bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between cortical microinfarcts, hippocampal atrophy, and cerebral small vessel disease
Authors: Sadaghiani Shokufeh , Dolui Sudipto , Khandelwal Pulkit , Taghvaei Mohammad , Shakibajahromi Banafsheh , Das Sandhitsu R. , Yushkevich Paul A. , Wolk David A. , Detre John A. 
Published: December 2022

AbstractBackgroundBrain cortical microinfarcts (CMI) are negatively correlated with cognitive function in both normal aging and Alzheimer’s disease (AD). High‐field structural magnetic resonance imaging (MRI) has facilitated in vivo detection of CMIs but their significance and underlying pathological mechanism remain uncertain. Here we assessed correlations between CMIs and medial temporal lobe (MTL) cortical thickness, white matter hyperintensity (WMH) volume, and relative periventricular white matter cerebral blood flow (PVWM CBF) in healthy individuals. PVWM CBF is thought to provide a measure of cerebral small vessel function.Method76 cognitively intact subjects age 65 ± 15 years were scanned using a hybrid 7T/3T protocol. CMIs were counted by visual inspection on T1‐weighted MP2RAGE (0.7mm3) and FLAIR (0.8mm3) scans obtained at 7T. T1‐weighted MPRAGE, FLAIR and 3D arterial spin labeling (ASL) data were also acquired at 3T and were used to calculate cortical thickness, WMH volume, and regional CBF. Spearman and Pearson bivariate tests were used for statistical analyses.Result185 CMIs were detected in 63 of 76 (83%) 7T scans (range:0‐8, 66% multiple CMIs). Age and sex were not significantly correlated with CMI number.A significant positive Pearson correlation was seen between the number of CMIs and log‐transformed WMH volume (r(74)= 0.23, p=0.04) and a more significant negative correlation between the number of CMIs and PVWM CBF normalized to global CBF was also observed (r(74)= ‐0.37, p=0.003).Significant negative correlations between CMI number and mean cortical thickness in Brodmann area 35 (BA35) (r(73)= ‐0.24, p=0.04) and parahippocampal cortex (r(73)= ‐0.26, p=0.03) was observed with nonsignificant trends in BA36 and entorhinal cortex.ConclusionSignificant correlations between the CMI number and both relative PVWM CBF and WMH volume suggests a contribution of small vessel ischemic disease in the development of CMIs. The negative correlation between CMIs and MTL cortical thickness supports the possibility of a mutual underlying pathway for CMIs and Alzheimer’s disease that may be mediated by cerebral amyloid angiopathy.
The Asian Cohort for Alzheimer’s Disease (ACAD) Pilot Study
Authors: Wang Li‐San , Ho Pei‐Chuan , Tee Boon Lead , Li Clara , Gu Yian , Yokoyama Jennifer S. , Vardarajan Badri N. , Reyes‐Dumeyer Dolly , Faber Kelley M. , Lee Wan‐Ping , Tzuang Marian , Choi Yun‐Beom , Feldman Howard H. , Henderson Victor , Hsiung Ging‐Yuek Robin , Mayeux Richard , Rosen Howard J. , Varma Rohit , Foroud Tatiana M. , Kukull Walter A. , Peavy Guerry M. , Lee Haeok , Yu W. Haung , Chui Helena C , Jun Gyungah R , Park Van Ta , Chow Tiffany W 
Published: December 2022

AbstractBackgroundAsian Americans and Canadians (ASACs) are the fastest growing minority group in the US and Canada. ASACs are under‐sampled in Alzheimer’s disease (AD) research. Culturally appropriate, community‐based approaches to recruit these understudied communities are urgently needed, and in 2021 the Asian Cohort for Alzheimer’s Disease (ACAD) began recruitment to the first large dementia genetics cohort to examine genetic and non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history and specific experience in leading AD and CBPR research.MethodThe ACAD pilot study has 8 recruiting sites (6 US and 2 Canadian), a coordinating site, and an analysis site. ACAD piloted a data collection packet (DCP) and pre‐screening/sample collection procedures. The Outreach workgroup translated the forms and an outreach campaign into Chinese (Mandarin and Cantonese), Vietnamese and Korean. Data Management created a central RedCap database. The Training workgroup developed a curriculum for the administration of the DCP and for culturally appropriate approaches to recruitment. We recruited in collaboration with community partners, clinics, and nursing homes that serve Asian communities.ResultACAD’s pilot study has consented 216 participants (142 Chinese, 20 Vietnamese and 54 Korean), and 126 (58%) have completed the DCP. The majority the consent (64.3%) were given by women. The age range of the sample is 60‐93 years. 60.3% have college or graduate level education. 101 of the 126 participants provided saliva (51) or blood (50) biosamples. Data entry is complete, with Consensus Diagnoses fully reviewed on 18 participants. Among 34 diagnosed participants, there are 19 healthy controls, 11 Subjective Cognitive Complaints, 3 Mild Cognitive Impairments, and 1 Probable or Possible AD case.ConclusionLessons learned during the pilot phase of ACAD will provide guidance for future studies to explore risk factors for AD and related dementias. In collaboration with ongoing consortium efforts in Alzheimer’s Disease Genetics Consortium (ADGC), insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD. Our long‐term goal will be to expand ACAD to have a larger sample size and include other Asian American subgroups .
Amyloid and tau‐driven signatures in hippocampal GFAP‐positive astrocytes
Authors: Bellaver Bruna , De Bastiani Marco Antônio , Brum Wagner S. , Ferreira Pamela C.L. , Povala Guilherme , da Rocha Andreia Silva , Ferrari‐Souza João Pedro , de Souza Débora Guerini , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick A , Zimmer Eduardo R 
Published: December 2022

AbstractBackgroundDespite the known heterogeneity of astrocyte responses to injuries, Alzheimer’s disease (AD) pre‐clinical and clinical research relies on the glial fibrillary acidic protein (GFAP) as a proxy of astrocyte reactivity. Recently, it was demonstrated that plasma GFAP levels differentially relate to AD hallmarks, associating with amyloid‐β (Aβ), but not with tau pathology. However, the molecular underpinnings behind this specificity are still unexplored. Here, we aim to uncover the molecular signatures of GFAP‐positive astrocytes driven by either by Aβ or tau pathology.MethodHippocampal GFAP‐positive astrocytes data from 6 month‐old TauP301S (n = 5), 11.5 months‐old APP/PS2 (n = 5) and their wild‐type littermates (WT, n = 5) were acquired from GEO datasets (GSE129770;GSE129797) and used to identify differentially expressed genes (DEGs) and enriched biological processes. DEGs were evaluated using the DESeq2 method. Further data analysis included Gene Ontology (GO) functional evaluation.ResultPrincipal component analysis clearly differentiated gene expression of GFAP‐positive astrocytes from APP/PS2, TauP301S and their WT controls (Fig.1A). Interestingly, only 30 DEGs overlapped among GFAP‐positive astrocytes from these two transgenic mouse models, revealing multiple DEGs specifically associated with Tau or Aβ (Fig.1B). The functional enrichment analysis revealed 36 GO terms enriched with DEGs altered in the PS2APP mice compared to WT. The most significantly enriched terms include processes such as “protein localization to cell periphery and plasma membrane”, “interleukin−6 production and regulation”, “exocytosis” and “neuron death” (Fig.1C). For the comparison of the TauP301S mice versus WT controls, the functional enrichment analysis using DEGs revealed 95 terms. Among the most significantly enriched terms, we found “learning”, “cognition”, and “small GTPase mediated signal transduction” (Fig.1C).ConclusionOverall, we observed a small overlap of DEGs between the Aβ and tau mouse models, indicating the unique nature of GFAP‐positive astrocytic responses to different aspects of AD pathology. The findings presented in this study allowed the identification of functional categories and biological processes particular to Aβ or tau burden. Characterizing how these upstream triggers influence GFAP‐positive astrocyte phenotypes may contribute to the biological interpretation of GFAP as a biomarker of AD pathology and pave the way to unravel novel mechanisms and context‐specific astrocyte biomarkers for AD.
Standardized preprocessed derivatives for the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) Study
Authors: Lussier Désirée , Clarke Natasha , Wang Hao‐Ting , Boré Arnaud , Tetrel Loic , Duchesne Simon , Devenyi Gabriel A. , Chakravarty M. Mallar , Descoteaux Maxime , Dixon Roger A. , Badhwar AmanPreet , Bellec Pierre 
Published: December 2022

AbstractBackgroundThe Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) cohort of the pan‐Canadian Consortium on Neurodegeneration in Aging (CCNA) provides imaging on participants following a standardized protocol. This imaging contribution to deep phenotyping is done to study the full spectrum of age‐related dementias in more than 1,100 individuals (50‐90y) with subjective or mild cognitive impairment, Alzheimer’s disease, other dementias, or otherwise cognitively unimpaired. To accelerate discovery, we propose to release biomarkers extracted from these acquisitions. Here we present preliminary (N=385, AD=39) preprocessing methods, quality control, and available derivatives of the resting‐state functional (rsfMRI), diffusion weighted (DWI), and structural magnetic resonance images.MethodfMRI data was preprocessed using fMRIprep v20.2.1. Sørensen–Dice similarity measure was computed between individual masks and group templates using our internal BIDS app. Functional connectome of 101 regions from Dictionary of Functional Modes (DiFuMo) 64 dimension atlas were calculated with confounds removed. Mean network connectivity for the Yeo7 networks was summarized from connectomes. DWI data underwent robust quality control and preprocessing using Tractoflow. Bundle extraction and mean metric computation was done using freewater_flow, rbx_flow and tractometry_flow. Structural scans were preprocessed and segmented using iterativeN3 and MAGeT‐brain to obtain subcortical and cerebellar volumes. As a validation, a subset of variables associated with aging in the literature was tested for association with participant age using simple correlation.ResultThe functional Dice score was 0.915 (SD=0.017, N=390) and structural was 0.988 (SD=0.004, N=381). Age was significantly associated with mean DMN connectivity (r=‐0.226, p<0.001), bilateral inferior fronto‐occipital fasciculus freewater (r=0.533, p<0.001), and bilateral thalamus volume (r=‐0.243, p<0.001).ConclusionDerivatives obtained include: functional connectomes using DiFuMo64, network connectivity from Yeo7, DWI measures for major fiber tracts, and segmented subcortical and cerebellar volumes. The results of the quality and validity checks indicate the derivatives would be useful for the study of age‐related dementias. Full quality control and release of the complete COMPASS‐ND preprocessed imaging dataset and derivatives should be completed in 2022. For information on access see ccna‐ccnv.ca.
Apolipoprotein E moderates the association between Non‐APOE Polygenic Risk Score for Alzheimer’s Disease and Aging on Preclinical Cognitive Function
Authors: Xu Yuexuan , Vasiljevic Eva , Deming Yuetiva , Jonaitis Erin M. , Koscik Rebecca Langhough , Lu Qiongshi , Johnson Sterling C. , Engelman Corinne D 
Published: December 2022

AbstractBackgroundApolipoprotein E4 (APOE‐ε4) is the strongest known risk factor for late‐onset Alzheimer’s disease (LOAD). Variation in cognitive decline patterns among cognitively unimpaired individuals suggests that additional LOAD‐related genetic factors may interact with APOE‐ε4 to influence cognitive decline during asymptomatic aging. In the present study, we aim to investigate whether any genome‐wide association studies (GWAS) and p‐value threshold (pT)‐informed non‐APOE polygenic risk scores (PRS) moderate associations between APOE‐ε4 and longitudinal cognition.MethodsWe leveraged 12 years of longitudinal data from the Wisconsin Registry for Alzheimer’s Prevention, and we built eight PRSs under various pTs for single nucleotide polymorphism selection using summary statistics from three GWAS meta‐analyses: International Genomics of Alzheimer’s Project (IGAP) case‐control study, UK‐biobank (UKBB) AD‐by‐proxy study, and a combined sample that merges IGAP and UKBB study results. All association analyses were fitted using a linear mixed effects model and adjusted for within‐individual/family correlation among 1,190 cognitively unimpaired individuals at baseline (Table 1). A set of sensitivity analyses were performed to assess the robustness of the main findings.ResultsWe found that the adverse effect of non‐APOE PRS on overall and memory‐related cognitive domains is more evident among APOE‐ε4 carriers as people age (Figure 1). There is a gradual, statistically significant difference in the rate of overall and memory‐related cognitive decline per unit change of non‐APOE PRSs between APOE‐ε4 carriers and non‐carriers for people over the age of 70 (Figure 2). Our study findings are consistent with a relatively stringent pT (p <= 5e‐8) and more evident when the PRSs are constructed using the case‐control GWAS study results, despite the smaller sample size (“Kunkle significant variants only” in Figures 1 and 2). Our findings are also robust to various sensitivity checks when we replace the dichotomous APOE‐ε4 predictor with the APOE genotype, use different PRS clumping parameters, and exclude cognitive measurements from the last test occasion, which has a smaller sample size.ConclusionWe recommend considering the interaction between non‐APOE PRS, APOE status, and age in modeling pre‐clinical cognitive phenotypes for LOAD. We also recommend leveraging a conservative p‐value threshold and using case‐control GWAS results in constructing the LOAD PRS.
Healthcare Resource Utilization Among Veterans with Alzheimer’s Disease
Authors: Aguilar Byron J. , Li Mingfei , Wang Ying , Morin Peter , Berlowitz Dan , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming 
Published: December 2022

AbstractBackgroundWe evaluated healthcare utilization patterns to understand the care pathways for Veterans with Alzheimer’s disease (AD) from the Department of Veterans Affairs (VA) healthcare system.MethodVA electronic health records (EHR) were used to extract data from clinical notes and identify patients with AD. The patient cohort was merged with the VA Informatics and Computing Infrastructure (VINCI) administrative database from October 2008–to October 2021 to obtain systematic healthcare utilization records including total inpatient admissions and outpatient visits. A control group was extracted for comparison and matched to the patient cohort using the propensity score on age, sex, and race. A linear mixed‐effects model was used to compare the total outpatient and inpatient utilization, adjusting for patient demographics and comorbidities.ResultWe extracted 21,442 AD patients from the EHR clinical notes. A cohort of 85,684 non‐AD and non‐dementia Veterans was constructed as a control group. In the AD vs control groups, the mean age was 82 vs 79 years, 83 vs 84% was White, and 97% were male in both groups. The number of annual outpatient visits 1 year before, and at 1 and 2 years after the first AD diagnosis code was 30, 34 and 27, respectively. The control group maintained 12 annual outpatient visits throughout the three‐year period. The average annual hospital admission rate was 1.8 vs 1.7 in the AD vs control group. The average length of inpatient stay in the year prior to the first AD diagnostic code was 23.1 days, increased to 27.4 days at year 1 after AD diagnosis, and declined back to 20.5 days at year 2, as compared to 13.1, 13.0, and 11.9 days, respectively, in the control group. The mixed‐effects analysis showed significantly higher healthcare utilization trends across VA outpatient and inpatient care settings (p<0.001) in the AD vs control groups, after controlling for age, gender, race, ethnicity, and select comorbidities.ConclusionHealthcare resource utilization in patients with AD identified from the medical notes is more than doubled that in outpatient care and nearly doubled in inpatient length of stay relative to the matched controls in the VA healthcare system.
Identification of Novel Modifiers of Tau Aggregation and Pathology using a Proximity Proteomics Approach
Authors: Lee Jannifer H , Morderer Dmytro , Khalil Bilal , Liu Feilin , Tsai Chih‐Wei , Croft Cara L , Carlomagno Yari , DeTure Michael , Salemi Michelle , Cook Casey , Phinney Brett , Dickson Dennis W. , Golde Todd E , Petrucelli Leonard , Rossoll Wilfried 
Published: December 2022

AbstractBackgroundAlzheimer's disease (AD) and related neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates. A defining hallmark of AD is the formation of neurofibrillary tangles (NFTs) by aggregation of the microtubule‐associated protein tau into pathological oligomers and fibrils. Although NFTs are believed to play a pivotal role in the disease process, we have a poor understanding of how their formation, toxicity, and spread across brain regions is regulated. Recent data suggest that the seeding behavior of tau is governed by patterns of posttranslational modifications and varying filament structures. Understanding how tau‐associated proteins regulate the oligomerization, pathological accumulation, and seeding of tau in affected neurons and glia is of critical importance for therapy development.MethodTo profile the interactome of tau aggregates, we have established proximity‐dependent biotin‐identification (BioID) as a novel method to identify the composition and proximal molecular environment of insoluble protein aggregates in the context of living brain cells and tissue. Using an in vitro and ex vivo model approach coupled with mass spectrometry, we are generating datasets containing top identified proteins, stratified based on significance and molecular pathway. Once we validate their co‐localization with NFTs in the context of human AD pathology, functional characterization of putative modifiers will be performed to assess their impact on tau‐aggregate and toxicity.ResultTo determine the physiological and aggregate specific interacting partners of tau, we are comparing wild type tau (TauWT) with mutant tau (Tau3xMUT) carrying three tauopathy‐associated mutations (A152T/P301L/S320F) that form hyper‐phosphorylated and thioflavin S‐positive aggregates even in the absence of seeding. The proteomic analysis from our pilot study revealed that significantly changed proteins included candidates involved in RNA processing, as well as protein ubiquitination and proteasome degradation.ConclusionThis study provides novel insights into cellular pathways and molecular mechanisms of neurodegeneration, by identifying in the context of living neurons and brain tissue different functional classes of tau‐associated proteins with relevance for AD pathophysiology. These are expected to include proteins that may mediate the toxic effect of NFTs, facilitate the formation or degradation of pathological tau aggregates, and catalyze posttranslational modifications of tau oligomers and associated proteins.
A Cross‐sectional HABS‐HD study of Plasma Biomarkers of Cognitive Decline across Diagnoses in a Diverse Community Cohort
Authors: Hall James , Petersen Melissa , Johnson Leigh , O'Bryant Sid E. 
Published: December 2022

AbstractBackgroundDue to their low cost, less invasive nature and ready availability, plasma biomarkers of Alzheimer’s disease have been proposed as one time screening tools for clinical trials and research. The impact of ethnoracial factors on these biomarkers has received little attention. The current study investigated the levels of Aβ40, Aβ42, total tau and NfL across diagnoses for each of the three major ethnoracial groups in the US in a community based cohort of older adults.Method1862 participants (852 Mexican Americans (MA); 775 Non‐Hispanic Whites (NHW) and 235 African Americans (AA)) drawn from The Health & Aging Brain Study – Health Disparities (HABS‐HD) study were included. Diagnoses were assigned using an algorithm (decision tree) verified by consensus review. Plasma samples were assayed using Simoa technology. Data were analyzed using ANOVA comparing the level of each biomarker across the cognitive diagnoses (Normal Cognition (NC), MCI & Dementia) within each ethnoracial group co‐varying age and sex.ResultFor NHW there were no significant differences between NC, MCI and Dementia groups in levels of Aβ40 or Aβ42. For t tau, MCI t tau was significantly higher than NC. The t tau level did not differ between the two cognitively impaired groups. There was a significant effect for diagnosis for NfL with the MCI NfL and the Dementia NfL level being significantly higher than the NC NfL level. The impaired groups did not differ in NfL between the impaired groups. For the MA significant differences across diagnoses were found only for NfL. The Dementia NfL level was significantly higher than the NC and significantly higher than the MCI. The only biomarker showing significant differences across diagnoses for AA was NfL. The Dementia NfL level was significantly higher than the NC and MCI levels.ConclusionAlthough cross‐sectional, the results suggest different patterns of plasma biomarkers across diagnoses for NHW as compared to MA and AA. NfL levels were highest in the Dementia group for all. Ongoing longitudinal research will show how biomarkers change as cognition declines.
ABCA7‐reducing mutation carriers have reduced CSF amyloid biomarker levels, suggestive of increased amyloid deposition
Authors: Duchateau Lena , Bjerke Maria , Timmers Maarten , Engelborghs Sebastiaan , Sleegers Kristel 
Published: December 2022

AbstractBackgroundThe Alzheimer’s disease (AD) risk gene ABCA7 has suggested functions in lipid metabolism and the immune system. Rare premature termination codon (PTC) mutations and an expansion of a variable number of tandem repeats (VNTR) polymorphism in the gene, both likely cause a lower ABCA7 expression and hereby increased risk for AD. However, the exact mechanism‐of‐action remains unclear. By studying CSF biomarkers reflecting different types of AD‐related pathological processes, we aim to get a better insight in those processes and establish a biomarker profile of mutation carriers.MethodThe study population consisted of 228 AD patients (27 PTC mutation and 16 pathogenic expansion carriers) for whom CSF was available and ABCA7 sequencing and VNTR genotyping had been performed. CSF levels of amyloid β (Aβ) 40 and 42, sAPP‐α and ‐β, YKL‐40 and hFABP were determined using ELISA and Meso Scale Discovery assays. We compared differences in levels of these biomarkers AD patients with or without an ABCA7 PTC mutation or expansion, and further stratified on APOE e4 status.ResultCarriers of ABCA7 mutations/expansions had significantly lower Aβ42 levels (p= 0.0031) and amyloid ratio (p=0.020) compared to non‐carrier patients, and were threefold more likely to have abnormal Aβ42 values. The effect on amyloid biomarkers remained significant when considering PTC mutations or VNTR expansions separately. APOE e4 carriers had significantly lower Aβ42 (p=0.0013) and amyloid ratio (p<0.001) compared to non‐APOE e4 carriers. When combined, both APOE e4 allele and ABCA7 carrier status influenced amyloid ratio and Aβ42 levels. Remarkably, within non‐APOE e4 carriers, ABCA7 mutation/expansion carriers did have significantly reduced Aβ42 levels (mean=540 pg/mL) compared to ABCA7 non‐carriers (812 pg/mL; p=0.0051), attaining lower levels as e4 carriers (612 pg/mL). Finally, in carriers of the pathogenic expansion we observed lower YKL40 levels (p=0.011), suggesting reduced neuroinflammation.ConclusionOur results highlight that carriers of ABCA7 PTC mutations and repeat expansions show more pronounced abnormalities in CSF amyloid beta markers than non‐carrier patients, especially in non‐APOE e4 carriers. Expansion carriers also had a decrease in neuroinflammation marker YKL40. Our results suggest that reduced ABCA7 expression leads to increase in amyloid pathology and potentially a reduced inflammatory response to damage.