Pages 1-12
Review
Jae-Hong Lee, Jianping Jia, Yong Ji, Nagaendran Kandiah, SangYun Kim, Vincent Mok, Ming-Chyi Pai, Vorapun Senanarong, Chong Hyun Suh, Christopher Chen
A Framework for Best Practices and Readiness in the Advent of Anti-Amyloid Therapy for Early Alzheimer’s Disease in Asia
Abstract: Advances in biomarker-based diagnostic modalities, recent approval of anti-amyloid monoclonal antibodies for early Alzheimer’s disease (AD; mild cognitive impairment or mild dementia due to AD) and late-stage clinical development of other disease-modifying therapies for AD necessitate a significant paradigm shift in the early detection, diagnosis and management of AD. Anti-amyloid monoclonal antibodies target the underlying pathophysiological mechanisms of AD and have demonstrated a significant reduction in the rate of clinical decline in cognitive and functional outcome measures in patients with early AD. With growing recognition of the benefit of early interventions in AD, an increasing number of people may seek diagnosis for their subjective cognitive problems in an already busy medical system. Various factors such as limited examination time, lack of expertise for cognitive assessment and limited access to specialized tests can impact diagnostic accuracy and timely detection of AD. To overcome these challenges, a new model of care will be required. In this paper, we provide practical guidance for institutional readiness for anti-amyloid therapies for early AD in Asia, in terms of best practices for identifying eligible patients and diagnosing them appropriately, safe administration of anti-amyloid monoclonal antibodies and monitoring of treatment, managing potential adverse events such as infusion reactions and amyloid-related imaging abnormalities, and cross-disciplinary collaboration. Education and training will be the cornerstone for the establishment of new pathways of care for the identification of patients with early AD and delivery of anti-amyloid therapies in a safe and efficient manner to eligible patients.
Pages 13-30
Systematic Review
Ayoub Boulares, Aurélien Pichon, Corentin Faucher, Nicola Luigi Bragazzi, Olivier Dupuy
Effects of Intermittent Hypoxia Protocols on Cognitive Performance and Brain Health in Older Adults Across Cognitive States: A Systematic Literature Review
Abstract: Background: The rise in the aging population highlights the need to address cognitive decline and neurodegenerative diseases. Intermittent hypoxia (IH) protocols show promise in enhancing cognitive abilities and brain health. Objective: This review evaluates IH protocols' benefits on cognition and brain health in older adults, regardless of cognitive status. Methods: A systematic search following PRISMA guidelines was conducted across four databases (PubMed, Scopus, Web of Science, and Cochrane Library) and two registers, covering records from inception to May 2024 (PROSPERO: CRD42023462177). Inclusion criteria were: 1) original research with quantitative details; 2) studies involving older adults, with or without cognitive impairment; 3) studies including IH protocols; 4) articles analyzing cognition and brain health in older adults Results: Seven studies and five registered trials met the criteria. Findings indicate that Intermittent Hypoxia Training (IHT) and Intermittent Hypoxia-Hyperoxia Training (IHHT) improved cognitive functions and brain health. Intermittent Hypoxic Exposure (IHE) improved cerebral tissue oxygen saturation, middle cerebral arterial flow velocity, and cerebral vascular conductance, particularly in cognitively impaired populations. IHT and IHHT had no significant effect on BDNF levels. There is a lack of studies on IHHE in older adults with and without cognitive impairment. Conclusions: Conclusion: IH protocols may benefit cognition regardless of cognitive status. IHT and IHE positively affect cerebral outcomes, with all protocols having limited effects on BDNF levels. Future research should standardize IH protocols, investigate long-term cognitive effects, and explore neuroprotective biomarkers. Combining these protocols with physical exercise across diverse populations could refine interventions and guide targeted therapeutic strategies.
Pages 31-48
Yan Liu, Weiyue Xu, Pan Yang, Xingshun Liu (Handling Associate Editor: Pankaj Gurjar)
Revealing Molecular Patterns of Alzheimer’s Disease Risk Gene Expression Signatures in COVID-19 Brains
Abstract: Background: Various virus infections are known to predispose to Alzheimer's disease (AD), and a linkage between COVID-19 and AD has been established. COVID-19 infection modulates the gene expression of the genes implicated in progression of AD. Objective: Determination of molecular patterns and codon usage and context analysis for the genes that are modulated during COVID-19 infection and are implicated in AD was the target of the study. Methods: Our study employed a comprehensive array of research methods, including relative synonymous codon usage, Codon adaptation index analysis, Neutrality and parity analysis, Rare codon analyses, and codon context analysis. This meticulous approach was crucial in determining the molecular patterns present in genes up or downregulated during COVID-19 infection. Results: G/C ending codons were preferred in upregulated genes while not in downregulated genes, and in both gene sets, longer genes have high expressivity. Similarly, T over A nucleotide was preferred, and selection was the major evolutionary force in shaping codon usage in both gene sets. Apart from stops codons, codons CGU – Arg, AUA – Ile, UUA – Leu, UCG – Ser, GUA – Val, and CGA – Arg in upregulated genes, while CUA – Leu, UCG – Ser, and UUA – Leu in downregulated genes were present below the 0.5%. Glutamine-initiated codon pairs have high residual values in upregulated genes. Identical codon pairs GAG-GAG and GUG-GUG were preferred in both gene sets. Conclusions: The shared and unique molecular features in the up- and downregulated gene sets provide insights into the complex interplay between COVID-19 infection and AD. Further studies are required to elucidate the relationship of these molecular patterns with AD pathology.
Pages 49-60
Stuart G. Foster*, Shibi Mathew*, Audrey Labarre, J. Alex Parker, Thomas A. Tompkins, Sylvie Binda *These authors contributed equally to this work.
Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179 Prolong Lifespan and Mitigate Amyloid-β Toxicity in C. elegans via Distinct Mechanisms
Abstract: Background: Recent advances linking gut dysbiosis with neurocognitive disorders such as Alzheimer’s disease (AD) suggest that the microbiota-gut-brain axis could be targeted for AD prevention, management, or treatment. Objective: We sought to identify probiotics that can delay Aβ-induced paralysis. Methods: Using C. elegans expressing human amyloid-β (Aβ)1-42 in body wall muscles (GMC101), we assessed the effects of several probiotic strains on paralysis. Results: We found that Lacticaseibacillus rhamnosus HA-114 and Bacillus subtilis R0179, but not their supernatants or heat-treated forms, delayed paralysis and prolonged lifespan without affecting the levels of amyloid-β aggregates. To uncover the mechanism involved, we explored the role of two known pathways involved in neurogenerative diseases, namely mitophagy, via deletion of the mitophagy factor PINK-1, and fatty acid desaturation, via deletion of the Δ9 desaturase FAT-5. Pink-1 deletion in GMC101 worms did not modify the life-prolonging and anti-paralysis effects of HA-114 but reduced the protective effect of R0179 against paralysis without affecting its life-prolonging effect. Upon fat5 deletion in GMC101 worms, the monounsaturated C14:1 and C16:1 FAs conserved their beneficial effect while the saturated C14:0 and C16:0 FAs did not. The beneficial effects of R0179 on both lifespan and paralysis remained unaffected by fat-5 deletion, while the beneficial effect of HA-114 on paralysis and lifespan was significantly reduced. Conclusions: Collectively with clinical and preclinical evidence in other models, our results suggest that HA-114 or R0179 could be studied as potential therapeutical adjuncts in neurodegenerative diseases such as AD.
Pages 61-73
Tania M. Setiadi, Jan-Bernard C. Marsman, Sander Martens, Shankar Tumati, Esther M. Opmeer, Fransje E. Reesink, Peter P. De Deyn, Mercedes Atienza, André Aleman, Jose L. Cantero (Handling Associate Editor: Ralph Buchert)
Alterations in Gray Matter Structural Networks in Amnestic Mild Cognitive Impairment: A Source-Based Morphometry Study
Abstract: Background: Amnestic mild cognitive impairment (aMCI), considered as the prodromal stage of Alzheimer’s disease, is characterized by isolated memory impairment and cerebral gray matter volume (GMV) alterations. Previous structural MRI studies in aMCI have been mainly based on univariate statistics using voxel-based morphometry. Objective: We investigated structural network differences between aMCI patients and cognitively normal older adults by using source-based morphometry, a multivariate approach that considers the relationship between voxels of various parts of the brain. Methods: Ninety-one aMCI patients and 80 cognitively normal controls underwent structural MRI and neuropsychological assessment. Spatially independent components (ICs) that covaried between participants were estimated and a multivariate analysis of covariance was performed with ICs as dependent variables, diagnosis as independent variable, and age, sex, education level, and site as covariates. Results: aMCI patients exhibited reduced GMV in the precentral, temporo-cerebellar, frontal, and temporal network, and increased GMV in the left superior parietal network compared to controls (pFWER<0.05, Holm-Bonferroni correction). Moreover, we found that diagnosis, more specifically aMCI, moderated the positive relationship between occipital network and Mini-Mental State Examination scores (pFWER<0.05, Holm-Bonferroni correction). Conclusions: Our results showed GMV alterations in temporo-fronto-parieto-cerebellar networks in aMCI, extending previous results obtained with univariate approaches.
Pages 75-89
Hengnian Qi*, Xiaorong Zhu*, Yinxia Ren, Xiaoya Zhang, Qizhe Tang, Chu Zhang, Qing Lang, Lina Wang *These authors contributed equally to this work.
A Study of Assisted Screening for Alzheimer’s Disease Based on Handwriting and Gait Analysis
Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is not easily detected in the early stage. Handwriting and walking have been shown to be potential indicators of cognitive decline and are often affected by AD. Objective: This study proposes an assisted screening framework for AD based on multimodal analysis of handwriting and gait and explores whether using a combination of multiple modalities can improve the accuracy of single modality classification. Methods: We recruited 90 participants (38 AD patients and 52 healthy controls). The handwriting data was collected under four handwriting tasks using dot-matrix digital pens, and the gait data was collected using an electronic trail. The two kinds of features were fused as inputs for several different machine learning models (Logistic Regression, SVM, XGBoost, Adaboost, LightGBM), and the model performance was compared. Results: The accuracy of each model ranged from 71.95% to 96.17%. Among them, the model constructed by LightGBM had the best performance, with an accuracy of 96.17%, sensitivity of 95.32%, specificity of 96.78%, PPV of 95.94%, NPV of 96.74%, and AUC of 0.991. However, the highest accuracy of a single modality was 93.53%, which was achieved by XGBoost in gait features. Conclusions: The research results show that the combination of handwriting features and gait features can achieve better classification results than a single modality. In addition, the assisted screening model proposed in this study can achieve effective classification of AD, which has development and application prospects.
Pages 91-97
Gihwan Byeon, Min Soo Byun, Dahyun Yi, Hyejin Ahn, Gijung Jung, Yun-Sang Lee, Yu Kyeong Kim, Koung Mi Kang, Chul-Ho Sohn, Dong Young Lee for the KBASE research group
Moderation of Amyloid-β Deposition on the Effect of Cholinesterase Inhibitors on Cognition in Mild Cognitive Impairment
Abstract: Background: Clinical trial findings on cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) are inconclusive, offering limited support for their MCI treatment. Given that nearly half of amnestic MCI cases lack cerebral amyloid-β (Aβ) deposition, a hallmark of Alzheimer’s disease; this Aβ heterogeneity may explain inconsistent results. Objective: This study aimed to assess whether Aβ deposition moderates ChEI effects on amnestic MCI cognition. Methods: We examined 118 individuals with amnestic MCI (ages 55–90) in a longitudinal cohort study. Baseline and 2-year follow-up assessments included clinical evaluations, neuropsychological testing, and multimodal neuroimaging. Generalized linear models were primarily analyzed to test amyloid positivity's moderation of ChEI effects on cognitive change over 2 years. Cognitive outcomes included Mini-Mental Status Examination score, the total score of the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery, and Clinical Dementia Rating-sum of boxes. Results: The analysis found no significant ChEI use x amyloid positivity interaction for all cognitive outcomes. ChEI use, irrespective of Aβ status, was associated with more cognitive decline over the 2-year period. Conclusions: Aβ pathology does not appear to moderate ChEI effects on cognitive decline in MCI.
Pages 99-109
Jeffrey J. Wing, Jenna I. Rajczyk, James F. Burke (Handling Associate Editor: Erin Abner)
Geographic Variation of Prevalence of Alzheimer’s Disease and Related Dementias in Central Appalachia
Abstract: Background: Alzheimer’s disease and related dementias (ADRD) prevalence varies geographically in the United States. Objective: To assess whether the geographic variation of ADRD in Central Appalachia is explained by county-level sociodemographics or access to care. Methods: Centers for Medicare and Medicaid Services Public Use Files from 2015–2018 were used to estimate county-level ADRD prevalence among all fee-for-service (FFS) beneficiaries with ≥1 inpatient, skilled nursing facility, home health agency, hospital outpatient or Carrier claim with a valid ADRD ICD-9/10 code over three-years in Central Appalachia (Kentucky, North Carolina, Ohio, Tennessee, Virginia, and West Virginia). Negative binomial regression was used to estimate prevalence overall, by Appalachian/non-Appalachian designation, and by rural/urban classification. Models were then adjusted for county-level: 1) FFS demographics (age, gender, and Medicaid eligibility), comorbidities; 2) population sociodemographics (race/ethnicity, education, aging population distribution, and renter-occupied housing); and 3) diagnostic access (PCP visits, neurology visits, and imaging scans). Results: Across the 591 counties in the Central Appalachian region, the average prevalence of ADRD from 2015-2018 was 11.8%. ADRD prevalence was modestly higher for Appalachian counties both overall (PR: 1.03; 95% CI: 1.02, 1.04) and after adjustment (PR: 1.02; 95% CI: 1.00, 1.03) compared to non-Appalachian counties. This difference was similar among rural and urban counties (p=0.326) but varied by state (p=0.0040). Conclusions: The relative variation in ADRD prevalence in the Appalachian region was smaller than hypothesized. The case mixture of the dual eligible population, accuracy of the outcome measurement, and impact of educational attainment in this region may contribute to this observation.
Pages 111-131
Oliver J. L'Esperance, Joshua McGhee, Garett Davidson, Suraj Niraula, Adam S. Smith, Alexandre A. Sosunov, Shirley Shidu Yan, Jaichandar Subramanian
Functional Connectivity Favors Aberrant Visual Network c-Fos Expression Accompanied by Cortical Synapse Loss in a Mouse Model of Alzheimer’s Disease
Abstract: Background: While Alzheimer's disease (AD) has been extensively studied with a focus on cognitive networks, visual network dysfunction has received less attention despite compelling evidence of its significance in AD patients and mouse models. We recently reported c-Fos and synaptic dysregulation in the primary visual cortex of a pre-amyloid plaque AD-model. Objective: We test whether c-Fos expression and presynaptic density/dynamics differ in cortical and subcortical visual areas in an AD-model. We also examine whether aberrant c-Fos expression is inherited through functional connectivity and shaped by light experience. Methods: c-Fos+ cell density, functional connectivity, and their experience-dependent modulation were assessed for visual and whole-brain networks in both sexes of 4–6-month-old J20 (AD-model) and wildtype (WT) mice. Cortical and subcortical differences in presynaptic vulnerability in the AD-model were compared using ex vivo and in vivo imaging. Results: Visual cortical, but not subcortical, networks show aberrant c-Fos expression and impaired experience-dependent modulation. The average functional connectivity of a brain region in WT mice significantly predicts aberrant c-Fos expression, which correlates with impaired experience-dependent modulation in the AD-model. We observed a subtle yet selective weakening of excitatory visual cortical synapses. The size distribution of cortical boutons in the AD-model is downscaled relative to those in WT mice, suggesting a synaptic scaling-like adaptation to bouton size. Conclusions: Visual network structural and functional disruptions are biased toward cortical regions in pre-plaque J20 mice, and the cellular and synaptic dysregulation in the AD-model represents a maladaptive modification of the baseline physiology seen in WT conditions.
Pages 133-145
Golnoosh Alipour-Haris, Melissa J. Armstrong, Amie J. Goodin, Jingchuan Serena Guo, Joshua D. Brown (Handling Associate Editor: Laura Bonanni)
End-of-Life Healthcare Utilization in Lewy Body Dementia
Abstract: Background: Lewy body dementia (LBD) is the second most common neurodegenerative dementia in the US, presenting unique end-of-life challenges. Objective: This study examined healthcare utilization and care continuity in the last year of life in LBD. Methods: Medicare claims for enrollees with LBD, continuously enrolled in the year preceding death, were examined from 2011-2018. We assessed hospital stays, emergency department (ED) visits, intensive care unit (ICU) admissions, life-extending procedures, medications, and care continuity. Results: We identified 45,762 LBD decedents, predominantly female (51.8%), White (85.9%), with average age of 84.1 years (SD 7.5). There was a median of 2 ED visits (IQR 1-5) and 1 inpatient stay (IQR 0-2). Higher age was inversely associated with ICU stays (Odds Ratio [OR] 0.96; 95% Confidence Interval [CI] 0.96-0.97) and life-extending procedures (OR 0.96; 95% CI 0.95-0.96). Black and Hispanic patients experienced higher rates of ED visits, inpatient hospitalizations, ICU admissions, life-extending procedures, and in-hospital deaths relative to White patients. On average, 15 (7.5) medications were prescribed in the last year. Enhanced care continuity correlated with reduced hospital (OR 0.72; 95% CI 0.70-0.74) and ED visits (OR 0.71; 95% CI 0.69-0.87) and fewer life-extending procedures (OR 0.71; 95% CI 0.64-0.79). Conclusions: This study underscored the complex healthcare needs of people with LBD during their final year, which was influenced by age and race. Care continuity may reduce hospital and ED visits and life-extending procedures.
Pages 147-157
Yahui Zhang, Yulin Li, Shangchen Song, Zhigang Li, Minggen Lu, Guogen Shan
Predicting Conversion Time from Mild Cognitive Impairment to Dementia with Interval-Censored Models
Abstract: Background: Mild cognitive impairment (MCI) patients are at a high risk of developing Alzheimer’s disease and related dementias (ADRD) at an estimated annual rate above 10%. It is clinically and practically important to accurately predict MCI-to-dementia conversion time by using easily available clinical data. Objective: It is clinically and practically important to accurately predict MCI-to-dementia conversion time by using easily available clinical data. Methods: The dementia diagnosis often falls between two clinical visits, and such survival outcome is known as interval-censored data. We utilized the semi-parametric model and the random forest model for interval-censored data in conjunction with a variable selection approach to determine the sensitive measures for predicting the conversion time from MCI to dementia. Two large AD cohort data sets were used to build, validate, and test the predictive model. Results: We found that the semi-parametric model can improve the prediction of the conversion time for patients with MCI-to-dementia conversion, and it also has good predictive performance for all patients. Conclusions: Interval-censored data should be analyzed by using the models that were developed for interval- censored data to improve the model performance.
Pages 159-173
Jun Chen, Jingwen Yang, Dayong Shen, Xi Wang, Zihao Lin, Hao Chen, Guiyun Cui, Zuohui Zhang, Alzheimer’s Disease Neuroimaging Initiative
A Predictive Model of the Progression to Alzheimer’s Disease in Patients with Mild Cognitive Impairment Based on the MRI Enlarged Perivascular Spaces
Abstract: Background: Mild cognitive impairment (MCI) is a heterogeneous condition that can precede various forms of dementia, including Alzheimer's disease (AD). Identifying MCI subjects who are at high risk of progressing to AD is of major clinical relevance. Enlarged perivascular spaces (EPVS) on MRI are linked to cognitive decline, but their predictive value for MCI to AD progression is unclear. Objective: This study aims to assess the predictive value of EPVS for MCI to AD progression and develop a predictive model combining EPVS grading with clinical and laboratory data to estimate conversion risk. Methods: We analyzed 358 patients with MCI from the ADNI database, consisting of 177 MCI-AD converters and 181 non-converters. The data collected included demographic information, imaging data (including perivascular spaces grade), clinical assessments, and laboratory test results. Variable selection was conducted using the Least Absolute Shrinkage and Selection Operator (LASSO) method, followed by logistic regression to develop predictive model. Results: In the univariate logistic regression analysis, both moderate (OR=5.54, 95% CI [3.04–10.18]) and severe ( OR=25.04, 95% CI [10.07–62.23]) enlargements of the centrum semiovale perivascular space (CSO-PVS) were found to be strong predictors of disease progression. LASSO analyses yielded 12 variables, refined to six in the final model: APOE4 genotype, ADAS11 score, CSO-PVS grade, and volumes of entorhinal, fusiform, and midtemporal regions, with an AUC of 0.956 in the training and 0.912 in the validation cohort. Conclusions: Our predictive model, emphasizing EPVS assessment, provides clinicians with a practical tool for early detection and management of AD risk in MCI patients.
Pages 175-182
Chukwuanugo Ogbuagu, Ekenechukwu Ogbuagu, Obiageli Emelumadu, Uzoma Okereke, Irene Okeke, Godswill Chigbo, Shireen Javendal, Bruce Miller, Victor Valcour, Isabel Elaine Allen, Collette Goode, Katherine L Possin, Richard Uwakwe
Feasibility and Determinants of Performance for a Tablet-Based Cognitive Assessment Tool in Rural and Urban Southeast Nigeria
Abstract: Background: Cognitive assessment is a key component of clinical evaluations for patients with dementia and Alzheimer’s disease in primary health care (PHC) settings. The need for well-validated, culturally appropriate, and easy-to-use assessments is especially urgent in low- and middle-income countries (LMICs) that are experiencing rapid growth in their older adult populations. Objective: To examine the feasibility and demographic determinants of performance for a tablet-based cognitive screening tool (TabCAT) battery, which includes subtests for four cognitive domains, among older PHC patients in southeast Nigeria. Methods: A cross-sectional mixed-method descriptive study evaluating the useability and performance of TabCAT. Results: We enrolled 207 participants (mean age of 64.7±13.5 years; 52% with only primary, 41% secondary, and 7% tertiary education). Most (91%) who initiated the assessment were able to complete it, requiring 10-15 minutes to complete. More years of education was associated with better test scores across all tests (p < 0.001). Living in a rural location was also associated with better performance (p < 0.05). Male compared to female sex did not associate with performance on any of the tests (all ps >0.05). Conclusions: Tablet-based cognitive assessment was feasible in rural and urban settings of Nigeria. Better performance on cognitive subtests linked to more education and residing in a rural area; however, sex did not predict performance. Digital cognitive assessment tools hold potential for widespread use in healthcare and educational contexts, particularly in regions with varying levels of urbanization and educational access.
Pages 183-195
Junyao Zhang, Yinglin Zhang, Yingying Zhang, Junyan Yao
The Association of Brain Insulin Resistance with Anesthesia/Surgery-Induced Cognitive Deterioration Is Female-Specific in 5XFAD Transgenic Mice
Abstract: Background: Our previous studies indicated that anesthesia/surgery could aggravate cognitive impairment and tau pathology in female 5XFAD transgenic (Tg) mice. However, it is unknown whether there are sex differences in the susceptibility of developing postoperative cognitive dysfunction in 5XFAD Tg mice. Objective: In this study, we aim to determine whether anesthesia/surgery can have different effects on female and male 5XFAD Tg mice, and to explore the underpinning mechanisms. Methods: The mice received abdominal surgery under isoflurane anesthesia. Morris water maze was used to assess the cognitive function. Hippocampal levels of p-tau (AT8), p-IRS1 (Ser612), IRS1, p-GSK3β (Tyr216), and p-GSK3β (Ser9) at postoperative day 1 were evaluated by western blot assays. Results: Anesthesia/surgery exaggerated cognitive impairment and tau pathology in female, but not male 5XFAD Tg mice. The anesthesia/surgery led to elevated hippocampus protein levels of p-IRS1 (Ser612)/IRS1 ratio and p-GSK3β (Tyr216) and reduced hippocampus protein levels of p-GSK3β (Ser9) in female, but not male 5XFAD Tg mice. Conclusions: This study demonstrated that female 5XFAD Tg mice were more susceptible to anesthesia/surgery-induced cognitive deterioration and tau pathology aggravation, potentially due to female-specific brain insulin resistance.
Pages 197-209
Xiaoyan Cui, Junqiao Wang, Xueting Tang, Ding Ding, Bei Wu, Qianhua Zhao, Jing Wang
Navigating the Journey of Living with Young-Onset Dementia: Experiences of Spousal Caregivers
Abstract: Background: Young-onset dementia (YOD) refers to dementia occurring before the age of 65, with Alzheimer’s disease being the most common form, posing distinct challenges for spousal caregivers. Objective: This study aims to investigate the unique experiences of spousal caregivers of persons with YOD in China, where dementia-specific community care services and primary healthcare professionals are relatively lacking, in order to inform the tailored support services development. Methods: This qualitative-design study utilized semi-structured interviews with 11 spousal caregivers of persons with YOD dwelling in the community. Traditional content analysis was employed to analyze the interview data. Results: Limited dementia-specific healthcare professionals and low public awareness made diagnosing and accepting YOD a prolonged and challenging journey. Spousal caregivers faced skepticism when seeking diagnosis, exacerbating their burden and emotional stress. Disparities in healthcare professionals and insufficient collaboration between institutions worsened the situation. YOD significantly impacted family dynamics and led to changes in emotional communication within the family. The stigma surrounding YOD raised concerns among spousal caregivers about their children’s future in marriage and career, emphasizing genetic risks. Conclusions: In settings where dementia-specific community care services and primary healthcare professionals are limited and unevenly distributed, integrating support services at both the primary and community levels is crucial for families dealing with YOD in the community. Additionally, raising public awareness about YOD can foster a more understanding and supportive environment, addressing challenges related to stigma faced by affected families, contributing to increased investment in supporting resources, and encouraging individuals to seek help early on.
Pages 211-221
Auob Rustamzadeh, Abbas Tafakhori, Armin Ariaei, Mahdi Heydari, Mehran Ebrahimi Shah-abadi, Farhad Seif
Targeting Caspases 3/6 and Cathepsins L/B May Decrease Laminopathy-Induced Apoptosis in Alzheimer’s Disease
Abstract: Background: Laminopathy is a pathological manifestation observed in Alzheimer's disease (AD), leading to neuronal apoptosis. Objective: Our objective was to assess inhibitors of enzymes involved in laminopathy. Methods: The mRNA expression of the cathepsins L and B, caspases 3 and 6, lamins b1 and b2, granzymes A and B, and lamins A and C were extracted and analyzed from GSE5281 and GSE28146 datasets. A total of 145 ligands were selected for molecular docking. Subsequently, 10 ns and 100 ns atomistic molecular dynamics (MD) and Martini 3 were performed with NAMD for two selected ligands (PubChem id: 608841 and ChEMBL id: 550872). Results: The mRNA expression level highlighted caspase 6 and lamin A/C upregulation in the hippocampus of the AD samples, in contrast to cathepsin B, lamin b2, and caspase 3. Moreover, there was a strong correlation between the expression level of cathepsin B, lamin A/C, and caspase 6 in the AD group. The MD results suggested molecule with ChEMBL id of 550872 had higher free binding energy, while in longer simulation the molecule with PubChem id of 608841 was suggested to be more stable in complex with the receptor. Conclusions: Our findings suggest that lamins A/C, cathepsins B/L, caspase 6, and lamin B2 are associated with laminopathy as potential factors contributing to apoptosis in AD. We propose that simultaneous inhibition of caspases 6 and cathepsins L may decrease the rate of apoptosis triggered by lamin degradation. Nevertheless, further studies are required to confirm these observations due to the lack of in vivo findings.
Pages 223-234
Knut Engedal, Jūratė Šaltytė Benth, Jørgen Wagle, Linda Gjøra, Geir Selbæk, Karin Persson (Handling Associate: Editor: Anne Fink)
Normative Scores on the Clock Drawing Test Among Older Adults from a Large Population Survey in Norway: The HUNT Study
Abstract: Background: The Clock Drawing Test (CDT) is used to screen for Alzheimer’s disease and other dementia disorders. Normative scores on the version from the Montreal Cognitive Assessment (MoCA) do not exist in the Nordic countries. Objective: To examine the normative scores of the CDT among adults aged 70 years and older. Methods: We included 4,023 cognitively healthy persons aged 70-97 years from a population survey in Norway. They were examined with the CDT, which has a total score between zero and three. A multiple multinominal regression model was applied with a CDT score as the dependent categorical variable and estimated the probabilities of scoring a particular score, stratified by age, sex, and education. These probabilities correspond to an expected proportion of the normative population scoring at, or below a given percentile. Results: None scored zero, 2.1% scored one, 14.9% scored two, and 83% scored three. Higher age, female sex and fewer years of schooling were associated with poorer performance. Scores of zero and one deviated from the normative score regardless of age, sex and education. A score of two was within the norm for a female older than 81 and a male older than 85. Conclusions: The majority (83%) of people 70 years and older had a score of three on the CDT. Lower age, male sex, and higher education were associated with a better performance. Scores of zero and one were below the normative score. Except for the very old, a score of two was also well below the normative score.
Pages 235-248
Meixiang Fan*, Qingfeng Li*, Tingting Yang, Yinghua Yang, Zhihua Chen, Guo Xuan, Ye Ruan, Shuangyuan Sun, Meng Wang, Xiaoli Chen, Yanyan Huang, Zhi Yang, Ying Wang *These authors contributed equally to this work.
Effect of Multimodal Intervention in Individuals with Mild Cognitive Impairment: A Randomized Clinical Trial in Shanghai
Abstract: Background: Previous trials have indicated that multimodal training could improve cognitive functions and moods in individuals with mild cognitive impairment (MCI). However, evidence was mainly obtained from studies in high-income countries. Objective: This trial aims to investigate the efficacy, safety, and potential mechanism of a multimodal intervention on cognitive function in individuals with MCI living in a community. Methods: In this single-blind, randomized controlled trial, 120 participants with MCI were randomly assigned to either the intervention group or the control group. The intervention group received the multimodal intervention, while the control group received regular health education. Neuropsychological tests and magnetic resonance imaging (fMRI) were conducted at baseline and after the 12-week intervention. Results: Fifty-nine and fifty-seven participants respectively in the intervention and control groups completed the trial. The intervention group shown improvements in primary outcome, Mini-Mental State Exam (MMSE) total score (mean difference -0.96, 95% CI [-1.58, -0.34], p=0.003), and secondary outcomes: MMSE recall (-0.39, 95% CI [-0.71, -0.07], p=0.019), MMSE language (-0.26, 95% CI [-0.44, -0.07], p=0.007), Auditory Verbal Learning Test instantaneous memory (-3.30, 95% CI [-5.70, -0.89], p=0.008), Digit Symbol Substitution Test total score (-2.91, 95% CI [-5.67, -0.15], p=0.039), digit span forwards (-1.25, 95% CI [-1.93, -0.56], p<0.001), and Digit Span Test (-1.33, 95% CI [-2.33, -0.34], p=0.009) compared to the control group. Improvements were observed in structural and functional connectivity related to language, concentration, executive function, memory, and recall functioning via MRI in the intervention group. Conclusions: The multimodal intervention improved cognitive function in individuals with MCI in cognitive performance and neuroimaging. Trial registration: ClinicalTrials.govNCT05483790. Trial registration date: July 24, 2022
Pages 249-258
Bárbara Avelar-Pereira, Curran Michael Phillips, S. M. Hadi Hosseini, for the Alzheimer’s Disease Neuroimaging Initiative
Convergence of Accelerated Brain Volume Decline in Normal Aging and Alzheimer’s Disease Pathology
Abstract: Background: Age represents the largest risk factor for Alzheimer’s disease (AD) but is typically treated as a covariate. Still, there are similarities between brain regions affected in AD and those showing accelerated decline in normal aging, suggesting that the distinction between the two might fall on a spectrum. Objective: Our goal was to identify regions showing accelerated atrophy across the brain and investigate whether these overlapped with regions involved in AD or where related to amyloid. Methods: We used a longitudinal sample of 137 healthy older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), who undwewent MRI. In addition, a total of 79 participants also had longitudinal PET data. We computed linear-mixed effects models for brain regions declining faster than the average to investigate variability in the rate of change. Results: 23 regions displayed a 0.5 SD above average decline over 2 years. Of these, 52% overlapped with regions showing similar decline in a matched AD sample. Beyond this, the left precuneus, right superior frontal, transverse temporal, and superior temporal sulcus showed accelerated decline. Lastly, atrophy in the precuneus was associated with increased amyloid load. Conclusions: Accelerated decline in normal aging might contribute to the detection of early signs of AD among healthy individuals.
Pages 259-276
Athira Nataraj, Annu Kala, Stephanie Lissette Proskauer Pena, Karel Jezek, Karel Blahna (Handling Associate Editor: Ling-Qiang Zhu)
Impaired Dynamics of Positional and Contextual Neural Coding in an Alzheimer’s Disease Rat Model
Abstract: Background: The hippocampal representation of space, formed by the collective activity of populations of place cells, is considered as a substrate of spatial memory. Alzheimer's disease (AD), a widespread severe neurodegenerative condition of multifactorial origin, typically exhibits spatial memory deficits among its early clinical signs before more severe cognitive impacts develop. Objective: To investigate mechanisms of spatial memory impairment in a double transgenic rat model of AD. Methods: In this study, we utilized 9-12-month-old double-transgenic TgF344-AD rats and age-matched controls to analyze the spatial coding properties of CA1 place cells. We characterized the spatial memory representation, assessed cells’ spatial information content and direction-specific activity, and compared their population coding in familiar and novel conditions. Results: Our findings revealed that TgF344-AD animals exhibited lower precision in coding, as evidenced by reduced spatial information and larger receptive zones. This impairment was evident in maps representing novel environments. While controls instantly encoded directional context during their initial exposure to a novel environment, transgenics struggled to incorporate this information into the newly developed hippocampal spatial representation. This resulted in impairment in orthogonalization of stored activity patterns, an important feature directly related to episodic memory encoding capacity. Conclusions: Overall, the results shed light on the nature of impairment at both the single-cell and population levels in the transgenic AD model. In addition to the observed spatial coding inaccuracy, the findings reveal a significantly impaired ability to adaptively modify and refine newly stored hippocampal memory patterns.
Pages 277-292
Amy Lastuka, Elye Bliss, Michael R. Breshock, Vincent C. Iannucci, William Sogge, Kayla V. Taylor, Paola Pedroza, Joseph L. Dieleman
Societal Costs of Dementia: 204 Countries, 2000–2019
Abstract: Background: Dementia prevalence is expected to increase as populations grow and age. Therefore, additional resources will be needed to meet the global demand for care for Alzheimer’s disease and related dementias (ADRD). Objective: Estimate global and country-level health care spending attributable to ADRD and the cost of informal care for people living with ADRD. Methods: We gathered data from three systematic literature reviews and the Global Burden of Disease 2019 study. We used spatiotemporal Gaussian process regression to impute estimates for the many countries without underlying data. We projected future costs to 2050 based on past trends in costs, diagnosis rates, and institutionalization rate. Results: We estimated that in 2019, the direct health care spending attributable to ADRD across 204 countries reached $260.6 billion (95% uncertainty interval [UI] 131.6−420.4) and the cost of informal ADRD care was $354.1 billion (95% UI 190.0−544.1). On average, informal care represents 57% (95% UI 38−75%) of the total cost of care. We estimated that direct health care spending attributable to ADRD will reach $1.6 trillion (95% UI 0.6−3.3) in 2050, or 9.4% (95% UI 3.9−19.6%) of projected health spending worldwide. We estimated the cost of informal care will reach $0.9 trillion (95% UI 0.3−1.7) in 2050. Conclusions: These cost estimates underscore the magnitude of resources needed to ensure sufficient resources for people living with ADRD and highlight the role that informal care plays in provision of their care. Incorporating informal care cost estimates is critical to capture the social cost of ADRD.
Pages 293-308
Ciro Rosario Ilardi, Alina Menichelli, Marco Michelutti, Tatiana Cattaruzza, Giovanni Federico, Marco Salvatore, Alessandro Iavarone, Paolo Manganotti (Handling Associate Editor: Carlo Abbate)
On the Clinimetrics of the Montreal Cognitive Assessment: Cutoff Analysis in Patients with Mild Cognitive Impairment due to Alzheimer’s Disease
Abstract: Background: In the era of disease-modifying therapies, empowering the clinical neuropsychologist’s toolkit for timely identification of mild cognitive impairment (MCI) is crucial. Objective: Here we examine the clinimetric properties of the Montreal Cognitive Assessment (MoCA) for the early diagnosis of MCI due to Alzheimer’s disease (MCI-AD). Methods: Data from 48 patients with MCI-AD and 47 healthy controls were retrospectively analyzed. Raw MoCA scores were corrected according to the conventional Nasreddine’s 1-point correction and demographic adjustments derived from three normative studies. Optimal cutoffs were determined while previously established cutoffs were diagnostically reevaluated. Results: The original Nasreddine’s cutoff of 26 and normative cutoffs (non-parametric outer tolerance limit on the 5th percentile of demographically-adjusted score distributions) were overly imbalanced in terms of Sensitivity (Se) and Specificity (Sp). The optimal cutoff for Nasreddine’s adjustment showed adequate clinimetric properties (≤23.50, Se = 0.75, Sp = 0.70). However, the optimal cutoff for Santangelo’s adjustment (≤22.85, Se = 0.65, Sp = 0.87) proved to be the most effective for both screening and diagnostic purposes according to Larner’s metrics. The results of post-probability analyses revealed that an individual testing positive using Santangelo’s adjustment combined with a cutoff of 22.85 would have 84% post-test probability of receiving a diagnosis of MCI-AD (LR+ = 5.06). Conclusions: We found a common (mal)practice of bypassing the applicability of normative cutoffs in diagnosis-oriented clinical practice. In this study, we identified optimal cutoffs for MoCA to be allocated in secondary care settings for supporting MCI-AD diagnosis. Methodological and psychometric issues are discussed.
Pages 309-320
Kiran Kumar Solingapuram Sai, Jennifer M. Erichsen, Krishna K. Gollapelli, Ivan Krizan, Mack Miller, Avinash Bansode, Mathew J. Jorgensen, Thomas Register, Charles Cazzola, Reenal Gandhi, Julie Suman, Suzanne Craft
First Biodistribution Study of [68Ga]Ga-NOTA-Insulin Following Intranasal Administration in Adult Vervet Monkeys
Abstract: Background: Intranasal insulin (INI) is being explored as a treatment for Alzheimer’s disease (AD). Improved memory, functional ability, and cerebrospinal fluid (CSF) AD biomarker profiles have been observed following INI administration. However, the method of intranasal delivery may significantly affect outcomes. Objective: To show reliable delivery of insulin to the brain using the Aptar Cartridge Pump System (CPS) intranasal delivery system. Methods: To visualize INI biodistribution, we developed a novel PET radiotracer, Gallium 68-radiolabeled (NOTA-conjugated) insulin, [68Ga]Ga-NOTA-insulin. We used the Aptar CPS to administer [68Ga]Ga-NOTA-insulin to anesthetized healthy adult vervet monkeys and measured brain regional activity and whole-body dosimetry following PET/CT scans. Results: We observed brain penetration of [68Ga]Ga-NOTA-insulin following intranasal administration with the Aptar CPS. Radioactive uptake was seen in multiple regions, including the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus. A safety profile and whole-body dosimetry were also established in a second cohort of vervets. Safety was confirmed: vitals remained stable, blood glucose levels were unchanged, and no organ was exposed to more than 2.5 mSv of radioactivity. Extrapolations from vervet organ distribution allowed for estimation of the [68Ga]Ga-NOTA-insulin absorbed dose in humans, and the maximum dose of [68Ga]Ga-NOTA-insulin that can be safely administered to humans was determined to be 185 MBq. Conclusions: The use of [68Ga]Ga-NOTA-insulin as a PET radiotracer is safe and effective for observing brain uptake in vervet monkeys. Further, the Aptar CPS successfully targets [68Ga]Ga-NOTA-insulin to the brain. The data will be essential in guiding future studies of intranasal [68Ga]Ga-NOTA-insulin administration in humans.
Pages 321-335
Tsz-lok Lee, Agnes S. Chan
Dose Response of Transcranial Photobiomodulation on Cognitive Efficiency in Healthy Older Adults: A Task-Related Functional Near-Infrared Spectroscopy Study
Abstract: Background: Alzheimer’s disease has become increasingly prevalent among the older population, leading to significant social and economic burdens. Transcranial photobiomodulation (tPBM) has shown promise as a cognitive intervention for enhancing cognitive efficiency in healthy older adults, and individuals with mild cognitive impairment and Alzheimer’s disease. However, determining the optimal tPBM dosage is crucial for ensuring effective and efficient intervention. Objective: This study aimed to compare the effects of different dosages in a single tPBM session on cognitive efficiency in healthy older adults. Methods: In this randomized controlled trial, 88 healthy older participants were assigned to either a single dose (irradiance = 30 mW/cm2, fluence = 10.8 J/cm2; n = 44) or a double dose (irradiance = 30 mW/cm2, fluence = 21.6 J/cm2; n = 44) tPBM session. Cognitive efficiency was assessed using functional near-infrared spectroscopy during a visual working memory span task. Results: The single dose group exhibited significantly greater cognitive efficiency enhancement, indicated by a more pronounced reduction in oxygenated hemoglobin during a challenging task level (span level 9) (p = 0.021, d = 0.50), and better working memory task performance (p = 0.045, d = 0.31). Furthermore, participants with better visuospatial abilities demonstrated greater improvement after a single dose (r = -0.42, p = 0.004). In contrast, participants with varying cognitive function did not exhibit additional benefits from a double dose (r = -0.22 – 0.15, p = 0.16 – 0.95). Conclusions: These findings suggest that higher tPBM dosages may not necessarily result in superior cognitive improvement in older adults.
Pages 337-352
Kuide Li*, Dan Mo*, Qian Yu, Rongjian Feng, Yamei Li *These authors contributed equally to this work.
Effect of Repetitive Transcranial Magnetic Stimulation on Post-Stroke Comorbid Cognitive Impairment and Depression: A Randomized Controlled Trial
Abstract: Background: There are currently no uniform treatments for post-stroke comorbid cognitive impairment and depression (PSCCID). Objective: To verify whether repetitive transcranial magnetic stimulation (rTMS) can improve PSCCID symptoms and explore the underlying roles of resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Thirty PSCCID patients were randomized in a 1:1 ratio to receive 4 weeks of rTMS (intervention group) or sham rTMS (control group) over the left dorsolateral prefrontal cortex (DLPFC). rs-fMRI was acquired to analyze the functional plasticity of brain regions at baseline and immediately after the last intervention. Results: Cognition, depression status, and neural electrophysiology were improved in both intervention and control groups after treatment (p=0.015-0.042), and the intervention group had more significant improvement than the control group. Analysis of functional connectivities (FCs) within the default mood network (DMN) showed that the connection strength of the left temporal pole/left parahippocampal cortex and right lateral temporal cortex/right retrosplenial cortex in the intervention group were enhanced compared with its pre-intervention and that in the control group after treatment (p<0.05), and the both FC values were positively correlated with MMSE scores (p<0.001). The intervention group had stronger FCs within the DMN compared with the control group after treatment, and some of the enhanced FCs were correlated with the P300 latency and amplitude. Conclusions: rTMS over the left DLPFC is an effective treatment for improving both cognitive impairment and depression among patients with PSCCID. The enhanced FCs within the DMN may serve as a compensatory functional recombination to promote clinical recovery.
Pages 353-367
Anuja Neve, Bibha Das, Jakub Wojtowicz, Zhiyue Huang, Szofia Bullain, Michelle Watki, Dominik Lott, Tobias Bittner, Paul Delmar, Gregory Klein, Carsten Hofmann, Geoffrey A. Kerchner, Janice Smith, Monika Baudler, Paulo Fontoura, Rachelle S. Doody
Long-Term Safety of Gantenerumab in Participants with Alzheimer’s Disease: A Phase III, Double-Blind, and Open-Label Extension Study (Marguerite RoAD)
Abstract: Background: Gantenerumab is an anti-amyloid-β immunoglobulin G1 monoclonal antibody for subcutaneous (SC) administration. The efficacy and safety of low-dose (105 mg or 225 mg) gantenerumab were investigated in Marguerite RoAD (MR; NCT02051608), a Phase III, double-blind (DB), placebo-controlled study in participants with mild Alzheimer’s disease (AD) dementia. Following a preplanned futility analysis of the SCarlet RoAD study (NCT01224106), MR was converted into an open-label extension (OLE). Objective: The DB study aimed to assess the efficacy of gantenerumab compared with placebo from baseline to Week 104 in participants with mild AD dementia. Following conversion to an OLE, this objective became exploratory, as the OLE assessed the long-term safety and tolerability of SC gantenerumab at doses of up to 1,200 mg every 4 weeks (Q4W) in OLE participants. Methods: Eligible DB study participants were offered the opportunity to receive gantenerumab up-titrated to 1,200 mg Q4W. Safety and tolerability were assessed using magnetic resonance imaging (MRI), physical and neurologic examinations, and adverse event monitoring. Results: Overall, 225 participants were rolled over from the DB part of MR and received ≥1 gantenerumab dose in the OLE. The median treatment duration was 123 weeks. Fifty-nine (26.2%) and 41 (18.2%) participants had amyloid-related imaging abnormality (ARIA)-edema and ARIA-hemorrhage MRI findings, respectively. ARIA findings were manageable with MRI monitoring and dose intervention; most were asymptomatic. There were no unexpected safety findings. Conclusions: SC gantenerumab at doses of up to 1,200 mg Q4W were well tolerated in participants with mild AD dementia.
Pages 369-377
Sandra Cardoso, Manuela Guerreiro, Alexandre Montalvo, Dina Silva, Luísa Alves, Alexandre de Mendonça
Amyloid-Negative, Neurodegeneration-Negative Amnestic Mild Cognitive Impairment
Abstract: Background: The concept of amnestic mild cognitive impairment (aMCI) was developed to identify patients at an initial stage of Alzheimer’s disease (AD). However, some patients with aMCI do not present biomarkers of amyloid pathology or neuronal injury. Objective: To know the natural history of amyloid-negative and neurodegeneration-negative patients with aMCI, namely to ascertain: 1) whether these patients remain cognitively stable or they present a slow decline in neuropsychological tests; 2) whether the memory complaints subside with the apparently benign clinical course of the disorder or if they persist along the time. Methods: Patients who fulfilled criteria for aMCI with no biomarkers of amyloid pathology or neuronal injury were selected from a large cohort of non-demented patients with cognitive complaints, and were followed with clinical and neuropsychological assessments. Results: Twenty-one amyloid-negative and neurodegeneration-negative aMCI patients were followed for 7.1±3.7 years. At the baseline they had more pronounced deficits in verbal learning (California Verbal Learning Test) and were also impaired in Word Recall and Logical Memory. However, they did not decline in any cognitive test during follow-up. The patients maintained a high level of subjective memory complaints from baseline (9.7±4.1) to the follow-up visit (9.2±4.1, a non-significant difference), in spite of a statistically significant decrease in the depressive symptoms, with Geriatric Depression Scale (15 items) score 4.9±2.8 at baseline and 3.2± 1.8 at the follow-up visit. Conclusions: Amyloid-negative, neurodegeneration-negative aMCI is a chronic clinical condition characterized by the long-term persistence of cognitive deficits and distressing memory complaints. Adequate strategies to treat this condition are needed.
