bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phosphorylated tau in the Down syndrome brain: Age related increases and comparison to late‐onset Alzheimer’s Disease
Authors: Pascual Jesse R. , Nguyen Halyma , Ngo Phong , Andrews Elizabeth J. , Kofler Julia , Ikonomovic Milos D , Lai Florence , Phelan Michael J. , Head Elizabeth ,   Alzheimer Biomarkers Consortium — Down Syndrome (ABC‐DS)
Published: December 2023

AbstractBackgroundIndividuals with Down Syndrome (DS) have an increased risk of developing Alzheimer’s Disease (AD) with nearly all individuals exhibiting neuropathological changes in the brain by age 40 years, and with a mean diagnosis of dementia by age ∼55 years. The purpose of this postmortem study was to characterize the age‐associated burden of several tau phosphorylation epitopes, including threonine (pT) 181, 217, and 231 by immunohistochemistry in the frontal cortex. We hypothesized that cerebral pT burden would increase with age in DS but not in controls and be higher in DS with AD neuropathology (DSAD) compared to late‐onset AD (LOAD).MethodWe examined 117 brains from: controls (non‐DS n = 53; ages 1‐91), DS without AD (n = 13; ages 1‐48), DSAD (n = 31; age 43‐68), and LOAD (n = 20; ages 63‐96). Serial sections from the frontal cortex were cut at 30µm and immunostained for phosphorylated tau pT181, pT217 and pT231. Whole slide images were digitized and analyzed by Aperio ImageScope software. The % area for each type of tau was quantified using positive pixel counts. Spearman rank correlations on log‐transformed data were used to test for positive age associations and t‐test was used to compare pT between DSAD and LOAD.ResultIn control cases, there was a positive correlation of age with pT181 (r = 0.47 p<0.001) but not with pT217 or pT231. In DS cases across the lifespan (DS and DSAD combined) displayed a positive correlation of age with pT181 (r = 0.70 p<.001), pT217 (r = 0.70 p<.001), and pT231 (r = 0.42 p = 0.005). DSAD cases had significantly higher pT181, pT217 and pT231 (p<.001) than late‐onset AD and control cases.ConclusionThese results suggest that tau phosphorylation for these epitopes is more positively correlated with age in people with DS than people without DS. Although pT181 increased with age in both cohorts, pT217 and pT231 showed a positive correlation with age in people with DS but not controls. Fluid biomarker studies focused on pTau in longitudinal cohorts of people with DS with subsequent brain donation will help reveal the link between peripheral and central pTau levels.
COVID‐19 vaccination hesitancy among people with dementia
Authors: Ciopleias Bogdan , Ungureanu Larisa , Rusu Diana , Diaconu Stefania , Irincu Laura , Despa Irina , Falup‐Pecurariu Oana , Zarnoveanu Anca , Opritoiu Bianca , Murasan Iulia , Kakucs Cristian , Cusnir Malina , Falup‐Pecurariu Cristian 
Published: December 2023

AbstractBackgroundpeople with dementia is a vulnerable category during COVID‐19 pandemic. COVID‐19 vaccination hesitancy was one of the main issues during pandemic with multiple factors involved. Aim of the study: to evaluate COVID‐19 vaccination hesitancy among people with dementia and factors involved.Methodprospective study on 134 patients (60.44% females) with a mean age of 73.45 ± 17.12 years. We used a standardised questionnaire to assess the attitude and risk factors of COVID‐19 vaccination hesitancy. There were two assessment periods: 1.) 01.07.2021 – 31.09.2021 and 2.) 01.02.2022‐ 31.04.2022.Resulta total of 25 (18.65%) people with different form of dementia were vaccinated during the first study period. For the remaining 110 patients, vaccination hesitancy involved (one or multiple factors): vaccine insufficient tested (61 patients, 55.45%), possible serious side effects (25 patients, 22.72%), safety of COVID‐19 vaccine over dementia (74 patients, 67.27%), and worsening of cognition symptoms (63 patients, 57.27%). A number of 51 patients (46.36%) were advised by the family and relatives to wait, not to vaccinate in that period. Intention to vaccinate in the future was expressed by 39 patients (35.45%): 10 very likely (25.64%) and 29 (74.35%) likely. Patients with dementia living in rural parts, with relatives with high frequency of vaccination hesitancy are more likely to hesitate to vaccinate. They get the information especially from family members and TV.ConclusionCOVID‐19 vaccination hesitancy among people with dementia involve concerns related to possible side effects of the vaccine and risk of worsening of dementia symptoms.
The NIA Genetics of Alzheimer’s Disease Data Storage Site API: a toolkit for exploring Alzheimer’s disease genetics and genomic annotations
Authors: Greenfest‐Allen Emily , Kuska Pavel P. , Lee Wan‐Ping , Leung Yuk Yee , Valladares Otto , Wang Li‐San 
Published: December 2023

AbstractBackgroundNIAGADS is a repository for genotypic data relating to the study of the genetics of Alzheimer’s disease and related dementias (AD/ADRD). To facilitate access to unrestricted data in the repository and support research collaborations with the AD Sequencing Project (ADSP), NIAGADS has created several public databases. Programmatic access to these resources is essential for many bioinformatics applications exploring AD/ADRD genetics. These databases include: the Alzheimer’s GenomicsDB, an interactive knowledgebase for mining NIAGADS summary statistics datasets that provides detailed reports of AD/ADRD‐risk associations for >250 million annotated variants and their potential gene targets; the AD Variant Portal (ADVP), a catalog of AD/ADRD genetic associations curated from recent literature in the context of both genes and variants; VariXam, which reports variants detected from the ADSP’s whole‐genome and whole‐exome sequencing data; and FILER, an indexed database of harmonized functional genomics and gene/variant annotations containing ∼80k searchable data tracks.MethodWe have created a RESTful Application Programming Interface (REST API) to support integration of NIAGADS datasets and annotations assembled in these public resources into software applications. Calls to the API are based on simple URLs that specify the feature type (e.g., gene, variant, or locus), feature identifier(s) and filter criteria (e.g., NIAGADS resource, or dataset and bio‐source properties), defining an intuitive interface for programmatic access. API calls for gene or variant records return functional annotations as well as genetic evidence for AD/ADRD‐risk. Queries can also be made against FILER or the GenomicsDB to retrieve functional annotations and risk‐associated variants within a genomic span of interest across one or multiple datasets. The API supports both single‐lookups and batch queries, with paginated results to improve query and response times.ResultThe NIAGADS API establishes a simple framework for sharing and integration of NIAGADS datasets and annotated gene and variant records into analysis pipelines. Use of the API requires only a HTTPS library and JSON parser, permitting large‐scale programmatic access independent of any specific programming language.ConclusionThe NIAGADS REST API promotes data sharing and reuse among the AD/ADRD research community. Information about accessing this toolkit as it becomes available can be found on the NIAGADS website (https://www.niagads.org).
Plasma biomarkers as stand‐alone tests in the diagnosis of Alzheimer’s disease
Authors: Therriault Joseph , Benedet Andrea Lessa , González Escalante Armand , Jonaitis Erin M. , Ashton Nicholas J. , Karikari Thomas K , Tissot Cécile , Servaes Stijn , Rahmouni Nesrine , Lussier Firoza Z , Stevenson Jenna , Milà‐Alomà Marta , Pascoal Tharick A. , Vitali Paolo , Gauthier Serge , Zetterberg Henrik , Johnson Sterling C. , Blennow Kaj , Suarez‐Calvet Marc , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackgroundSeveral recent studies have provided evidence for high diagnostic performance of plasma biomarkers for AD, with Area Under the Curve values sometimes exceeding 90%. However, positive and negative predictive values are rarely reported yet are critical for interpreting individual‐level screening test results.MethodWe determined positive and negative predictive values of plasma biomarkers (p‐tau181, p‐tau217, p‐tau231, GFAP and NfL) for biological AD (A+T+, determined either with PET or CSF) in the TRIAD, WRAP, ALFA+, BIODEGMAR, ADNI and McGill memory clinic cohorts (total n = 2219). We also determined positive and negative predictive values for specific clinical scenarios: MCI and mild AD – two populations that may benefit from disease‐modifying therapies in AD. Prevalence estimates of biological AD in these groups were taken from the Mayo Clinic Study of Aging.ResultP‐tau217 had the highest positive and negative predictive values of all biomarkers in all cohorts, with above 80% positive and negative predictive values. In individuals with MCI, an etiologically heterogeneous syndrome, plasma p‐tau217 had sufficiently high performance to rule out biological AD in differential diagnosis. In mild AD dementia, plasma p‐tau217 could rule in biological AD, but follow‐up with PET/CSF will likely be needed to confirm the absence of AD.ConclusionPlasma biomarkers have the potential to be used as stand‐alone diagnostic tools in specific clinical scenarios. In MCI, a negative plasma p‐tau217 could rule out AD as a cause of cognitive impairment, but a positive result should be followed up with PET/CSF. In mild AD dementia, a positive plasma p‐tau217 result can rule in biological AD, but a negative result should be followed up with PET/CSF.
Drivers of underreport of memory loss in mild cognitive impairment due to Alzheimer’s and vascular disease
Authors: Briggs Anthony Q , Tall Sakina Ouedraogo , Bernard Mark A , Masurkar Arjun V. 
Published: December 2023

AbstractBackgroundWe examined self‐ and informant‐based report of memory loss in mild cognitive impairment due to Alzheimer’s disease (AD‐MCI) and vascular disease (Va‐MCI). We hypothesized that drivers of underreport would differ based on etiology and participant characteristics.MethodThis retrospective cross‐sectional study included participants with AD‐MCI (n = 2874) and Va‐MCI (n = 376) in the National Alzheimer’s Coordinating center dataset (NACC). Report of memory loss by the participant and informant was recorded as a binary (yes/no) value. We examined the role of demographic variables (age, sex, education, race, ethnicity) and neuropsychological variables (anxiety, depression on NPI‐Q) in driving underreporting of memory loss using Fisher’s exact test.ResultCompared to AD‐MCI, Va‐MCI was associated with significantly more underreport of memory loss by participants (24.5% vs 19.7%, p = 0.031) and informants (31.4% vs 21.6%, p<0.0001). Black/African American participants displayed higher rates of underreport in both AD‐MCI (27.1% vs. 18.4%, p<0.0001) and Va‐MCI (37.8% vs. 20.8%, p = 0.0022). Informant underreport was increased in both AD‐MCI and Va‐MCI for participants who were female (AD: 24.3% vs 18.6%, p = 0.0002; Va:38.1% vs 22.2%, p = 0.0011) and Black/African American (AD: 35.1% vs 19.3%, p<0.0001; Va: 48.8% vs. 26.5%, p = 0.0002), and in AD‐MCI for participants who had less than 16 years of education (AD: 23.9% vs 20.3%, p = 0.0262). In both AD‐MCI and Va‐MCI, anxiety associated with less underreport in both participants (AD: 13.1% vs 22.0%, p<0.0001; Va: 15.91% vs. 31.2%, p = 0.0071) and informants (AD: 10.8% vs. 25.5%, p<0.0001; Va: 15.9% vs. 37.4%, p = 0.0002). Underreport was similarly lowered with depression in participants (AD: 14.7% vs 21.4%, p<0.0001; Va: 15.1% vs 28.3%, p = 0.0146) and informants (AD: 11.5% vs 25.2%, p<0.0001; Va: 17.4% vs. 36.8%, p = 0.0008).ConclusionPersons with MCI and who have likely vascular presentations, or who are female, Black/African American, or have lower education are at increased risk for self‐ and/or informant‐based underreport of memory loss. Affective symptoms appear to increase the likelihood of correctly reporting memory loss. These factors may be particularly important in influencing interview‐based MCI detection and would suggest extra vigilance in persons at‐risk for self‐ or informant‐based misreport.
Biological Domain Network Analysis Identifies Potential Triadic Interaction between Mitochondria, Nuclear Epigenetics, and Synaptic Viability
Authors: Wiley Jesse C , Cary Gregory A. , Levey Allan I. , Carter Gregory W , Greenwood Anna K 
Published: December 2023

AbstractBackgroundThe AD endophenotypes initially described in the Common Alzheimer’s Disease Research Ontology (CADRO) were augmented and transformed into computationally implementable definitions for 19 discrete Biological Domains. These AD biological domains were employed in the development of molecular interaction networks depicting the signaling and protein‐protein interaction as a central bioinformatics resource for the TREAT‐AD consortium.Method19 AD biological domains were identified by iterative literature culling and model testing based on gene set enrichment analysis and gene ontology term identification. All 19 biological domains are defined by an exhaustive set of GO terms, allowing scientists everywhere to use the same criteria to define their large datasets in an unbiased manner. Network models were constructed from the leading‐edge genes from all AD‐risk enriched GO terms within each biological domain. The network models incorporate data from over 1700 transcriptomic brain studies and 1100 proteomic brains studies examining shifts in gene expression. These are employed as a reference tool for the formulation of specific hypotheses.ResultThe analysis of mitochondrial gene expression changes at both the transcriptomic and proteomic level identify deficits in both mitochondrial energy production and metabolism along with a decrease in acetyl‐CoA production, a necessary element for many reactions including histone acetylation. This suggests that mitochondrial metabolic tone may modify epigenetic regulation through lysine acetyltransferase (KATs) independently from ATP production. Examination of decrements in KAT activity from other model systems suggest a particularly robust impact on synaptic gene expression, implying a potential interaction between mitochondrial metabolism and synaptic gene expression independent of energy production. Intriguingly, some elements of a protein module identified by TREAT‐AD large‐scale deep proteomic analysis found to be most tightly associated with AD pathology and cognitive decline, are tightly associated with this model.ConclusionThe biological domains were constructed as a computational resource to facilitate hypothesis generation within the TREAT‐AD consortium, and here are implemented to highlight one emerging interaction between domains that may imply new mechanisms of disease regulation coupling between mitochondria and synaptic viability through shifts in epigenetic regulation.
Depression and the relationship between neurocognition and functional status and decline within ethnoculturally diverse middle and older adults
Authors: Breen Elizabeth Anne , Arentoft Alyssa , Cham Heining , Oleas Denise S. , Slaughter Alex W. , Camuy Alicia M , Schuck Lauren A , Hart Rebecca , Talavera Sandra , Mindt Monica Rivera ,   The Study of African‐Americans and Latinas/os for Understanding Dementia (SALUD)
Published: December 2023

AbstractBackgroundEthnoculturally diverse (e.g., non‐Latinx Black (NLB), Latinx) older adults are up to twice as likely as non‐Latinx White (NLW) older adults to experience depressive symptoms. While the relationship between neurocognition (NC) and functional status (e.g., everyday functioning) in older adults is well‐established, the impact of depression remains unclear in diverse populations. We assessed the influence of depression on the relationship between NC and functional status in a sample of Latinx, NLB, and NLW middle‐aged/older adults.MethodThis cross‐sectional study included 50 NLB, 45 Latinx, and 38 NLW (N = 133) adults (59% female; 39% with HIV; M
age = 65.3, SD = 6.69; M
ed = 13.9, SD = 3.22) who completed the Beck Depression Inventory‐II (BDI‐II), Activities of Daily Living (ADL) scale, and a comprehensive NC battery. Demographically‐corrected T‐scores were used to compute global NC and domain average T‐scores (global cognition, executive function, learning, memory, verbal fluency). The BDI‐II Total Score (BDI‐tot), Cognitive‐Affective Subscale (BDI‐cog), Functional‐Somatic Subscale (BDI‐som), current functional status (ADL‐tot), and decline over time (ADL‐dec) were computed. A series of hierarchical linear regressions (HLRs; Step 1: BDI‐tot; Step 2: NC global/domain NP T‐scores) were computed to predict ADL‐dec in each ethnocultural group. To assess age effects in this relationship, additional HLRs (Step 1: BDI‐tot, age, BDI‐tot×age and Step 2: NC global T‐score) were computed.ResultBDI‐tot, BDI‐cog, and BDI‐som were significantly correlated with ADL‐dec (r
s = .58‐.64, ps<.01) in NLW adults. However, in NLB adults, only BDI‐cog was correlated with ADL‐dec (r = .51, p<.01), while in Latinx adults, both BDI‐tot and BDI‐som were significantly related to ADL‐dec (r
s = .38, ps <.05). Within NLB adults, BDI‐tot accounted for 15‐16% of the variance in ADL‐dec (ps<.05), but NC scores did not uniquely contribute to the model/s (ΔR
2 = 0‐.11, ps>.05). Across ethnocultural groups, BDI‐tot×age did not significantly predict ADL‐dec. However, in the NLW group BDI‐tot×age was a significant predictor of ADL‐tot (ΔR
2 = .53, p<.05).ConclusionDepressive symptoms are associated with functional decline, particularly in NLB middle/older adults. Cognitive‐affective symptoms may better predict functional status in middle/older NLB adults, while somatic‐functional symptoms are associated with functional decline in Latinx middle/older adults. Future studies should examine the longitudinal impact of depression on functional status/NC within ethnoculturally diverse older adults.
Antidepressant exposure and long‐term dementia risk in a nationwide study on U.S. Veterans with major depressive disorder
Authors: Cejudo Jaime Ramos , Corrigan June , Zheng Chunlei , Swinnerton Kaitlin N. , Jacobson Sean R , La Jennifer , Betensky Rebecca A , Osorio Ricardo S , Madanes Sharon , Pomara Nunzio , Iosifescu Dan , Brophy Mary T , Do Nhan V , Fillmore Nathanael R 
Published: December 2023

AbstractBackgroundMajor depressive disorder (MDD) is associated with dementia risk. The use of antidepressants in MDD has been reported to influence long term risk of Alzheimer’s disease and related dementias (ADRD), but studies are conflicting.MethodsWe used inverse probability weighted Cox models with time‐varying covariates in a retrospective cohort study among Veterans with MDD within the US Veterans Affairs health‐care system from 1/1/2000 to 6/1/2022. We focused on patients receiving their first diagnosis of MDD at the age of 60 or above. Our outcome was incident ADRD and unrelated death was considered as a competing risk event. Exposed intervals were defined using prescription data. Models were weighted for the inverse probability of falling in each of the treatment arms (exposed or not) at the beginning of each treatment period based on demographic and clinical covariates updated with most recent information (1‐year prior). The cumulative effect of antidepressant exposure (No. days) was also studied.ResultA total of 24,964 patients with MDD were identified, of which 45% were on antidepressants (Table 1). Median treatment time was 4.10 years [2.56, 6.10]. No relationship was observed between the number of days on antidepressants and the risk of ADRD (Figure 1). No significant associations were seen for the effect of being exposed to antidepressants (any) vs unexposed (HR = 0.94, 95%; CI: 0.81‐1.09) or exposed to each antidepressant drug classes vs unexposed (SSRI HR = 0.93, 95%; CI: 0.79‐1.10; NDRI HR = 0.80, 95%; CI: 0.42‐1.54; SNRI HR = 0.87, 95%; CI: 0.54‐1.41). (Table II). In sensitivity analysis stratified by sex, a reduction in risk due to antidepressant exposure was suggested in female patients, however the number of cases was small (HR = 0.30, 95%; CI: 0.12‐0.81; P = 0.02)).ConclusionOur study conducted in a large population and after accounting for confounders shows that antidepressant exposure has no effect on ADRD risk. Our result suggesting an association in female patients should be interpreted with caution due to a small sample size and deserves further attention. Replication of results in an external population with a larger representation of female patients is needed for further validation
Aging drives chronic exacerbated interactions of disease associated microglia and CD8+ T cells following traumatic brain injury
Authors: Gebhardt Jessica , Ashley Clair , Wendell Ben , Goulding Danielle S. , Schwartz James , Morganti Josh M. 
Published: December 2023

AbstractBackgroundAged individuals are highly susceptible to adverse outcomes following traumatic brain injury (TBI). Despite worsened correlates related to functional outcomes following injury, as well as increased likelihood to acquire a TBI, our understanding of the cellular mechanisms governing the poorer outcomes associated with aged individuals post‐TBI are not well‐characterized.MethodIn the current study, we examined microglial heterogeneity following TBI, in our mouse model of focal TBI across both acute (3d) and chronic (28d) intervals in both young (4m) and aged (18m) male C57B6J mice. At the appropriate interval, brains were collected and processed for single cell RNAseq (scRNAseq), spatial transcriptomics, and histology. A follow up study examining the interaction of TBI and aging upon T cell receptor (TCR) sequences was utilized to examine clonal expansion and lymphocyte heterogeneity in young and aged mice chronically after TBI.ResultOur findings demonstrate that TBI drives diverse transcriptional heterogeneity of microglia in both the young and aged condition. Acutely at 3 days post injury an inflammatory response is seen both in the young and aged mice. However, chronically at 28 days post injury, the microglia from young animals more closely resemble their pre‐injury (i.e. Sham) phenotypes, in comparison to the aged brain where there is a persistence of Apoe‐linked ‘DAM‐like’ microglial response. Inferential analyses point toward these aging‐related chronic populations of microglia as having distinct transcription factor utilization and metabolic pathway enrichment, including Hif1α upregulation and interferon gamma (INFγ) signaling. Furthermore, linkage with chronically accumulated CD8+ T cells and interferon signaling may underlie these phenotypes. Using single cell TCR sequencing, we demonstrate stark contrasts in the responses due to aging and TBI in the clonal expansion of infiltrated CD8+ T cells chronically following TBI.ConclusionOur studies demonstrate that aging is a centrally associated with the persistence of chronically reactive microglia in the brain and that these responses are linked, in part, with the protracted accumulation of CD8+ T cells following TBI.