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Background: Latin American countries present major health-related inequities due to historical, cultural, and social aspects. Recent evidence highlights that factors related to social and health disparities outweigh classic demographic factors in determining healthy brain aging in these populations. However, these analyses have not been conducted with the Brazilian population, the largest and most ethnically diverse population in Latin America., Methods: Here, we evaluated demographic, social, and health factors for healthy brain ageing using a machine learning model in a Brazilian population-based cohort (n=9412) and in additional cohorts from other Latin American countries, including Colombia (n=23 694), Chile (n=1301), Ecuador (n=5235), and Uruguay (n=1450)., Findings: In the Brazilian population and other Latin American countries, social and health disparities were more influential than demographic factors for cognition and functional ability. Uniquely in Brazil, education emerged as the primary risk factor impacting cognitive outcomes, diverging from other Latin American countries where mental health symptoms played more prominent roles. In terms of functional ability, Brazil displayed a distinct pattern, with mental health symptoms identified as the primary contributing factor., Interpretation: Our findings indicate that Brazil converges with other Latin American countries to show that heterogeneous factors impacted more than demographic factors, but also showed a unique set of health factors when compared with other Latin American countries. Therefore, our study emphasises that social and health disparity factors are relevant predictors of healthy brain ageing in Latin America, but population-specific analyses are necessary to identify the specific risk profiles of each country., Funding: None., Translations: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests WVB is a cofounder and a minority shareholder at masima and receives financial support from Alzheimer's Association (AACSF-D-22928689). CSA is supported by Global Brain Health Institute, Alzheimer's Society (GBHI ALZ UK-23–971089), and Alzheimer's Association (24AACSF-1200375). MADB is a cofounder and a minority shareholder at masima and receives financial support from the Alzheimer's Association (AARF-D-23-1148735). ERZ receives financial support from CNPq (312410/2018-2; 435642/2018-9; 312306/2021-0; 409066/2022-2), ARD/FAPERGS (21/2551-0000673-0), Alzheimer's Association (AARGD-21- 850670), CNPQ/FAPERGS/PRONEX (16/2551-0000475-7), the Brazilian National Institute of Science and Technology in Excitotoxicity and Neuroprotection (465671/2014-4), Instituto Serrapilheira (Serra-1912-31365), and Alzheimer's Association and National Academy of Neuropsychology (ALZ-NAN-22-928381). CKS receives support from CNPq Research Productivity Fellowship (303883/2021-9). AI served on scientific advisory board of the Alzheimer's Association, Lilly, Cumulus, and Roche; and is supported by grants from ReDLat (National Institutes of Health and the Fogarty International Center, National Institutes of Aging [R01 AG057234, R01 AG075775, R01 AG21051, R01 AG083799, and CARD-NIH], Alzheimer's Association [SG-20–725707], Rainwater Charitable Foundation—The Bluefield project to cure FTD, and Global Brain Health Institute), ANID/FONDECYT Regular (1210195, 1210176, and 1220995); and ANID/FONDAP/15150012. TAP reports royalties or licences from the Alzheimer's Association and National Institute on Aging and support for attending meetings or travel from the Alzheimer's Association. PR-N has served in the scientific advisory board of Novo Nordisk, Eisai, and Ely Lilly; and as a consultant to Eisai and Cerveau radiopharmaceuticals. LPS has served on the scientific advisory board of Biogen, Knight Therapeutics, Novo Nordisk, and Roche. ERZ has served in the scientific advisory board of Nintx, Novo Nordisk, and masima, and is a cofounder and a minority shareholder at masima. JCdC reports grants or contracts from Conselho Nacional de Desenvolvimento Científico e Tecnológico and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul. All other authors declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

There is a growing understanding of the presymptomatic stages of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and nascent efforts aiming to prevent these devastating neurodegenerative diseases have emerged. This progress is attributable, in no small part, to the altruism of people living with pathogenic variants at elevated genetic risk for ALS/FTD via their willingness to participate in natural history studies and disease prevention trials. Increasingly, this community has also highlighted the urgent need to develop paradigms for providing appropriate clinical care for those at elevated risk for ALS and FTD. This manuscript summarises recommendations emanating from a multi-stakeholder Workshop (Malvern, Pennsylvania, 2023) that aimed to develop guidance for at-risk carriers and their treating physicians. Clinical care recommendations span genetic testing (including counselling and sociolegal implications); monitoring for the emergence of early motor, cognitive and behavioural signs of disease; and the use of Food and Drug Administration-approved small molecule drugs and gene-targeting therapies. Lifestyle recommendations focus on exercise, smoking, statin use, supplement use, caffeine intake and head trauma, as well as occupational and environmental exposures. While the evidence base to inform clinical and lifestyle recommendations is limited, this guidance document aims to appraise carriers and clinicians of the issues and best available evidence, and also to define the research agenda that could yield more evidence-informed guidelines., Competing Interests: Competing interests: MB reports consulting fees from Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB and uniQure. The University of Miami has licensed intellectual property to Biogen to support design of the ATLAS study. TDH-P reports participation in medical advisory boards with Amylyx, MT Pharma America and Novartis. JC-K reports no competing interests. DB reports consulting fees from Enliven, Xencor, Elevation Oncology and Atavistik. KBC reports no competing interests. SAG reports scientific advisory from Edivera. MV reports no competing interests. LD reports consulting fees from Passage Bio, Sano Genetics, and Biogen. JJA reports no competing interests. JS reports no competing interests. MRT reports salary support from the Motor Neurone Disease Association; royalties or licenses from Oxford University Press, Oneworld and Karger; speakers’ honoraria from University of Miami; and participation in advisory board for Biogen and Novartis. AA-C reports consultancies or advisory boards for Amylyx, Apellis, Biogen, Brainstorm, Clene Therapeutics, Cytokinetics, GenieUs, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, Sano, Sanofi and Wave Pharmaceuticals., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

There is rising public health concern surrounding dual sensory impairment (DSI), or comorbid hearing and vision impairments. Its global prevalence and the magnitude of its association with cognitive decline (CD) is unclear. Three databases were searched for epidemiological studies examining DSI prevalence or its association with CD. Independent reviewers selected studies, extracted data, and evaluated bias. Random-effects meta-analyses were performed. Projections were estimated using United Nations data. The population attributable fraction of DSI-associated CD was calculated. Among 43 studies with 5,246,796 participants, clinically assessed DSI prevalence was 5.50% (95% confidence interval [CI] = 2.88%-10.26%), with regional/ethnic/age variations. DSI prevalence is projected to increase by 27.2% from 2025 to 2050. Approximately 59.83% (95%CI = 41.03-76.12) of DSI patients had cognitive impairment. Baseline DSI was associated with incident CD (odds ratio [OR] = 1.72, 95%CI = 1.37-2.15). Globally, 3.81% (95%CI = 1.05-10.55) of incident CD may be attributed to DSI. DSI is globally prevalent, growing, and associated with CD, highlighting the need for better health policy and resource allocation. HIGHLIGHTS: The global prevalence of DSI is 5.50%, with geographical, ethnical and age variations. The prevalence of DSI rises with age and is projected to increase by 27.2% by 2050. Approximately 60% of individuals with DSI may have measurable cognitive impairment. DSI was associated with a 72% greater longitudinal risk of incident CD. Globally, 3.81% of CD cases may be attributable to DSI., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Nonmydriatic ocular fundus photography has been studied with demonstrated benefit in the evaluation of emergency department neurological complaints, particularly in triaging headache and focal neurological deficits. Likewise, portable fundus camera usage may be practical for inpatients with neurological complaints, although feasibility has not been studied in a neurology teaching service. Purpose: The objective of this study is to determine if a portable, nonmydriatic fundus camera could be integrated into routine clinical care by neurology inpatient housestaff at a tertiary medical center. Research Design: Housestaff were asked to obtain fundus photographs for patients with specific indications for fundoscopy. Study Sample: During a 1-month pilot period, housestaff were successfully able to upload images from 21 patients, which were reviewed by a neuro-ophthalmology attending, with input from on-call ophthalmology if desired. Results: Surveys of housestaff before (n = 13) and after (n = 12) implementation demonstrated increased confidence in camera operation and in ocular structure identification, description, and interpretation. Thematic analysis on qualitative feedback suggested benefits in clinical (improving fundus visualization, aiding in triage, sharing images with offsite staff), health systems (reducing length of stay, reducing ophthalmology consultations, reduced unnecessary testing), and educational domains (facilitating group discussions of images, sharing photographs with patients). Conclusions: Overall, inpatient portable fundus photography was shown to be feasible and effective for rapid fundus visualization for neurological inpatients, enhancing the ability to share, document, and compare examinations among neurology housestaff. Further work is needed to confirm clinical and educational benefits of portable fundus photography usage by neurology residents, as suggested by this healthcare quality improvement pilot study., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2025.)

Introduction: Plasma amyloid beta 42 /amyloid beta 40 (Aβ 42 /Aβ 40 ) and phosphorylated tau217 (p-tau217) identify individuals with primary Alzheimer's disease (AD). They may detect AD co-pathology in the setting of other primary neurodegenerative diseases, but this has not been systematically studied., Methods: We compared the clinical, neuroimaging, and neuropathological associations of plasma Aβ 42 /Aβ 40 (mass spectrometry), p-tau217 (electrochemiluminescence), and neurofilament light ([NfL], single molecule array [Simoa]), as markers of AD co-pathology, in a sporadic frontotemporal dementia (FTD) cohort ( n  = 620)., Results: Aβ 42 /Aβ 40 showed no clinicopathological associations. High p-tau217 was present in amnestic dementia (AmD) presumed to be due to FTD, logopenic primary progressive aphasia (lvPPA), and APOEε4 carriers, and correlated with worse baseline and longitudinal clinical scores, lower hippocampal volumes, and more severe AD co-pathology (Braak Stage). NfL was elevated in all FTD phenotypes, and correlated with clinical scores and frontotemporal brain volumes., Discussion: Plasma p-tau217 has clinical, neuroimaging, and neuropathological correlates in sporadic FTD and may identify FTD cases with AD co-pathology., Highlights: Alzheimer's disease (AD) features could be identified with plasma phosphorylated tau217 (p-tau217) in frontotemporal lobar degeneration (FTLD).Plasma p-tau217 is a better discriminator of AD co-pathology and AD-associated features in FTLD than plasma amyloid beta 42 /amyloid beta 40 (Aβ 42 /Aβ 40 ) and neurofilament light (NfL).In FTLD, plasma p-tau217, but not Aβ 42 /Aβ 40 or neurofilament light, has phenotypical, neurocognitive, and neuroimaging correlates suggestive of AD co-pathology., Competing Interests: Binita Rajbanshi, Igor Prufer Q C Araujo, Lawren VandeVrede, Peter A. Ljubenkov, Hilary W. Heuer, Argentina Lario Lago, Leonard Petrucelli, Tania Gendron, William W. Seeley, Lea T. Grinberg, Salvatore Spina, Randall J. Bateman, Howard J. Rosen, Bradley F. Boeve, and Adam L. Boxer have no conflict of interest to disclose. Adam M. Staffaroni has received research support from the NIA/NIH, Bluefield Project to Cure FTD, the Alzheimer's Association, the Larry L. Hillblom Foundation, and the Rainwater Charitable Foundation, and has provided consultation to Alector, Lilly/Prevail, Passage Bio, and Takeda. Eliana Marisa Ramos receives research support from the NIH. Jeffrey L. Dage is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents and/or compositions of matter for p‐tau assays and Aβ targeting therapeutics. He has served as a consultant or on advisory boards for Eisai, Abbvie, Genotix Biotechnologies Inc, Gates Ventures, Karuna Therapeutics, AlzPath Inc., Cognito Therapeutics, Inc., and received research support from ADx Neurosciences, Fujirebio, AlzPath Inc., Roche Diagnostics and Eli Lilly and Company in the past 2 years. He has received speaker fees from Eli Lilly and Company and is a founder and advisor for Monument Biosciences. Dr. Dage has stock or stock options in Eli Lilly and Company, Genotix Biotechnologies, AlzPath Inc. and Monument Biosciences. Julio C. Rojas is a site PI for clinical trials sponsored by Eli‐Lilly, Eisai and Amylyx. He receives consulting fees from Roon Health, Inc and Ferrer International, S.A. This work was supported by K23AG059888, AlzOut and the John Douglas French Alzheimer's Foundation for J.C.R. Samples from the National Centralized Repository for Alzheimer Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG021886) awarded by the National Institute on Aging (NIA), were used in this study. The ALLFTD consortium is funded by the NIA and the National Institute of Neurological Diseases and Stroke (NINDS) (U19: AG063911). The former ARTFL and LEFFTDS consortia received funding from the NIA, NINDS and National Center for Advancing Translational Science (U54 NS092089, U01 AG045390). Author disclosures are present in supporting information., (© 2025 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Objective: To assess the utility and challenges of using natural language processing (NLP) in electronic health records (EHRs) to ascertain health-related social needs (HRSNs) among older adults., Study Setting and Design: We extracted HRSN information using the NLP system Clinical Text Analysis and Knowledge Extraction System (cTAKES), combined with Concept Unique Identifiers and Systematized Nomenclature for Medicine codes. We validated cTAKES performance, via manual chart review, on two HRSNs: food insecurity, which was included in the healthcare system's HRSN screening tool, and housing insecurity, which was not., Data Sources and Analytic Sample: De-identified EHRs in a large California healthcare system (January 2013 through October 2022) from 119,127 patients aged 55+ in primary and emergency care settings (n = 1,385,259 clinical notes)., Principal Findings: Although cTAKES had a moderate positive predictive value (77.5%) for housing insecurity, housing challenges among older adults frequently did not align with the concepts the algorithm recognized. cTAKES performed poorly for food insecurity (positive predictive value: 18.5%) because this NLP system incorrectly flagged structured fields from the screening tool., Conclusion: Unstandardized terminology and poor integration of HRSN screeners in EHR remain important barriers to identifying older adults' food and housing insecurity using cTAKES., (© 2025 The Author(s). Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Prions are assemblies of misfolded prion protein that cause several fatal and transmissible neurodegenerative diseases, with the most common phenotype in humans being sporadic Creutzfeldt-Jakob disease (sCJD). Aside from variation of the prion protein itself, molecular risk factors are not well understood. Prion and prion-like mechanisms are thought to underpin common neurodegenerative disorders meaning that the elucidation of mechanisms could have broad relevance. Herein we sought to further develop our understanding of the factors that confer risk of sCJD using a systematic gene prioritization and functional interpretation pipeline based on multiomic integrative analyses. We integrated the published sCJD genome-wide association study (GWAS) summary statistics with publicly available bulk brain and brain cell type gene and protein expression datasets. We performed multiple transcriptome and proteome-wide association studies (TWAS & PWAS) and Bayesian genetic colocalization analyses between sCJD risk association signals and multiple brain molecular quantitative trait loci signals. We then applied our systematic gene prioritization pipeline on the obtained results and nominated prioritized sCJD risk genes with risk-associated molecular mechanisms in a transcriptome and proteome-wide manner. Genetic upregulation of both gene and protein expression of syntaxin-6 (STX6) in the brain was associated with sCJD risk in multiple datasets, with a risk-associated gene expression regulation specific to oligodendrocytes. Similarly, increased gene and protein expression of protein disulfide isomerase family A member 4 (PDIA4), involved in the unfolded protein response, was linked to increased disease risk, particularly in excitatory neurons. Protein expression of mesencephalic astrocyte derived neurotrophic factor (MANF), involved in protection against endoplasmic reticulum stress and sulfatide binding (linking to the enzyme in the final step of sulfatide synthesis, encoded by sCJD risk gene GAL3ST1), was identified as protective against sCJD. In total 32 genes were prioritized into two tiers based on the level of evidence and confidence for further studies. This study provides insights into the genetically-associated molecular mechanisms underlying sCJD susceptibility and prioritizes several specific hypotheses for exploration beyond the prion protein itself and beyond the previously highlighted sCJD risk loci through the newly prioritized sCJD risk genes and mechanisms. These findings highlight the importance of glial cells, sulfatides and the excitatory neuron unfolded protein response in sCJD pathogenesis., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)

This study evaluated the diagnostic performance of plasma biomarkers for Alzheimer's disease (AD) using an automated platform. In a cohort of 74 consecutive patients, plasma p-Tau181 levels were significantly higher in AD compared to non-AD groups and showed correlation with cerebrospinal fluid biomarkers. Plasma p-Tau181 demonstrated high diagnostic accuracy for AD, with an area under the curve of 0.854. The findings suggest that plasma biomarkers, particularly p-Tau181, could improve the accessibility and efficiency of AD diagnostics in clinical settings, offering a less invasive and cost-effective alternative to traditional methods., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Cognitive impairment is a growing concern in Southeast Asian populations, where the burden of cerebrovascular disease (CeVD) is high. Currently, there is no point-based scoring system for identifying cognitive impairment in these populations., Objective: To develop and validate a simple point-based Cognitive Impairment Scoring System (CISS) for identifying individuals with cognitive impairment no dementia (CIND) and concomitant CeVD in Southeast Asian populations., Design: A cross-sectional study using data from two population-based studies., Setting: Community-based setting in Southeast Asia., Participants: 1,511 Southeast Asian adults (664 with CIND, 44.0 %)., Measures: Two CISS measures were developed: a basic measure including 11 easily assessable risk factors, and an extended measure incorporating seven additional neuroimaging markers. Performance was evaluated using receiver operating characteristic analysis (AUC) and calibration plots., Results: The AUC for CISS-basic and CISS-extended were 0.81 (95 %CI, 0.76-0.86) and 0.85 (95 %CI, 0.81-0.89), respectively. Calibration plots indicated satisfactory fit for both the basic measure (p=0.82) and the extended measure (p=0.17). The basic measure included age, gender, ethnicity, education, systolic blood pressure, BMI, smoking history, diabetes, hyperlipidemia, stroke history, and mild/moderate depression. The extended measure added neuroimaging markers of CeVD and brain atrophy., Conclusion: The CISS provides a quick, objective, and clinically relevant tool for assessing cognitive impairment risk in Southeast Asian populations. The basic measure is suitable for initial community-based screenings, while the extended measure offers higher specificity for probable diagnosis. This point-based system enables rapid estimation of cognitive status without requiring complex calculations, potentially improving early detection and management of cognitive impairment in clinical practice., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to report., (Copyright © 2025. Published by Elsevier Masson SAS.)

Background: Left ventricular (LV) geometric patterns are associated with cognitive impairment and cerebral small vessel disease. As a novel magnetic resonance imaging marker of cerebral small vessel disease and a risk factor for cognitive dysfunction, cortical cerebral microinfarcts (CMIs) have been associated with heart disease through mechanisms including cardioembolism and cerebral hypoperfusion. Further investigation is required to determine whether cortical CMIs could arise from hemodynamic changes related to LV geometry, thus elucidating the connection between LV geometry and cognitive function. This study aims to investigate the cross-sectional relationship between LV geometric patterns, cortical CMIs, and cognition., Methods and Results: A total of 261 patients, aged 75.3±6.8 years, were enrolled from a memory clinic study. LV dimensions were obtained using 2-dimensional echocardiography. LV mass index and relative wall thickness were determined to categorize LV geometric patterns. Cortical CMIs were graded on 3T magnetic resonance imaging. Cognition was assessed using neuropsychological tests and clinical diagnosis. Linear, zero-inflated Poisson, and logistic regression were employed for continuous, count, and binary outcomes, respectively. Mediation analysis was conducted to examine the mediation effect of cortical CMIs. A significant association was observed between concentric LV hypertrophy and cortical CMI counts (rate ratio, 3.85 [95% CI, 1.85-8.01]), as well as the odds of having dementia (odds ratio, 2.86 [95% CI, 1.07-7.89]), in the fully adjusted model. Cortical CMIs may partly explain the relationship between concentric LV hypertrophy and cognitive function., Conclusions: Concentric LV hypertrophy was associated with cortical CMIs and dementia. Further verification is warranted to determine the role of cortical CMIs in the association between LV geometry and cognition.

Introduction: Young-onset neurocognitive symptoms result from a heterogeneous group of neurological and psychiatric disorders which present a diagnostic challenge. To identify such factors, we analysed the Biomarkers in Younger-Onset Neurocognitive Disorders cohort, a study of individuals <65 years old presenting with neurocognitive symptoms for a diagnosis and who have undergone cognitive and biomarker analyses., Methods: Sixty-five participants (median age at assessment of 56 years, 45% female) were recruited during their index presentation to the Royal Melbourne Hospital Neuropsychiatry Centre, a tertiary specialist service in Melbourne, Australia, and categorized as either early-onset Alzheimer's disease ( n = 18), non-Alzheimer's disease neurodegeneration ( n = 23) or primary psychiatric disorders ( n = 24). Levels of neurofilament light chain, glial fibrillary acidic protein and phosphorylated-tau 181, apolipoprotein E genotype and late-onset Alzheimer's disease polygenic risk scores were determined. Information-theoretic model selection identified discriminatory factors., Results: Neurofilament light chain, glial fibrillary acidic protein and phosphorylated-tau 181 levels were elevated in early-onset Alzheimer's disease compared with other diagnostic categories. A multi-omic model selection identified that a combination of cognitive and blood biomarkers, but not the polygenic risk score, discriminated between early-onset Alzheimer's disease and primary psychiatric disorders (area under the curve ⩾ 0.975, 95% confidence interval: 0.825-1.000). Phosphorylated-tau 181 alone significantly discriminated between early-onset Alzheimer's disease and non-Alzheimer's disease neurodegeneration causes (area under the curve = 0.950, 95% confidence interval: 0.877-1.00)., Discussion: Discriminating between early-onset Alzheimer's disease, non-Alzheimer's disease neurodegeneration and primary psychiatric disorders causes of young-onset neurocognitive symptoms is possible by combining cognitive profiles with blood biomarkers. These results support utilizing blood biomarkers for the work-up of young-onset neurocognitive symptoms and highlight the need for the development of a young-onset Alzheimer's disease-specific polygenic risk score., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Introduction: Cross-sectional resting-state functional magnetic resonance imaging (rsfMRI) studies have revealed altered complexity with advanced Alzheimer's disease (AD) stages. The current study conducted longitudinal rsfMRI complexity analyses in AD., Methods: Linear mixed-effects (LME) models were implemented to evaluate altered rates of disease progression in complexity across disease groups., Results: The LME models revealed complexity of the higher frequency in the CNtoMCI group (those converted from cognitively normal [CN] to mild cognitive impairment [MCI]) decayed faster over time versus CN in the prefrontal and lateral occipital cortex; complexity of the lower frequency decayed faster in AD versus CN in various frontal and temporal regions ( p  < 0.05 & Benjamini-Hochberg corrected with q  < 0.05)., Discussion: Local functional brain activities decayed in the early stage of the disease, and long-range communications were impacted in the later stage. Our study demonstrated longitudinal changes in AD-related rsfMRI complexity, indicating its potential as an imaging biomarker of AD., Highlights: We conducted longitudinal resting state functional magnetic resonance imaging (rsfMRI) complexity analyses using the Alzheimer's Disease Neuroimaging Initiative dataset.Higher-frequency complexity in the CNtoMCI group (those transitioning from cognitively normal [CN] to mild cognitive impairment [MCI]) was found to decay faster over time compared to CN, specifically in the prefrontal and lateral occipital cortex.Lower-frequency complexity was found to decay faster in AD versus CN in various frontal and temporal regions.This study demonstrated that longitudinal changes in rsfMRI complexity could serve as a potential imaging biomarker for Alzheimer's disease., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2025 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate 'pro-aging' or 'pro-youthful' effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer's disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (M age = 49.6; 50% female; 43% C9orf72 , 24% GRN , 33% MAPT ) and 62 non-carriers (M age = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (M visits = 3 years, range 1-7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer's disease cohort included 35 adults with sporadic Alzheimer's disease (M age = 69.4; 60% female) and 56 controls (M age = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting 'pro-youthful' levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer's disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer's disease and related dementias and warrant further investigation., Competing Interests: B.F.B. has served as an investigator for clinical trials sponsored by Alector, Biogen, Transposon and Cognition Therapeutics. He serves on the Scientific Advisory Board of the Tau Consortium, which is funded by the Rainwater Charitable Foundation. He receives research support from NIH. H.B. receives research support from the NIH. A.L.B. receives research support from the NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association. He has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, TrueBinding and Wave and received research support from Biogen, Eisai and Regeneron. A.L.B. receives research support from the NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association. He has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, TrueBinding, Wave, Merck and received research support from Biogen, Eisai and Regeneron. K.D.-R. receives research support from the NIH and serves as an investigator for a clinical trial sponsored by Lawson Health Research Institute. K.F. receives research support from the NIH. A.F. has served as a consultant for DiamiR, Diadem, Roche Diagnostics, Siemens Healthcare Diagnostics, Cyclo Therapeutics, Inc. J.A.F. receives research support from the NIH and is a consultant for Alector. T.F. receives research support from the NIH. L.F. receives research support from the NIH. R.G. receives research support from the NIH. T.F.G. receives research support from the NIH. N.G. has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) and the A4 (The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease) trial. She receives research support from Tau Consortium and the Association for Frontotemporal Dementia and is funded by the NIH. J.G. receives research support from the NIH, Huntington’s Disease Society of America and the New York State Department of Health (RFA 1510130358). J.G.-R. receives research support from the NIH and is on the editorial board of Neurology. N.G.-R. receives royalties from UpToDate and has participated in multi-centre therapy studies by sponsored by Biogen, TauRx and Lilly. He receives research support from the NIH. M.G. receives grant support from the NIH, Avid and Piramal; participates in clinical trials sponsored by Biogen, TauRx and Alector; serves as a consultant to Bracco and UCB; and serves on the editorial board of Neurology. G.-Y.H. has served as an investigator for clinical trials sponsored by AstraZeneca, Eli Lilly and Roche/Genentech. He receives research support from the Canadian Institutes of Health Research and the Alzheimer Society of British Columbia. E.D.H. receives research support from the NIH. D.I. receives support from the NIH, BrightFocus Foundation and Penn Institute on Aging. D.T.J. receives research support from the NIH and the Minnesota Partnership for Biotechnology and Medical Genomics. K.K. served on the Data Safety Monitoring Board for Takeda Global Research and Development Center and data monitoring boards of Pfizer and Janssen Alzheimer Immunotherapy and received research support from Avid Radiopharmaceuticals, Eli Lilly, the Alzheimer’s Drug Discovery Foundation and the NIH. D. K. serves on the data and safety monitoring board of the DIAN-TU study; is a site principal investigator for clinical trials sponsored by Biogen, Lilly and the University of Southern California; and is funded by the NIH. J. K. has provided expert witness testimony for Teva Pharmaceuticals in Forest Laboratories Inc. et al. v. Teva Pharmaceuticals USA, Inc., case numbers 1:14-cv-00121 and 1:14-cv-00686 (D. Del. filed 31 January 2014 and 30 May 2014 regarding the drug Memantine) and for Apotex/HEC/Ezra in Novartis AG et al. v. Apotex Inc., case number 1:15-cv-975 (D. Del. filed 26 October 2015 regarding the drug Fingolimod). He has also given testimony on behalf of Puma Biotechnology in Hsingching Hsu et al., versus Puma Biotechnology, Inc., et al. 2018 regarding the drug Neratinib. He receives research support from the NIH. W.K. receives research funding from AstraZeneca, Biogen, Roche, the Department of Defense and the NIH. M.I.L. receives research support from the NIH. I.L.'s research is supported by the National Institutes of Health grants: 2R01AG038791-06A, U01NS100610, U01NS80818, R25NS098999; U19 AG063911-1 and 1R21NS114764-01A1; the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Centogene. EIP-Pharma, Biohaven Pharmaceuticals, Novartis, Brain Neurotherapy Bio and United Biopharma SRL—UCB. She is a Scientific advisor for Amydis and Rossy Center for Progressive Supranuclear Palsy University of Toronto. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. R.R. receives research funding from the NIH and the Bluefield Project to Cure Frontotemporal Dementia. R.R. is on the scientific advisory board of Arkuda Therapeutics and receives royalties from progranulin-related patent. She is also on the scientific advisory board of the Fondation Alzheimer. E.M.R. receives research support from the NIH. K.P.R. receives research support from the NIH and the National Science Foundation and serves on a medical advisory board for Eli Lilly. K.R. receives research support from the NIH. E.D.R. has received research support from the NIH, the Bluefield Project to Cure Frontotemporal Dementia, the Alzheimer's Association, the Alzheimer's Drug Discovery Foundation, the BrightFocus Foundation, and Alector; has served as a consultant for AGTC and on a data monitoring committee for Lilly; and owns intellectual property related to tau and progranulin. J.C.R. receives research support from the NIH and is a site principal investigator for clinical trials sponsored by Eli Lilly and Eisai. H.J.R. has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience, Ionis Pharmaceuticals, Eisai Pharmaceuticals, and Genentech, and receives research support from the NIH and the state of California. R.S. receives support from the NIA, the National Institute of Neurological Disorders and Stroke, the Parkinson’s Disease Foundation and Acadia Pharmaceuticals. A.M.S. received research support from the NIA/NIH, the Bluefield Project to Cure FTD, and the Larry L. Hillblom Foundation. He has provided consultation to Alector, Lilly, Passage Bio, and Takeda. M.C.T. has served as an investigator for clinical trials sponsored by Biogen, Avanex, Green Valley, Roche/Genentech, Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals and Janssen. She receives research support from the Canadian Institutes of Health Research., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Using an Asian cohort with high prevalence of concomitant cerebrovascular disease (CeVD), we evaluated the performance of a plasma immunoassay for tau phosphorylated at threonine 217 (p-tau217) in detecting amyloid beta positivity (Aβ+) on positron emission tomography and cognitive decline, based on a three-range reference, which stratified patients into low-, intermediate-, and high-risk groups for Aβ+., Methods: Brain amyloid status (Aβ- [n = 142] vs Aβ+ [n = 73]) on amyloid PET scans was assessed along with the plasma ALZpath p-tau217 assay to derive three-range reference points for PET Aβ+ based on 90% sensitivity (lower threshold) and 90% specificity (upper threshold)., Results: Plasma p-tau217 (area under the curve [AUC] = 0.923) outperformed routine clinical assessments (AUC = 0.760-0.819; p ≤ 0.003) and other plasma biomarkers (AUC = 0.817-0.834; p < 0.001). The high-risk group showed significantly higher rates of cognitive decline than the low-risk group., Discussion: Risk stratification for PET Aβ+ based on a plasma p-tau217 assay demonstrated potential diagnostic and prognostic utility in an Asian cohort with concomitant CeVD., Highlights: The utility of plasma p-tau217 to detect brain amyloid beta pathology (Aβ+) was studied in an Asian cohort with concomitant cerebrovascular disease Plasma tau phosphorylated at threonine 217 (p-tau217) showed superior utility in detecting Aβ+ compared to neuroimaging measures, clinical workup, or other blood biomarkers including p-tau181, glial fibrillary protein (GFAP), and Aβ Higher plasma p-tau217 correlated with faster cognitive decline Plasma p-tau217 shows promise as an Alzheimer's disease (AD) diagnostic and prognostic biomarker in diverse populations., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: Cerebrovascular reactivity (CVR) represents the ability of cerebral blood vessels to regulate blood flow in response to vasoactive stimuli and is related to cognition in cerebrovascular and neurodegenerative conditions. However, few studies have examined CVR in the medial temporal lobe, known to be affected early in Alzheimer disease and to influence memory function. We aimed to examine whether medial temporal CVR is associated with memory function in older adults with and without mild cognitive impairment (MCI)., Methods: In this observational study, independently living older adults free of dementia or stroke were recruited from the community and underwent brain MRI, neuropsychological assessment, and blood draw in an academic research setting. pCASL MRI quantified medial temporal lobe cerebral perfusion during CVR response to hypercapnia. Hypercapnia was induced by visually guided breathing exercises (15 seconds breath holds) during capnographic monitoring. MCI diagnosis and memory performance were assessed through comprehensive neuropsychological assessment. Aβ42/40 and pTau181 levels were quantified in blood plasma. Logistic and hierarchical linear regression examined medial temporal CVR in relation to MCI diagnosis and memory function., Results: In a sample of 144 older adults (mean age = 69.6 years; SD = 7.4%; 34.7% male; mean education = 16.6 years, SD = 2.3), CVR to hypercapnia in the medial temporal lobe was attenuated in individuals with MCI after adjusting for age, sex, education, apolipoprotein ε4 carrier status, Aβ42/40 and pTau181 levels, and vascular risk factors (OR = 0.87, 95% CI [0.77-0.97], p = 0.013). Cerebrovascular reactivity to hypercapnia was associated with verbal memory performance for stories (B = 0.33, 95% CI [0.09-0.57], p = 0.009), a word list (B = 0.10, 95% CI [0.001-0.20], p = 0.048), and visual memory (B = 0.33, 95% CI [0.09-0.57], p = 0.008)., Discussion: Deficits in medial temporal CVR are observed in older adults with MCI and are related to worse memory function. Findings suggest that medial temporal cerebrovascular dysfunction is related to cognition and memory before the onset of dementia, independent of changes in Alzheimer pathophysiologic markers. Limitations of the study include the cross-sectional design. Future longitudinal studies are warranted to examine whether early cerebrovascular changes can predict progressive memory decline.

Introduction: Diagnostic performance of optical coherence tomography (OCT) to detect Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains limited. We aimed to develop a deep-learning algorithm using OCT to detect AD and MCI., Methods: We performed a cross-sectional study involving 228 Asian participants (173 cases/55 controls) for model development and testing on 68 Asian (52 cases/16 controls) and 85 White (39 cases/46 controls) participants. Features from OCT were used to develop an ensemble trilateral deep-learning model., Results: The trilateral model significantly outperformed single non-deep learning models in Asian (area under the curve [AUC] = 0.91 vs. 0.71-0.72, p  = 0.022-0.032) and White (AUC = 0.84 vs. 0.58-0.75, p  = 0.056- < 0.001) populations. However, its performance was comparable to that of the trilateral statistical model (AUCs similar, p  > 0.05)., Discussion: Both multimodal approaches, using deep learning or traditional statistical models, show promise for AD and MCI detection. The choice between these models may depend on computational resources, interpretability preferences, and clinical needs., Highlights: A deep-learning algorithm was developed to detect Alzheimer's disease (AD) and mild cognitive impairment (MCI) using OCT images.The combined model outperformed single OCT parameters in both Asian and White cohorts.The study demonstrates the potential of OCT-based deep-learning algorithms for AD and MCI detection., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information., (© 2025 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: The potential diagnostic value of plasma amyloidogenic beta residue 42/40 ratio (Aβ42/Aβ40 ratio), neurofilament light (NfL), tau phosphorylated at threonine-181 (p-tau181), and threonine-217 (p-tau217) has been extensively discussed in the literature. We have also previously described the association between retinal biomarkers and preclinical Alzheimer's disease (AD). The goal of this study was to evaluate the association, and a multimodal model of, retinal and plasma biomarkers for detection of preclinical AD., Methods: We included 82 cognitively unimpaired (CU) participants (141 eyes; mean age: 67 years; range: 56-80) from the Atlas of Retinal Imaging in Alzheimer's Study (ARIAS). Blood samples were assessed for concentrations of Aβ42/Aβ40 ratio, NfL, p-tau181, and p-tau217 (ALZpath, Inc.) using Single molecule array (SIMOA) technology. The Spectralis II system (Heidelberg Engineering) was used to acquire macular centered Spectral Domain Optical Coherence Tomography (SD-OCT) images for evaluation of putative retinal gliosis surface area and macular retinal nerve fiber layer (mRNFL) thickness. For all participants, correlations (adjusted for age and correlation between eyes) were assessed between retinal and blood-based biomarkers. A subgroup cohort of 57 eyes from 32 participants with recent Aβ positron emission tomography (PET) results, comprising 18 preclinical patients (Aβ PET + ve, 32 eyes) and 14 controls (Aβ PET -ve, 25 eyes) with a mean age of 69 vs. 66, p = 0.06, was included for the assessment of a multimodal model to distinguish between the two groups. For this subgroup cohort, receiver operating characteristic (ROC) analysis was performed to compare the multimodal model of retinal and plasma biomarkers vs. each biomarker alone to distinguish between the two groups., Results: Significant correlation was found between putative retinal gliosis and p-tau217 in the univariate mixed model (β = 0.48, p = 0.007) but not for the other plasma biomarkers (p > 0.05). This positive correlation was also retained in the multivariate mixed model (β = 0.43, p = 0.022). The multimodal ROC model based on retinal (gliosis area, inner inferior RNFL thickness, inner superior RNFL thickness, and inner nasal RNFL thickness) and plasma biomarkers (p-tau217 and Aβ42/Aβ40 ratio) had an excellent AUC of 0.97 (95% CI = 0.93-1.01; p < 0.001) compared to unimodal models of retinal and plasma biomarkers., Conclusions: Our analyses show the potential of integrating retinal and blood-based biomarkers for improved detection and screening of preclinical AD., Competing Interests: Declarations. Ethics approval and consent to participate: The study adhered to the tenets of the Declaration of Helsinki, and informed consent from all subjects was obtained prior to experimental data collection after explanation of the nature and possible consequences of the study. The study was part of the Atlas of Retinal Imaging in Alzheimer’s Study (ARIAS; PJS served as principal investigator for ARIAS) which took place at the University of Rhode Island and Butler Hospital Memory and Aging Program, Providence, RI between 2020 and 2022, and was approved by the BayCare Institutional Review Board (IRB). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Brain serotonin dysregulation is associated with dementia and neuropsychiatric symptomology. However, the prognostic utility of circulating serotonin levels in detecting features of prodromal dementia including functional decline, cognitive impairment, mild behavioural impairment and brain atrophy remains unclear. In this prospective study of memory clinic subjects followed-up for ≤5 years, dementia-free subjects, classified as having no cognitive impairment or cognitive impairment, no dementia at baseline, underwent annual neuropsychological assessments including Montreal Cognitive Assessment, Global Cognition Z- scores and Clinical Dementia Rating Scale Global Scores (where a ≥ 0.5 increment from baseline denotes functional decline). Mild behavioural impairment was measured using baseline and annual Neuropsychiatric Inventory assessments, while brain atrophy was evaluated using cortical and medial temporal atrophy scores from baseline MRI scans. Baseline serum serotonin was then associated with the neuropsychological and neuroimaging measures cross-sectionally and longitudinally. Furthermore, associations of serum serotonin with cross-sectional brain atrophy scores were studied. Of the 191 elderly subjects included in the study, 63 (33.0%) had no cognitive impairment while 128 (67.0%) had cognitive impairment, no dementia. Fourteen subjects (9.0%) showed baseline mild behavioural impairment. Compared with the highest tertile, subjects within the lowest tertile of serotonin had greater Cortical Atrophy scores (adjusted odds ratio = 2.54, 95% confidence interval=1.22-5.30, P = 0.013). Serotonin levels were not significantly associated with cross-sectional neuropsychological or mild behavioural impairment scores (all P > 0.05). Of the 181 subjects with longitudinal cognitive follow-up (median duration 60.0 months), 56 (30.9%) developed functional decline, while incident mild behavioural impairment occurred in 26/119 (21.8%) subjects. Compared with the highest tertile, lower serotonin levels were associated with higher hazards of functional decline (lowest tertile: adjusted hazards ratio = 2.15, 95% confidence interval = 1.04-4.44, P = 0.039), and incident mild behavioural impairment (lowest tertile: adjusted hazards ratio = 3.82, 95% confidence interval = 1.13-12.87, P = 0.031, middle tertile: adjusted hazards ratio = 3.56, 95% confidence interval =1.05-12.15, P = 0.042). The association between the lowest serotonin tertile and functional decline was mediated via its effect on incident mild behavioural impairment (adjusted odds ratio = 3.96, 95% confidence interval = 1.15-13.61, P = 0.029). In conclusion, low circulating serotonin may be associated with cortical atrophy at baseline, as well as act as an early prognostic marker for functional decline and mild behavioural impairment in elderly, dementia-free subjects., Competing Interests: The authors have no competing interests., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. Methods: The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered. A modified Delphi approach was used to rate each scenario by consensus as "rarely appropriate," "uncertain," or "appropriate." Ratings were performed separately for amyloid and tau PET as stand-alone modalities. Results: For amyloid PET, 7 scenarios were rated as appropriate, 2 as uncertain, and 8 as rarely appropriate. For tau PET, 5 scenarios were rated as appropriate, 6 as uncertain, and 6 as rarely appropriate. Conclusion: AUC for amyloid and tau PET provide expert recommendations for clinical use of these technologies in the evolving landscape of diagnostics and therapeutics for Alzheimer's disease., (© 2025 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: White matter hyperintensities (WMH) have been implicated in the pathogenesis of neuropsychiatric symptoms of dementia but the functional significance of WMH in specific white matter (WM) tracts is unclear. We investigate whether WMH burden within major WM fibre classes and individual WM tracts are differentially associated with different neuropsychiatric syndromes in a large multicentre study., Method: Neuroimaging and neuropsychiatric data of seven memory clinic cohorts through the Meta VCI Map consortium were harmonised. Class-based analyses of major WM fibres (association, commissural and projection) and region-of-interest-based analyses on 11 individual WM tracts were used to evaluate associations of WMH volume with severity of hyperactivity, psychosis, affective and apathy syndromes., Results: Among 2935 patients (50.4% women; mean age=72.2 years; 19.8% subjective cognitive impairment, 39.8% mild cognitive impairment, and 40.4% dementia), larger WMH volume within projection fibres (B=0.24, SE=0.10, p=0.013) was associated with greater apathy. Larger WMH volume within association (B=0.31, SE=0.12, p=0.009), commissural (B=0.47, SE=0.17, p=0.006) and projection (B=0.39, SE=0.16, p=0.016) fibres was associated with greater hyperactivity, driven by the inferior fronto-occipital fasciculus (B=0.50, SE=0.18, p=0.006), forceps major (B=0.48, SE=0.18, p=0.009) and anterior thalamic radiation (B=0.49, SE=0.19, p=0.011), respectively. Larger WMH volume in the uncinate fasciculus (B=1.82, SE=0.67, p=0.005) and forceps minor (B=0.61, SE=0.19, p=0.001) were additionally associated with greater apathy. No associations with affective and psychosis were observed., Conclusions: Tract-syndrome specificity of WMH burden with apathy and hyperactivity suggests that disruption of strategic neuronal pathways may be a potential mechanism through which small vessel disease affects emotional and behavioural regulation in memory clinic patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder characterized by physical, cognitive, and behavioral impairments. The PSP Rating Scale (PSPRS) is a widely used and validated, clinical scale to monitor disease progression. Here we show the modification of PSPRS to improve clinical meaningfulness and sensitivity. A conceptual framework was used to select meaningful items. Datasets were analyzed to improve the psychometric properties, understand factor structure, and develop a scoring algorithm. Fifteen items of the PSPRS were selected based on whether the items reflect concepts specific to the disease and those responsive to change over 12 months. Some items were rescored to reflect meaningful changes and to improve discrimination and reliability. The rescored 15-item PSPRS was more interpretable and sensitive to disease progression over 12 months. The approach to develop the 15-item PSPRS provides an example of how to modify an existing clinical outcome assessment for use as a primary endpoint in a clinical trial of a progressive neurological disorder., Competing Interests: Competing interests: Tien Dam, Lili Yang, Colin Gillis, Yumeng Li, Barbara Kolb, and Samantha Budd Haeberlein are former employees of and may hold stock/stock options in Biogen. John O’Gorman is an employee of and may hold stock in Biogen. Adam Boxer receives research support from the National Institutes of Health, Tau Research Consortium, Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Association, Biogen, Eisai, and Regeneron and has served as a consultant for AGTC, Alector, Arkuda, Arvinas, AviadoBio, AZTherapeutics, Boehringer Ingelheim, GSK, Humana, Life Edit Therapeutics, Oligomerix, Roche, TrueBinding, and Wave. Lawrence Golbe has received research support from Biogen, travel support from CurePSP, and Consultant fees from AI Therapeutics, Amylyx, Apellis, Aprinoia, Ferrer, Mitochon, Roche, and UCB. These analyses were funded by Biogen (Cambridge, MA, USA). The 4 Repeat Tauopathy Imaging Initiative is funded by National Institutes of Health grant R01AG038791., (© 2025. The Author(s).)

Accumulation of damaged biomolecules in body tissues is the primary cause of aging and age-related chronic diseases. Since this damage often occurs spontaneously, it has traditionally been regarded as untreatable, with typical therapeutic strategies targeting genes or enzymes being ineffective in this domain. In this report, we demonstrate that an antibody targeting the isoDGR damage motif in lung tissue can guide immune clearance of harmful damaged proteins in vivo, effectively reducing age-linked lung inflammation. We observed age-dependent accumulation of the isoDGR motif in human lung tissues, as well as an 8-fold increase in isoDGR-damaged proteins in lung fibrotic tissues compared with healthy tissue. This increase was accompanied by marked infiltration of CD68+/CD11b + macrophages, consistent with a role for isoDGR in promoting chronic inflammation. We therefore assessed isoDGR function in mice that were either naturally aged or lacked the isoDGR repair enzyme. IsoDGR-protein accumulation in mouse lung tissue was strongly correlated with chronic inflammation, pulmonary edema, and hypoxemia. This accumulation also induced mitochondrial and ribosomal dysfunction, in addition to features of cellular senescence, thereby contributing to progressive lung damage over time. Importantly, treatment with anti-isoDGR antibody was able to reduce these molecular features of disease and significantly reduced lung pathology in vivo., (© 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Objective: Metastatic breast cancer (MBC) is associated with burdensome side effects, including cognitive changes that require ongoing monitoring. Cognitive ecological momentary assessments (EMAs) allow for assessment of individual cognitive functioning in natural environments and can be administered via smartphones. Accordingly, we sought to establish the feasibility, reliability, and validity of a commercially available cognitive EMA platform., Methods: Using a prospective design, clinical cognitive and psychosocial assessments (cognitive batteries; patient reported outcomes) were collected at baseline, followed by a 28-day daily EMA protocol that included self-ratings for symptoms and mobile cognitive tests (memory, executive functioning, working memory, processing speed). Satisfaction and feedback questions were included in follow-up data collection. Feasibility data were analyzed using mixed descriptive methods. Test-retest reliability was examined using intraclass correlation coefficients (ICCs) for each EMA, and Pearson's correlation were used to evaluate convergent validity between cognitive EMAs and baseline clinical cognitive and psychosocial variables., Results: Fifty-one women with MBC ( n  = 51) completed this EMA study. High satisfaction (median 90%), low burden (median 19%), high adherence rates (mean 94%), and 100% retention rate were observed. ICCs for cognitive tests of working memory, executive function, and processing speed were robust (>0.90) and ICC for memory tests acceptable (>0.66). Other correlational findings indicated strong convergent validity for all cognitive and psychosocial EMAs., Conclusion: Cognitive EMA monitoring for 28 days is feasible and acceptable in women with MBC, with specific cognitive EMAs (mobile cognitive tests; cognitive function self-ratings) demonstrating strong reliability and validity., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RCM is a co-founder of KeyWise AI, Inc. and a co-founder of NeuroUX. The terms of this arrangement have been reviewed and approved by UC San Diego in accordance with its conflict-of-interest policies. AMH was a consultant for Prodeo, Inc. The terms of this arrangement have been reviewed and approved by University of Texas at Austin in accordance with its conflict-of-interest policies., (© The Author(s) 2025.)

Mild cognitive impairment (MCI) refers to cognitive alterations with preservation of functionality. Individuals with this diagnosis have a higher risk of developing dementia. Non-pharmacological interventions, such as physical exercise, are beneficial for the cognition of this population. However, the impact of resistance training (RT) on the brain anatomy of older adults with MCI has not yet been clarified. This study aimed to investigate the effects of RT on cognition and brain anatomy in MCI. Forty-four older adults with MCI, 22 in the training group and 22 in the control group, were evaluated in neuropsychological tests and magnetic resonance imaging at the beginning and end of the study, which lasted 24 weeks. We used repeated measures ANOVA. The training group showed better performance in verbal episodic memory after intervention. The control group showed a decrease in gray matter volume in the hippocampus and precuneus, while the training group showed no reduction in the right hippocampus and precuneus. However, it showed a decrease in the volume of these regions on the left side and in the left superior frontal gyrus. In the analysis of white matter integrity, fractional anisotropy increased in the training group and decreased in the control group. Axial diffusivity decreased in the training group, while radial diffusivity increased in the control group, and mean diffusivity varied according to the tract evaluated. RT improves memory performance, positively influences white matter integrity parameters, and plays a protective role against atrophy of the hippocampus and precuneus in MCI., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to American Aging Association.)

A 24-30 Centiloid (CL) threshold was collectively considered by a group of global dementia experts as a practical and implementable cut-off for anti-amyloid therapy intervention, in Alzheimer's disease patients who have been diagnosed at the mild cognitive impairment or mild dementia stage of their disease. Though additional validation is needed, knowledge of this threshold would be valuable to those involved in diagnosing and treating patients in the new AD care pathways, as well as entry into clinical trials. Therapy monitoring to determine future treatment response and assess amyloid clearance can be accomplished with amyloid PET with some technical details still to be elucidated., Competing Interests: Declaration of competing interest GF is an employee of GE Healthcare who hold the Marketing Authorisation for Vizamyl(TM.) CW is a full-time employee of the Alzheimer's Association GR has served on scientific advisory boards and/or as a consultant for Eli Lilly, Genenetech/Roche, GE Healthcare, Alector and Merck, payments from Efficient LLC, JAMA Neurology (Associate Editor), Miller Medical Communications, paid for participation on a Data Safety Monitoring Board or Advisory Board for Johnson & Johnson., (Copyright © 2024. Published by Elsevier Masson SAS.)

Introduction: The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET., Methods: The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered. A modified Delphi approach was used to rate each scenario by consensus as "rarely appropriate," "uncertain," or "appropriate." Ratings were performed separately for amyloid and tau PET as stand-alone modalities., Results: For amyloid PET, seven scenarios were rated as appropriate, two as uncertain, and eight as rarely appropriate. For tau PET, five scenarios were rated as appropriate, six as uncertain, and six as rarely appropriate., Discussion: AUC for amyloid and tau PET provide expert recommendations for clinical use of these technologies in the evolving landscape of diagnostics and therapeutics for Alzheimer's disease., Highlights: A multidisciplinary workgroup convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging updated the appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. The goal of these updated AUC is to assist clinicians in identifying clinical scenarios in which amyloid or tau PET may be useful for guiding the diagnosis and management of patients who have, or are at risk for, cognitive decline These updated AUC are intended for dementia specialists who spend a significant proportion of their clinical effort caring for patients with cognitive complaints, as well as serve as a general reference for a broader audience interested in implementation of amyloid and tau PET in clinical practice., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Aims: Vitamin B12 deficiency has been associated with neuropsychiatric symptoms (NPS), but the relationship between vitamin B12 and NPS remains unclear prior to the onset of dementia. The study aims to examine the association between vitamin B12 and NPS in dementia-free Asian older adults., Methods: This is a cross-sectional population-based study where multi-ethnic community-dwelling Asian participants (i.e. Chinese, Malay, Indian) aged ≥60 years underwent comprehensive neuropsychological and clinical assessments including the examination of clinical history and the collection of blood samples. NPS and subsyndromes were evaluated using the Neuropsychiatric Inventory (NPI). Serum vitamin B12 and homocysteine (Hcy) concentration were measured by competitive immunoassays. To analyse the relationship between vitamin B12 and NPS, hierarchical linear regression, multinomial regression and moderation analyses were performed., Results: A total of 798 dementia-free individuals (age = 69.7 ± 6.5 years old, F = 408 (51.1 %)) were included in the current study. There were 80 (10 %) individuals with clinically relevant NPS (i.e. NPI scores ≥4). Higher vitamin B12 was associated with lower NPI total scores (p = 0.030) and apathy (p = 0.005), after controlling for age, sex, ethnicity, cognitive functioning, socioeconomic status and Hcy concentration. Participants with higher vitamin B12 was also less likely to have clinically relevant apathy (p = 0.007). The moderation effect of Hcy and cognitive functioning on the inverse association between vitamin B12 and NPS was observed., Conclusions: A protective effect of vitamin B12 on NPS and subsyndromes was observed in a multi-ethnic Asian cohort of dementia-free individuals. Future longitudinal studies are required to further elucidate the pathophysiological mechanisms between vitamin B12 and NPS in diverse ethnic groups., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Purpose: Little is known about cancer-related cognitive impairments (CRCI) in women with metastatic breast cancer (MBC). The purpose of this study is to (1) comprehensively describe CRCI and any associated psychosocial and behavioral symptoms, (2) determine observable sociodemographic and clinical risk factors for CRCI, and (3) explore cognitive and psychosocial predictors of quality of life and social functioning in women living with MBC., Methods: Using a cross-sectional design, women with MBC completed assessments (objective and subjective measures of CRCI including 3 open-ended questions, measures of psychosocial and behavioral factors, and assessments of quality of life and social function), and data were analyzed using descriptive statistics, qualitative content analysis, correlation analyses, t tests, analysis of variance, and linear regression models., Results: Data from 52 women were analyzed. 69.2% of the sample reported clinically significant CRCI and 46% of the sample scored < 1 standard deviation below the standardized mean on one or more cognitive tests. Those with triple-negative MBC (compared to HER2+), recurrent MBC (compared to de novo), and no history of chemotherapy had worse subjective CRCI, and those without history of surgery and older age had worse objective CRCI. Subjective CRCI, but not objective CRCI, was significantly associated with quality of life and social functioning., Conclusion: Subjective and objective CRCI are likely a common problem for those with MBC. Subjective CRCI is associated with poorer quality of life and lower social functioning. Healthcare providers should acknowledge cognitive symptoms, continually assess cognitive function, and address associated unmet needs across the MBC trajectory., Competing Interests: Declarations. Conflict of interest: R.C.M. is a co-founder of KeyWise AI, Inc. and a co-founder of NeuroUX. The terms of this arrangement have been reviewed and approved by UC San Diego in accordance with its conflict-of-interest policies. A.M.H is a consultant for Prodeo, Inc. The terms of this arrangement have been reviewed and approved by University of Texas at Austin in accordance with its conflict-of-interest policies. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. The University of Texas at Austin Institutional Review Board reviewed and monitored all study related procedures (STUDY00002393). Consent to participate: Participants provided informed written consent. Consent for publication: Not Applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Neurocognitive and neuropsychiatric symptoms are essential clinical manifestations of age-related cognitive impairment, yet their patterns of co-existence remain unclear through the cognitive continuum., Objective: To examine the associations of person-centered cluster-derived patterns, based on a comprehensive collection of domain-specific cognitive and neuropsychiatric assessments, with neuroimaging markers and dementia risk., Methods: 641 participants were included in the analysis from memory clinics in Singapore. Latent class analysis was applied to define clusters of individuals with different clinical patterns. The associations between identified clinical groups with neuroimaging markers of cerebrovascular diseases and neurodegeneration were analyzed using logistic regression models. Cox proportional hazard models were applied for incident dementia., Results: Three latent classes differing in neurocognitive and neuropsychiatric impairment were identified (Class 1 "memory impairment only"; Class 2 "global cognitive impairment"; Class 3 "global cognitive and neuropsychiatric impairment"). Compared with Class 1, Class 2 and 3 were associated with smaller brain volumes, moderate-to-severe cortical atrophy and medial temporal lobe atrophy, and the presence of all cerebrovascular lesions. Moreover, compared with Class 2, Class 3 had smaller brain volumes, moderate-to-severe cortical atrophy and presence of intracranial stenosis. Additionally, compared to Class 1, Class 2 (hazard ratio [HR] = 3.84, 95%CI 2.11-7.00), and Class 3 (HR = 6.92, 95%CI 2.84-16.83) showed an increased risk of incident dementia., Conclusions: Participants characterized by multi-domain cognitive impairment and co-occurrence of cognitive and neuropsychiatric impairment showed the highest risk of incident dementia, which may be attributed to both neurodegenerative and cerebrovascular pathologies., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Hypertension, a major modifiable risk factor for cardiovascular diseases, is linked to late-life neurocognitive disorders such as vascular dementia and Alzheimer's disease (AD). This study explores the associations between hypertension, intracranial atherosclerotic disease (ICAD), cerebral small vessel disease (cSVD), and Alzheimer's disease neuropathologic change (ADNC) in a large community-based autopsy study. This cross-sectional study used data from the Biobank for Aging Studies of the University of São Paulo Medical School. Sociodemographic and clinical information was gathered from a reliable next-of-kin informant. Neurofibrillary tangles, neuritic plaques, lacunar infarcts, hyaline arteriolosclerosis, and cerebral amyloid angiopathy were evaluated. Causal mediation analyses with natural effect models were performed to examine indirect associations of hypertension with cerebrovascular pathologies and ADNC through morphometric measurements of intracranial artery lumen obstruction. Hypertensive participants (n = 354) presented a higher rate of stenosed arteries (obstruction ≥ 50 %), critically stenosed arteries (obstruction ≥ 70 %), and more severe ICAD, shown by higher maximum and mean obstruction indexes compared to nonhypertensive participants (n = 166). These measurements of atherosclerosis were associated with neurofibrillary tangles and cSVD lesions. Hypertension was indirectly associated with hyaline arteriolosclerosis and lacunar infarcts through the pathway of ICAD. Presenting hypertension indirectly increased the odds of displaying hyaline arteriolosclerosis by 26 % (95 % CI: 1.08, 1.45, p = 0.002) and lacunar infarcts by 17 % (95 % CI: 1.01, 1.35, p = 0.029). Cognitive and APOE ε4 carrier status did not alter the investigated associations. In this community sample, hypertension was indirectly associated with cSVD through ICAD., Competing Interests: Competing interests and disclosures The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

HIV stigma is associated with suboptimal clinical outcomes and has been cross-sectionally linked to cognitive deficits in people with HIV (PWH). However, it is unclear whether HIV stigma precedes cognitive decline or vice versa. We examined associations in 303 adult PWH (mean age 50.01 (11.91) years; 46% female; 67% non-Hispanic Black) between the abbreviated Berger Stigma Scale score and longitudinal change across the NIH Toolbox Cognition Battery measures. 89% of participants reported experiencing HIV stigma. In unadjusted analyses, greater HIV stigma was associated with worse attention performance at yearly follow-up visits (B = -0.07, 95% CI = -0.13 - -0.01, p = 0.025). When adjusting for clinicodemographic variables, HIV stigma was associated with worse processing speed and global cognition at yearly follow-up visits. This finding suggests that HIV stigma precedes subsequent cognitive decline and highlights the importance of reducing stigma to improve cognitive functioning among PWH., Competing Interests: Declarations. Competing Interests: The authors declare that they have no relevant competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metabolite concentration estimates from magnetic resonance spectroscopy (MRS) are typically quantified using water referencing, correcting for relaxation-time differences between metabolites and water. One common approach is to correct the reference signal for differential relaxation within three tissue compartments (gray matter, white matter, and cerebrospinal fluid) using fixed literature values. However, water relaxation times (T 1 and T 2 ) vary between brain locations and with age. MRS studies, even those measuring metabolite levels across the lifespan, often ignore these effects, because of a lack of reference data. The purpose of this study is to develop a water relaxometry atlas and to integrate location- and age-appropriate relaxation values into the MRS analysis workflow. One hundred one volunteers (51 men, 50 women; ~10 male, and 10 female participants per decade from the 20s to 60s) were recruited. T 1 -weighted MPRAGE images ((1-mm) 3 isotropic resolution) were acquired. Whole-brain water T 1 and T 2 measurements were made with DESPOT ((1.4 mm) 3 isotropic resolution) at 3T. T 1 and T 2 maps were registered to the JHU MNI-SS/EVE atlas using affine and LDDMM transformation. The atlas's 268 parcels were reduced to 130 by combining homologous parcels. Mean T 1 and T 2 values were calculated for each parcel in each subject. Linear models of T 1 and T 2 as functions of age were computed, using age - 30 as the predictor. Reference atlases of "age-30-intercept" and age-slope for T 1 and T 2 were generated. The atlas-based workflow was integrated into Osprey, which co-registers MRS voxels to the atlas and calculates location- and age-appropriate water relaxation parameters for quantification. The water relaxation aging atlas revealed significant regional and tissue differences in water relaxation behavior across adulthood. Using location- and subject-appropriate reference values in the MRS analysis workflow removes a current methodological limitation and is expected to reduce quantification biases associated with water-referenced tissue correction, especially for studies of aging., (© 2024 John Wiley & Sons, Ltd.)

Background: Poor affect recognition is an early sign of frontotemporal dementia (FTD). Here, we applied the abbreviated version of the Comprehensive Affect Testing System (CATS-A) battery to Italian FTD cases and healthy controls (HC) to provide cut-offs of emotional dysfunction in the whole group and in different FTD clinical syndromes., Methods: One hundred thirty-nine FTD patients (60 behavioural variant [bvFTD],13 semantic behavioural variant of FTD [sbvFTD], 28 progressive supranuclear palsy [PSP], 21 semantic [svPPA] and 17 nonfluent [nfvPPA] variants of primary progressive aphasia) and 116 HC were administered the CATS-A, yielding an Affective Recognition Quotient (ARQ), which was used as outcome measure. Age- and education-adjusted, regression-based norms were derived in HC. In patients, the ARQ was assessed for its internal reliability, factorial validity and construct validity by testing its association with another social cognition paradigm, the Story-Based Empath Task (SET). The diagnostic accuracy of the ARQ in discriminating patients from HC, genetic cases from HC and patient groups among each other was tested via ROC analyses., Results: In the whole FTD cohort, CATS-A proved to be underpinned by a mono-component factor (51.1%) and was internally consistent (McDonald's ω = 0.76). Moreover, the ARQ converged with the SET (r(122) = 0.50; p < 0.001) and optimally discriminated HC from both the whole cohort (AUC = 0.89) and each clinical syndrome (AUC range: 0.83-0.92). Conversely, CATS-A subtests were able to distinguish patient groups., Conclusions: The ARQ score from the CATS-A distinguishes FTD clinical syndromes from HC with high accuracy, making it an excellent tool for immediate use in clinical practice., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Education is strongly associated with cognitive outcomes at older ages, yet the extent to which these associations reflect causal effects remains uncertain due to potential confounding., Methods: Leveraging changes in historical measures of state-level education policies as natural experiments, we estimated the effects of educational attainment on cognitive performance over 10 years in 20,248 non-Hispanic Black and non-Hispanic White participants, aged 45+ in the Reasons for Geographic and Racial Disparities in Stroke cohort (2003-2020) by (1) using state- and year-specific compulsory schooling laws, school-term length, attendance rate, and student-teacher ratio policies to predict educational attainment for US Census microsample data from 1980 and 1990, and (2) applying policy-predicted years of education (PPYEd) to predict memory, verbal fluency, and a cognitive composite. We estimated overall and race- and sex-specific effects of PPYEd on level and change in each cognitive outcome using random intercept and slope models, adjusting for age, year of first cognitive assessment, and indicators for state of residence at age 6., Results: Each year of PPYEd was associated with higher baseline cognition (0.11 standard deviation [SD] increase in composite measure for each year of PPYEd, 95% confidence interval [CI] = 0.07, 0.15). Subanalyses focusing on individual cognitive domains estimate the largest effects of PPYEd on memory. PPYEd was not associated with the rate of change in cognitive scores. Estimates were similar across Black and White participants and across sex., Conclusions: Historical policies shaping educational attainment are associated with better later-life memory, a major determinant of dementia risk., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Latinos living in the US are disproportionately impacted by Alzheimer's disease and related dementias (ADRD). To develop culturally-informed interventions, a first step is engaging with key stakeholders. The present study aimed to explore perspectives on brain health and aging among middle-aged Latinos living in Chicago, IL., Methods: Individual, semi-structured interviews were conducted with 30 English- or Spanish-speaking Latinos between 35 to 64 years old. Questions from a previously used interview guide were leveraged and addressed knowledge about the brain, perceptions of healthy and unhealthy aging, ideas of how to care for the brain, where knowledge was acquired, and suggestions for disseminating brain health education. Responses were analyzed using thematic analysis., Results: The following themes were identified: (1) Understanding of the brain is varied (including cognitive, behavioral, anatomical, and psychological descriptions); (2) Perceptions surrounding healthy aging are broad and demonstrate a depth of understanding (e.g., physical and cognitive abilities, independence, positive emotions, and sociability), yet understanding of signs of an unhealthy brain is somewhat limited (e.g., focus on memory); (3) Brain health promotion is largely viewed as actionable (spanning physical health, cognitively stimulating activities, emotional wellbeing, medical self-management, and social connectedness); (4) Suggestions for disseminating education included media, clinics, churches, libraries, and community centers, with consideration of possible barriers and facilitators to behavior change (e.g., finances, prioritizing family)., Conclusions: Results showed significant heterogeneity in understanding of the brain, albeit with promising attitudes that actions can be taken to protect one's brain from ADRD., Practice Implications: Takeaways include the need for increasing education on normative versus nonnormative memory loss and signs of ADRD beyond memory impairment. Messaging may benefit from utilizing analogies, considering familism and spirituality, and highlighting lifestyle changes that do not carry a financial burden or place blame on individuals., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Wolf reports grants from the NIH during the conduct of the study; grants from Merck, the Gordon and Betty Moore Foundation, the NIH, and Eli Lilly outside the submitted work; and personal fees from Sanofi, Pfizer, GlaxoSmithKline, Lundbeck, Bristol Myers Squibb, and Luto outside the submitted work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: The current study aimed to evaluate the relationship between subjective cognitive complaints (SCC) and compensatory strategy (CS) use in a diverse sample of non-Latinx White (NLW), Black, and Latinx American older adults., Method: 807 older adults ( M age  = 65.38, 62.7% female) were recruited through Amazon's Mechanical Turk (MTurk) and Qualtrics Panel to complete questionnaires on SCC and CS use. Kruskall-Wallis tests were used to evaluate differences in SCC across groups given non-normal distributions. Analysis of variance (ANOVA) was used to evaluate group differences in CS use. The PROCESS macro for SPSS was used to examine whether demographic factors moderated the relationship between SCC and CS use., Results: NLWs reported higher levels of SCC and greater overall use of CS in comparison to Latinx and Black individuals. Several demographic and psychosocial factors including age, ethno-racial group, education, and anxiety level were found to be associated with CS use. Education was found to moderate the association between SCC and CS use., Conclusion: Inconsistent with prior studies, our study found that NLWs reported the highest levels of SCC. CS were used across all racial/ethnic groups, but the frequency of CS use may be impacted by education level. While all education groups increased their CS in response to higher levels of SCC, this increase was more substantial for those with lower levels of education. Future work should consider individuals' cultural and educational background when examining SCC and/or developing CS-based intervention for the aging population.

Introduction: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment., Methods: One hundred sixty-one older adults free of dementia or major neurological/psychiatric disorders were recruited. Participants underwent clinical interviews, cognitive testing, venipuncture for Alzheimer's disease (AD) biomarkers, and brain magnetic resonance imaging. Spontaneous CVR was quantified during 5 minutes of rest. Respiratory gases analyzed through nasal cannula to quantify end-tidal carbon dioxide ( ET CO 2 ) levels were used to estimate CVR., Results: Whole brain CVR was negatively associated with age, but not MCI. Lower CVR in the parahippocampal gyrus (PHG) was found in participants with MCI and was linked to worse memory performance on memory tests. Results remained significant after adjusting for AD biomarkers and vascular risk factors., Discussion: Spontaneous CVR deficits in the PHG are observed in older adults with MCI and memory impairment, suggesting medial temporal microvascular dysfunction is observed in cognitive decline., Highlights: Aging is associated with decline in whole brain spontaneous cerebrovascular reactivity (CVR). Older adults with mild cognitive impairment exhibit deficits in spontaneous CVR in the parahippocampal gyrus (PHG). Memory impairment is correlated with reduced spontaneous CVR in the PHG., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)