bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potentially Inappropriate Medications and cognitive performance: cross‐sectional results from the ELSA–Brasil study
Authors: Santos Adriana Nancy Medeiros , Benseñor Isabela M. , Goulart Alessandra C. , Brunoni Andre R , Viana Maria Carmen , Lotufo Paulo A. , Suemoto Claudia Kimie 
Published: December 2023

AbstractBackgroundPotentially inappropriate medications (PIM), especially those with potential effects on the central nervous system, can increase the risk of cognitive impairment. We investigated the association of the use of PIM with cognitive performance among older adults.MethodIn this cross‐sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA‐Brasil), 2,626 participants were included (mean age = 65.1±4.1 years old, 54% women, and 61% White). PIM was defined by the 2019 American Geriatrics Society Beers criteria. We calculated global cognition and memory, verbal fluency, and Trail Making Test B version (TMT‐B) z‐scores. Linear regression models adjusted for sociodemographic and clinical variables were used to investigate the association between PIM and cognition.Result27% of the sample used at least one PIM. PIM use was associated with worse performance in the TMT‐B (β = ‐0.17, 95% Cl = ‐0.29; ‐0.05, p = 0.007).ConclusionThe use of PIM was associated with worse executive function among older adults.
Sex‐specific impact of brain estrogen deficiency on astrocyte reactivity, neurodegeneration, and memory loss in aromatase knockout mouse models
Authors: Halle Ariel , Rodriguez Guadalupe , Locci Andrea , Coon John , Kujawa Stacy , Dong Hongxin , Bulun Serdar E , Zhao Hong 
Published: December 2023

AbstractBackgroundNearly two‐thirds of Americans with Alzheimer’s disease (AD) are women, however, the molecular mechanisms underlying this sex difference in AD vulnerability remain unclear. Prior research has reported that women with AD have lower brain estrogen. Yet, how estrogen deficiency modulates this sex difference in AD is not well understood. Aromatase, the key enzyme for estrogen biosynthesis, is expressed in both neurons and astrocytes of the brain, with high levels in the hippocampus. To explore the underlying mechanism of estrogen deficiency in sex‐specific AD vulnerability, we generated mouse models with brain‐specific aromatase knockout (bArKO) and whole‐body total aromatase knockout (tArKO).MethodWe performed a series of memory and behavior tests including spontaneous alternation, social interaction, and tail suspension tests on 6‐ and 19‐month‐old bArKO and tArKO mice with both sexes (n = 10/group). Hippocampus tissues from these mice (n = 3∼4) were collected for bulk RNA‐seq and qPCR. Brain tissues (n = 5) were fixed and stained for astrocytes and neurons by immunofluorescence. Serum and tissue estrogen were measured using liquid chromatography‐mass spectrometry.ResultAromatase deletion decreased brain estrogen levels in bArKO mice and circulating and brain estrogen levels in tArKO mice. Impairments of spatial working memory and social interaction behavior were found in 19‐month‐old female bArKO and tArKO mice. Female tArKO mice also displayed depression‐like behavior at 6‐ and 19‐month‐old. The number of neurons in the CA1 region was significantly decreased in 19‐month‐old female (but not male) tArKO mice. Bulk RNA‐seq showed abnormal expression of genes associated with astrocyte reactivity (e.g., Gfap, Ctgf, Apoe, Lcn2, Sparc, Bdnf, Col1a1, Col1a2) only in aged female bArKO mice. Given growing evidence indicating a causal relationship between neurotoxic reactive astrocytes and neurodegeneration, this finding indicates brain estrogen deficiency triggering neurotoxic astrocyte reactivity in the hippocampus of aged female bArKO mice.ConclusionOur findings provide novel mechanisms that link estrogen deficiency to sex‐specific astrocyte reactivity in the hippocampus, and neurodegeneration and memory loss in aged female mice. Future studies will focus on defining impact of estrogen signaling deficiency on AD mouse models and identifying druggable targets to inform the development of new therapeutic strategies for the prevention and treatment of AD.
TREM2 AD risk variants impact pTau and microglia and astrocyte related biomarkers in cognitively unimpaired subjects
Authors: Hsiao‐Nakamoto Jennifer , Davis Sonnet , Suh Jung , Model Fabian , Lee Sven J , van der Flier Wiesje M. , Pijnenburg Yolande A.L. , Van Bokhoven Pieter , Teunissen Charlotte E. , Scearce‐Levie Kimberly , Huang Fen 
Published: December 2023

AbstractBackgroundIn the central nervous system, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is expressed primarily in microglia. TREM2 receptors are important for microglial functions including phagocytosis, lipid metabolism and inflammatory responses. TREM2 coding variants (e.g. R47H rs75932628 and R62H rs143332484) increase the risk of late onset Alzheimer’s Diseases (AD). However, the impact of TREM2 risk variants on microglial cell functions in humans remains to be elucidated.MethodCSF and plasma samples were collected from AD patients (n = 120) and cognitively unimpaired control subjects (n = 53) with subjective complaints who do not meet biomarker‐based criteria for AD diagnosis. TREM2 AD risk variant carriers (n = 52) were screened from over 6000 samples of the Amsterdam dementia cohort using a combination of genotype array and exome sequencing. We performed extensive biomarker analysis of CSF and plasma samples with multidisciplinary approaches. We compared the effect of TREM2 mutations on AD disease and microglial and astrocytic biomarkers in AD patients and in cognitively unimpaired control subjects, respectively. A linear model was used with age and gender adjusted for the data analysis.ResultWe found higher levels of pTau181 and pTau231 in CSF and plasma in cognitively unimpaired TREM2 mutation carriers compared to non‐carriers, while no difference was observed between TREM2 genotype among the AD patients. Microglia and astrocyte biomarkers including sTREM2, FABP3, OLR1, YKL40 and GFAP were higher in the CSF from cognitively unimpaired TREM2 mutation carriers compared to non‐carriers, but no difference was detected between TREM2 genotype among the AD patients. We also found different levels of lipid metabolites in CSF and plasma samples from the TREM2 mutation carriers compared to non‐carriers in both AD patients and cognitively unimpaired control subjects.ConclusionTREM2 AD risk variants in cognitively unimpaired subjects increase pTau biomarkers and microglial and astrocytic related biomarkers. In AD patients, the biomarker differences between TREM2 genotype are diminished likely due to the extensive microglial responses to AD pathology. Moreover, our data indicates TREM2 AD risk variants may impact lipid‐metabolic processes in microglial cells. These data provide the biomarker insights on how TREM2 mutations may increase the risk of AD.
Allele‐specific histone acetylation in Alzheimer’s disease brain
Authors: Urbanaviciute Paulina , Nott Alexi , Marzi Sarah 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is associated with cell type‐specific H3K27ac signatures, an epigenetic modification that marks active enhancers and promoters. Genomic regions marked by H3K27ac, particularly enhancers, are enriched for AD genetic risk. We aim to identify nearby genetic variants regulating histone acetylation to better understand the link between genetic risk and disease.MethodFor the first time we have performed allelic specific analysis of histone epigenetic modifications in AD. We used H3K27ac ChIP‐seq data from human post‐mortem entorhinal cortex samples from AD cases (n = 24) and controls (n = 23) (Marzi et al., 2018) to differentiate the histone acetylation signal originating from both alleles in an individual.ResultsWe identified 844 significant loci with allele‐specific histone acetylation by testing individual samples, and 344 by testing across samples. Both sets featured an FDR‐significant acetylation imbalance in a region predicted to be regulating SETD1B, a histone lysine methyltransferase previously found to be elevated in AD patients (Cao et al., 2020). Using linear regression, we also identified 329 SNPs associated with histone acetylation levels. Cell type deconvolution of the overlap between the SNP‐associated H3K27ac regions and genomic regions differentially acetylated in AD highlighted multiple brain cell types. In addition, there was an enrichment for biological processes involving myelination, and cell type‐specific regions were enriched for oligodendrocytes.ConclusionGenetic variants are associated with levels of H3K27ac in genomic regions regulating disease‐related processes.
Characterizing the yes‐no reversal phenomenon in patients with primary progressive apraxia of speech
Authors: Meade Gabriela , Schwarz Christopher G. , Clark Heather M , Duffy Joseph R , Botha Hugo , Whitwell Jennifer L , Josephs Keith A , Utianski Rene L 
Published: December 2023

AbstractBackgroundPatients with a yes‐no reversal verbally and non‐verbally respond “yes” when they mean “no” and vice versa. They are typically aware of the error and able to correct it given additional time. This symptom commonly, but not exclusively, occurs in patients with primary progressive apraxia of speech (PPAOS). PPAOS is a form of frontotemporal dementia associated with hypometabolism in the supplementary motor area (SMA; e.g., Utianski et al., 2018); as the disease progresses, a wider network of frontal and subcortical regions become implicated. Behaviorally, this symptom seems to reflect poor response inhibition, but the specific anatomical underpinning is not yet understood. Given the brain regions known to be involved in PPAOS, we hypothesized that yes‐no reversals emerge due to degeneration of regions near the SMA and/or frontostriatal regions.MethodWe conducted an exploratory retrospective study of 28 patients who presented with PPAOS and had an FDG‐PET scan; 14 (50%) endorsed yes‐no reversals (see Table 1 for group characteristics). Clinically, AOS severity was measured using clinician ratings (0 = absent, 4 = severe) and frontal dysfunction was captured by the Frontal Assessment Battery (FAB) and the Frontal Behavioral Inventory (FBI). We also measured median standardized uptake value ratios (SUVRs) in the SMA and pre‐SMA, as well as the head and body of the caudate with automated, in‐house software. The caudate ROI was selected based on visual comparison of the FDG‐PET scans between groups and the association between this region and inhibition during response interference (e.g., Schmidt et al., 2020).ResultNeither AOS severity nor hypometabolism in the pre‐SMA/SMA regions differed significantly between groups. In contrast, patients with a yes‐no reversal demonstrated significantly lower scores on the FAB and greater hypometabolism in the caudate body relative to patients without (see Figure 1).ConclusionResults suggest that yes‐no reversals relate to frontostriatal dysfunction rather than AOS severity or SMA activity in these patients. Further research is needed to address why a disproportionate number of patients with PPAOS develop this symptom.
Social determinants of modifiable dementia risk in Māori and Non‐Māori: Results of the New Zealand Health, Work and Retirement study
Authors: Röhr Susanne , Gibson Rosemary , Alpass Fiona , Stephens Christine 
Published: December 2023

AbstractBackgroundDementia risk varies along the social gradient, which needs to be considered in risk reduction and prevention strategies. Revealing links of social determinants of health (SDOH) and modifiable health and lifestyle factors for dementia holds clues towards maximizing dementia risk reduction opportunities, especially for vulnerable populations. Therefore, the aim was to investigate associations of SDOH and a dementia risk score in Indigenous Māori and Non‐Māori (mainly European descent) in midlife and early late‐life.MethodA subsample of the New Zealand Health, Work and Retirement study completed standardized face‐to‐face cognitive assessments (adapted ‘Kiwi’ Addenbrooke’s Cognitive Examination/ACE‐R) in 2010. We computed the Lifestyle for Brain Health (LIBRA) dementia risk score, comprising 8 risk factors (low/moderate alcohol consumption, heart disease, physical inactivity, chronic kidney disease, diabetes, smoking, hypertension, depression). Higher scores indicate higher dementia risk/poorer lifestyle (range = ‐1;+9.2). First, we assessed associations of LIBRA and cognition. Second, we performed adjusted regression analysis for area‐based (socioeconomic deprivation, health care access, neighborhood safety) and individual SDOH (education, employment status, net income, social loneliness) with LIBRA stratified for Māori and Non‐Māori.ResultsIn 918 participants (age: M = 62.9 years, SD = 6.7, range = 48‐75; females = 52.8%; Māori = 26.2%), a higher LIBRA score (M = 1.8, SD = 1.6, observed range = ‐1; +7.4) was associated with lower cognitive functioning (b = ‐0.30, 95%CI = [‐0.48;‐0.11], p = .002) and cognitive impairment (OR = 1.41, 95%CI = [1.10;1.81], p = .007), adjusted for age, sex, education, ethnicity and area‐based socio‐economic deprivation. Higher area‐based socio‐economic deprivation was associated with higher LIBRA in Māori (b = .10, 95%CI = [0.02;0.18], p = .020), but not in Non‐Māori (b = 0.01, 95%CI = [‐.03;0.05], p = .677). Employment status and lower neighborhood safety were associated with higher LIBRA in Non‐Māori only. Health care access difficulties and social loneliness were associated with higher LIBRA in both populations, while education and net income were not.ConclusionSODH are differentially associated with dementia risk in midlife and early late‐life New Zealanders. Area‐based socioeconomic deprivation was linked to dementia risk in Indigenous Māori, but not in Non‐Māori. This points to systematic inequities in dementia risk, which require equity‐focused policy‐based public health approaches to risk reduction.
The role of the Default Mode Network and Striatal Circuits in the Expression of Depressive Symptoms in Premanifest Huntington’s Disease
Authors: Barta Tamrin , Novelli Leonardo , Georgiou‐Karistianis Nellie , Stout Julie , Loi Samantha M , Glikmann‐Johnston Yifat , Razi Adeel 
Published: December 2023

AbstractBackgroundHuntington’s Disease (HD) is increasingly being conceptualised as a circuitopathy (Hannan 2018) and two large‐scale brain networks surmised to contribute to the expression of depressive symptoms in premanifest HD (pre‐HD) include frontostriatal circuitry and the default mode network (DMN). The effective connectivity of these networks in pre‐HD in association with depression was investigated using Dynamic Causal Modelling.MethodWe analysed 3T resting state fMRI data from 93 pre‐HD participants (51.6% females; mean age = 42.7). Neuropsychological assessment included history of depression, the Beck Depression Inventory, 2nd Edition (BDI‐II) and the Hospital Anxiety and Depression Scale, depression subscale (HADS‐D). An optimal cut‐off score recommended for use in HD populations categorised clinically significant depressive symptoms (De Souza, Jones, and Rickards 2010). Brain regions of interest included the medial prefrontal cortex, posterior cingulate cortex, bilateral hippocampus, bilateral caudate, and bilateral putamen. Spectral Dynamic Causal Modelling (Friston et al. 2014; Razi et al. 2015) was used to estimate subject level connectivity and Parametric Empirical Bayes (Friston et al. 2016) was employed to estimate group level effective connectivity changes between participants with a history of depression and those without.ResultVarious pathways that differed between pre‐HD participants, with and without history of depression, showed associations with both measures (BDI‐II and HADS‐D). These associations, shown in Figure 1, included: a negative relationship between left putamen self‐connectivity and clinical cut‐offs for both measures for those with history of depression, whereas this was a positive relationship for those without history of depression; a negative relationship between left caudate self‐connectivity and both measures for pre‐HD participants with a history of depression; a negative relationship between right putamen self‐connectivity and both measures for pre‐HD participants without a history of depression.ConclusionPatterns in effectivity connectivity changes in association with state measures of depressive symptoms differed between pre‐HD people with or without a previous history of depression. This is the first study, to our knowledge, that demonstrates a relationship between depression and the effective connectivity of the striatum and DMN in premanifest HD. These findings suggest that large scale network dysfunction contributes to the expression of depression in Huntington’s disease.
Objective Sleep and Circadian Rest‐Activity Rhythms and Multiple Domains of Cognitive Function in Older Men and Women
Authors: Stone Katie L , Barnes Haley , Blackwell Terri , Glynn Nancy W. , Esser Karyn , Kritchevsky Stephen B , Cummings Steve , Newman Anne B , Cawthon Peggy 
Published: December 2023

AbstractBackgroundEmerging evidence from experimental and epidemiologic studies suggests that sleep and circadian rest‐activity rhythms (RAR) play a key role in dementia and Alzheimer Disease (AD) pathology. Studies with objective measures of sleep and RAR and multiple domains of cognition in older adults remain limited.MethodWe studied 820 older men and women enrolled in the Study of Muscle, Mobility, and Aging (SOMMA), a unique cohort designed to study the cellular biology of aging and related loss of mobility. In this initial cross‐sectional analysis, participants wore wrist actigraphs for a mean of 8.0 consecutive days; recordings were processed for traditional sleep‐wake measures including total sleep time (TST) and sleep efficiency (SE); as well as parametric (acrophase, pseudo‐F) and non‐parametric (interdaily stability [IS], intradaily variability [IV], and relative amplitude [RA]) 24‐hour RAR variables. Measures of cognitive function included global cognition (the Montreal Cognitive Assessment), executive function (Trails B test), memory (California Verbal Learning Test‐short form; and psychomotor performance (Digit‐Symbol Coding Test). In models adjusted for age, sex, clinic site and education, we examined adjusted mean cognitive test scores by quartiles or categories of sleep and RAR exposures.ResultMean age of the cohort was 76 years, 58% were female, and 15% were non‐white. Mean TST and SE were 6.9 hours and 85%, respectively. Higher RA, reflecting a more robust 24‐hour RAR, was associated with better cognition on all tests (p for trend <0.05). The association of higher pseudo‐F, a parametric measure or robustness of RAR, to cognition was limited to psychomotor performance (p<0.03). Better psychomotor performance was also related to higher IS (consistency of RAR across days); whereas those with delayed timing (acrophase) had worse psychomotor performance (p<.0006). Lower SE was related to worse cognitive function (psychomotor performance, global cognition, memory; p<.05). There were no associations between TST and any cognitive measures.ConclusionSE and RAR were variably associated with both global and specific domains of cognition in older men and women. The RA in particular was strongly related to multiple domains of cognition related to AD, and may be useful in identifying individuals at risk. Additional analyses will explore gender differences and longitudinal associations.
Prevalence of Alzheimer’s dementia in the 50 U.S. states and 3142 counties: A population estimate using the 2020 bridged‐race postcensal from the National Center for Health Statistics
Authors: Dhana Klodian , Beck Todd , Desai Pankaja , Wilson Robert S. , Evans Denis A , Rajan Kumar B 
Published: December 2023

AbstractBackgroundEstimating the prevalence and number of people with Alzheimer’s dementia in 50 U.S. states and 3142 counties can provide a better understanding of region‐specific disease burden.MethodWe utilized cognitive data from the Chicago Health and Aging Project (CHAP), a population‐based study, and combined it with the National Center for Health Statistics (NHCS) 2020 bridged‐race population estimates and determined the state‐ and county‐specific prevalence of Alzheimer’s dementia for adults 65 years and older.ResultA higher prevalence of Alzheimer’s dementia was estimated in the East and Southeastern regions of the U.S., with the highest in Maryland (12.9%), New York (12.7%), Mississippi (12.5%), and Florida (12.5%). California and Illinois were also among the 10 states with a higher prevalence of Alzheimer’s. U.S. states. California had the highest number of people with Alzheimer’s dementia, with 719.7 (95%CI 665.0, 774.4) thousand, Texas with 579.9 (95%CI 539.9, 620.0) thousand, and Florida with 459.3 (95%CI 422.7, 496.0) thousand. The top 3 counties with the highest prevalence, 16.6%, respectively, were Miami‐Dade County in Florida, Baltimore city in Maryland, and Bronx County in New YorkConclusionThe state‐ and county‐specific estimates could help public health officials to understand the burden of disease (e.g., demand for caregiver counseling and institutional care) and develop strategies for identifying and caring for people with Alzheimer’s dementia
Subjective cognitive impairment score associate with regional amyloid burden and brain atrophy in subjective cognitive decline subjects
Authors: Lee Chonghwee , Yang Dong Won , Hong Yun Jeong , Ho SeongHee , Jeong Jee Hyang , Park Kee Hyung , Kim SangYun , Wang Min Jeong , Choi Seong Hye 
Published: December 2023

AbstractBackgroundSubjective cognitive decline (SCD) is now regarded as the first preclinical stage of Alzheimer’s disease (AD) spectrum disorders. It is important to predict which patients would progress to dementia, and screening tools might be helpful. In this study, we aimed to investigate the possible correlations between AD biomarkers‐regional amyloid burden and volume changes‐and Korean Dementia Screening Questionnaire‐Cognition (KDSQ‐C) score in SCD.MethodThis study analyzed SCD data from prospective population cohort study from July 2018 to December 2020. Brain magnetic resonance imaging (MRI) volumetry, visual and standardized uptake value ratio (SUVR) analysis of 18F‐Florbetaben brain amyloid Positron Emission Tomography (PET) were performed. Demographics, physical data, social and physiological functions were also obtained.KDSQ‐C was administered to SCD subjects as part of the clinical evaluation at the 36 month follow‐up visit. KDSQ‐C included 15 questions that assess 3 dimensions: memory impairment (items 1‐5), other cognitive impairments including language impairments (items 6‐10), and the ability to perform complex tasks in daily life (items 11‐15).ResultPrevalence of subjective cognitive impairment (KDSQ‐C ≧6) among 86 subjects was 73.3%.. No significant difference was observed between groups in terms of demographic characteristics including age, sex and APOE Ɛ4 status and neuropsychological test. However, regional SUVR (amygdala, inferior temporal gyrus and precuneus) and global SUVR were significantly higher in subjectively cognitive impaired group(p<0.05). There were no brain volume differences between groups.For volumetry and KDSQ‐C correlation analysis, partial correlation analysis controlled for age, sex and APOE Ɛ4 status showed significant negative correlation between left entorhinal cortex, right hippocampal volume and KDSQ‐C (r = ‐0.230, p = 0.046; r = ‐0.226, p = 0.049). Similar association was also found between KDSQ‐C memory domain score and brain volume.ConclusionKDSQ‐C can be a useful tool for screening SCD patients at a higher risk with higher amyloid deposition and brain atrophy.This study was supported by a grant from the Ministry of Health and Welfare, HI18C0530