bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractBackgroundWomen 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.MethodWe 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.Result63% 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).ConclusionOur 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

AbstractBackgroundPrior 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.MethodTo 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.Result1,916 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).ConclusionThese 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

AbstractBackgroundDigital 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.MethodMemory 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.ResultaMCI 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).ConclusionWhen 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

AbstractBackgroundCholinesterase 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.ObjectiveExamine the prevalence, timing, and types of ChEI prescriptions before and after dementia diagnosis including prescribing patterns by patient sex and race.MethodsWe 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.ResultsA 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).ConclusionDonepezil 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

AbstractBackgroundThe 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.MethodWe 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.ResultIn 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.ConclusionThere 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

AbstractBackgroundNonhuman 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.MethodWe 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.ResultLogGFAP 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.ConclusionAlterations 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

AbstractBackgroundSemantic 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.MethodMemory 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.ResultThe 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.ConclusionIn 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

AbstractBackgroundSeveral 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.MethodWe 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.ResultFor 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.ConclusionBiological 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

AbstractBackgroundThis 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.MethodOvercoming 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.ResultsThe 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.ConclusionThis 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.