bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tau and Amyloid Plasma Biomarker Analysis in Alzheimer’s Disease Cohorts from Diverse Genetic Ancestries
Authors: Griswold Anthony J. , Rajabli Farid , Gu Tianjie , Garcia‐Serje Catherine , Arvizu Jamie , Golightly Charles G. , Whitehead Patrice , Hamilton‐Nelson Kara L. , Adams Larry D. , Celis Katrina , Sanchez Jose Javier , Tejada Sergio J. , Mena Pedro R. , Starks Takiyah D. , Cornejo‐Olivas Mario , Illanes‐Manrique Maryenela Z , Silva‐Vergara Concepcion , Cuccaro Michael L. , Vance Jeffery M. , Feliciano‐Astacio Briseida E. , Byrd Goldie S. , Beecham Gary W. , Haines Jonathan L. , Pericak‐Vance Margaret A. 
Published: December 2023

AbstractBackgroundPlasma concentrations of phosphorylated threonine‐181 of Tau (pTau181) and the ratio of amyloid beta isoforms Ab42/Ab40 are biomarkers for differential diagnosis and preclinical detection of Alzheimer disease (AD). However, measurement of these biomarkers is mostly from individuals of non‐Hispanic, European ancestry. Given differences in AD risk, generalizability of these findings is not assured in individuals of diverse ancestry. This study evaluates the utility of plasma pTau181 and Ab42/Ab40 in discriminating clinically diagnosed AD from cognitively intact, age‐matched controls in ancestrally diverse, admixed cohorts.MethodWe measured plasma pTau181 and Aβ42/Aβ40 with Simoa chemistry using the pTau181 AdvantageV2 and NEUROLOGY 3‐PLEX A assays, respectively. Our cohorts consisted of: 642 African Americans (162 AD and 480 cognitively intact (CI)), 906 Puerto Ricans (385 AD and 521 CI), 149 Peruvians (49 AD and 100 CI), 60 Cubans (26 AD and 34 CI), and 246 non‐Hispanic, European ancestry (22 AD and 224 CI). Linear mixed‐effect regression models adjusted for age, sex, population substructure and relatedness followed by Bonferroni correction was applied to identify differences across AD status. Diagnostic performance and construct receiver operator characteristic (ROC) curves were created from logistic regression models.ResultPlasma pTau181 concentrations were increased in individuals with AD compared to CI (p < 2×10−16) taking into account all individuals and in each cohort separately (African Americans, p = 1.2×10−9; Puerto Ricans, p = 7.6×10−9; Peruvians, p = 0.02), and European ancestry, p = 2.2×10−8) except for the Cubans where there was a trend. There was no significant difference in the plasma Aβ42/Aβ40 ratio, however there was a trend towards a decreasing concentration in AD. Using the area under the ROC, pTau181 was more accurate at predicting status than the Aβ42/Aβ40 ratio, but the classification improved when both biomarkers were combined. The accuracy varied widely over the individual cohorts with AUC from 0.845 for African Americans to 0.683 for Peruvians.ConclusionThese results suggest AD biomarkers are generalizable across ancestries, though the predictive value may differ depending on specific ancestral backgrounds. Ultimately, combining genomic and biomarker data from diverse individuals will increase understanding of genetic risk and refine clinical diagnoses in individuals of diverse ancestries.
The contribution of Oculomotor and Motor Deficits in The Assessment of Executive Function in Progressive Supranuclear Palsy Patients
Authors: Khoja Abeer , Monteiro Marta , Morales‐Rivero Alonso , Cordero Indira Ruth Garcia , Gold David , Antwi Jeffrey , Sasitharan Johnathan , Bhakta Puja , Couto Blas , Tsang Michelle , Kovacs Gabor , Fox Susan , Tang‐Wai David F. , Lang Anthony E , Tartaglia Carmela 
Published: December 2023

AbstractBackgroundProgressive supranuclear palsy (PSP) was first described in 1964 and is associated with motor, oculomotor, and cognitive deficits. Cognitive assessments often assume intact physical function. Some tests like The Trail Making Test (TMT), a measure of executive function may be impacted by oculomotor and motor impairments. Our aim was to investigate the impact of oculomotor impairments and arm dysfunction on the TMT.Method71 patients from the Rossy PSP Center that met criteria for probable PSP and underwent a neuropsychological test battery, the Toronto Cognitive Assessment (TorCA), were included. Data from the following tests and assessments were used for this study: TMT A and B time, digit forwards and backwards, verbal and animal fluency, Benson copy, and Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) delayed recall, PSP Rating Scale (PSPRS) total score and its oculomotor subscore, MDS‐Unified Parkinson’s Disease Rating Scale (MDS‐UPDRS part III) subscore of the dominant hand was used to rate the motor impairment. We performed spearman correlations and used false discovery rate test correction for multiple comparisons.ResultThe PSP patients (60.6% male, mean age 71.3+/‐6.61) had mean PSPRS score of 41.5+/‐15, PSPRS‐oculomotor subscore 8.0+/‐3, and MDS‐UPDRS III subscore dominant hand 6.5+/‐3.3. We found a positive correlation between PSPRS‐oculomotor subscore and TMT A (r = 0.43 p = 0.005) and TMT B (r = 0.35 p = 0.008). We also found negative correlations between PSPRS‐oculomotor subscore and digits backward (r = ‐0.39 p = 0.005), Benson copy (r = ‐0.39 p = 0.005), CERAD delayed recall (r = ‐0.29 p = 0.034), and animal fluency (r = ‐0.44 p = 0.004). No tests were related to MDS‐UPDRS part III subscore of the dominant hand.ConclusionOculomotor but not motor function affect TMT A and B. However, oculomotor function also relates to other executive and non‐executive tests that do not require visual scanning. Although important to factor in physical deficits when doing cognitive assessments, the TMT appears to be a reliable test for assessing cognitive function in patients with PSP who can perform the test.
Physiological and pathological 3R and 4R tau expression in marmoset brain
Authors: Huhe Hasi , Choi Sang‐Ho , Kofler Julia , Mou Yongshan , Ha Seung‐Kwon , Silva Afonso C , Rizzo Stacey J Sukoff 
Published: December 2023

AbstractBackgroundCommon marmosets (Callithrix jacchus) have recently emerged as an important model for studying aging and neurodegenerative disorders, including Alzheimer’s disease (AD). Amyloid‐β deposits in the cerebral cortex of marmosets present naturally with aging, which has now been widely reported. However, the role of tau in the marmoset brain has been understudied. The purpose of the present studies was to comprehensively examine 3R and 4R tau isoform expression in the marmoset brain.MethodsThe mRNA expression in the marmoset brain was confirmed by RT‐PCR. The total mRNA was isolated from frozen tissue of various age groups and reverse transcribed to cDNA, which was used for RT‐PCR. The sequence of each fragment was confirmed by the Sanger sequencing method. The tau protein expression in Sarkosyl soluble and insoluble fractions was examined by western blot using tau‐specific antibodies, and expression levels of 3R/4R were quantified by Dot blot. Synaptic tau expression was analyzed from crude synaptosome extractions of the frontal cortex. Pathological tau aggregates in cryo‐slices of a 10‐year‐old marmoset brain were visualized by immunohistochemistry.Results3R and 4R tau were expressed in the marmoset brain, with 3R tau predominately expressed in neonatal brains and 4R tau in adult/aged brains. 3R and 4R tau were also localized in synaptic regions of the frontal cortex. The Sarkosyl soluble tau was phosphorylated on T181, T217, and T231 sites with evidence of oligomers. Insoluble tau was phosphorylated on S396/S404 and S202/S205 sites and contained high molecular weight aggregates comprising 3R and 4R tau. Moreover, a 10‐year‐old marmoset brain case study demonstrated a paired helical filament structure in the hippocampus and intracellular 3R and 4R tau accumulation.ConclusionsOur results reveal physiological and pathological 3R/4R tau distributions in the frontal and temporal cortex of the marmoset brain, confirming the presence of 3R tau and AD‐like pathological tau in aging marmosets. These data support the utility of common marmosets as appropriate models for studying AD and neurodegenerative disorders.
The AD Knowledge Portal: an open‐access platform for sharing data, tools, and results of aging and dementia research
Authors: Linden Abby Vander , Leanza Zoë , Britton Jessica S , Kallaher Amelia , Heath Laura M , Beck Jaclyn , Peña Anthony , Poehlman William L. , Yaxley Richard , Hendrickson Jared V , Wiley Jesse C , Leal Karina , Greenwood Anna K 
Published: December 2023

AbstractBackgroundThe AD Knowledge Portal (https://adknowledgeportal.org) is a community‐driven resource developed to support transparent evaluation and broad use of resources generated within the translational research portfolio of the National Institute on Aging (NIA). This open access platform aims to accelerate Alzheimer’s disease (AD) research and maximize therapeutic discovery through sharing and re‐use of data in adherence with FAIR (Findable, Accessible, Interoperable, and Reproducible) principles. The AD Portal allows the AD research community to find curated and contextualized data, evaluate hypotheses via independent experiments, and prioritize new mechanisms for therapeutic development.MethodThe AD Portal empowers researchers to share multi‐omics human and non‐human data with appropriate attribution for re‐use, and in compliance with necessary data governance and ethical guardrails. This is accomplished through the use of the secure Synapse data sharing platform–an NIH‐supported generalist repository–and a user‐friendly data portal website.ResultThe AD Portal currently hosts resources from nine research consortia and more than 50 grants related to dementia and aging. Data from over 15,000 individuals and 30,000 specimens–encompassing central and peripheral samples from brain banks, longitudinal cohorts, and model systems–are available. While the organizing focus is aging and dementia, the provided data are generated through a broad array of modalities, including genomics, transcriptomics, epigenetics, imaging, immunoassays, mass spectrometry‐based proteomics and metabolomics, behavioral assays, and more. In addition to raw and processed data, portal users can explore open‐access experimental mouse models, computational tools, publications, and summarized evidence for putative AD targets via integrated results explorers.ConclusionThe AD Knowledge Portal offers the research community an accessible source of data, tools, and results for the study of AD and related dementias.
LC‐MS/MS‐based proteome profiling of CSF‐derived extracellular vesicles in Alzheimer’s disease
Authors: Tamayo Natalia Valle , Hirschberg Yael , Belbin Olivia , Cervantes‐González Alba , Sánchez‐Aced Érika , Gil Laia Lidón , Dolcet Sònia Sirisi , Lleó Alberto , Mertens Inge , Iulita Maria Florencia , Dols‐Icardo Oriol , Fortea Juan 
Published: December 2023

AbstractBackgroundExtracellular vesicles (EVs) participate in the spread of pathological proteins between cells, contributing to the progression of neurodegenerative disorders, including Alzheimer’s disease (AD). As cerebrospinal fluid (CSF) reflects the biochemical environment of the brain, EVs from CSF constitutes a promising source to investigate novel biomarkers and therapeutic targets. We aimed to explore the unbiased proteome profile of CSF‐derived EVs from individuals with AD by label‐free quantitative liquid chromatography mass spectrometry (LC‐MS/MS).MethodEVs were obtained from 500 µL of CSF from sex and age‐matched cognitively healthy donors (HC, n = 10, mean age = 73±1.4) and patients with AD dementia (AD, n = 10, mean age = 76.2±0.9) by a high‐throughput size exclusion chromatography method (SmartSEC). Resultant EV fractions were characterized by nanoparticle tracking analysis (NTA). EVs were lysed and proteins were trypsinized overnight via S‐Trap filters (Protifi). The peptides were separated on an Evosep nano LC system and analyzed by the TimsTOF Pro (Bruker) mass spectrometer. Peptides were identified using PEAKS Online software (1% FDR). DAVID Bioinformatics Resources 6.8 was used to determine the gene ontology (GO) enrichment. We normalized log2 peptide intensities (quantiles) and determined the differential protein expression across groups by a linear mixed effects (fixed effects = diagnosis, random effects = peptide sequence) model using the MsqRob package in R. P‐values were adjusted using Benjamini‐Hochberg.ResultNTA showed homogeneous EV size profiles (mean size = 113.4±1.41nm). We identified 2096 proteins with at least 1 proteotypic peptide. GO enrichment analyses showed “extracellular exosome” as the most statistically significant enriched term (p = 1.8×10−212), confirming the enrichment of EVs. Statistical inference analysis revealed 18 differentially expressed proteins between both diagnostic groups (adj.p<0.05), all of them increased in the AD group. (Fig 1). Some of the greatest changes include CLUS (log2FC = 0.61, adj.p = 8.38×10−4, Fig.2), SPB1 (log2FC = 1.15, adj.p = 1.23×10−2, Fig.3), LRP1 (log2FC = 3.43, adj.p = 1.23×10−2), KLK7 (log2FC = 2.59, adj.p = 1.23×10−2), SAP3 (log2FC = 2.09, adj.p = 3.1×10−2) and SHPS1 (log2FC = 1.03, adj.p = 4.25×10−3), which are proteins that have been previously associated with inflammation.ConclusionOur results reveal novel protein changes in CSF‐derived EVs from individuals with AD, which could be explored further to their applicability in distinguishing the different clinical stages across the AD continuum.
Study of TMEM106B expression levels under neurodegenerative conditions
Authors: Picard Cynthia , Miron Justin , Poirier Judes 
Published: December 2023

AbstractBackgroundTMEM106B is a transmembrane protein involved in dendrite morphogenesis and lysosome trafficking. TMEM106B was identified as a susceptibility gene for frontotemporal lobar degeneration with TDP‐43 inclusions (FTLD‐TDP). Brain tissue from patients with FTLD‐TDP showed increased mRNA levels of TMEM106B compared to normal controls (Van Deerlin et al, Nat Genet 2010). Our goal is to study TMEM106B expression levels in other neurodegenerative conditions such as progressive supranuclear palsy (PSP), Alzheimer’s disease (AD) and a well‐established mouse model of entorhinal cortex lesions (ECL).MethodUnilateral electrolytic lesions to the entorhinal cortex were conducted on two‐to‐three months old male C57BL/6j mice by stereotaxic surgery. For sham‐operated animals, the electrode was lowered only 1 mm without current and sacrifices were performed on the same day. All other lesioned mice were sacrificed 2, 7, 14, 21 or 40 days post‐lesion (DPL). Total RNA was extracted from frozen ipsilateral and contralateral hippocampi and expression profiles were measured with the Affymetrix Mouse ClariomTM D Assay. The Mayo Clinic Brain Bank collected RNA samples from temporal cortex and measured gene expression levels using next‐generation RNA sequencing (RNAseq). Results are available for 274 subjects with the following conditions: PSP, N = 84; AD, N = 82; pathological aging (PA), N = 30; and cognitively unimpaired (CU), N = 78.ResultIn the ECL mouse model, ipsilateral Tmem106b expression levels were significantly reduced during the deafferentation phase (DPL2: p = 0.046) and reached maximum levels during the reinnervation phase (DPL14: p = 0.030 and DPL21: p = 0.019), compared to sham‐operated animals. In human temporal cortices, TMEM106B expression increased progressively from CU (10.76±0.62), to PSP (11.25±0.43), PA (12.13±1.27) and finally AD (13.10±0.44) (mean CPM ±SEM). TMEM106B mRNA levels were significantly higher in AD compared to CU (p = 0.002) and PSP (p = 0.003).ConclusionElevated levels of TMEM106B in FTLD‐TDP, AD and during the reinnervation phase of the ECL mouse model suggest an active response to tissue damage that is consistent with compensatory synaptic and terminal remodeling, independently from tau‐mediated pathology. This hypothesis is consistent with TMEM106B levels found in PSP, which is characterized by abundant neurofibrillary tangles that differ in both distribution and composition from those associated with AD.
Physiological and behavioral characteristics of SuperAgers from everyday activities: An NIH U19 SuperAging Research Initiative study protocol
Authors: Roberts Angela C , Van Ooteghem Karen , Lim Andrew , Swartz Richard H. , Beyer Kit B. , Geula Changiz , Mesulam Marsel , Rogalski Emily J , McIlroy William 
Published: December 2023

AbstractBackgroundStudying factors contributing to exceptional memory performances beyond the 8th decade, can be a valuable model for understanding dementia risk, prevention, and underlying mechanisms. Age‐associated changes in biological and physiological complexity, or system responsivity, form the foundation of the loss of complexity hypothesis in aging (Lipsitz & Goldberger, JAMA, 1992). Project 1 under the multisite NIH U19 SuperAging Research Initiative uses state‐of‐the‐art wearable technology, and data from real‐world contexts, to test the supposition that SuperAgers have preserved physiologic and behavioral complexity relative to their Controls in the domains of physical activity, autonomic responsiveness, sleep, and social engagement.MethodSuperAgers are enrolling from five U.S. and Canadian sites of the SuperAging Research Initiative. SuperAgers refer to individuals aged 80 and older who have memory capacity considered average for those 2‐3 decades younger. In a fully remote data collection protocol, participants wear a multi‐sensor array comprised of 1 skin‐mounted trunk sensor (with ECG) and 2 wearable limb sensors, continuously over a 14‐day period with scheduled rest breaks every 3‐4 days. Participants complete a baseline orientation visit, and three brief check‐in visits with the study team over video conference. Using custom algorithms, developed by our research team, we will examine time‐varying changes in indices of physiologic and behavioral complexity, across multiple body systems, using both volume‐based and established multi‐scale entropy approaches to quantify differences between SuperAgers and their typically aging Controls. We plan to analyze sensor derived complexity metrics in relation to self‐reports of life‐space mobility.ResultWe will overview our remote data collection protocol and semi‐automated analytics pipeline. Barriers and facilitators to remote data collection will be discussed Preliminary data (N = ∼ 40) will be presented, with select case study examples. We will provide preliminary sensor adherence and user‐feedback from the cohort, comprised of a diverse sample of SuperAgers and Controls.ConclusionThis is the first study to test the loss of complexity hypothesis across multiple physiological and behavioral domains simultaneously and in exceptional cognitive aging. Using sensitive tools to capture dynamic and complex behaviors, we will characterize SuperAgers in a way not afforded by point‐in‐time assessments that dominate the current literature.
Proteomics signatures of cerebrovascular pathology in TGFß1 overexpressing mice
Authors: Haqqani Arsalan S. , Stanimirovic Danica B. , Hamel Edith , Badhwar AmanPreet 
Published: December 2023

AbstractBackgroundVascular cognitive impairment and dementia (VCID), the second most prevalent of the age‐related dementias, develops as a consequence of various types of cerebrovascular insults that damage brain function (Corriveau et al. 2016). Accumulating lines of evidence point to a link between VCID, both sporadic (Kim et al. 2006) and genetic (Hara et al. 2009, Zellner et al. 2018) forms, and the transforming growth factor beta (TGFB) family signaling. Transgenic mice overexpressing a constitutively active form of TGFβ1 in the brain (TGF mice) recap the cerebrovascular pathology seen in VCID (Wyss‐Coray et al. 2000, Tong et al. 2015), and develop VCID when submitted to a comorbid cardiovascular risk factor for dementia (Trigiani et al. 2020). Our aim was to characterize the cerebrovascular proteome of TGF mice using mass spectrometry‐based quantitative proteomics.MethodEighteen, 6‐month‐old‐TGF and ‐wildtype (WT) mice (N = 9/group) were transcardially perfused and pial arteries harvested under a dissecting microscope. Arterial proteins were extracted, trypsin‐digested, fractionated by strong cation exchange (SCX, gel‐free method) and analyzed by nanoLC‐MS/MS using nanoAcquity UPLC and ESI‐LTQ Orbitrap. For total and/or differentially‐expressed proteins (≥2‐fold change, p≤0.01) we i) performed characterization of proteins, and demonstrated presence of ii) protein RNA‐transcript in mouse and human brain vascular cells using transcriptomics datasets, and iii) identified proteins present in human‐extracellular‐vesicles (EVs) using Vesiclepedia.ResultWe identified 3602 proteins in brain vessels of WT and TGF mice, including canonical vascular proteins (e.g. Claudin‐5), and 103 direct (N = 103) and indirect (N = 1,942) interactors of TGFβ1 (Fig1). We also identified 83 proteins demonstrating significantly altered levels in TGF mice. Level dysregulation in these proteins point to perturbations in brain vessel vasomotricity, remodeling, and inflammation. We further demonstrated that several of the differentially‐expressed mouse proteins are i) expressed in the human brain vasculature, and ii) found as cargo proteins in EVs.ConclusionWe characterized the deleterious impact of TGFβ1 overproduction on the cerebrovascular proteome. Given the growing popularity of extracellular vesicles in blood as a novel and minimally invasive biomarker discovery platform for the age‐related dementias, including VCID, several of the proteins identified by us can serve as protein biomarkers in human.