bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of cognitive impairment, functional decline and depression with the risk of all‐cause and cardiovascular mortality: a longitudinal study in the Chilean elderly population
Authors: Orellana Paulina , Celis‐Morales Carlos , Duran‐Aniotz Claudia , Ibañez Agustin , Nazar Gabriela , Ochoa‐Rosales Carolina 
Published: January 2025

AbstractBackgroundIn Chile, the cases of cognitive impairment and dementia are on the rise and are expected to triple by 2050. Additionally, older adults face life changes that may contribute to depression onset. We studied the relationship between cognitive impairment (CI), functional decline (FD) and depression with the risk of all‐cause and cardiovascular event mortality in the Chilean population aged ≥60 years.MethodProspective cohort study based on the Chilean National Health Survey 2009‐2010, a nationally representative prevalence study. Data on mortality status were available until 2020. We included n = 1,227 participants aged ≥60 years. A case of CI was defined as a score <13 in the abbreviated Mini‐Mental State Examination (score from 1‐19). FD in daily activities was defined as a score >6 in the Pfeffer Functional Activities Questionnaire test (score from 0‐33). Depression was defined as the presence of ≥5 depressive symptoms during the last year, assessed with the CIDI‐SF scale.Survival probabilities were obtained through Kaplan‐Meier estimators. The associations of CI, FD, and depression (independent variables) with all‐cause and cardiovascular mortality (dependent variables) were investigated using multivariate Cox proportional hazard models. Results were expressed as Hazard Ratios and 95%CI (HR; 95%CI).ResultParticipants were on average 71.7 years old and 60.3% were women. During the follow‐up, 431 individuals died from any cause and 107 from a cardiovascular event. Survival probabilities were lower among those with CI, FD and depression (Figure 1). CI was associated with higher risk of all‐cause and cardiovascular mortality by 60% (HR:1.60; 95%CI 1.25‐2.05) and 107% (2.07; 1.28‐3.34), respectively. FD and depression were associated with higher all‐cause mortality risk by 89% (1.89; 1.19‐3.01) and 69% (1.69; 1.25‐2.28), respectively. No significant associations were observed for FD and depression with cardiovascular mortality.ConclusionThis is the first study in the Chilean elderly population to link CI, FD or depression with a higher risk of premature mortality. Public health policies aimed to preserve mental and cognitive health in this age group are warranted to promote healthy aging.
Determining APOE ε4 carriership by NUcleic acid Linked Immuno‐Sandwich Assay (NULISA)
Authors: TAN Kübra , Benedet Andrea L. , Zhang Bingqing , Rahmouni Nesrine , Brum Wagner Scheeren , Pola Ilaria , Molfetta Guglielmo Di , Blennow Kaj , Ashton Nicholas J. , Zetterberg Henrik 
Published: January 2025

AbstractBackgroundThe APOE ε4 variant is the largest known genetic risk factor for late‐onset sporadic Alzheimer's disease (AD). Recent blood biomarker models include APOE ε4 status with plasma p‐tau217 for higher accuracy for AD pathology. Thus, protein assays that can accurately determine ε4 carriership simultaneously with plasma p‐tau217 would be advantageous for clinical use. This study aims to evaluate the concordance between the NULISA ApoE4 protein assay and conventional genetic testing for APOE measurement.MethodWe included two independent cohorts; cohort 1 (Translational Biomarker for Aging and Dementia Cohort [TRIAD]) consisted of 341 participants (mean [SD] age, 64.8[16.1] years; 213 females[62.4%]) and cohort 2 consisted of 38 participants (72.1[16.1] years; 21 females[55.2%]). APOE genotyping was determined by the TaqMan® SNP Genotyping Assay. In cohort 1, ApoE4 and p‐tau217 levels (NPQ) were quantified by the NULISAseq CNS disease panel from Alamar Biosciences. In cohort 2, ApoE4% (ApoE4/ApoEtotal) were quantified by a prototype singleplex assay from Alamar BiosciencesResultIn cohort 1, we included 341 participants with APOE genotyping (ε4 non‐carriers=221; ε4 carriers=120). ApoE4 NPQ values correctly identified 88.3% of carriers and 94.1% of non‐carriers (Figure 1A). Homozygous ε2 and ε4 carriers were entirely identified. Higher ApoE4 NPQ levels were observed in ε4/ε4 carriers (median [SD], 16.4[0.52]) compared to ε3/ε4 carriers (12.3[5.11]; P<0.0001) but an overlap remained. In these participants, the simultaneously measurement of NULISA plasma p‐tau217 was significantly increased in Aβ+ participants compared to Aβ‐ participants (AUC=0.941; P<0.0001). In cohort 2, we included 38 participants with APOE genotyping (ε3/ε3, n=26; ε3/ε4, n=9; ε4/ε4, n=6) and calculated the ApoE4% from a prototype singleplex NULISA method. Here, ε3/ε3 (0.03 [1.43]), ε3/ε4 (9.37 [1.61] and ε4/ε4 (41.9 [18.0]) individuals were classified with 100% accuracy (Figure 1B).ConclusionOur study assessed ApoE protein assays to determine APOE genotype. The ApoE4 assay within the NULISAseq CNS panel demonstrated high accuracy in distinguishing APOE ε4 carriers from non‐carriers, with some discordance. The reason for the discordance subject to further studies. However, ApoE4% quantification using a prototype singleplex assay distinguished ε4 homozygous, ε4 heterozygous, and non‐carriers with 100% accuracy. This pilot study demonstrates the ability to concurrently determine APOE status and p‐tau217 levels for more accurate diagnostic models of AD pathology.
Preliminary Effectiveness of a Simultaneous, Aerobic Exercise and Cognitive Training Telerehabilitation Program in Subjective Cognitive Decline. The Exergames Study
Authors: Salisbury Dereck L. , Pituch Keenan A , Yu Fang 
Published: January 2025

AbstractBackgroundSubjective cognitive decline (SCD) represents an important therapeutic target to prevent future cognitive decline associated with aging as well as neurodegenerative diseases such as Alzheimer’s disease. One such therapy is the “dual‐task” exergaming with concurrent aerobic exercise (AEx) and cognitive training. The primary aim of this Stage IB randomized controlled trial (RCT) was to test the preliminary effects of a dual‐task exergaming telerehabilitation intervention on cognition and aerobic fitness, in comparison to AEx only and attention control (stretching) in older adults with SCDMethodThis RCT randomized 39 participants on a 2:1:1 allocation ratio to supervised exergame (Figure 1) (n = 20), AEx (n = 11), and stretching (n = 8), 3 times a week for 12 weeks. The dual‐task exergaming was concurrent moderate‐intensity cycling and BrainFitRx® cognitive telerehabilitation. Cognition was assessed by NIH Toolbox Cognitive Battery and aerobic fitness by 6‐minute walk test (6MWT) and shuttle walk test.ResultThe participants were 74.6 (7.4) years old with 17.7 (2.3) years of education, and 69% were female. The effect of time was significant, F(1,23.9) = 13.16, p = .001, for the Fluid Composite score, and significant within‐group changes were seen for the exergame group, t(14.08) = 2.53, p = .024, d = 0.33. Between‐group changes did not reach significant levels for any cognitive test. Between‐group changes for the 6MWT were not significant, but the change score (21m) seen in the exergame group is considered clinically significant change for older adults.ConclusionThe exergame participants further improved their fluid cognition, while the AEx and stretching groups did not, indicating a potential synergistic effect from AEx and cognitive training. The aerobic fitness changes were similar between the exergame and AEx only groups, indicating that the feasibility of adding cognitive training to AEx concurrently without sacrificing gains in aerobic fitness from AEx. Studies with larger sample sizes than our study are needed to duplicate our findings.
Influence of BDNF polymorphisms on the neuronal‐enriched extracellular vesicle proBDNF/BDNF ratio and DMN activity in participants of the rrAD trial
Authors: Yanev Pavel G. , Scheel Norman , Zhang Rong , Zhu David C , Stowe Ann M , Trout Amanda 
Published: January 2025

AbstractBackgroundExtracellular vesicles (EVs) are lipid bilayer nanoparticles (30‐10,000 nm) released from all cells that facilitate cell‐to‐cell communication. Cell type‐specific EVs can be enriched using cell‐specific surface markers. Neuronal‐enriched EVs (NEVs) contain measurable neurotrophins, pro‐ and mature brain‐derived neurotrophic factor (BDNF), that have opposing action in neuronal plasticity. Exercise shifts the proBDNF/BDNF ratio toward BDNF, potentially enhancing brain health. This study investigates the relationship between NEV proBDNF/BDNF, Default Mode Network (DMN), and a BDNF polymorphism (Val66Met) in the context of the NIH‐funded "Risk Reduction for Alzheimer’s Disease" (rrAD) trial (NCT02913664).MethodrrAD is a phase‐II randomized controlled trial with banked plasma and neuroimaging from 512 cognitively normal subjects (ages 60‐85, 34% aged 65‐85) with a family history of Alzheimer's Disease (AD) and/or memory complaints. The 372 subjects that provided DNA consent were genotyped for Val66Met (Rs6265). EVs were isolated using ExoQuick followed by anti‐NCAM‐L1 immunoprecipitation and analyzed for size/concentration with a Zetaview NTA. Levels of proBDNF/BDNF protein were quantified by ELISA in baseline, 12, and 24‐month plasma samples. MRI was performed on 3T scanners. Resting state functional (rs‐f) MRI data was pre‐processed using AFNI and ICA‐based strategy was used for noise reduction.ResultOf 372 consenting rrAD participants, 68% were Val/Val and 32% Met‐carriers (Val/Met and Met/Met). Of Met carriers, 56% were male (sex vs. Met‐carrier, P=0.33). A preliminary blinded cohort of EV isolation in n=21 subjects showed a substantial impact of BDNF Val66Met polymorphism on the proBDNF/BDNF ratio at baseline and 12 months. Higher BDNF in NEVs coincided with significantly stronger rs‐fMRI connectivity in the ventral and dorsal DMN (P =0.02). However, the precise nature of this relationship and how it relates to rrAD intervention responses remains to be fully understood.ConclusionThe study highlights the potential of BDNF polymorphisms in affecting the proBDNF/BDNF ratio and DMN activity, offering a valuable tool for disease prognosis and therapeutic effectiveness. It also suggests that AD trials need to account for BDNF polymorphisms to determine whether interventions aimed at slowing/preventing dementia are influenced by genetic factors and/or sex.
The role of sex in the association between peripheral insulin and cortical thickness in cognitively intact older adults by amyloid status
Authors: Tsiknia Amaryllis A , Tubi Meral A , Lee Noelle , Hall Brandon J , Petersen Melissa , Large Stephanie E , Toga Arthur W. , O'Bryant Sid E. , Yaffe Kristine , Braskie Meredith N 
Published: January 2025

AbstractBackgroundCompared to men, insulin‐resistant women have more brain atrophy, cognitive impairment, and higher dementia risk, but the mechanisms for this sex difference are unknown. We examined sex differences in how blood insulin relates to cortical thickness in cognitively intact older adults. Gaining a better understanding of the relationship between insulin and brain health could help inform the development of insulin‐targeting treatments and reduce the risk of dementia associated with insulin resistance.MethodWe performed MRI and florbetaben (amyloid PET) scanning and acquired fasting blood insulin on 1026 cognitively normal participants from the Health & Aging Brain Study – Health Disparities (50‐90 years; 645 female) (Table 1). Amyloid positivity (AB+) was defined as global SUVR>1.08, using a whole cerebellum reference region. We used linear regressions to relate blood insulin to cortical thickness in 34 mean bilateral Freesurfer‐derived brain regions and left and right hippocampal volume (FDR‐corrected for 36 regions). We additionally conducted separate linear regressions within each sex and tested for a sex*insulin interaction on cortical thickness and hippocampal volume. Covariates included age, sex, blood glucose levels, abdominal circumference, years of education, and income.ResultIn the full sample, higher insulin was associated with thicker superior parietal (β=0.11, p‐corrected=0.02), inferior parietal (β=0.10, p‐corrected=0.03) and lateral occipital cortex (β=0.12, p‐corrected=8.14e‐03). In women, but not men, higher insulin was associated with thicker cortex in several frontal, parietal, and occipital regions (Figure 1). A sex*insulin interaction on cortical thickness was significant in the pars triangularis (β=‐0.18, p‐corrected=0.04), lateral orbitofrontal (β=‐0.23, p‐corrected=6.80e‐03), superior parietal (β=‐0.17, p‐corrected=0.04), and inferior parietal cortex (β=‐0.18, p‐corrected=0.02), even after controlling for hypertension and cardiovascular disease presence, which differed between sexes. Higher insulin was associated with thicker cortex in several frontal and parietal regions in AB‐ but not AB+ women, with an amyloid status*insulin interaction in the pars orbitalis (β=‐0.42, p‐corrected=0.03).ConclusionHigher blood insulin correlates with thicker cortex in cognitively intact women, particularly those who are AB‐, but not in men. Future research on how sex hormones affect insulin signaling and the potential modulating role of amyloid could further our understanding of neurodegenerative processes and guide targeted interventions in dementia prevention.
Fluid biospecimens and genetic data collection and dissemination: new pipelines to serve the dementia research community from the UCSF Memory and Aging Center
Authors: Lago Argentina Lario , Webb Julia D , Young Taylor M , George Rose , Smith Karen , Tyler Ana , Ramos Eliana Marisa , Heuer Hilary W. , Koestler Mary , VandeVrede Lawren , Joie Renaud La , Rabinovici Gil D. , Miller Bruce L. , Rojas Julio C. , Casaletto Kaitlin B. , Yokoyama Jennifer S. , Boxer Adam L. 
Published: January 2025

AbstractBackgroundCollection, storage, and distribution of human fluid biospecimens in a scientifically rigorous manner is challenging. It requires physical space availability and robust infrastructure. Nonetheless, it is key to contribute to research in Alzheimer’s Disease and Related Disorders, including Frontotemporal Dementia (FTD). These specimens facilitate fluid biomarker discovery and validation studies. At the UCSF Memory and Aging center (MAC) we support 31 protocols, from both clinical and observational studies, including international ones (e.g. ALLFTD). Besides specimens, our Biospecimens and Genetics Program (BsGP) stores and shares fluid biomarker and genetic data associated with specimens collected under such studies. Here, we aim to report results of a single center’s operational efforts to create a platform for biospecimens and biospecimens‐related data management that functions seamlessly allowing for collaborative research.MethodOver the past three years, we developed infrastructure to support biospecimen research, both locally and internationally. Our program is led by a PhD neuroscientist and supported by four faculty members. We have a dedicated data manager, an administrative coordinator, and five members in our processing lab. We doubled our laboratory equipment (acquired two centrifuges) and implemented a superior version of our Laboratory Information Management System. We maintained and expanded partnerships with entities like UCSF‐IHG, UCLA, NCRAD, ATRI. We strengthened our technological infrastructure by hiring a dedicated programmer. We transitioned towards a de‐centralized biobanking strategy.ResultDuring 2023, the BsGP supported 16 investigators who submitted 20 genetic data requests. We supported our Fibroblast, Genetic, and Neuropathology Cores by providing quarterly customized genetic datasets. Our BsGP Committee reviewed 31 biospecimens requests, including 11 from non‐UCSF affiliated investigators (from academic institutions and industry). They all required heavily leveraging internal resources to provide additional clinical and biomarker data. We began to build a bespoke bioinformatics solution for our program: SYNC. SYNC will facilitate tracking and searching for biospecimens (and associated fluid biomarker and genetic data) easily, so that accessing existing resources is not a roadblock for research.ConclusionThe MAC BsGP can serve as a model for centers interested in improving their biospecimen research programs, which requires dedicated investments in infrastructure, especially hiring and supporting qualified personnel.
Unique Pattern of White Matter Hyperintensities in Middle Age and Older Adults with History of Repetitive Head Impact Exposure
Authors: Groh Jenna R. , Miner Annalise E. , Farris Chad , Tripodis Yorghos , Nowinski Christopher J. , Cui Anna , Pettway Erika C. , Tuz‐Zahra Fatima , Alshikho Mohamad J. , Brickman Adam M. , Lenio Steven , Ly Monica T. , Altaras Caroline , Budson Andrew E. , Turk Katherine W. , Qiu Wendy , Goldstein Lee E , Martin Brett , Palmisano Joseph N. , Steinberg Eric G. , Stern Robert A. , Stein Thor D. , McKee Ann C. , Mez Jesse , Alosco Michael L. 
Published: January 2025

AbstractBackgroundRepetitive head impacts (RHI) from contact sports can lead to long‐term white matter injury visualized on FLAIR scans as white matter hyperintensities (WMH). The goal of this study was to preliminarily characterize the unique pattern and features of WMH in middle aged‐ to older adults with remote history of exposure to RHI from contact sports.Method76 participants (38 with substantial RHI, 38 with minimal or no RHI) from the Boston University Alzheimer’s Disease Research Center had a FLAIR MRI during their annual study visit. The presence of moderate‐severe WMH was adjudicated by a panel of clinicians (including of a neurologist and neuroradiologist) during a multidisciplinary diagnostic consensus. Previously, we observed small, spherical, discrete lesions proximal to the gray matter in individuals exposed to RHI. Therefore, the number of discrete, spherical WMH within 1.0cm of the cortex was counted. Regression and analysis of variance models examined group effects as well as years of American football play (proxy for duration of RHl), controlling for age at MRI and vascular risk factors.ResultsSample characteristics are in Table 1. Sources of RHI were American football, hockey, soccer, wrestling, field hockey, lacrosse, mixed martial arts, and rugby. The RHI group was judged to have greater burden of WMH compared to non‐RHI (n=15 vs n=5, p=0.042). Years of football play was associated with greater odds for having moderate‐severe WMH (OR =1.10, p=0.023). RHI participants had a greater number of unique, distinguishable WMH within 0.5cm (p=0.006) and 1.0cm (p=0.008) of the cortex (Figure 1). Qualitatively, we visualized small, punctate lesions close to the gray matter, clustered around the depths of the sulci in the RHI cohort, distinct from the patterns typically seen with chronic ischemic disease and neuro‐inflammatory conditions (Figure 2).ConclusionWe propose RHI induces a unique pattern of WMH characterized by small, spherical, punctate lesions proximal to the deep gray matter distributed throughout the cerebrum. The lesion location corresponds to areas susceptible to RHI and p‐tau in chronic traumatic encephalopathy. Future research targets include quantitative analysis to better characterize features and patterns of WMH, clarify specificity to RHI, and study biological correlates.
Brain Age Gap has a Small Association with Cognition in Cognitively Normal Older Adults
Authors: Best Charlotte , Petersen Kalen , Millar Peter R , McKay Nicole S. , Aschenbrenner Andrew J. , Gordon Brian A. , Balota David A. , Schindler Suzanne E. , Benzinger Tammie L.S. , Braskie Meredith N , Toga Arthur W. , O'Bryant Sid E. , Ances Beau , Wisch Julie K. ,   the HABS‐HD Study Team
Published: January 2025

AbstractBackgroundBrain Age Gap (BAG) describes the difference between predicted brain age and chronological age, where a higher BAG suggests accelerated brain aging. It is estimated using machine learning techniques. The Preclinical Alzheimer Cognitive Composite (PACC) is a combination of neuropsychological tests employed in Alzheimer Disease (AD) research. It is sensitive to subtle change in cognition across the preclinical period of AD. BAG associates with change in Clinical Dementia Rating (CDR), but its relevance to subtle cognitive decline as compared to a biomarker of preclinical AD (amyloid PET) is unknown.MethodLongitudinal data were collected from the Knight AD Research Center (ADRC; N = 652, mean duration of cognitive follow‐up = 9.3 years) and cross‐sectional data from the Health & Aging Brain Study‐Health Disparities (HABS‐HD; N = 1421). All participants were CDR=0. We estimated BAG using DeepBrainNet, adjusting for age and scanner. Amyloid PET was collected using [18F]florbetaben in HABS‐HD and both [18F]florbetaben and [11C]PiB (converted to Centiloids) in the Knight ADRC. We calculated PACC using previously published methods, relying on different tests in each cohort. We evaluated cross‐sectional relationships between PACC and both BAG and amyloid PET in both cohorts, and longitudinal relationships in the Knight ADRC cohort. Analyses were adjusted for age, education, and gender.ResultThere was no cross‐sectional association between PACC and either BAG or amyloid status. Longitudinally, there were baseline differences by both BAG (βscaled = ‐0.06, p = 0.01) and amyloid status (βscaled = ‐0.15, p = 0.02) and significant interactions between BAG and time since baseline visit (βscaled = ‐0.02, p = 0.04) as well as amyloid positivity and time since baseline visit (βscaled = ‐0.12, p < 0.001) in the Knight ADRC. The baseline difference in PACC for amyloid positive participants equates to the same effect as roughly +15 year in BAG.ConclusionIn a cohort with extensive longitudinal follow‐up, we observed a decline in cognitive performance over time associated with both BAG and amyloid positivity. Amyloid positivity may have a stronger effect on cognitive performance because it represents a disease trajectory, while BAG may more closely approximate typical aging.