bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between plasma cortisol with the neuropathology of patients across the Alzheimer’s disease continuum
Authors: Souza Laura Willers , Bieger Andrei , Borelli Wyllians Vendramini , Antônio De Bastiani Marco , Bauer‐Negrini Guilherme , DuBois Jonathan M. , Zimmer Eduardo R. , Lab Zimmer Neuroimaging 
Published: December 2023

AbstractBackgroundThe relationship between high cortisol levels and brain atrophy in patients across the Alzheimer’s disease (AD) continuum has been relatively unexplored. Thus, this study sought to investigate the association between plasma cortisol levels and brain cortical thickness in patients across the biological and clinical continuum of AD.MethodParticipants with baseline plasma cortisol concentrations (n = 544), structural MRI, and CSF Aβ1‐42 and CSF p‐tau181 were selected from the ADNI database. Three general linear models (GLMs) were constructed to assess the association between cortical thickness and cortisol levels (Freesurfer’s v7.1.1): (1) cortisol as an independent variable; (2) cortisol, cognitive status, and interaction; (3) cortisol, neuropathology (measured by Aβ1‐42 and p‐tau181 positivity), and interaction. These analyses were corrected for multiple comparisons through cluster formation (p<0.01) and permutation (Monte Carlo simulation of 10,000 iterations).ResultDemographics are depicted in Table 1. The cortical thickness showed a negative correlation with plasma cortisol concentrations in the following clusters (first GLM; Figure 1 and 2): left hemisphere – superior parietal (pcc = ‐0.13; p = 0.0002); superior frontal (pcc = ‐0.13; p = 0.0004); superior parietal (pcc = ‐0.13; p = 0.013); precentral (pcc = ‐0.12; p = 0.02); isthmus cingulate (pcc = ‐0.13; p = 0.02); caudal middle frontal (pcc = ‐0.11; p = 0.031); fusiform (pcc = ‐0.12; p = 0.046); right hemisphere – inferior parietal (pcc = ‐0.13; p = 0.0004); precuneus (pcc = ‐0.12; p = 0.0014); superior frontal (pcc = ‐0.12; p = 0.003); parahippocampal (pcc = ‐0.12; p = 0.003); superior parietal (pcc = ‐0.12; p = 0.041). Interestingly, no interactions between cortisol and AD cognitive status and neuropathology were identified (second and third GLMs – data not shown).ConclusionThis cross‐sectional study identified a negative correlation between plasma cortisol concentrations and cortical thickness in brain regions typically affected by AD, which was found to be independent of AD diagnosis and neuropathology. This finding suggests that high peripheral cortisol levels may create a vulnerability that is independent of AD neuropathology in regions commonly affected by the disease, which may accelerate disease progression.
Mass spectrometry identifies tau C‐terminal phosphorylation signature of neuronal hyperexcitation
Authors: Schneeweis Amanda , Lama Tsering , Ma Junfeng , Pak Daniel T.S. 
Published: December 2023

AbstractBackgroundTau pathology has been reported to be exacerbated during hyperexcitation, a characteristic of AD.MethodPrimary hippocampal cultures (DIV20) were treated with 100µM picrotoxin for 24hrs. Tau was isolated from cultures using immunoprecipitation. Unbiased mass spectrometry was performed to identify specific tau sites phosphorylated during hyperexcitation. Subsequently, we transfected primary hippocampal neurons with these identified tau sites mutated to phosphor‐mimetic or phosphor‐null sites. We used fluorescent microscopy to identify any changes associated with tau localization, neuronal morphology, and spine morphology.ResultsSites S409, S412, S413, T414, S416, S422, and T427 are uniquely phosphorylated during hyperexcitation. When all identified sites contain the phosphonull mutation, PSD‐95 intensity is significantly higher compared to control levels, and the mutated tau levels are significantly higher in dendrites compared to control levels.ConclusionThere are unique sites of tau phosphorylated during hyperexcitation. These sites regulate PSD95 levels and tau localization.
Validation of a Video Adaptation of the UDSv3 Cognitive Battery (VCog): Study Design and Preliminary Participant Satisfaction Results
Authors: Sachs Bonnie C. , Latham Lauren , Craft Suzanne , Barnes Lisa L. , Clark Lindsay R. , Dodge Hiroko H , Duff Kevin , Farias Sarah Tomaszewski , Fischer Eric , Gaussoin Sarah A. , Goldstein Felicia C , Hampstead Benjamin M. , Jayadev Suman , Jicha Gregory A , Kaye Jeffrey A , Kukull Walter A. , O'Connell Abigail H , Mechanic‐Hamilton Dawn , Neugroschl Judith A. , Papp Kathryn V. , Saykin Andrew J. , Sewell Margaret , Rapp Stephen R. 
Published: December 2023

AbstractBackgroundThe Uniform Data Set Neuropsychological Battery, Version 3 (UDSv3) was designed for face‐to‐face assessment of cognition within Alzheimer’s Disease Research Centers (ADRCs) in the USA. However, there are many reasons research participants may be unable to meet face‐to‐face for assessments. This inter‐ADRC, multi‐site study will validate a video‐administered adaptation of the UDSv3 battery in a diverse sample of ADRC participants. Here, we present study methods and summarize preliminary participant satisfaction ratings with VCog procedures.MethodRemote video cognitive assessments (Vcog) are being administered 4‐8 weeks before or after annual in‐person UDSv3 cognitive assessments, in counterbalanced order, to 500 participants from 12 ADRCs. Participants were previously classified as having normal cognition (NC), MCI, and mild dementia. Participant ratings of satisfaction, acceptability, and preference for test modality are being obtained, and psychometric characteristics of the video battery relative to face‐to‐face administration evaluated. Concordance between adjudicated outcomes (NC, MCI, dementia) between modalities is also being examined.ResultOf currently enrolled participants from four sites (N = 29 (NC = 14, MCI = 13 and dementia = 2); age: 72.9 (8.9) years; education: 16.2 (2.5) years; 62.1% female; 82.8% non‐Hispanic white), 85% report using video‐conferencing platforms more frequently because of COVID‐19 and 83% of that group anticipate continued use in the future. Participants reported (1 = very easy/likely to agree; 5 = very difficult/likely to disagree) that the testing was convenient (M = 1.14 (.44)), visits were very easy to initiate (M = 1.34 (.72)), technology was very easy to use (M = 1.00 (.00)), and task instructions were easily understood (M = 1.28 (.80)). Seventy‐six percent found video testing to be more convenient than in‐person testing and 24% found it equally convenient. Forty‐eight percent said they would choose video sessions in the future, 21% chose either video or in‐person, and 31% chose in person.ConclusionVideo‐based remote neuropsychological assessments have the potential to greatly benefit research and reduce participant burden. Initial findings from this large validation study of the UDSv3 suggest that older adults of varying cognitive statuses find the video‐adapted UDSv3 cognitive battery to be convenient and easy to use. Additional available data regarding participant satisfaction data will be reviewed.
Microtubule‐associated protein tau (MAPT) in the lens of the eye in non‐transgenic and transgenic tau mutant (P301S) mice
Authors: Moncaster Juliet A , Minaeva Olga , Goldstein Lee E 
Published: December 2023

AbstractBackgroundWe previously discovered that Aβ accumulates in the cortical/supranuclear region of the lens in people with Alzheimer’s Disease (AD) (Goldstein et al., 2003) and Down Syndrome (DS; (Moncaster et al., 2010). We also demonstrated Aβ in the Tg2576 APP Swedish mutation AD mouse model (Moncaster et al., 2022). Another protein that is involved in AD is Microtubule‐Associated Protein Tau (MAPT). Tau is expressed in the brain and becomes hyperphosphorylated in AD eventually forming neurofibrillary tangles. Tau has previously been reported to be expressed in the mouse lens (Bai et al., 2007; Zhao et al., 2013) but the results vary depending on the mouse model. Here we investigated whether tau protein was expressed in non‐transgenic mouse lenses and in a transgenic tau mutant (P301S) mouse model. We also studied whether cataracts may develop in this P301S tau mutant mouse model.MethodP301S tau mutant transgenic and non‐transgenic mice were bred and maintained at Boston University. Breeder mice were purchased from The Jackson Laboratory, Bar Harbor, ME. Male and Female transgenic and non‐transgenic mice were sacrificed throughout their lifespan at ages 3‐12 months. Mice were perfused with phosphate buffer saline, lenses were isolated and then imaged under two different sources of light using a D70 digital Nikon camera and a custom‐adapted Zeiss stereophotomicroscope. Lenses were then snap frozen and analyzed by Western Blotting using tau antibodies.ResultP301S transgenic and non‐transgenic mouse lenses all expressed tau during their lifespan when analyzed by Western blot. P301S transgenic lenses demonstrated an additional higher molecular weight band compared to the non‐transgenic mice. No cataract phenotype was observed in transgenic or non‐transgenic mouse lenses.ConclusionThere was no overt difference in lens phenotype between the P301S transgenic and non‐transgenic mice. However, the banding pattern observed by Western blot for P301S transgenic mice compared to non‐transgenic was different. Our data suggest the P301S tau mutation affects tau processing but does not result in a cataract phenotype. Based on our current and previous results, the data suggests that Aβ may play a more significant role than tau in lens pathology in AD.
Analytical Validation of Novel microRNA Panel for Risk Stratification of Cognitive Impairment
Authors: Kunwar Arzu , Ablordeppey Kenny K , Mireskandari Alidad , Sheinerman Kira S. , Kiefer Michael , Umansky Samuil R. , Kumar Gyanendra 
Published: December 2023

AbstractBackgroundWe have been developing a novel approach to identify risk of early cognitive impairment in patients by profiling of brain‐enriched and inflammation‐associated microRNA (miRNA) biomarkers, isolated from the plasma of cognitively normal and cognitively impaired patients. Here, we present the analytical validation of a miRNA panel, (CogniMIR®), for the expression of 24 miRNAs for large‐scale testing of plasma specimens in a clinical laboratoryMethodmiRNA from plasma specimens was isolated using the MagMAX mirVana kit (ThermoFIsher). 24 synthetic miRNAs oligos (IDT) werecombined and diluted to create quantification markers for making standard curves. RT was performed using miRCURY LNA RT kit. qPCR for miRNA profiling was carried out using custom plates (Qiagen), pre‐plated with lyophilized miRCURY LNA‐based primers for 24 miRNAs of the (CogniMIR®) panel. qPCR was perfomred on a Quantstudio 7 Flex instrument.ResultSynthetic RNA dilution series for 24 miRNAs (200,000 copies, 20000 copies, 2000 copies, 200 copies and 20 copies in a qPCR reaction) were tested on two different days. Average slope of the standard curves for all 24 miRNAs were determined to be in ‐3.3 to ‐3.7 range, and average R2 was 0.99 to 1. The data demonstrates that all 24 synthetic miRNAs of the (CogniMIR®) panel can be reliably and consistently detected even if the sample input is 20 copies in a qPCR reaction.Intra‐run repeatability analysis, using plasma samples from four subjects was tested by two operators on two different days. The data demonstrated that both operators generated repeatable and consistent Cts in both replicates on both days as seen by R2 value of 0.94 to 0.99. The inter‐run data analysis, using the same four samples tested by two operators on two different days, showed that reproducible Ct data were obtained by both operators when the experiment was repeated on the next day as demonstrated by R2 value of 0.96 to 0.97.ConclusionThese results indicate the utility of the (CogniMIR®) panel for miRNA profiling, and demonstrate that our miRNA detection technology is reliable, reproducible, and operationally friendly to test a large scale of specimens in any CAP/CLIA certified clinical laboratory.
Uncovering Novel Modifiers of Tau Aggregation and Pathology using a Proximity Proteomics Approach (BioID)
Authors: Lee Jannifer H , Morderer Dmytro , Khalil Bilal , Smith Courtney L , Wren Melissa C , Tsai Chih‐Wei , Liu Feilin , Croft Cara L , Carlomagno Yari , DeTure Michael , Dickson Dennis W. , Cook Casey N. , Golde Todd E , Petrucelli Leonard , Rossoll Wilfried 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is characterized by the accumulation of neurofibrillary tangles (NFTs), comprised primarily of microtubule‐associated protein tau. NFTs are defining hallmarks of AD and its accumulation into pathological oligomers and fibrils has been associated with cognitive decline in AD and other tauopathies. Despite its pivotal role in the disease process, we still have a poor understanding of how their formation, toxicity, and spread across brain regions is regulated via tau‐associated proteins that regulate the oligomerization, pathological accumulation, and seeding of tau in affected cell types and vulnerable brain regions.MethodWe have established two proximity‐dependent biotin‐identification (BioID) models as novel approaches to identify the composition and proximal molecular environment of tau aggregates. Using an in vitro and ex vivo model approach coupled with mass spectrometry, we have identified proteins that were primarily associated with mutant tau aggregates vs. soluble wildtype tau and stratified them based on significance, molecular pathway and druggability. Immunoblotting and immunofluorescence were performed to assess the interaction of endogenous and overexpressed top candidates with tau, along with visualization with NFTs in the context of human AD pathology to assess their impact on tau‐aggregate formation 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). The proteomic analysis from our combined proteomic datasets revealed that significantly changed proteins included candidates involved in RNA processing, as well as protein ubiquitination and proteasome degradation. We have begun validating proteins that are enriched in mutant tau in human tissue of AD, as well as primary tauopathies, that may be druggable targets for tauopathies.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.
Mapping cognitive trajectories in older adults with essential tremor
Authors: Dargie Samantha A. , Chapman Silvia , Nguyen Diep , Berry Diane S. , Ghanem Ali , Powell Allison , Rizer Sandra , Tsapanou Angeliki , Huey Edward D. , Louis Elan D. , Cosentino Stephanie 
Published: December 2023

AbstractBackgroundOlder adults with essential tremor (ET) are at increased risk for Alzheimer’s disease (AD) and related disorders. Examining cognitive trajectories within this population will enable better identification of individuals who evidence accelerated rates of change. Here we examine how variability in baseline cognitive performance affects trajectories of cognitive change within three subgroups of cognitively normal older adults: 1) those whose baseline neuropsychological scores were entirely within normal limits (WNL); 2) those with at least one low score considered to have unlikely clinical significance (UCS); and 3) those with at least one low score considered to have possible clinical significance (PCS).MethodOlder adults with ET completed comprehensive neuropsychological testing and clinical interviews, and 159 received a consensus diagnosis of cognitively normal. Participants were then subdivided into one of three categories defined above: WNL (N = 66, 75.38 ± 8.96 years of age), UCS (N = 54, 76.35 ± 10.25 years), and PCS (N = 37, 80.22 ± 9.00 years). Generalized estimating equations (GEE) were used to compare rates of change in global cognition, memory, executive function, attention, visuospatial, and language z‐scores over time across these groups. Participants were seen for two to four visits (24.98 ± 20.29 months). Models were adjusted for age, gender, and years of education.ResultAll three groups, WNL (β = ‐.005, p = .028), UCS (β = ‐.006, p = .011), and PCS (β = ‐.012, p = .002), evidenced decline in their memory performance over time, with the latter groups declining faster than the WNL group. Relative to the WNL and UCS groups, the PCS group also declined faster over time in overall cognition (β = ‐.010, p = .029) and in language (β = ‐.024, p = .035).ConclusionHeterogeneity in cognitive performance among cognitively normal older adults with ET predicts trajectories of cognitive decline longitudinally. Specifically, rates of decline were slowest in those with entirely normal test scores, and greatest in those whose scores were considered to have possible clinical significance. These preliminary results provide a starting point for further inquiry into the role of nuanced cognitive profiles in predicting rates of decline, impairment, and dementia in ET cases who may initially be labeled as “cognitively normal.”
Mitochondrial Mechanisms of Endothelial Cell Damage in Alzheimer’s Disease and Cerebral Amyloid Angiopathy
Authors: Parodi‐Rullan Rebecca M , Fossati Silvia 
Published: December 2023

AbstractBackgroundCerebrovascular endothelial cells (EC) are crucial regulators of cerebral homeostasis and function through the maintenance of the blood‐brain barrier (BBB). ECs damage and/or dysfunction may result in defects in brain clearance and perfusion, microhemorrhages, inflammation, and neurodegeneration. Damage to the ECs may result from cardiovascular risk factors (CVRF) such as high levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy). In Alzheimer’s Disease (AD) and Cerebral Amyloid Angiopathy (CAA), the presence of a CVRF may further exacerbate cerebrovascular function and neurodegeneration. EC do not rely highly on mitochondrial ATP production as they are glycolytic cells. Instead, EC mitochondria serve mostly as signaling organelles, which sense cellular damage and mediate downstream pathways such as inflammation. In this study, we aim to understand the mechanistic nature of endothelial mitochondrial dysfunction and its elicited pathways in Aβ‐ and mixed (Aβ+HHcy)‐mediated vascular pathologies. Understanding the mechanisms by which the mitochondria mediate EC inflammation, may pave the way to new roads for therapeutic advancements in the field.MethodHuman brain microvascular ECs were challenged with Aβ, Hcy, or the combination. Mitochondrial metabolic function, inflammatory cascades and signals, and EC barrier function were assessed.ResultThe presence of Aβ, but not Hcy, induced deficits in mitochondrial respiration and ATP production. In addition, there is evidence of mitochondrial fragmentation and the expression of fission proteins. Preliminary results further suggest a release of mitochondrial danger associated molecular patterns (mtDAMPs) that can promote an inflammatory cascade. The mitochondrial damage and subsequent inflammatory response are associated with an increase in EC barrier permeability and cytokine release, which is exacerbated in the presence of Hcy.ConclusionThe EC dysfunction associated with Aβ is accompanied by severe deficits in mitochondrial metabolism and the release of mtDAMPS. The presence of Hcy exacerbates some of the detrimental effects of Aβ, particularly on mtDAMPS and BBB function, but Hcy does not appear to affect mitochondrial metabolic changes. Overall, our results reveal a novel role for mtDAMPs in vascular dysfunction in the presence of Aβ and/or Hcy.
The prevalence of young‐onset dementia in the Netherlands: a prospective study
Authors: Bodde Hanna E. , Kolman Guy , Bakker Christian , Peetoom Kirsten , van der Flier Wiesje M. , Raymond Koopmans , Verhey Frans R.J. , de Vugt Marjolein , Papma Janne M. ,   the PRECODE consortium
Published: December 2023

AbstractBackgroundAlthough dementia is often associated with old age, it also occurs below the age of 65. People with so called young‐onset dementia (YOD) have different needs compared to people with late‐onset dementia (LOD), however, most health care facilities are primarily directed at older patients. Accurate numbers of the prevalence of YOD are necessary to determine the required budget, set priorities by policy makers and ensure sufficient and appropriate health care.MethodIn this study we investigated the 1 year prevalence of YOD in two predefined catchment areas in the Netherlands: an urban and a rural area, together representative for the Dutch population. We recruited health care professionals working with individuals with YOD (case managers, neurologists, psychologists, psychiatrists and nursing home staff) and asked them to register each YOD patient they encountered. Cases were included if persons had a diagnosis of YOD before the age of 70 or displayed symptoms before the age of 65, and lived within the catchment area. The collection of minimal personal identifiers per patient resulted in a unique personal code, which was used to prevent double counting.ResultHealth care professionals registered 409 individuals with YOD within the urban area and 209 individuals within the rural area, which translates to respectively 41.5 and 36.6 per 100.000 population in the group aged 30 to 65 years. Alzheimer disease was the most common diagnosis (52,3% and 53,8%), followed by vascular dementia (26,3% and 11,2%) and frontotemporal dementia (7,3% and 8.6%). Other characteristics such as living situation, as well as cultural background will be analyzed.ConclusionPreliminary data point out that the prevalence of people with YOD in the Netherlands is between 36.6 and 41.5 per 100.000 population. This prospective case finding study also shed light on methodological issues in prevalence research. Advantages are a more accurate case finding. Disadvantages are higher costs and a great dependency on other health care professionals.