bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex‐associated differences in plasma and cerebrospinal fluid biomarkers in Early‐onset Alzheimer’s disease
Authors: Nemes Sára , Logan Paige E. , Dage Jeff L. , Hammers Dustin B. , Fagan Anne M. , Manchella Mohit K. , Eloyan Ani , Foroud Tatiana M. , Zetterberg Henrik , Koeppe Robert , Aisen Paul S. S , Carrillo Maria C. , Blennow Kaj , Schindler Suzanne E. , Gray Julia D , Dickerson Brad C. , Rabinovici Gil D. , Apostolova Liana G. 
Published: December 2023

AbstractBackgroundFemale sex is associated with greater atrophy, amyloid and tau burden in Early‐onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE‐ε4 non‐carrier‐status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE‐ε4 on plasma and cerebrospinal fluid (CSF) biomarkers of AD. Plasma markers included: neurofilament light chain (NfL), plasma glial fibrillary acidic protein (GFAP), Aβ 42/40, and pTau231. CSF markers included: Aβ 42/40, neurogranin, tTau, pTau181, synaptosomal‐associated protein‐25 (SNAP25), YKL‐40, and visinin‐like protein‐1 (VILIP1).MethodWe included 201 amyloid‐positive EOAD, 64 amyloid‐negative Early‐onset cognitively impaired (EOnonAD), and 86 Cognitively Normal (CN) LEADS participants with plasma biomarker data. Of these 100 EOAD, 35 EOnonAD, and 38 CN participants also had CSF data. Participants were stratified by sex and APOE‐ε4 genotype. Demographics (age, education, APOE‐ε4, MMSE) and biomarker differences were compared using ANOVA within each diagnostic group. ANCOVAs were run to control for the effects of age and education on biomarkers.ResultCompared to men, EOAD women showed greater levels of plasma NfL (p = .03), and GFAP (p<.001) while Aβ 42/40, and pTau231 were comparable. In CSF, EOAD women showed higher levels of neurogranin (p = .01), tTau (p = .01), pTau181 (p = .01) and VILIP1 (p = .02). EOnonAD women showed significantly greater plasma GFAP levels (p = .02). In the CN cohort, women had greater CSF SNAP25 levels (p = .03) while men showed a trend for higher plasma pTau231 levels (p = .05).
APOE‐ε4 carrier‐status was not associated with differences in levels of plasma or CSF biomarkers in either sex.ConclusionAs highly selective and specific AD fluid biomarkers emerge, understanding sex‐based differences in CSF and plasma is imperative. Female sex is associated with higher levels of neurodegeneration (NfL, tTau, pTau181, neurogranin, VILIP1) in EOAD and astrogliosis (GFAP) in both EOAD and EOnonAD.This data supports our previous findings that greater pathology burden is associated with female sex. This paves the way for further examination of sex and APOE‐ε4 genotype‐based differences in imaging and fluid biomarkers, their associations, and utility in early diagnosis.
Life course neighborhood social determinants of health and longitudinal changes in cognition in three Alzheimer’s Disease Research Center cohorts
Authors: Besser Lilah M , Meyer Oanh L. , Bateman James R. , George Kristen M , Adkins‐Jackson Paris AJ , Morris John C , Galvin James E 
Published: December 2023

AbstractBackgroundSeminal studies on exposure to life course social determinants of health, such as neighborhood racial segregation and neighborhood poverty, suggest detrimental associations with poorer cognitive function. We aimed to test the opposite by examining the relationship between self‐reported exposure to health‐promoting neighborhood environments over the life course and cognitive function among older adults.MethodParticipants were persons living without dementia at three US Alzheimer’s Disease Research Centers (University of California, Davis in Sacramento (UCD); Washington University in Saint Louis (WU); and Wake Forest University in Winston‐Salem (WFU)). An ancillary study (K01AG063895, PI: Besser) included the Life Course Sociodemographics and Neighborhood Questionnaire (LSNEQ) comprised of indices like neighborhood measures of socioeconomic status (NSES), walking and biking frequency, and greenness from childhood, midlife, and late life. LSNEQ data were linked with late‐life cognitive test z‐scores (Animals and Vegetables Category Fluency, Trail Making Parts A and B) from the National Alzheimer’s Coordinating Center Uniform Data Set. Multivariable linear mixed effects models tested associations between the LSNEQ index scores (composite values over childhood and mid‐ and late‐life) and baseline and longitudinal change in cognitive function controlling for demographics, Center, and baseline global Clinical Dementia Rating (0 or 0.5).ResultThe sample (n = 322) included 65% women, 17% Black, 76% White, and 7% other/mixed racialized group participants and was, on average, 70±7 years old and followed for 2.5±3.2 years. Life Course NSES was lower for UCD (mean = 12.7, SD = 3.5) versus WU (mean = 13.9, SD = 3.2) and WFU (mean = 14.3, SD = 3.2). Life Course Neighborhood Walking and Biking frequency did not differ by Center. Life Course Neighborhood Greenness differed across Centers, and was lowest for WU (mean = 4.8, SD = 1.3) and highest for WFU (mean = 5.6; SD = 1.2). In multivariable analyses, greater Life Course Neighborhood Walking and Biking was associated with higher baseline Trail A scores (estimate = 0.83, 95% CI = 0.08‐1.58) and slower decline on Animals over time (estimate = 0.024, 95% CI = 0.002‐0.045). Greater Life Course Neighborhood Greenness was associated with slower decline on Vegetables over time (estimate = 0.035, 95% CI = 0.001‐0.069).ConclusionThese preliminary findings suggest self‐reported, life course neighborhood exposures and behaviors (i.e., greenness and neighborhood walking/biking) may be associated with better cognition and slower decline in later life.
Different typologies of neighborhood resources are associated with cognitive function
Authors: Sol Ketlyne , Clarke Philippa , Zahodne Laura B. 
Published: December 2023

AbstractBackgroundNeighborhood resources (NRes) such as libraries, grocery stores, and child/family centers may promote cognitive health via opportunities for cognitive stimulation and other health benefits. Resources are distributed differently across neighborhoods, but many studies examine effects of individual NRes on health outcomes. This study uses typologies of NRes and examines whether different types of NRes patterns contribute to Black‐White disparities in cognitive function.MethodThis cross‐sectional study of 462 non‐Hispanic Black and White older adults (Mage = 63.6; 53% Black) was drawn from the Michigan Cognitive Aging Project, a regionally‐representative, prospective longitudinal study of adults transitioning to late life in the Detroit metropolitan area. Participants’ current addresses were geocoded and linked to neighborhood data from the National Neighborhood Data Archive for the year 2017. First, a latent class analysis (LCA) using Mplus identified typological classes of NRes using fifteen indicators across all 2,813 census tracts in Michigan. Next, path analysis estimated associations among race, NRes class, and global cognition, operationalized as a composite of five factor scores (episodic memory, executive function, processing speed, language, visuospatial ability). Models adjusted for age, sex/gender, education, and population size.ResultLCA indicated three classes of NRes: low‐resourced (48%), well‐resourced (42%), and highly‐resourced (10%) neighborhoods. Black participants had lower cognitive health and were more likely to live in low‐resourced or highly‐resourced neighborhoods than White participants. White participants were more likely to live in well‐resourced neighborhoods than Black participants. Surprisingly, living in well‐resourced neighborhoods was associated with worse cognition, compared to living in low‐resourced neighborhoods, but this association was only found among Black participants (βBlack = ‐.181, βWhite = .008). Living in highly‐resourced neighborhoods was not associated with cognition, but only 4% of the sample lived in these neighborhoods.ConclusionParadoxical findings suggest additional work is needed to better disentangle the role of NRes in cognitive disparities. Findings may be driven by factors such as racial residential differences (i.e., home rental and homeownership) and/or access to resources within a neighborhood, as well as neighborhood social climate. This study adds to—and highlights the need for more comprehensive models in—research on neighborhoods and ADRD inequalities.
Spatial transcriptomics identifies disrupted circadian gene expression in a mouse model of Alzheimer’s disease
Authors: Romero Haylie K , Gerber Alon , Akhmetova Laila , Mukamel Eran A , Desplats Paula 
Published: December 2023

AbstractBackgroundDisruptions in circadian rhythm are a common symptom of Alzheimer’s disease (AD), which occur early in disease progression and may contribute to the neurodegenerative process. However, the mechanisms that link alterations in rhythmic transcription and disease pathology are poorly understood. Here we used brain‐wide spatial transcriptomics to elucidate progressive disruptions in diurnal transcriptional rhythms in a mouse model of AD.MethodUsing Visium spatial transcriptomic technology, we investigated transcriptional changes with spatiotemporal resolution in APP23 transgenic mice, which overexpress human APP with the Swedish mutation. Sagittal brain slices from APP23 and littermate control mice were collected at 4 Zeitgeber times (ZT). We used community detection to cluster the spatial locations according to shared patterns of gene expression, which corresponded to major anatomical brain regions. Pseudobulk profiles were computed for each cluster in each sample, and these were used in subsequent differential expression analysis using DESeq2. Rhythmic gene expression was modeled as a sinusoidal function of ZT, while controlling for covariates (sex, genotype, and age) and their interaction with time. Results were further validated using non‐parametric tests for rhythmicity implemented in Metacycle.ResultOur analysis revealed a large increase in the number of diurnally rhythmic genes in APP23 mice in several brain structures, including regions affected by neurodegeneration in AD like the hippocampus and the cortex. Additionally, many genes showed increased rhythmicity or altered circadian phase in APP23 mice in specific brain regions, when compared to controls. For example, the expression of Slc5a3, a gene involved in osmotic stress response and deregulated in human AD brains, presented strong circadian rhythms in both APP23 and controls in cortical clusters, but the amplitude of expression was significantly larger in the dentate gyrus only in APP23 mice. Importantly, this effect was observed before and after the onset of amyloid pathology.ConclusionThese data map the changes in rhythmic gene expression over the course of AD progression in the spatiotemporal context of cortical and subcortical brain regions. Our findings elucidate molecular disruptions occurring early in the development of AD, which may drive disease progression.
Cerebral microbleeds in Down syndrome: association with demographic, genetic, fluid and imaging biomarkers of Alzheimer’s disease
Authors: Zsadanyi Sara E. , Morcillo‐Nieto Alejandra O. , Aranha Mateus Rozalem , Aragón Irina , Montal Victor , Pegueroles Jordi , Vaqué‐Alcázar Lídia , Benejam Bessy , Videla Laura , Barroeta Isabel , Fernandez Susana , Giménez Sandra , González‐Ortiz Sofía , Bargalló Núria , Ribas Laia , Arranz Javier , Rodríguez‐Baz Íñigo , Belbin Olivia , Alcolea Daniel , Blesa Rafael , Lleó Alberto , Fortea Juan , Carmona‐Iragui Maria , Bejanin Alexandre 
Published: December 2023

AbstractBackgroundWith the development of amyloid‐modifying therapeutic agents that can lead to cerebral microhaemorrhages, it is critical to meticulously characterise the natural history of cerebral microbleeds (MBs) in populations genetically predisposed to develop Alzheimer’s disease (AD), such as Down syndrome (DS). We aimed to investigate MB prevalence in a large cohort of adults with DS and define associations with demographic, genetic, fluid and imaging biomarkers of AD, and cognitive performance.MethodsCross‐sectional design. Adults with DS and euploid controls from the Down Alzheimer Barcelona Neuroimaging Initiative underwent a 3T‐MRI protocol, including susceptibility‐weighted imaging (SWI) acquisition. Manual tracing of MBs was performed by two independent raters using ITK‐SNAP. Participants were classified according to MB status (MB‐/MB+) and severity (0, 1, 2+ MBs). Non‐parametric statistical tests were used to assess the effect of MBs on demographic, clinical, genetic, CSF and neuroimaging AD biomarkers, and cognitive tests.ResultsWe included 247 participants with DS along the AD continuum, and 167 euploid controls (Table 1). The proportion of MB+ was higher in DS participants than controls, and progressively increased with AD clinical stages and age in the DS group (Fig. 1). By contrast, MB status did not differ by APOEε4 status, intellectual disability, or sex. In DS, the MB+ group had increased white matter hyperintensity volume and decreased hippocampal volumes compared to MB‐. DS MB+ also had lower CSF Aβ42/40 ratio, higher CSF t‐tau and p‐tau‐181 concentrations, and tended toward worse cognitive performance. Most effects gradually evolved with MB severity, although significant differences were mainly between MB‐ vs MB 2+ (Fig. 2). Finally, sensitivity analyses showed that most results became non‐significant when comparing DS MB+ to a 1:1 DS MB‐ group matched for age, sex, intellectual disability and/or AD diagnosis.ConclusionMB presence and severity are increased in adults with DS, and worsen with clinical progression and AD pathology. Yet, matched group analyses suggest that MB have limited impact on cognition and neurodegeneration. These results provide better characterisation of the presence and effect of MB in a population with an ultra‐high risk of developing AD who could benefit from new disease modifying drugs.
Longitudinal white matter hyperintensities in Down’s syndrome
Authors: Morcillo‐Nieto Alejandra O. , Zsadanyi Sara E. , Montal Victor , Aranha Mateus Rozalem , Pegueroles Jordi , Vaqué‐Alcázar Lídia , Benejam Bessy , Videla Laura , Barroeta Isabel , Fernandez Susana , Giménez Sandra , González‐Ortiz Sofía , Bargalló Núria , Ribas Laia , Arranz Javier , Belbin Olivia , Alcolea Daniel , Blesa Rafael , Carmona‐Iragui Maria , Fortea Juan , Bejanin Alexandre 
Published: December 2023

AbstractBackgroundDown’s syndrome (DS) is a genetically determined form of Alzheimer’s disease (AD). Typically not complicated by systemic vascular risk factors, the DS population represents a unique opportunity to unravel the complex relationship between AD and cerebrovascular disease. Here, we aim at studying the evolution over time of white matter hyperintensities (WMHs), a key hallmark of cerebrovascular disease frequently found in AD, and to assess their topographical progression and associations with AD biomarkers in adults with DS.MethodThis longitudinal study included 43 DS adults (age = 39.8±10.4y; females = 41.9%; n = 37 asymptomatic AD, n = 6 symptomatic AD) and 81 euploid controls (age = 53.7±6.2y; females = 67.3%) from the Down‐Alzheimer Barcelona Neuroimaging Initiative, with at least 2 MRI visits with T1 and FLAIR acquisitions (time delay = 3.4±1.6y). WMHs were segmented using the Lesion Prediction Algorithm implemented in the Lesion Segmentation Toolbox (SPM12). WMH volumes were extracted in 36 regions of interest and used to compute total and regional annual volume changes. Non‐parametric statistical tests were performed to assess the effect of disease severity on WMH volume changes over time and define associations between longitudinal WMHs and baseline demographic and genetic data, and fluid biomarkers.ResultTotal annual WMH volume change increased in symptomatic DS compared to both asymptomatic DS and controls (Figure 1A). Regionally, WMH load increased in regions showing WMH at baseline in all groups (Figure 2). These changes were greater and more distributed, involving layers more distant from the ventricles (especially in occipito‐parietal regions) in symptomatic DS. Age, but not sex, intellectual disability, or APOEε4 status, was associated with longitudinal WMH in DS (Figure 1B‐F): the annual WMH volume changes in DS differed from controls at age ∼45y. Finally, WMH volume changes were negatively related to CSF‐Aβ42/40 and positively related to plasma and CSF ptau‐181 and neurofilament light (Figure 3).ConclusionPathological increases in WMH volume start ∼10 years before the mean age at onset for AD (53.8y) in DS and relate to underlying AD pathology and neurodegeneration. Regional analyses suggest that WMH volume changes increase with disease progression and progressively involve deeper white matter areas. Together, these results support that WMHs are tightly related to AD pathogenesis.
Pseudo‐longitudinal trajectories of cerebrovascular disease biomarkers in adults with Down syndrome across the lifespan
Authors: Lao Patrick J. , Sedaghat Amirreza , Edwards Natalie C. , Lippert Rafael V. , Rizvi Batool , Smith Anna C. , Tudorascu Dana , Rosas H. Diana , Yassa Michael A. , Handen Benjamin L. , Christian Bradley T. , Gutierrez Jose , Wilcock Donna M. , Head Elizabeth , Brickman Adam M. ,   Alzheimer’s Biomarker Consortium‐Down Syndrome
Published: December 2023

AbstractBackgroundAdults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, but it is unknown when cerebrovascular disease emerges across the lifespan.MethodsAdults with DS from the multisite Alzheimer’s Biomarker Consortium‐Down Syndrome study (ABC‐DS; n = 241; age = 25‐72, 44±10; 45% women; 77/11/12% Cognitively‐Stable/MCI‐DS/AD dementia) underwent harmonized MRI and received a cognitive diagnosis at a consensus conference. Cross‐sectional white matter hyperintensity volume (WMH; ischemic small vessel disease), enlarged perivascular space score (PVS; impaired toxin clearance), chronic infarcts (large vessel disease), and microbleeds (hemorrhagic small vessel disease/cerebral amyloid angiopathy) were fit against piece‐wise, left null regression models with age to estimate the age inflection point at which these cerebrovascular markers emerged. The residuals for each biomarker (i.e., more than expected for their age) were then regressed on diagnosis.ResultsTotal WMH volume (0.01‐31.7, 4±4.6 cm3), enlarged PVS score (0‐26, 8±5), infarcts (15% have at least one), and microbleeds (12% have at least one) were present in this lifespan sample of adults with DS. There was a significant inflection point in the fourth decade of life for total WMH (37±6, p = 7E‐3), enlarged PVS (31±6, p = 3E‐6), and infarcts (31±9, p = 2E‐3), but not microbleeds (36±21, p = 0.7). Regionally, there were significant inflection points for frontal (36±6, p = 3E‐3), parietal (36±7, p = 0.02), and occipital (42±6, p = 0.02), but not temporal WMH (33±14, p = 0.3). AD dementia was associated with higher residuals in parietal (0.5±0.2, p = 0.02) and occipital WMH (0.6±0.3, p = 0.02).ConclusionIn adults with DS, there is cerebrovascular pathology on MRI that emerges around the same age as what has been reported for amyloid PET positivity and tau PET accumulation in this population. More posterior small vessel disease for a given age may arise with a diagnosis of AD, suggesting a cerebrovascular process in AD pathogenesis. Longitudinal assessment in relation to AD biomarkers, including amyloid and tau PET, will provide additional insight.
Assessing the psychological impact of COVID‐19 on rural informal caregivers of persons living with dementia in the United States
Authors: Santoyo‐Olsson Jasmine , Romo Elizabeth Macias , Chesla Catherine , Covinsky Kenneth E , Ramirez Giselle Aguayo , Yank Veronica A. 
Published: December 2023

AbstractBackgroundInformal caregivers of persons living with dementia (PLWD) in rural areas of the United States (U.S.) are a vulnerable population. During the COVID‐19 pandemic, rural communities experienced heightened disparities in social services, healthcare[1], and mortality[2], including suicides[3,4]. Yet, how the pandemic affected rural caregivers is largely unknown. We examined predictors of depression and stress, as well as self‐perceived impact of COVID‐19, among rural caregivers of PLWD.MethodAs part of the Rural Dementia Caregiver Project[5], U.S. rural informal caregivers of PLWD completed an online survey from March 1, 2021, through April 30, 2022. We conducted a mixed‐method analysis of responses to validated scales and an open‐ended question. Caregiver outcome measures include depressive symptoms[6] and stress[7]. Predictors include caregiver COVID‐19 limitations[8], loneliness[9], social isolation[10], and burden[11]. Linear regression analyses examined independent associations of predictors with outcomes, adjusting for age, sex, and caregiving hours spent per week. We completed thematic analysis of responses to the question, “How has COVID impacted your life as a caregiver?” to contextualize quantitative findings.ResultA total of 152 rural caregivers completed the survey, and of those 127 responded the open‐ended question. Most (81%) caregivers were aged 50 years and older, and 82% were female. Factors positively associated with caregiver depressive symptoms were loneliness (β = 0.72, p<0.0001) and burden (β = 3.18, p<0.01). Factors positively associated with caregiver stress were loneliness (β = 0.22, p<0.05) and burden (β = 1.28, p<0.05). COVID‐19 limitations and social isolation were not associated with depressive symptoms or stress. Qualitative results confirmed quantitative results (e.g., loneliness, increased burden) and revealed other aspects of the psychosocial context of pandemic caregivers including both negative (e.g., worry, decline in care partner health) and positive (e.g., increased time with care partner) factors (Table 1).ConclusionWe found that loneliness and care burden contributed to the psychological distress of rural caregivers of PLWD during the COVID‐19 pandemic, and identified other contextual factors of their experiences. The pandemic exacerbated existing vulnerabilities and exposed new ones. Rural caregivers should receive increased support to address the psychosocial stressors and burdens endured during the current pandemic and future catastrophic events.