnosed with dementia. CONCLUSIONS: Although rare, autopsy-confirmed AD can be present in APOEɛ2/ɛ2 carriers.

Patient Characteristics and Outcomes Associated with Receiving an Earlier Versus Later Diagnosis of Probable Alzheimer's Disease. - Kirson, Noam Y; Scott Andrews, J; Desai, Urvi; King, Sarah B; Schonfeld, Sophie; Birnbaum, Howard G; Ball, Daniel E; Kahle-Wrobleski, Kristin (J Alzheimers Dis, 2018)
BACKGROUND: Effectiveness of Alzheimer's disease (AD) treatments may depend critically on the timeliness of intervention. OBJECTIVE: To compare characteristics and outcomes of patients diagnosed with probable AD (prAD) based on time elapsed from first onset of cognitive decline. METHODS: Patients with ≥1 prAD diagnosis and ≥1 follow-up visit were selected from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS; 9/2005-6/2015) and stratified based on the time between the perceived onset of cognitive decline at baseline and first prAD diagnosis (i.e., earlier versus later diagnosis). Characteristics at baseline and prAD diagnosis, clinically meaningful progression, and medication use following prAD diagnosis were compared. RESULTS: Median time from perceived onset of cognitive decline to prAD diagnosis was 4.5 years (earlier diagnosis: ≤3.46; later diagnosis: >5.71). Earlier-diagnosed patients (n = 1,476) were younger at baseline (74.3 versus 76.3 years) and had better cognitive and functional scores than later-diagnosed patients (n = 1,474). At first prAD diagnosis, earlier-diagnosed patients had lower mean global Clinical Dementia Rating (CDR) score (0.8 versus 1.1), higher mean Mini-Mental State Examination (MMSE) (22.6 versus 20.0), and lower mean Functional Activities Questionnaire (11.6 versus 17.3). Earlier- and later-diagnosed patients experienced similar time to a decrease of ≥3 points in MMSE (median 23.2 versus 23.1 months, p = 0.83), but earlier-diagnosed patients had longer time to a CDR score of ≥2 points, and longer times to initiation of AD medication and antipsychotic agents (all p < 0.01). CONCLUSION: Earlier prAD diagnosis in NACC data is associated with higher cognitive function and lower functional impairment at diagnosis.
Keywords: Age of Onset; Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Cohort Studies; Datasets as Topic; Disease Progression; Female; Humans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Statistics, Nonparametric; Time Factors

Patient Engagement: The Fundació ACE Framework for Improving Recruitment and Retention in Alzheimer's Disease Research. - Boada, Merce; Santos-Santos, Miguel A; Rodríguez-Gómez, Octavio; Alegret, Montserrat; Cañabate, Pilar; Lafuente, Asunción; Abdelnour, Carla; Buendia, Mar; de Dios, Maria José; Morera, Amèrica; Sanabria, Ángela; Campo, Laura; et al. (J Alzheimers Dis, 2018)
Alzheimer's disease (AD) research is at a critical time. The global society is increasingly aware of the frightening rate of growth of the human and financial burden caused by this condition and of the urgent need to halt its progression. Consequently, the scientific community holds great responsibility to quickly put in place and optimize the machinery necessary for testing new treatments or interventions. In this context demand for participants for AD research is at an all-time high. In this review, we will focus on a methodological factor that is increasingly recognized as a key factor that shapes trial populations and affects validity of results in clinical trials: patient engagement, recruitment, and retention. We outline specific problems relevant to patient engagement in AD including recruiting enough participants, difficulties in participant retention, ensuring the recruited sample is representative of the general AD population, the burden of screening failures, and new challenges related to recruiting in preclinical disease. To address the urgent need for more research studying the applicability and cost-effectiveness of different recruitment strategies across different settings and nationalities, we describe the Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project, a public-private partnership promoted by the Innovative Medicine Initiative (IMI), which will provide a large multinational quantitative analysis comparing different innovative recruitment models. We also discuss strategies that address each problem and draw on the experience of Fundació ACE to argue that focusing resources on comprehensive AD centers that offer coordinated clinical and social care and participate in basic and clinical research, is an effective and efficient way of implementing many of the discussed strategies.

Patients with Dementia in Primary Care: Who Is Referred to a Neurologist/Psychiatrist and What Patient-Oriented Factors Are Associated with the Visit? - Strohmaier, Urs; Keller, Felix; Kilimann, Ingo; Michalowsky, Bernhard; Wucherer, Diana; Zwingmann, Ina; Teipel, Stefan; Hoffmann, Wolfgang; Thyrian, Jochen René (J Alzheimers Dis, 2018)
BACKGROUND: The current guidelines imply that basic medical diagnostics for dementia should be provided by general practitioners in cooperation with other specialists such as neurologists and psychiatrists. OBJECTIVES: The aims of this paper were to 1) compare the dementia patients of general practice residents whose care is co-managed by neurology/psychiatry residents with those whose care is not; 2) identify the patient variables associated with the utilization of neurological and psychiatric specialists; and 3) describe the frequency of imaging used for dementia patients in primary care. METHODS: The analyses utilized data from 485 individuals who screened positive for dementia in primary care (PWD). Clinical variables and the utilization of specialists were assessed via medical records and face-to-face interviews. The factors associated with the utilization of specialists were assessed using multivariate linear regression and included age, sex, relationship status, cognitive impairment, depression, activities of daily living, and formal diagnosis of dementia. RESULTS: Our results show that 89 out of 485 study participants (18.4%) were referred to specialists 12 months prior to assessment. Of these 89 individuals, 14.6% (n = 13) did not receive imaging diagnostics, while 39.3% (n = 35) received brain imaging by CT scan and 46.1% (n = 41) by MRI. PWD referred to specialists differed from those not referred, in age, relationship status, and the presence of a formal diagnosis. Our multivariate analysis revealed that younger age (OR = 0.95; 95% -confidence interval 0.90-0.99; p = 0.04) and higher functional impairment (OR = 1.15; 95% -confidence interval 1.02-1.30; p = 0.02) were associated with a visit to a specialist. DISCUSSION: Only 1 out of every 4 to 5 individuals who have screened positive for dementia have visited a specialist in psychiatry or neurology. While in general, women utilized specialists less often than men, younger and more functionally impaired patients were more likely to be sent to a specialist by their treating general practitioner. Almost 90% of the patients sent to a specialist received cranial neuroimaging, suggesting high adherence to diagnostic guidelines in specialized care.

Patterns of Neuropsychological Dysfunction and Cortical Volume Changes in Logopenic Aphasia. - Owens, Tyler E; Machulda, Mary M; Duffy, Joseph R; Strand, Edythe A; Clark, Heather M; Boland, Sarah; Martin, Peter R; Lowe, Val J; Jack, Clifford R; Whitwell, Jennifer L; Josephs, Keith A (J Alzheimers Dis, 2018)
BACKGROUND: Neuropsychological assessment can add essential information to the characterization of individuals presenting with the logopenic variant of primary progressive aphasia (lvPPA). OBJECTIVE: This study examined the neuropsychological characteristics of lvPPA patients. We also examined differences in regional and whole brain atrophy based on neuropsychological profiles. METHODS: We conducted a hierarchical cluster analysis on memory, executive functioning, and visuospatial neuropsychological test data for 56 individuals with lvPPA. We then compared resultant clusters to left middle temporal, inferior parietal, and superior parietal regions-of-interest using multivariate analysis of covariance. We also performed voxel-level analyses. RESULTS: We identified three clusters characterized as lvPPA with no neurocognitive impairment (n = 5), lvPPA with mild neurocognitive deficits (n = 23), and lvPPA with marked cognitive deficits (n = 28). WAB-AQ was associated with left middle temporal volume. Superior parietal volumes were smaller for the lvPPA group with marked cognitive symptoms compared to the less severe groups. Voxel-level analyses showed greater atrophy in temporal, parietal, lateral occipital, and frontal regions, left worse than right. Age, disease duration, gender, WAB-AQ, and PiB-PET did not account for differences between groups. CONCLUSIONS: LvPPA patients without cognitive deficits in other domains were relatively uncommon while 50% of our sample exhibited pronounced neurocognitive deficits outside the language domain. Pronounced cognitive deficits in lvPPA are associated with widespread atrophy, left worse than right. Our study underscores the importance of examining neuropsychological function in addition to language in patients with lvPPA.

Patterns of Physical Activity and Sedentary Behavior for Older Adults with Alzheimer's Disease, Mild Cognitive Impairment, and Cognitively Normal in Hong Kong. - Lu, Zhihui; Harris, Tamara B; Shiroma, Eric J; Leung, Jason; Kwok, Timothy (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, and mild cognitive impairment (MCI) is a transitional phase between healthy cognition and dementia. Physical activity (PA) has protective effects on cognitive decline. However, few studies have examined how PA and sedentary behavior is structured throughout the day in older adults across varied cognitive status in Hong Kong. OBJECTIVE: This study aimed to compare patterns of PA and sedentary behavior among individuals with AD, MCI, or normal cognition living in Hong Kong. METHODS: Participants in the MrOs and MsOs Hong Kong cohort study and the Hong Kong AD biomarker study (n = 810) wore a wrist-worn accelerometer for 7 days in free-living environment. Patterns of PA in wake time and in-bed time, and detailed analysis of sedentary bouts were compared between groups using analysis of covariance adjusting for covariates. RESULTS: Participants with MCI and low MoCA only did not differ from their cognitively normal peers in PA and sedentary behavior. Nevertheless, when comparing to the others, participants with AD exhibited significantly lower average daily counts per minute during the day (p < 0.05), and tended to start their activity later in the morning. AD participants spent a larger proportion of time in sedentary behavior (p < 0.05) and had more sedentary bouts≥30 minutes (p < 0.05). CONCLUSIONS: The pattern of PA and sedentary behavior was different between individuals with AD and the others. Cognitive status may alter the purpose and type of PA intervention for AD individuals.

Patterns of Regional Cerebral Blood Flow as a Function of Age Throughout the Lifespan. - Amen, Daniel G; Egan, Sachit; Meysami, Somayeh; Raji, Cyrus A; George, Noble (J Alzheimers Dis, 2018)
BACKGROUND: Understanding the influence of aging on the brain remains a challenge in determining its role as a risk factor for Alzheimer's disease. OBJECTIVE: To identify patterns of aging in a large neuroimaging cohort. METHODS: A large psychiatric cohort of 31,227 individuals received brain SPECT at rest and during a concentration task for a total of 62,454 scans. ANOVA was done to identify the mean age trends over the course of the age range in this group, 0- 105 years. A regression model in which brain SPECT regions of interest was used to predict chronological age (CA) was then utilized to derive brain estimated age (BEA). The difference between CA and BEA was calculated to determine increased brain aging in common disorders in our sample such as depression, dementia, substance use, and anxiety. RESULTS: Throughout the lifespan, variations in perfusion were observed in childhood, adolescence, and late life. Increased brain aging was seen in alcohol use, cannabis use, anxiety, bipolar, schizophrenia, attention-deficit/hyperactivity disorder, and in men. CONCLUSION: Brain SPECT can predict chronological age and this feature varies as a function of common psychiatric disorders.

PCSK9 Concentrations in Cerebrospinal Fluid Are Not Specifically Increased in Alzheimer's Disease. - Courtemanche, Hélène; Bigot, Edith; Pichelin, Matthieu; Guyomarch, Béatrice; Boutoleau-Bretonnière, Claire; Le May, Cédric; Derkinderen, Pascal; Cariou, Bertrand (J Alzheimers Dis, 2018)
The role of PCSK9 in Alzheimer's disease (AD) is controversial. We compared cerebrospinal fluid (CSF) PCSK9 concentrations in 36 AD and 31 non-AD patients. CSF PCSK9 levels did not differ between AD and non-AD groups (2.80 versus 2.62 ng/mL). However, PCSK9 CSF levels were increased in AD and non-AD patients with other neurodegenerative process (non-AD ND, n = 20) compared to patients without neurodegenerative disorders (non-ND, n = 11): 2.80 versus 2.30 (p < 0.005) and 2.83 versus 2.30 ng/mL (p = NS), respectively. CSF PCSK9 were positively correlated with AD biomarkers (Aβ1-42, T-tau, and P-tau). PCSK9 concentrations in CSF are increased in neurodegenerative disorders rather than specifically in AD.

Periodontal Pathogens and Associated Intrathecal Antibodies in Early Stages of Alzheimer's Disease. - Laugisch, Oliver; Johnen, Andreas; Maldonado, Alejandra; Ehmke, Benjamin; Bürgin, Walter; Olsen, Ingar; Potempa, Jan; Sculean, Anton; Duning, Thomas; Eick, Sigrun (J Alzheimers Dis, 2018)
BACKGROUND: Recent studies suggest a link between periodontitis and Alzheimer's disease (AD). OBJECTIVE: Verification of the presence of periodontal pathogens and the intrathecal generation of pathogen-specific antibodies in 20 patients with AD and 20 with other forms of dementia (DEM-noAD). METHODS: Clinical periodontal indices were recorded. Cerebrospinal fluid (CSF) was analyzed for total tau protein (T-tau) and amyloid-β (Aβ1-42). In serum and CSF, antibody levels against Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Treponema species were quantified. The presence of selected bacteria and inflammatory biomarkers were determined in periodontium, serum, and CSF. RESULTS: In line with diagnoses, CSF-levels of Aβ1-42 were significantly lower in AD than DEM-noAD patients. Periodontal destruction and inflammation were omnipresent with no difference between groups. P. gingivalis, T. forsythia, and Treponema species were detected in more than 50% of subgingival biofilm samples, but neither in serum nor in the CSF. Elevated levels of anti-pathogen antibodies in CSF of 16 patients (7 AD; 9 DEM-noAD) compared to serum highlight a possibility of the intrathecal immune response to pathogens. There was no significant difference in antibodies levels against selected bacteria in CSF and serum between groups. Multivariate regression analysis and general linear models revealed an association of the T-tau level in AD group with both serum levels of anti-P. gingivalis antibodies and MCP-1/CCL-2. CONCLUSION: Periodontal pathogens may enter the brain and stimulate a local immune response. However, in patients with dementia at the age up to 70 years, periodontal pathogens do not act as a trigger for developing AD.

Personality Modulates the Efficacy of Art Intervention on Chronic Pain in a Population of Patients with Alzheimer's Disease. - Rouch, Isabelle; Pongan, Elodie; Leveque, Yohana; Tillmann, Barbara; Trombert, Béatrice; Getenet, Jean Claude; Auguste, Nicolas; Krolak-Salmon, Pierre; Laurent, Bernard; Dorey, Jean-Michel (J Alzheimers Dis, 2018)
BACKGROUND: Alzheimer's disease (AD) mainly occurs in elderly individuals. Comorbidities and chronic pain are frequent in this population. Previous studies revealed that personality modulates both chronic pain (CP) andADoccurrence and evolution. Moreover, as pain treatments can induce side-effects, non-drugs treatments, such as art interventions, are interesting alternative therapies for decreasing CP in these patients. OBJECTIVE: Our aim was to assess the potential role of personality traits on art intervention efficacy for reducing CP in a population of patients with mild AD. METHODS: Design: multicenter randomized controlled trial. Fifty mild AD patients underwent a 12-week art intervention including singing and painting groups. Personality was assessed with the Big Five Inventory before the sessions. CP was measured with Numeric Rating Scale (NRS) [Usual pain (NRS-U) and most Intense pain (NRS-I)], Simple Visual Scale [Usual pain (SVS-U) and most Intense pain (SVS-I)] and Brief Pain Inventory (BPI) before and after the sessions. The influence of personality traits on CP evolution before and after art intervention was assessed with multiple linear regression models. RESULTS: A positive association was observed between neuroticism and the evolution of three CP measures including NRS-U (B = 0.34, p = 0.01), SVS-U (B = 0.20, p = 0.04), and BPI-U (B = 0.46, p = 0.02) evolution. No significant relationship was observed between neuroticism and NRS-I, SVS-I and BPI-R evolution. CONCLUSIONS: Our findings suggest that neuroticism can decrease the efficacy of group art intervention on pain in patients with mild AD. Individual therapies could be more appropriate for these patients. These results emphasize the interest of taking into account patients' personality before proposing them to participate to a group therapy.

Perspectives on Communicating Biomarker-Based Assessments of Alzheimer's Disease to Cognitively Healthy Individuals. - Milne, Richard; Bunnik, Eline; Diaz, Ana; Richard, Edo; Badger, Shirlene; Gove, Dianne; Georges, Jean; Fauria, Karine; Molinuevo, Jose-Luis; Wells, Katie; Ritchie, Craig; Brayne, Carol (J Alzheimers Dis, 2018)
In clinical trials which target pathophysiological mechanisms associated with Alzheimer's disease, research participants who are recruited based on biomarker test results should be informed about their increased risk of developing Alzheimer's dementia. This paper presents the results of a qualitative focus group study of attitudes and concerns toward learning information about biomarker-based risk status among healthy research participants in the United Kingdom and Spain and people with dementia and their supporters/caregivers from countries represented in the European Working Group of People with Dementia of Alzheimer Europe. The study identified expectations related to learning risk status and preferences related to the content, quality, and follow-up of the disclosure process. The latter emphasize distinctions between risk and diagnoses, the importance of clear information about risk, and suggestions for risk reduction, as well as expectations for follow up and support. The implications of these preferences for practice are discussed. Providing details of research participants' experience and views may serve as a guide for the development of processes for the responsible disclosure of Alzheimer's disease biomarkers.
Keywords: Adult; Aged; Alzheimer Disease; Biomarkers; Caregivers; Disclosure; Female; Focus Groups; Humans; Male; Middle Aged; Qualitative Research; Risk Factors; Spain; United Kingdom

Perspectives on Oxidative Stress in Alzheimer's Disease and Predictions of Future Research Emphases. - Butterfield, D Allan (J Alzheimers Dis, 2018)
Oxidative stress, an overproduction of free radicals or a diminution of free radical scavenging ability relative to those of cognitively aged-matched controls, is widely recognized as a critical component of the pathogenesis and progression of Alzheimer's disease (AD). This recognition arose in significant part from the work in the author's laboratory, complemented by research from others' laboratories. The Butterfield laboratory discovered the oxidative stress associated with oligomeric amyloid-β peptide manifested primarily as elevated oxidative modification of proteins and peroxidation of lipids. Such oxidative damage caused neuronal death, which undoubtedly underlies the progressive loss of cognition in AD. Identification of specific oxidatively modified brain proteins in subjects with AD or amnestic mild cognitive impairment was achieved by the methods of redox proteomics, pioneered in the author's laboratory. The importance and significance of the research emanating from the Butterfield laboratory rest on the paradigm shift of thinking regarding the roles of oxidative stress and resulting damage to key proteins and biochemical pathways in the pathogenesis and progression of AD. Predictions of future research directions also are presented. Given the enormous financial and personal burden placed upon citizens (and governments) of the US from AD, and the surety that the number of AD patients will greatly increase over the next 20-30 years, greater understanding of the molecular basis of pathogenesis and progression of AD is essential. Our laboratory is privileged to have contributed to better understanding of AD and provided rationales to identify effective therapeutic targets for this devastating dementing disorder.

Phenomenological Characteristics of Future Thinking in Alzheimer's Disease. - Moustafa, Ahmed A; El Haj, Mohamad (J Alzheimers Dis, 2018)
This study investigates phenomenological reliving of future thinking in Alzheimer's disease (AD) patients and matched controls. All participants were asked to imagine in detail a future event, and afterward, were asked to rate phenomenological characteristics of their future thinking. As compared to controls, AD participants showed poor rating for reliving, travel in time, visual imagery, auditory imagery, language, and spatiotemporal specificity. However, no significant differences were observed between both groups in emotion and importance of future thinking. Results also showed lower rating for visual imagery relative to remaining phenomenological features in AD participants compared to controls; conversely, these participants showed higher ratings for emotion and importance of future thinking. AD seems to compromise some phenomenological characteristics of future thinking, especially, visual imagery; however, other phenomenological characteristics, such as emotion, seem to be relatively preserved in these populations. By highlighting the phenomenological experience of future thinking in AD, our paper opens a unique window into the conscious experience of the future in AD patients.

Physical Activity and Hippocampal Sub-Region Structure in Older Adults with Memory Complaints. - Siddarth, Prabha; Rahi, Berna; Emerson, Natacha D; Burggren, Alison C; Miller, Karen J; Bookheimer, Susan; Lavretsky, Helen; Dobkin, Bruce; Small, Gary; Merrill, David A (J Alzheimers Dis, 2018)
BACKGROUND: Physical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited. OBJECTIVE: To examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints. METHODS: Twenty-nine subjects aged ≥60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day determined. Subjects were categorized into two groups: those who walked ≤4000 steps/day (lower PA) and those with >4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups. RESULTS: Twenty-six subjects aged 72.7(8.1) years completed the study. The higher PA group (n = 13) had thicker fusiform gyrus (median difference = 0.11 mm, effect size (ES) = 1.43, p = 0.001) and parahippocampal cortex (median difference = 0.12 mm, ES = 0.93, p = 0.04) compared to the lower PA group. The higher PA group also exhibited superior performance in attention and information-processing speed (median difference = 0.90, ES = 1.61, p = 0.003) and executive functioning (median difference = 0.97, ES = 1.24, p = 0.05). Memory recall was not significantly different between the two groups. CONCLUSION: Older non-demented individuals complaining of memory loss who walked >4000 steps each day had thicker MTL sub-regions and better cognitive functioning than those who walked ≤4000 steps. Future studies should include longitudinal analyses and explore mechanisms mediating hippocampal related atrophy.
Keywords: Aged; Aged, 80 and over; Cognition; Cross-Sectional Studies; Executive Function; Exercise; Female; Geriatric Assessment; Hippocampus; Humans; Magnetic Resonance Imaging; Male; Memory; Memory Disorders; Middle Aged; Neuropsychological Tests

Physical Fitness and Aortic Stiffness Explain the Reduced Cognitive Performance Associated with Increasing Age in Older People. - Kennedy, Greg; Meyer, Denny; Hardman, Roy J; Macpherson, Helen; Scholey, Andrew B; Pipingas, Andrew (J Alzheimers Dis, 2018)
BACKGROUND: Greater physical fitness is associated with reduced rates of cognitive decline in older people; however, the mechanisms by which this occurs are still unclear. One potential mechanism is aortic stiffness, with increased stiffness resulting in higher pulsatile pressures reaching the brain and possibly causing progressive micro-damage. There is limited evidence that those who regularly exercise may have lower aortic stiffness. OBJECTIVE: To investigate whether greater fitness and lower aortic stiffness predict better cognitive performance in older people and, if so, whether aortic stiffness mediates the relationship between fitness and cognition. METHODS: Residents of independent living facilities, aged 60-90, participated in the study (N = 102). Primary measures included a computerized cognitive assessment battery, pulse wave velocity analysis to measure aortic stiffness, and the Six-Minute Walk test to assess fitness. Based on hierarchical regression analyses, structural equation modelling was used to test the mediation hypothesis. RESULTS: Both fitness and aortic stiffness independently predicted Spatial Working Memory (SWM) performance, however no mediating relationship was found. Additionally, the derived structural equation model shows that, in conjunction with BMI and sex, fitness and aortic stiffness explain 33% of the overall variation in SWM, with age no longer directly predicting any variation. CONCLUSIONS: Greater fitness and lower aortic stiffness both independently predict better SWM in older people. The strong effect of age on cognitive performance is totally mediated by fitness and aortic stiffness. This suggests that addressing both physical fitness and aortic stiffness may be important to reduce the rate of age associated cognitive decline.

Phytochemicals from Achillea fragrantissima are Modulators of AβPP Metabolism. - Bartolotti, Nancy; Disouky, Ahmed; Kalinski, Arthur; Elmann, Anat; Lazarov, Orly (J Alzheimers Dis, 2018)
Plant derivatives offer a novel and natural source of therapeutics. The desert plant Achillea fragrantissima (Forssk) Sch. Bip (Af) is characterized by protective antioxidative and anti-inflammatory properties. Here, we examined the effect of two Af-derived phytochemicals on learning and memory, amyloid-β protein precursor (AβPP) metabolism, and tau phosphorylation in the familial Alzheimer's disease-linked APPswe/PS1ΔE9 mouse model. We observed that mice that were injected with the phytochemicals showed a trend of improvement, albeit statistically insignificant, in the Novel Object Recognition task. However, we did not observe improvement in contextual fear conditioning, suggesting that the benefits of treatment may be either indirect or task-specific. In addition, we observed an increase in the full-length form of AβPP in the brains of mice treated with Af-derived phytochemicals. Interestingly, both in vivo and in vitro, there was no change in levels of soluble Aβ, oligomeric Aβ, or the carboxyl terminus fragments of AβPP (APP-CTFs), suggesting that the increase in full length AβPP does not exacerbate AβPP pathology, but may stabilize the full-length form of the molecule. Together, our data suggest that phytochemicals present in Af may have a modest positive impact on the progression of Alzheimer's disease.

PICALM Gene Methylation in Blood of Alzheimer's Disease Patients Is Associated with Cognitive Decline. - Mercorio, Roberta; Pergoli, Laura; Galimberti, Daniela; Favero, Chiara; Carugno, Michele; Dalla Valle, Elisabetta; Barretta, Francesco; Cortini, Francesca; Scarpini, Elio; Valentina, Valentina Bollati; Pesatori, Angela Cecilia (J Alzheimers Dis, 2018)
Epigenetic mechanisms might be involved in Alzheimer's disease (AD). Genetic polymorphisms in several genes, including APOE (Apolipoprotein E), PSEN1 (Presenilin 1), CR1 (Complement receptor 1), and PICALM (Phosphatidylinositol binding clathrin assembly protein), have been associated to an increased AD risk. However, data regarding methylation of these specific genes are lacking. We evaluated DNA methylation measured by quantitative bisulfite-PCR pyrosequencing in 43 AD patients and 38 healthy subjects (HS). In a multivariate age- and gender-adjusted model, PICALM methylation was decreased in AD compared to HS (mean = 3.54 and 4.63, respectively, p = 0.007). In AD, PICALM methylation level was also positively associated to Mini-Mental Scale Examination (MMSE) score (percent change 3.48%, p = 0.008). Moreover, a negative association between PICALM methylation and age was observed only in HS (percent change - 2.29%, p = 0.002). In conclusion, our data suggest a possible role of PICALM methylation in AD, particularly related to cognitive function. Given the small study sample and the associative nature of our study, further prospective investigations are required to assess the dynamics of DNA methylation in the early stages of AD development.

Pink1 Regulates Tyrosine Hydroxylase Expression and Dopamine Synthesis. - Lu, Lingling; Jia, Huanzhen; Gao, Ge; Duan, Chunli; Ren, Jing; Li, Yi; Yang, Hui (J Alzheimers Dis, 2018)
PTEN induced putative kinase 1 (PINK1), also known as PARK6, is causally linked to familial Parkinsonism, and heterozygous loss of PINK1 is a risk factor for sporadic Parkinson's disease. However, little is known about its physiological function. Its deficiency was shown to decrease dopamine without significant loss of dopaminergic neurons. We investigated the mechanistic basis for this observation in the present study using dopaminergic MN9D cells. We found that PINK1 knockdown resulted in dopamine content to decrease with suppressed tyrosine hydroxylase expression in cells. Conversely, PINK1 overexpression increased tyrosine hydroxylase protein level. We also found that PINK1 deficiency blocked the nuclear translocation and activity of nuclear receptor-related 1, a transcription factor regulating tyrosine hydroxylase gene expression. These data suggest that PINK1 regulates tyrosine hydroxylase gene expression and dopamine content by modulating the transcriptional activity of nuclear receptor-related 1. Taken together, our results reveal a novel function of PINK1 in dopamine homeostasis.

Plasma Amyloid-β (Aβ42) Correlates with Cerebrospinal Fluid Aβ42 in Alzheimer's Disease. - Teunissen, Charlotte E; Chiu, Ming-Jang; Yang, Che-Chuan; Yang, Shieh-Yueh; Scheltens, Philip; Zetterberg, Henrik; Blennow, Kaj (J Alzheimers Dis, 2018)
The 42 amino acid form of amyloid-β (Aβ42) plays a key role in the pathogenesis of Alzheimer's disease (AD) and is a core biomarker for the diagnosis of AD. Numerous studies have shown that cerebrospinal fluid (CSF) Aβ42 concentrations are decreased in AD, when measured by enzyme-linked immunosorbent assay (ELISA) and other conventional immunoassays. While most studies report no change in plasma Aβ42, independent studies using the immunomagnetic reduction (IMR) technique report an increase in plasma Aβ42 levels in AD. To confirm the opposite changes of Aβ42 levels in CSF and plasma for AD, we assayed the levels of Aβ42 in plasma of subjects with known CSF Aβ42 levels. In total 43 controls and 63 AD patients were selected at two sites: the VU University Medical Center (n = 55) and Sahlgrenska University Hospital (n = 51). IMR and ELISA were applied to assay Aβ42 in plasma and CSF, respectively. We found a moderately negative correlation between plasma and CSF Aβ42 levels in AD patients (r = -0.352), and a weakly positive correlation in controls (r = 0.186). These findings further corroborate that there are opposite changes of Aβ42 levels in CSF and plasma in AD. The possible causes for the negative correlation are discussed by taken assay technologies, Aβ42 transport from brain to peripheral blood, and sample matrix into account.

Plasma Antioxidant Status in Patients with Alzheimer's Disease and Cognitively Intact Elderly: A Meta-Analysis of Case-Control Studies. - Mullan, Kathryn; Cardwell, Chris R; McGuinness, Bernadette; Woodside, Jayne V; McKay, Gareth J (J Alzheimers Dis, 2018)
Serum antioxidants may afford neuroprotection against Alzheimer's disease (AD) via correction of the pro-oxidative imbalance but findings reported have been inconsistent. We compared the pooled mean difference in serum levels of ten dietary antioxidants between patients with AD and cognitively intact controls from 52 studies in meta-analyses using random-effects models. Patients with AD had significantly lower plasma levels of α-carotene, β-carotene, lycopene, lutein, vitamin A, C, and E, and uric acid. No significant difference was observed for plasma levels of β-cryptoxanthin and zeaxanthin. Considerable heterogeneity was detected across studies. The lower serum levels of dietary antioxidants from the carotene and vitamin subclasses observed in individuals with AD suggest reduced systemic availability of these subclasses in this prevalent form of dementia. To our knowledge, these are the first meta-analyses to demonstrate lower serum lycopene and to evaluate β-cryptoxanthin, lutein, and zeaxanthin levels in AD. In light of the significant heterogeneity detected across studies, caution should be exercised in the interpretation of the data and therapeutic intervention approaches considered through supplementation measures. Our data may better inform interventions to improve antioxidant status in a condition of major public health importance.

Platelets: Peripheral Biomarkers of Dementia? - Akingbade, Oluwatomi E S; Gibson, Claire; Kalaria, Raj N; Mukaetova-Ladinska, Elizabeta B (J Alzheimers Dis, 2018)
Dementia continues to be the most burdening neurocognitive disorder, having a negative impact on the lives of millions. The search for biomarkers to improve the clinical diagnosis of dementia is ongoing, with the focus on effective use of readily accessible peripheral markers. In this review, we concentrate on platelets as biomarkers of dementia and analyze their potential as easily-accessible clinical biomarkers for various subtypes of dementia. Current platelet protein biomarkers that have been investigated for their clinical utility in the diagnosis of dementia, in particular Alzheimer's disease, include amyloid-β protein precursor (AβPP), the AβPP secretases (BACE1 and ADAM10), α-synuclein, tau protein, serotonin, cholesterol, phospholipases, clusterin, IgG, surface receptors, MAO-B, and coated platelets. Few of them, i.e., platelet tau, AβPP (particularly with regards to coated platelets) and secreted ADAM10 and BACE1 show the most promise to be taken forward into clinical setting to diagnose dementia. Aside from protein biomarkers, changes in factors such as mean platelet volume have the potential to play a very specific role in both the dementia diagnosis and prognosis. This review raises a number of research questions for consideration before application of the above biomarkers to routine clinical setting. It is without doubt that there is a need for more clarification on the effects of dementia on platelet morphology and protein content before these changes can be clinically applied as dementia biomarkers and explored further in differentiating distinct dementia subtypes.

Polypharmacy and Potentially Inappropriate Medication in People with Dementia: A Nationwide Study. - Kristensen, Rachel Underlien; Nørgaard, Ane; Jensen-Dahm, Christina; Gasse, Christiane; Wimberley, Theresa; Waldemar, Gunhild (J Alzheimers Dis, 2018)
BACKGROUND: Polypharmacy (use of ≥5 different medications) and potentially inappropriate medication (PIM) are well-known risk factors for numerous negative health outcomes. However, the use of polypharmacy and PIM in people with dementia is not well-described. OBJECTIVE: To examine the prevalence of polypharmacy and PIM in older people with and without dementia in a nationwide population. METHODS: Cross-sectional study of the Danish population aged ≥65 in 2014 (n = 1,032,120) based on register data, including information on diagnoses and dispensed prescriptions. Polypharmacy and PIM use among people with (n = 35,476) and without dementia (n = 994,231) were compared, stratified by living situation and adjusted for age, sex, and comorbidity. The red-yellow-green list from the Danish Institute for Rational Pharmacotherapy and the German PRISCUS list were used to define PIM. RESULTS: People with dementia were more frequently exposed to polypharmacy (dementia: 62.6% versus no-dementia: 35.1%, p < 0.001) and likewise PIM (red-yellow-green: 45.0% versus 29.7%, p < 0.001; PRISCUS: 24.4% versus 13.2%, p < 0.001). After adjustments for age, sex, and comorbidity, the likelihood of polypharmacy and PIM was higher for community-dwelling people with dementia than without dementia (odds ratio (OR); [95% confidence interval (CI)] polypharmacy: 1.50 [1.45-1.55]; red-yellow-green: 1.27 [1.23-1.31]; PRISCUS: 1.25 [1.20-1.30]). In contrast, dementia slightly decreased the odds of polypharmacy and PIM in nursing home residents. CONCLUSION: Use of polypharmacy and PIM were widespread in the older population and more so in people with dementia. This could have negative implications for patient-safety and demonstrates the need for interventions to improve drug therapy in people with dementia.

The Positive Effects of Viewing Gardens for Persons with Dementia. - Goto, Seiko; Shen, Xuting; Sun, Minkai; Hamano, Yutaka; Herrup, Karl (J Alzheimers Dis, 2018)
Dementia is highly prevalent among the worldwide elderly population. Only a small number of the currently marketed drugs are effective in controlling its symptoms, and none has any effect on its progression. Further, as the condition advances, even these pharmaceuticals lose their efficiency, and new research into interventions that might improve the life quality of patients at the end stage of dementia and their families is increasingly rare. In our previous studies, we explored the benefits of exposure to nature, in the form of a Japanese garden, for persons with advanced dementia. In the current work, we extended our observations to two new locations and a new set of subjects with a different ethnic composition with the goal of identifying interventions that might improve their quality of life. We found that, even in these new settings, garden observation not only relieved physiological stress, it improved qualitative measures such as verbalization and memory retrieval. We present data that viewing the garden is a holistic experience rather a solely visual stimulus. Our new data further support the conclusion that garden observation is worth including in the care planning schedule of advanced dementia patients. Its low cost and easy availability make it an economical adjunct to current pharmacological methods that has the potential to improve the quality of life of people with dementia.

Positive Feedback Loops in Alzheimer's Disease: The Alzheimer's Feedback Hypothesis. - Doig, Andrew J (J Alzheimers Dis, 2018)
The dominant model for Alzheimer's disease (AD) is the amyloid cascade hypothesis, in which the accumulation of excess amyloid-β (Aβ) leads to inflammation, excess glutamate and intracellular calcium, oxidative stress, tau hyperphosphorylation and tangle formation, neuronal loss, and ultimately dementia. In a cascade, AD proceeds in a unidirectional fashion, with events only affecting downstream processes. Compelling evidence now exists for the presence of positive feedback loops in AD, however, involving oxidative stress, inflammation, glutamate, calcium, and tau. The pathological state of AD is thus a system of positive feedback loops, leading to amplification of the initial perturbation, rather than a linear cascade. Drugs may therefore be effective by targeting numerous points within the loops, rather than concentrating on upstream processes. Anti-inflammatories and anti-oxidants may be especially valuable, since these processes are involved in many loops and hence would affect numerous processes in AD.

Possible Role of Chitin-Like Proteins in the Etiology of Alzheimer's Disease. - Lomiguen, Christine; Vidal, Luis; Kozlowski, Piotr; Prancan, Arthur; Stern, Robert (J Alzheimers Dis, 2018)
Chitin is a β-linked straight chain carbohydrate matrix monopolymer prominent in invertebrates, from fungi to arthropods. Surprisingly, chitin is now documented in vertebrates, including humans, a component of vertebrate physiology that has been neglected until now. Chitin levels are elevated in Alzheimer's disease (AD) patients, not only in the central nervous system but also in the cerebrospinal fluid and plasma. Elevated levels of chitin lectin have been reported in patients with AD. Chitinase activity varies widely in the human population. Chitin levels can increase in individuals with intrinsically low chitinase activity. Elevated amounts of chitin can reflect accumulation of the small chitin fragments that remain wherever rapid hyaluronan synthesis occurs. Another source of chitin may be from remote fungal infections. Chitin can be toxic for neurons, and its accumulation may lead to the development of AD. We present new suggestions for animal models and treatment modalities that could prove useful in future research endeavors. An unexpected connection with Gaucher's disease patients and their heterozygote relatives is also identified. These chitin-related mechanisms are novel approaches to AD whose etiology until now has defied explication.

Post Traumatic Stress Disorder Heralding the Onset of Semantic Frontotemporal Dementia. - Bonanni, Laura; Franciotti, Raffaella; Martinotti, Giovanni; Vellante, Federica; Flacco, Maria Elena; Di Giannantonio, Massimo; Thomas, Astrid; Onofrj, Marco (J Alzheimers Dis, 2018)
BACKGROUND: Post traumatic stress disorder (PTSD) is associated with cognitive decline. The dementia type following PTSD is unclear. OBJECTIVE: To assess whether PTSD is associated with a specific dementia. METHODS: Prospective study: 46 PTSD patients (DSM-IV-TR) were followed for 6-10 years with clinical, neuropsychological, imaging evaluations for possible development of dementia.Retrospective study:849 dementia patients followed during 1999-2014 (509 Alzheimer's disease, AD; 207 dementia with Lewy bodies, DLB; 90 vascular dementia, VaD; 43 frontotemporal dementia, FTD) and 287 patients with any neurological condition (including patients with/without dementia) were evaluated for the presence of PTSD in their history. RESULTS: Prospective study: 8 patients developed dementia; 1 AD, 1 DLB, 6 semantic FTD (13.0% of the PTSD population). Retrospective study: 38 patients (4.5%) had a history of PTSD; 3.5% of AD, 4.3% of DLB, 14.0% of FTD, 5.6% of VaD. The percentage was higher in FTD than in AD or DLB (χ2 = 10, p = 0.001, and χ2 = 6, p = 0.02). At difference with AD, DLB, or VaD, FTD incidence among dementia patients with PTSD history (38 patients) was higher than in the dementia population overall (16% versus 5%, χ2 = 8, p = 0.005). The impact of possible demographical/clinical confounders (age, gender, MMSE) was excluded by Poisson regression. PTSD prevalence in the comparative group without dementia matched the prevalence in the Italian general population (1.1%). PTSD prevalence in the demented comparative group matched the prevalence in our dementia retrospective cohort, 3.7%). DISCUSSION: PTSD was associated with the development of semantic FTD.

Postmortem T2*- Weighted MRI Imaging of Cortical Iron Reflects Severity of Alzheimer's Disease. - Bulk, Marjolein; Kenkhuis, Boyd; Graaf, Linda M van der; Goeman, Jelle J; Natté, Remco; Weerd, Louise van der (J Alzheimers Dis, 2018)
The value of iron-based MRI changes for the diagnosis and staging of Alzheimer's disease (AD) depends on an association between cortical iron accumulation and AD pathology. Therefore, this study determined the cortical distribution pattern of MRI contrast changes in cortical regions selected based on the known distribution pattern of tau pathology and investigated whether MRI contrast changes reflect the underlying AD pathology in the different lobes. T2*-weighted MRI was performed on postmortem cortical tissue of controls, late-onset AD (LOAD), and early-onset AD (EOAD) followed by histology and correlation analyses. Combining ex vivo high-resolution MRI and histopathology revealed that: 1) LOAD and EOAD have a different distribution pattern of AD pathological hallmarks and MRI contrast changes over the cortex, with EOAD showing more severe MRI changes; 2) per lobe, severity of AD pathological hallmarks correlates with iron accumulation, and hence with MRI. Therefore, iron-sensitive MRI sequences allow detection of the cortical distribution pattern of AD pathology ex vivo.

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer's Disease Neuropathology. - Zolochevska, Olga; Bjorklund, Nicole; Woltjer, Randall; Wiktorowicz, John E; Taglialatela, Giulio (J Alzheimers Dis, 2018)
Some individuals, here referred to as Non-Demented with Alzheimer's Neuropathology (NDAN), retain their cognitive function despite the presence of amyloid plaques and tau tangles typical of symptomatic Alzheimer's disease (AD). In NDAN, unlike AD, toxic amyloid-β oligomers do not localize to the postsynaptic densities (PSDs). Synaptic resistance to amyloid-β in NDAN may thus enable these individuals to remain cognitively intact despite the AD-like pathology. The mechanism(s) responsible for this resistance remains unresolved and understanding such protective biological processes could reveal novel targets for the development of effective treatments for AD. The present study uses a proteomic approach to compare the hippocampal postsynaptic densities of NDAN, AD, and healthy age-matched persons to identify protein signatures characteristic for these groups. Subcellular fractionation followed by 2D gel electrophoresis and mass spectrometry were used to analyze the PSDs. We describe fifteen proteins which comprise the unique proteomic signature of NDAN PSDs, thus setting them apart from control subjects and AD patients.