bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential association of moderate alcohol use with neurodegeneration, cerebrovascular disease, and cognition by racial, ethnic and sex/gender groups in middle age
Authors: Guzmán Diana S. , Rentería Miguel Arce , Avila Justina F , Turney Indira C. , Johnson Aubrey S. , Smith Anna C. , Okafor Amarachukwu , Houlihan Hannah M. , Heuer Lauren B. , Alshikho Mohamad J. , Morales Clarissa , Mazen Jessica , Gu Yian , Manly Jennifer J. , Brickman Adam M. , Lao Patrick J.
Published: January 2025

Background

Moderate alcohol use may be associated with brain and cognitive benefits compared to heavy alcohol use. However, results have varied. We hypothesized that the relationship between alcohol use and cognition is mediated by neurodegenerative and cerebrovascular measures in a diverse middle‐aged sample of non‐alcohol dependent community‐dwelling adults in Northern Manhattan.

Method

Participants (N=451; age=53±10 years; 36 Black Men (BM), 68 Black Women (BW), 95 Latinx Men (LM), 198 Latinx Women (LW), 17 White Men (WM), 37 White Women (WW)) from the Offspring study of Racial and Ethnic Disparities in Alzheimer’s Disease underwent structural and vascular MRI (total brain volume (TBV), cortical thickness in AD signature regions, hippocampal volume, white matter hyperintensities (WMH)). Moderate alcohol use was assessed by the Alcohol Use Disorder Identification Test–Concise (AUDIT‐C≤9). Mediation models tested whether the association of alcohol use on cognition (SRT total and delayed; Animal and letter fluency; Digit Span Backwards) is mediated by brain measures, stratified in sex/gender by racial and ethnic groups.

Result

Greater moderate alcohol use was associated with lower cortical thickness and hippocampal volume LM (cortical thickness: ‐0.005 mm [‐0.008, 0.001], p=0.005; hippocampal volume: ‐25.0 mm3 [‐45.0, ‐4.7], p=0.02), greater vascular burden in BM (temporal WMH: 0.07 cm3 [0.001, 0.121], p=0.05), and lower TBV in WM (‐24.0 cm3 [‐27.5, ‐20.4], p=0.01), but not associated with brain measures in women. Greater moderate alcohol use was associated with lower animal fluency for LM (ADE: ‐0.25 to ‐0.21, p≤0.04), but higher letter fluency for LW (ADE: 0.24 to 0.25, p≤0.04) and BW (ADE: 0.43 to 0.43, p≤0.05), accounting for brain to cognition associations. However, mediation pathways (ACME) were not significant.

Conclusion

Men had lower cortical thickness and brain volume, greater WMH volume, and lower cognitive measures, while women had higher cognitive measures with greater moderate alcohol use in midlife. Neurodegenerative and vascular associations with moderate alcohol use differed by race and ethnicity in men, while the directionality of associations between moderate alcohol use and fluency differed by sex/gender. Future work should explore alcohol use factors (e.g., context of use, duration of use), and the relationship to brain and cognitive changes over the life course.
Medial temporal lobe vulnerability in women: the interactive effect of tau and depressive symptoms on atrophy trajectories
Authors: Palpatzis Eleni , Aguillar Pablo , Akinci Muge , Arenaza‐Urquijo Eider M
Published: January 2025

Background

Women show greater atrophy in medial temporal lobe (MTL) compared to men, irrespective of amyloid burden. We examined whether depressive symptoms, which are more prevalent in women and also linked to MTL atrophy, interact with tau accumulation on MTL atrophy trajectories across 7 years differently among men and women.

Method

We included 71 non‐demented ADNI participants with available baseline data on depressive symptoms (Geriatric Depression Scale; GDS), MTL tau accumulation (AV1451 PET BRAAK I/II SUVR [entorhinal and hippocampus]), Centiloids derived from [18F]florbetaben and [18F]florbetapir and with at least 3 structural MRI visits (mean time = 6.8 years, SD = 2.1). Individual slopes indicating GM volume change of MTL structures (hippocampus, parahippocampus, entorhinal cortex, fusiform and amygdala) were calculated with linear‐mixed effects models. To assess the specificity of the results to the MTL, the inferior temporal lobe and the anterior cingulate (ACC) were selected as control regions. Presence of depressive symptoms was measured with GDS (0 = no symptoms, 1≥depressive symptoms). We performed linear regression models to examine the effects of tau accumulation, depressive symptoms and the sex/gender‐related effects of tau*depressive symptoms on MTL, inferior temporal and ACC atrophy trajectories. Covariates included baseline age, years of education, total intracranial volume and baseline amyloid burden.

Result

63% of participants were women and there were no differences in presence/absence of depressive symptoms by sex/gender (Table 1). Tau accumulation was associated with longitudinal atrophy in all brain regions while presence of depressive symptoms was not (Table 2). The presence of depressive symptoms interacted with tau in a sex/gender‐specific manner on fusiform, ACC and inferior temporal lobe, such that, women who reported depressive symptoms had higher atrophy rates as a function of tau accumulation compared to men (Figure 1).

Conclusion

Our findings indicate that the presence of depressive symptoms amplify the impact of tau on GM atrophy trajectories in women. Contrary to expectations, the results do not substantiate a specific vulnerability in the MTL, but rather reveal a broader susceptibility encompassing tau‐related inferior temporal areas and the anterior limbic system. In women, depressive symptoms may contribute to regional brain vulnerability downstream amyloid deposition by amplifying the effects of tau.
ALS Diagnostic Delays in Hispanic/Latinx Patients
Authors: Hromas Gabrielle , Wang Chen‐Pin , Fernandez Roman A. , Jackson Carlayne , Sullivan A. Campbell
Published: January 2025

Background

Prior research identified delays in diagnosis of Amyotrophic Lateral Sclerosis (ALS) amongst ethnic and racial minorities. This study examined differences in diagnostic delays and symptom severity between White non‐Hispanic and Hispanic/Latinx patients.

Method

To increase the number of Hispanic/Latinx cases, data from the Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT), a database including clinical trial participants from nine contributing entities, were combined with a sample of patients recruited from the multidisciplinary ALS clinic at UT Health San Antonio. Two sample T‐test and multivariable regression adjusted for inverse propensity scores weights of ethnic group were conducted to compare ethnic difference in the length of diagnostic delay as well as scores on the ALS Functional Rating Scale‐Revised (ALSFRS‐R; higher scores = less severe symptoms) at the time of first study/medical appointment.

Result

1,916 patients (165 Hispanic/Latinx) with ALS were included in the final sample. Mean ALSFRS‐R scores: 37.8 (5.4) for White non‐Hispanic, 34.2 (7.0) for Hispanic/Latinx. Mean length of diagnostic delay: 390 (392) for White non‐Hispanic, 658 (995) for Hispanic/Latinx. Linear regression showed that White non‐Hispanic patients had shorter delays in diagnosis (p<0.001) and higher (less severe) scores on the ALSFRS‐R (p<0.001).

Conclusion

These results support prior research showing diagnostic delays in non‐White patients with ALS. Results also show that Hispanic/Latinx patients had more severe symptoms at the time of diagnosis than White non‐Hispanic patients. Diagnostic delays slow access to pharmacological interventions and supportive services. These results highlight the need to improve access to medical care across different cultures and ethnicities in the United States.
A Brief Digital Neuropsychological Protocol – II: Using Artificial Intelligence to Assess Verbal Serial List Learning Recognition Latency
Authors: Libon David J. , Swenson Rodney , Tobyne Sean E , Price Catherine C. , Lamar Melissa , Cosentino Stephanie , Banks Russell , Jannati Ali , Showalter John , Bates David , Pascual‐Leone Alvaro
Published: January 2025

Background

Digital neuropsychological assessment easily captures behavior previously not obtainable by traditional pencil‐and‐paper tests. Verbal serial list learning tests are commonly used to assess for putative neurogenerative syndromes. Recognition test performance is often expressed compiling simple ‘yes/ no’ responses, but fail to assess process metrics such as the latency to respond to individual recognition test items.

Method

Memory clinic patients were assessed with the a digital neuropsychological protocol where cluster analysis of traditional metrics classified patients into normal (nl= 23), amnestic MCI (aMCI= 17), dysexecutive MCI (dMCI= 23), and dementia (dem= 14) groups. Verbal episodic memory was assessed with a 6‐word Philadelphia (repeatable) Verbal Learning Test. P(r)VLT delayed recognition memory was assessed using a forced multiple‐choice format where the iPad both displayed and verbally administered six trials containing the target word, a prototypic semantic foil (e.g., “apple”) and a generic semantic foil (e.g., “pear”). The patient was asked to touch the word that was part of the original word list as quickly as possible.

Result

aMCI and dementia groups endorsed more recognition foils that other groups (Table 1; dementia > all groups, p< 0.001; aMCI > dMCI & nl groups, p< 0.001). Serial list learning recognition latency was slower for aMCI versus dMCI and nl groups; p< 0.005); and dementia versus dMCI and nl groups (p< 0.001). Regression analysis (dv= recognition latency; block 1= age, education, sex; block 2= recognition prototypic & generic foils) was significant (R2= 0.463, p< 0.001); and found slower recognition latency was associated with greater numbers of prototypic recognition foils (beta= 0.551; p< 0.001). Regression analysis (dv= recognition latency; block 1= age, education, sex; block 2= all free recall cluster responses, all free recall extra‐list intrusion errors) also found slower recognition latency was associated with fewer semantic cluster responses (beta= ‐0.252, p< 0.021), but greater numbers of extra‐list intrusion errors (beta= 0.266, p< 0.017).

Conclusion

When brought to scale, automated analysis of recognition latency along with other serial list learning process metrics could help identify early, emergent neurodegenerative illness.
Cholinesterase inhibitors for patients with dementia: Patterns of prescribing and disparities in treatment
Authors: Negida Ahmed , Barrett Matthew J , Wyman‐Chick Kathryn A , Chrenka Ella A , Bayram Ece , Kane Joseph PM , Werner Ann M , Rossom Rebecca C
Published: January 2025

Background

Cholinesterase inhibitors (ChEIs) are cornerstones in the symptomatic treatment of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) and are also prescribed for vascular dementia (VD). Despite their widespread use, patterns of prescribing ChEIs are not fully understood.

Objective

Examine the prevalence, timing, and types of ChEI prescriptions before and after dementia diagnosis including prescribing patterns by patient sex and race.

Methods

We analyzed electronic health record and claims data for patients diagnosed with AD, DLB, or VD between October 2015 and August 2022 from a large healthcare system in the U.S. Claims for ChEI prescriptions (donepezil, galantamine, rivastigmine) were identified in the ±3 years surrounding dementia diagnosis. Repeated measures logistic regression was used to estimate the likelihood of ChEI prescription by time‐period, dementia type, and time x dementia type interaction to determine if change in prescription patterns significantly differed by diagnosis.

Results

A total of 3166 eligible patients were identified (AD n = 2478; DLB n = 175; VD n = 513, Table 1). The number of patients with a ChEI prescription was higher in the post‐index period for all diagnosis groups. Patients with DLB had the highest prevalence of ChEI prescriptions both pre‐and post‐diagnosis (39% and 59%, respectively) compared to patients with AD (28% and 38%) and VD (13% and 14%; Table 2). For patients with a ChEI prescription post‐diagnosis, the first ChEI prescription was most likely to be donepezil (96%). When accounting for differences in age, sex, and race, patients with VD were found to have significantly lower rates of ChEI prescriptions compared to patients with DLB (OR: 0.47, 95% CI 0.3, 0.8). There was no difference in ChEI prescriptions observed between DLB and AD patients. In the fully adjusted model, females (OR: 0.81, 95% CI: 0.71, 0.91) and non‐white patients (OR: 0.74, 95% CI: 0.62, 0.88) were less likely to have a prescription for a ChEI (Table 3).

Conclusion

Donepezil was the most frequently prescribed ChEI for AD, DLB, and VD. Patients with DLB had the highest prevalence of ChEI prescriptions both pre‐ and post‐diagnosis. Females and non‐white patients were less likely to receive ChEI prescriptions, underscoring potential disparities in treatment patterns.
APOE and Brain Amyloid and Tau Levels
Authors: Luu Danielle , Wheeler Koral V , Lee Noelle , Hand Maxwell W , Barber Robert , Phillips Nicole , Toga Arthur W. , O'Bryant Sid E. , Yaffe Kristine , Braskie Meredith N
Published: January 2025

Background

The ɛ4 allele and promoter region variant, rs405509, of APOE are risk factors for late onset Alzheimer’s Disease (LOAD) (Raulin et al., 2022, Logue et al., 2023). Limited research exists on how these alleles affect LOAD pathology across ethno‐racial groups. We related risk allele dosage to brain amyloid and tau positron emission tomography (PET) signal.

Method

We examined 2832 individuals (574 mild cognitive impaired, 2258 cognitively intact, mean age=65±8.5 years) from the Health and Aging Brain Study‐Health Disparities. This cohort includes self‐reported ethnoracial data including Non‐Hispanic White (NHW), Hispanic (H), and African American/Black (AA). Tau PET scans (PI 2620) had the medial temporal lobe (MTL), posterior cingulate (PC), and lateral parietal (LP) as ROIs and the inferior gray matter of the cerebellum as the reference region. We used amyloid (florbetaben) PET scans and calculated global amyloid as a mean of standardized uptake value ratio (SUVR) in frontal, cingulate, lateral parietal, and lateral temporal lobes with the whole cerebellum as the reference region. We ran linear regressions between risk allele dosage and amyloid/tau PET levels in the overall sample and stratified by race/ethnicity. Covariates included age, sex, education level, cognitive diagnosis, time between clinical visit and scan, and first two components from principal component analysis. We covaried for ɛ4‐positivity when available (Table 1) and scanner and corrected for multiple comparisons using Bonferroni correction.

Result

In the total sample, more ɛ4 alleles were associated with more tau in the MTL (β= 0.38, p= 5.24e‐07) and LP (β= 0.26, p= 7.28e‐04). In NHW participants alone, this association persisted in the MTL (β= 0.38, p= 6.51e‐06) and LP (β= 0.31, p= 4.94e‐04), although without a significant race/ethnicity interaction. Amyloid and tau weren’t associated with rs405509 genotype in the overall sample, in subsets with/without an ɛ4 allele, or in ethnoracial subsets.

Conclusion

There was a positive relationship between ɛ4 dosage and tau in the MTL and LP, particularly in NHW participants. There were no significant findings of rs405509 on amyloid/tau, or of either allele on tau in the PC.
Blood biomarkers and cognitive status in aged common marmosets
Authors: Bharadwaj Anusha , Rothwell Emily S. , Freire‐Cobo Carmen , Padilla Stephanie L. , Hof Patrick R , Lacreuse Agnès
Published: January 2025

Background

Nonhuman primates are arguably the best models for Alzheimer’s disease (AD), due to close similarities with humans in physiology and behavior, brain structure and function, and aging patterns. The common marmoset (Callithrix jacchus) is particularly valuable because it has the shortest lifespan of all anthropoids (10‐12 years), exhibits sex differences in age‐related cognitive decline and develops AD‐like pathology with age. In the present study, we investigated blood‐based biomarkers in male and female marmosets with cognitive and neuropathological assessments.

Method

We analyzed the concentrations of several AD biomarkers from blood samples of male and female marmosets (n = 13, age range 6.8‐9.36 years) characterized for age‐related cognitive decline and neuropathology. AD biomarker concentrations were measured using the commercially available S‐PLEX neurology panel 1 kit (NHP) from Mesoscale Discovery. The kit, designed for GFAP, NfL, and tau detection, employs electrochemiluminescence to discern femtogram concentrations. Similar to ELISA, the emitted light intensity in S‐PLEX assays directly correlates with analyte amounts in the sample. Log‐transformed biomarker data were subjected to analyses of variance, with Sex and Cognitive Status as factors, and Age as a covariate.

Result

LogGFAP concentrations were significantly higher in cognitively impaired (F (1, 8) = 15.50, p < .01) than unimpaired animals. Other biomarkers did not differ significantly based on cognitive status. All biomarkers exhibited non‐significant Sex effects (all ps < .10), suggesting higher levels in males. A non‐significant Sex x Cognitive Status interaction for LogGFAP (F (1, 8) = 4.12, p < .08) indicated higher levels in males among the impaired group. Although we found no significant association between blood biomarkers and neuropathological data, substantial correlations were noted within the impaired group. Analyses with a larger sample size are in progress.

Conclusion

Alterations in biomarker concentrations serve as early indicators of cognitive decline, preceding AD diagnosis. Elevated blood GFAP, indicative of inflammation, differentiated impaired and non‐impaired aged marmosets, with sex influencing biomarker levels, predominantly higher in males. The absence of significant correlations between blood biomarkers and neuropathology necessitates further validation with a larger subject cohort.

Supported by NIH R01 AG046266 and SAGA 23
A Brief Digital Neuropsychological Protocol: III ‐ Using Artificial Intelligence to Measure Semantic Memory with the ‘Animal’ Fluency Test
Authors: Libon David J. , Swenson Rodney , Tobyne Sean , Price Catherine C. , Lamar Melissa , Cosentino Stephanie , Banks Russell , Jannati Ali , Showalter John , Bates David , Pascual‐Leone Alvaro
Published: January 2025

Background

Semantic memory refers to knowledge of attributes associated with common objects. Quantifying the strength of semantic association between successive ‘animal’ fluency responses can be challenging. The current research assessed between‐group differences for ‘animal’ fluency total output and selected verbal serial list learning, episodic memory measures.

Method

Memory clinic patients were assessed with a digital neuropsychological protocol. Cluster analysis classified patients into normal (nl= 23), amnestic MCI (aMCI= 17), dysexecutive MCI (dMCI= 23), and dementia (dementia= 14) groups. During the protocol, patients were given 60secs to provide animal exemplars. Memory was assessed with the P(r)VLT, a 6‐word verbal serial list learning test. Using artificial intelligence assisted scoring all ‘animal’ fluency and P(r)VLT outcome variables including the ‘animal’ Association Index (AI), where the mean number of shared attributes between successive responses were automatically tallied.

Result

The nl group generated more animal exemplars than all other groups (p< 0.001; Table 1). aMCI and dMCI patients generated more responses than dementia patients (p< 0.043, both analyses). NL and dMCI patients produced a higher, more semantically connected, ‘animal’ AI than dementia patients (nl > dem; p< 0.025, both analyses). Regression analysis (dv= ’animal’ AI; block 1= age, education, sex; block 2= recognition prototypic & generic foils) was significant (R2= 0.145, p< 0.023); and found that a reduced, more impaired ‘animal’ AI was associated with increasing numbers of P(r)VLT prototypic recognition foils (beta= ‐0.276; p< 0.024). Regression analysis (dv= ’animal’ AI; block 1= age, education, sex; block 2= P(r)VLT semantic cluster responses, P(r)VLT extra‐list intrusion errors) was not significant.

Conclusion

In addition to commonly used outcome measures such as total ‘animal’ responses, this digital neuropsychological protocol scores a number of process variables, including the ‘animal’ AI. The association between reduced ‘animal’ AI and greater numbers of list learning prototypic recognition foils suggests combined episodic memory and semantic‐related impairment in selected patients. When brought to scale, automated analysis of neuropsychological process variables may aide in identifying emergent neurodegenerative illness.
Longitudinal associations of epigenetic aging clocks with cognitive decline in diverse Hispanics/Latinos
Authors: Xia Rui , Márquez Freddie , Tarraf Wassim , Gallo Linda C , Talavera Gregory A , Sofer Tamar , Decarli Charles , Gonzalez Hector M , Fornage Myriam
Published: January 2025

Background

Several epigenetic clocks based on DNA methylation (DNAm) have been developed to estimate an individual’s biological age. Age acceleration, the deviation of the DNAm‐estimated age from the chronological age, has been proposed as a novel biomarker to predict age‐associated conditions and life expectancy. Due to the paucity of longitudinal DNAm data, especially among diverse Hispanic/Latino adults, the association between changes in age acceleration over time and cognitive aging phenotypes has not been investigated.

Method

We estimated epigenetic age acceleration from 5 PC‐based epigenetic clocks in 2667 Hispanic and Latino adults (58.2 years; 55.9% women) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), who had available blood DNAm data and neurocognitive assessment at two visits (approximately 6 years apart). These included first generation clocks, Horvath and Hannum clocks; second generation PhenoAge and GrimAge; and third generation DunedinPACE (Pace of Aging). We used survey linear regression weighted least square models to estimate the association of each of these measures with change in general cognitive function score and cognitive decline status between the two visits. All models adjusted for age, gender, Hispanic background, and years of education.

Result

For all epigenetic clocks, measures of age acceleration at visit 1 (V1) and visit 2 (V2) were strongly correlated (r=0.80 to 0.93; P <0.001). A higher GrimAge acceleration at V1 and V2 was associated with a greater decline in general cognitive function score between the two visits, while a higher V1 and V2 GrimAge acceleration and a higher V2 PhenoAge and DunedinPACE (POA) acceleration were associated with a greater likelihood of having cognitive decline at V2 (Table). An increase in GrimAge and PhenoAge acceleration between visits was associated with greater decline in global cognitive function score and presence of cognitive decline at V2 and these effects were stronger than single‐time point estimates.

Conclusion

Biological aging is associated with lower cognitive function score and greater cognitive decline in diverse Hispanic and Latino adults. Longitudinal assessment of change in age acceleration for second generations clocks, GrimAge and PhenoAge may provide additional value in predicting cognitive decline beyond single time point assessment.
Dynamic and static functional network connectivity distinguish symptomatic and non‐symptomatic individuals with CADASIL
Authors: Bockholt Henry J , Paulsen Jane S , Baker Bradley T , Petropoulos Helen , Caprihan Arvind , Johnson Kevin M. , Geschwind Michael D , Eisenmenger Laura B. , Liebeskind David S , Clemsen Jordan , Pasley Nicholas , Adams William H. , Newton Michael A , Calhoun Vince D
Published: January 2025

Background

This study focuses on Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a key model for studying arterial degradation and its impact on brain network communication. We explore functional network connectivity in CADASIL patients, shedding light on how arterial changes affect brain network interactions.

Method

Overcoming COVID‐19 challenges, we've enrolled over 200 participants for longitudinal assessments. The study compares Symptomatic (SYM) individuals (Rankin Scale scores 1‐3) with Non‐Symptomatic (NSYM) counterparts. The SYM group, mainly females (63) and Caucasians (101), shows lower cognitive performance (average MOCA score 25.2) and processing speed (SDMT average 43.7) compared to NSYM's higher scores (MOCA 26.8, SDMT 51.4). Additionally, the SYM group, older on average (53 years), exhibits more functional impairment (average WHODAS 9.1) than NSYM (47.7 years, WHODAS 3.1). Advanced neuroimaging (3T Siemens Prisma Fit or 3T Signa Premier scanners) and Spatially Constrained Independent Component Analysis are used for dynamic functional network connectivity (dFNC) analysis.

Results

The SYM and NSYM groups display significant cognitive and functional differences. Connectivity analyses reveal moderate to substantial differences in both static and dynamic states, particularly in Visual and Cognitive Control domains. Static analysis identifies disparities in 8 intrinsic connectivity networks across 5 domains, while dynamic analysis shows 3 of 4 states with significant differences in cognitive control networks.

Conclusion

This research underlines the profound impact of CADASIL on brain network connectivity, notably in cognitive control and visual processing. The findings, integral to the USA CADASIL Consortium, aim to characterize CADASIL's clinical and biological markers. These results are pivotal for global efforts to understand and treat vascular contributions to cognitive impairment and dementia, enhancing the landscape of CADASIL research and therapy development.
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

Background

In 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.

Method

Prospective 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).

Result

Participants 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.

Conclusion

This 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

Background

The 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.

Method

We 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 Biosciences

Result

In 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).

Conclusion

Our 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

Background

Subjective 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 SCD

Method

This 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.

Result

The 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.

Conclusion

The 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

Background

Extracellular 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).

Method

rrAD 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.

Result

Of 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.

Conclusion

The 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

Background

Compared 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.

Method

We 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.

Result

In 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).

Conclusion

Higher 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

Background

Collection, 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.

Method

Over 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.

Result

During 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.

Conclusion

The 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

Background

Repetitive 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.

Method

76 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.

Results

Sample 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).

Conclusion

We 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

Background

Brain 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.

Method

Longitudinal 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.

Result

There 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.

Conclusion

In 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.