bluuebunny/crossref_metadata_2025_split huggingface dataset:
SAA‐Determined α‐Synuclein in Early AD ADNI Participants: Contribution to cognitive trajectories from a sex differences perspective
Authors: Milà‐Alomà Marta , Hausle Zachary , Schaap Tamar M 
Published: January 2025

AbstractBackgroundα‐synuclein (αSyn) aggregates are a common co‐pathology in Alzheimer’s disease (AD) and can be identified in CSF with high reliability using the Seed Amplification Assay (SAA). While AD prevalence and impact on cognition are higher in women, the opposite pattern is found for α‐synucleinopathies. Our objective was to study the independent and joint contributions of αSyn, Aß and p‐tau on cognitive trajectories in early AD individuals from a sex differences perspective.MethodWe studied 529 ADNI participants (39.1% women) meeting criteria for early AD (CSF Aß+, MMSE 20‐28, and CDR 0.5 or 1.0) with baseline Aß42, p‐tau181 and αSyn determinations in CSF, and longitudinal cognition (mean follow‐up time of 5.4 years). We used logistic regressions to compare baseline cognition and biomarker levels between SAA groups in each sex. Additional models were adjusted by p‐tau181/Aß42 ratio to determine whether the impact of SAA‐positivity (SAA+) on baseline cognition was independent from the degree of AD pathology. Sex‐stratified linear mixed‐effect models were run to evaluate the contributions of baseline αSyn, Aß and p‐tau to cognitive trajectories over time. Additional models included the interaction term with sex. Age, APOEe4 and education were added as covariates in all models.ResultNo sex differences were found in SAA+ prevalence. At baseline, p‐tau181 positivity was higher in women, particularly among SAA‐. Neither Aß burden nor cognitive scores differed by sex. SAA‐positivity at baseline was associated with higher Aß burden, particularly in men. SAA‐positivity associated with lower baseline cognitive performance in all tested cognitive domains specifically in men, and the effect was maintained after adjusting for p‐tau181/Aß42 (Table 1). Baseline SAA‐positivity also had an independent contribution to longitudinal cognitive trajectories specifically in men, with significant interactions between sex, SAA status and time in global cognition and in memory (Table 2, Figure 1).ConclusionThere are no sex differences in the prevalence of αSyn pathology in individuals with early AD. However, baseline αSyn, Aß and p‐tau181 independently associate with cognitive decline in men, but not in women. Further research is warranted to elucidate sex‐specific contributions of pathologies to cognitive decline and implications for clinical trials targeting the early AD population.
Plasma NfL, P‐Tau181 and and P‐Tau181/Aβ42 Ratio are associated with incident mild behavioural impairment in dementia‐free individuals
Authors: Liao Yingqi , Chong Joyce R , Kan Cheuk Ni , Zhao Xuhao , Chai Yuek Ling , Lai Mitchell Kim Peng , Chen Christopher , Xu Xin 
Published: January 2025

AbstractBackgroundMild behavioural impairment (MBI) is associated with accelerated cognitive decline and conversion to dementia. However, the relationship between Alzheimer’s disease (AD)‐related pathological mechanisms and MBI remains unclear. This study aimed to examine whether baseline plasma neurofilament light chain (NfL), phosphorylated tau‐181 (P‐Tau181) and the P‐Tau181‐to‐Amyloid beta 42 (P‐Tau181/Aβ42) ratio are associated with incident MBI in an Asian cohort of dementia‐free individuals.MethodDementia‐free participants were recruited from the community and memory clinics and underwent cognitive, neuropsychiatric and clinical assessments annually and brain MRI scans biennially at baseline and over a maximum of 5 years in an ongoing longitudinal study. Plasma NfL, P‐Tau181 and Aβ42 were measured using Single molecule array (Simoa) assays. Baseline MBI was defined as the presence of NPS at baseline and Y1 using the Neuropsychiatric Inventory, while incident MBI was defined as the development of new NPS persisting over any two consecutive years of follow‐up. The associations between baseline plasma biomarkers and incident MBI were examined using generalized estimating equation modelling. Additionally, competition risk survival analyses based on the Fine‐Gray model were performed to account for the competing risk of incident dementia. All models were adjusted for age, gender, education, clinical diagnosis (i.e. No cognitive impairment (NCI) vs. Cognitively impaired‐No dementia (CIND)) and the presence of cerebrovascular diseases (CeVD) at baseline.ResultThree hundred and five participants with complete NPI data and plasma biomarkers were included (age 72.1 ± 7.8 years, 52.5% female). Among the 248 without baseline MBI, 25.3% (n = 55) developed incident MBI. Elevated levels of plasma NfL (OR[95%CI] = 5.72(2.00, 16.36), p = 0.001) and P‐Tau181/Aβ42 ratio (OR[95%CI] = 3.54(1.03, 12.21), p = 0.05) were individually associated with incident MBI. Furthermore, when accounting for the presence of incident dementia and CeVD and plasma NfL, high levels of plasma P‐Tau181 were independently associated with an increased likelihood of incident MBI (HR[95% CI] = 2.44 (1.01, 5.86), p = 0.047).ConclusionThe relationship of plasma P‐Tau181, P‐Tau181/Aβ42 ratio and NfL with incident MBI suggests an association between AD‐pathology and neurodegeneration with late‐life behavioural changes. Therefore, combining clinical assessments with AD‐related plasma biomarkers may improve the early identification of at‐risk individuals for behavioural disturbances in dementia.
Investing in Healthy Brain Aging: Why Africa Must Reform Social Pension Programs
Authors: Mostert Cyprian M 
Published: January 2025

AbstractBackgroundAfrican social pension schemes have irregularities. We discuss these irregularities and highlight potential reforms that may be introduced to improve healthy brain aging.MethodThis analysis is based on comprehensive data from reputable sources such as the World Bank, the World Health Organisation, the United Nations, and the Organisation for Economic Co‐operation and Development. The use of such reliable data ensures the accuracy and validity of our findings.ResultWe demonstrate that the current social pension scheme eligibility criteria are not designed to enforce healthy brain aging. Healthy life expectancy, which captures the number of years a person can expect to live in good health, is lower than the age for social pension eligibility criteria. For example, women’s life expectancy at birth in sub‐Saharan Africa was 66 years in 2017. However, healthy life expectancy was only 56 years, meaning that women spent four years in poor health before earning a social pension at 60 years and die 6 years later. For men, life expectancy at birth was 61 years in 2017, and healthy life expectancy was 53 years, which means men in sub‐Saharan Africa spend 12 years of their lives in poor health before earning a social pension at 65 years. Majority of these men die before earning the pension.ConclusionOur analysis underscores the urgent need for pension reforms in Africa. We propose that pension payouts should commence from the onset of poor health in elderly citizens. The current system of delayed payouts is counterproductive to the goal of promoting healthy brain aging.
GPR3‐biased signaling is involved in microglial activation in a preclinical Alzheimer’s disease mouse model
Authors: Espinosa Diego Rolando Hernandez , Guimaraes Thais Rafael , Huang Yunhong , Thathiah Amantha 
Published: January 2025

AbstractBackgroundMicroglia play a crucial role in clearing amyloid‐beta (Aβ) plaques, one of the primary pathological hallmarks of AD. We previously showed that G protein‐biased signaling by the G protein‐coupled receptor GPR3 reduces soluble Aβ levels and leads to an increase in Aβ plaque compaction and a reduction in Aβ plaque area in the preclinical AppNL‐G‐F
AD mouse model. These results suggest a protective microglial response that may limit Aβ plaque formation in G protein‐biased GPR3 AD mice. However, the precise mechanism by which biased GPR3 signaling in microglia restricts the growth of Aβ plaques remains unknown.MethodWe utilized a CRISPR/Cas9 genome editing strategy to mutate six serine/threonine residues in the GPR3 C‐terminus to phosphorylation‐deficient alanine residues to generate a G protein‐biased GPR3 mouse model. We also introduced a hemagglutinin (HA) tag in the N‐terminus of GPR3 to determine the expression and localization of the GPR3 protein in vivo. We crossed the AppNL‐G‐F AD mouse model with our GPR3HA/HA and G protein‐biased GPR3HA/Ala mice. We then performed bulk RNAseq on cortical brain samples from AppNL‐G‐F, GPR3HA/HA (AD KI), and AppNL‐G‐F, G protein‐biased GPR3 (Biased AD KI) mice. To characterize the microglia phenotype, we are conducting Flow cytometry (FC) of Biased AD KI relative to AD KI brains at 6, 12, and 18 months of age (early‐, mid‐, and late‐stage pathology).ResultThe bulk RNAseq data reveal that microglial activation in Biased AD KI mice is consistent with a disease‐associated microglia (DAM) profile. The DAM profile includes upregulation of phagocytosis‐ and endolysosomal‐related genes, such as Trem2, Lyz2, Itgax, Cst7, Clec7a, and Cd68. Specifically, we observe an upregulation of Trem2 and Tyrobp (DAP12), congruent with our observed increase in the total area occupied by microglia, Aβ plaque coverage area, and Aβ plaque compaction in Biased AD KI mice. Preliminary FC analysis also indicates differential expression of DAM markers in microglia isolated from our Biased AD KI mice.ConclusionOur findings provide compelling evidence for the involvement of biased GPR3 signaling in regulating microglial function and the response to the accumulation of Aβ pathology in AD.
Evaluation of neuropsychological test performance between minoritized and White individuals with frontotemporal degeneration
Authors: Matyi Melanie A , Rhodes Emma , Emrani Sheina , Jin Hannah A , Irwin David J , McMillan Corey T , Massimo Lauren 
Published: January 2025

AbstractBackgroundMinoritized groups are an understudied population in frontotemporal degeneration (FTD) research. Recently, we demonstrated distinct neuropsychiatric symptom profiles in Black relative to White individuals with FTD but cognition across these groups has not been reported. This knowledge gap has potential implications for the care of individuals with FTD from minoritized groups. Here we evaluated neuropsychological performance across Black and White individuals with FTD using the National Alzheimer’s Coordinating Center (NACC) Uniform Dataset (UDS).MethodsIndividuals with a behavioral variant FTD or primary progressive aphasia diagnosis, neuropsychological data, and self‐identified as non‐Hispanic White (n = 1318) or Black (n = 30‐76) were included. Data from UDS versions (1‐3) were adjusted for age, sex, and education using established norms. Linear regressions examined the association between race and normative cognitive scores (see Table 1 for measures and sample sizes), covarying for CDR‐Global. Chi‐square tests then examined group differences in the proportion of participants classified as impaired (≤‐1.5 normative score).ResultsBlack individuals on average had lower scores (Fig. 1) and greater likelihood of impairment (Fig. 2) on measures of global cognition (β = ‐3.07; χ2 = 9.65), digits backward (β = ‐.624; χ2 = 4.53), trails A (β = ‐2.22; χ2 = 19.54) and B (β = ‐1.20; χ2 = 7.79), and naming (β = ‐1.79; χ2 = 12.4). We did not identify any neuropsychological tests where White individuals performed worse than Black individuals.ConclusionsNeuropsychological data in representative populations is severely lacking in the NACC cohort diagnosed with FTD, comprised of only 3% Black individuals and 7% other minoritized groups. We observed that on average Black individuals have reduced performance relative to their White counterparts on several cognitive domains. Importantly, performance differences translated to the classification of a greater proportion of Black, compared to White, individuals as impaired, in part because available norms do not account for race. Of note, our ability to i) explore differences in cognition across minoritized groups and ii) assess for differences in cognitive decline was hampered by the limited sample of participants from minoritized groups with available data. Future efforts must focus on increasing research participation in underrepresented populations with FTD to evaluate potential sources of the observed differences across racial groups and support the diverse needs of all individuals.
Sleep, Alzheimer pathology and risk of clinical progression in cognitively unimpaired older adults
Authors: Mohammediyan Bery , Baril Andree‐Ann , Fajardo Alfonso , Poirier Judes , Soucy Jean‐Paul , Villeneuve Sylvia 
Published: January 2025

AbstractBackgroundIncreasing evidence suggests a link between sleep and Alzheimer disease’s (AD) pathology and cognitive decline. We investigated whether sleep disturbances might be accompanied by faster AD pathology accumulation and/or cognitive decline before the onset of cognitive symptoms.MethodWe investigated cross‐sectional and longitudinal associations between sleep quality, AD pathology and cognition in 220 participants from the PREVENT‐AD cohort. A subsample of 99 participants had longitudinal amyloid and tau PET data (mean follow‐up:4.33±0.53y, range: 1.59 – 6.11y) and a subsample of 218 had longitudinal cognitive evaluations (mean follow‐up:0.80±0.50y, range 1‐9). We used the PSQI global score and the actigraphy day‐to‐day sleep efficiency and fragmentation index variability, amyloid and tau‐PET to measure amyloid and tau respectively and the Repeated Battery for the Assessment of Neuropsychological Status (RBANS) to assess cognition. All participants were cognitively unimpaired at their first sleep measurement and 32 individuals developed mild cognitive impairment (MCI) during the study. In supplementary analyses individuals were classified as having high or low to moderated levels of amyloid based on a centiloid of 40. We used robust linear models (RLM) and ANOVAs to assess the association between sleep, and AD pathology and cognition.ResultWe found that higher levels of amyloid pathology were associated with greater day‐to‐day sleep efficiency and fragmentation index variability (Fig. 1). Higher levels of tau pathology were associated with greater day‐to‐day sleep efficiency and fragmentation variability (Fig. 1). We further found longitudinal associations between annual amyloid change and greater day‐to‐day sleep efficiency variability (Fig. 1). These associations were only present in individuals who had centiloid values lower than or equal to 40 (Fig. 2). While no association was found between sleep quality and cognition, individuals who developed MCI (n = 32) had higher baseline PSQI scores (Fig. 3) and greater day‐to‐day sleep efficiency (Fig. 3) years before they were classified as MCI.ConclusionHigher variability in sleep quality and worst self‐reported sleep relates to AD pathology. Subjective and objective sleep impairments were also present years prior the development of MCI. Sleep variability and subjective sleep assessment changes might precede sleep disruptions observed later in the disease, which could promote further pathological processes in the brain.
Lipid peroxidation in patients with vascular mild cognitive impairment from a memory and antioxidants in vascular impairment trial (MOVE‐IT)
Authors: Kang Yejin , Chen Jinghan Jenny , Mah Ethan , Survilla Kate , Vieira Danielle , Herrmann Nathan , Gallagher Damien , Andreazza Ana C. , Black Sandra E , Oh Paul I. , Swardfager Walter , Graham Simon J. , Ramirez Joel , Marzolini Susan , Lanctôt Krista L. 
Published: January 2025

AbstractBackgroundOxidative stress (OS) has been a target of interest for vascular dementia, given its implications in pathogenesis. OS may be important in prodromal stage, such as vascular mild cognitive impairment (vMCI), and examining OS markers in vMCI may help better understand biological processes in the onset of cognitive impairment. Our study compared OS levels in vMCI vs controls, and explored whether OS markers predicted the response to antioxidant treatments in vMCI.MethodCardiac rehabilitation patients with cardiovascular risk factors (CVRFs) were recruited as vMCI (1SD below norms in executive function (EF), memory, processing speed or working memory) or cognitively‐healthy controls. vMCI patients were classified as probable vMCI if they had neuroimaging evidence of vascular pathology. vMCI patients were randomized to 2400mg N‐acetylcysteine (NAC) or placebo in a 24‐week, double‐blind trial. Serum 8‐isoprostane (8ISO), 4‐hydroxynonenal (4HNE) and lipid hydroperoxides (LPH) collection and cognitive assessments were done at three time points. ANCOVA models adjusting for age, sex and CVRFs compared OS markers between groups at baseline. Linear mixed‐effects models were used for longitudinal analyses.ResultLPH levels were significantly lower in vMCI (n = 60) compared to controls (n = 16) (0.86±0.45 vs 1.18±0.31, F(1,62) = 7.0, p = 0.011). 4HNE were significantly higher in vMCI compared to controls (1.03±0.06 vs 0.99±0.04, F(1,70) = 6.6, p = 0.012). vMCI patients had significantly higher 4HNE/LPH (0.17±0.44 vs –0.18±0.29, F(1,62) = 9.3, p = 0.003) and (8ISO+4HNE)/LPH ratio (0.41±0.45 vs 0.13±0.38, F(1,62) = 5.9, p = 0.018) compared to controls. In probable vMCI group (n = 25), there was significant decreases in 4HNE/LPH (β = ‐0.68, SE = 0.27, p = 0.02) and (8ISO+4HNE)/LPH ratio (β = ‐0.65, SE = 0.28, p = 0.028) after NAC treatment. A significant time by baseline 8ISO effect on EF in the NAC group was observed (β = 0.78, SE = 0.26, p<0.01) after adjusting for age, sex and education.ConclusionThis study showed that the ratios of late‐ to early‐phase lipid peroxidation markers were significantly elevated in vMCI groups compared to controls. This aligns with existing literature that altered lipid peroxidation may be implicated in vMCI. Antioxidant treatments decreased OS in probable vMCI groups, and higher baseline 8ISO was associated with greater improvement in EF in the NAC group, suggesting that probable vMCI patients with high OS may be appropriately targeted for antioxidant treatments.
Association between Amyloid Burden and Health‐Related Resource Use
Authors: Zhu Carolyn W , Hedden Trey , Elder Gregory A. , Grossman Hillel , Neugroschl Judith A. , Schimming Corbett , Aloysi Amy , Sano Mary 
Published: January 2025

AbstractBackgroundSeveral disease modifying treatment (DMT) in early AD have shown effectiveness in reducing rate of decline on cognition and function. Earlier analyses using participants who are likely targets for clinical trial and treatment showed treatment effects may have important effects on patients’ work capacity and need for informal care. However, amyloid pathology was not examined. This study explores the relationship between amyloid burden and health‐related resource use.MethodParticipants enrolled in the Mount Sinai Alzheimer’s Disease Research Center with CDR = 0.5 or 1 and clinical diagnosis of MCI or AD. Health‐related resource use was self‐reported by participant and/or study partner using the Resource Use Inventory (RUI). Amyloid images received a clinical read by a neuro‐radiologist who was blinded to patient characteristics used to determine amyloid status. Two‐part or hurdle models were used adjusting for age, sex, race/ethnicity, education, comorbidities, baseline CDR Sum of Boxes (CDR‐SB), and years of follow up.ResultSample included 56 participants (28 amyloid positive, 28 negative) who had 1 or more RUI assessments (average follow up = 2.6±1.5 years). At baseline, average age = 73±8, 17±3 years of schooling, 54% female, 66% White, 20% Black, 11% Hispanic. 91% CDR = 0.5, 13% cognitively normal, 63% MCI, 25% AD; MMSE = 26±3, CDR‐SB = 1.8±1.8, comorbidities = 5.5±2.5.There were no statistically significant differences (at p = 0.05) in participants' characteristics except that proportion of participants who were White was higher in those who were amyloid positive (86%) than negative (46%) (p = 0.002). No Hispanic participant was amyloid positive. Follow up was longer in those who were amyloid negative (3±1.4 years) than amyloid positive (2.2±1.4 years). Baseline RUI items were not statistically significantly different by amyloid positivity.At baseline, amyloid positivity was associated with lower likelihood of participation in employment/volunteering. Among those who used help, amyloid positivity was associated with higher home health care hours. Over time, likelihood of receiving informal help increased and participation in employment/volunteering decreased. Data did not reveal any interaction between amyloid positivity and time.ConclusionResults from this small sample of participants that reflects AD clinical trial populations suggest amyloid burden may be associated with higher health‐related resource use.
Reliability of the remote digital self‐administered Stricker Learning Span, Symbols Test and Mayo Test DRIVE Screening Battery Composite
Authors: Hughes Morgan A , Frank Ryan D. , Fan Winnie Z. , Christianson Teresa J. , Kremers Walter K. , Stricker John L. , Boots Elizabeth A. , Machulda Mary M. , Fields Julie A. , Hassenstab Jason J. , Aduen Paula , Lucas John A. , Graff‐Radford Jonathan , Vemuri Prashanthi , Jack Clifford R. , Knopman David S. , Petersen Ronald C. , Stricker Nikki H. 
Published: January 2025

AbstractBackgroundMayo Test DRIVE (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based multi‐device (smartphone, tablet, personal computer) platform optimized for remote self‐administered cognitive assessment that includes a computer‐adaptive word list memory test (Stricker Learning Span; SLS), a measure of processing speed/executive functioning (Symbols Test) and a score combining both the memory and processing speed/executive functioning measures (MTD Composite). We aimed to determine the reliability of MTD measures across follow‐up sessions.MethodIndividuals participating in this ancillary study who completed at least two and up to four complete MTD sessions were included, resulting in 1,293 participants (mean age = 70.6, SD = 11.6; mean education = 15.6, SD = 2.3; 48.6% male; 96.9% White; 99.1% non‐Hispanic; 97.1% cognitively unimpaired) from parent studies (see Table 1). MTD raw scores were winsorized at 1% and 99% to minimize the impact of outliers. Test‐retest reliability was assessed using single‐rating, absolute‐agreement, and two‐way mixed ICCs and results are described using descriptives from Koo et al. (2016). ICCs for in‐person‐administered traditional neuropsychological measures are also reported alongside MTD for a subset of participants newly enrolled into the MCSA (to ensure participants were test naïve to both MTD and in‐person tests).ResultReliability was good for the MTD Composite raw [total ICC = 0.78; see Table 2 for session‐to‐session ICCs and 95% CIs], and moderate‐to‐good for the primary outcome variables for each subtest [total ICC = 0.74 for both SLS and Symbols]. Weighting by accuracy negatively impacted reliability of Symbols and the Composite; without this weighting, MTD Composite and Symbols variables showed higher reliability (MTD Composite z total ICC = 0.80; Symbols response time total ICC = 0.84; see Table 2). Alternative methods of defining response time on Symbols showed nearly identical reliability values. SLS sum of trials (primary variable) had subtly higher reliability than separate measures of learning (1‐5 correct, max span) or delay. Reliability of remote MTD and in‐person‐administered measures and select comparisons are provided in Table 3.ConclusionMTD showed moderate to good reliability, similar to in‐person‐administered traditional neuropsychological tests. Future work will examine the effect of demographics, device type, and session interference on reliability.