bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactive association of type 2 diabetes and subclinical CeVD markers with cognitive decline and incident dementia: A memory‐clinic study
Authors: Cui Jiangbo , Chen Christopher , Hilal Saima 
Published: January 2025

AbstractBackgroundAssociation of type 2 diabetes with cognitive decline and incident dementia in older adults remains inconsistent. In this study, we aim to investigate whether subclinical cerebrovascular disease (sCeVD) would modify this relationship.MethodA total of 654 participants underwent brain MRI at baseline, from whom 592 individuals with at least one follow‐up were selected for longitudinal analysis. Cognitive assessments, including Clinical Dementia Rating Sum‐of‐boxes (CDR‐SOB) and detailed neuropsychological tests, were performed annually for up to 5 years. sCeVD markers of interest were lacunes, white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), intracranial stenosis (ICS), and cortical infarcts.ResultDiabetes was associated with presence of lacunes, WMHs and ICS in multivariate‐adjusted model. Notably, a significant interaction term (diabetes × WMHs × time) was observed, especially among stroke‐free individuals, suggesting an interactive effect on cognition. Subgroup analyses showed association of diabetes with cognitive decline was stronger in participants with high WMHs but not significant in those with low WMHs. Moreover, participants with both diabetes and high WMHs showed the greatest cognitive decline in CDR‐SOB, global cognition, language, and memory, along with the highest risk of dementia.ConclusionOlder adults with diabetes compared those without had more sCeVD lesions, and the impact of diabetes on cognitive decline is contingent on the presence of high load WMHs. Our findings suggested that WMHs could be used for risk stratification among older adults with diabetes.
Transcriptomic changes preceding neurodegeneration in a C. elegans model of tau and TDP‐43 co‐pathology
Authors: Jadhav Vaishnavi , Eck Randall , Smukowski Samuel , Toscano Laura Garcia , Latimer Caitlin S , Valdmanis Paul N , Kraemer Brian C. , Liachko Nicole F 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD), the most common aging‐associated neurodegenerative dementia disorder, is defined by the presence of amyloid beta (Aβ) and tau aggregates in the brain. However, more than half of patients also exhibit aggregates of the protein TDP‐43 as a secondary pathology. Clinically, AD patients with secondary TDP‐43 pathology have more severe cognitive impairment, more rapid cognitive decline, worse brain atrophy, and a shorter disease course. TDP‐43 is already implicated in neurodegenerative disease as the major pathological protein aggregate in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD‐TDP), two other devastating neurodegenerative diseases. In patients with mixed Aβ, tau and TDP‐43 pathology, TDP‐43 dysfunction may synergize with neurodegenerative processes in AD, worsening disease. Using C. elegans models of mixed pathology in AD, we have shown that TDP‐43 specifically synergizes with tau but not Aβ, resulting in enhanced neuronal dysfunction, selective neurodegeneration, and increased accumulation of pathological tau.MethodTo identify cellular responses to mixed tau and TDP‐43, we have identified distinct transcriptomic signatures from two disease‐relevant timepoints preceding frank neuronal loss in C. elegans.ResultWe find that early disease associated changes are driven by tau, but a unique gene expression signature characteristic of co‐morbid tau and TDP‐43 emerges during aging. Using gene ontology and differential splicing analyses, we find significant changes in genes and pathways including lysosomal mediated degradation, lipid metabolism. We have characterized novel modifiers of tau and TDP‐43 identified from their responsive gene expression profiles in tau and TDP‐43 co‐expressing C. elegans.ConclusionEstablishing early cellular responses to co‐morbid tau and TDP‐43 is critical for understanding protective and pathogenic responses to mixed proteinopathies, and an important step in developing therapeutic strategies protecting against pathological tau and TDP‐43 in AD.
Loss of TDP‐43 function accelerates tauopathy and death of vulnerable neurons by promoting caspase 3‐mediated endoproteolytic cleavage of tau
Authors: Baghel Meghraj Singh , Burns Grace D , Tsapatsis Margarita , Mallika Aswathy P , Marx Shaelyn R , Li Tong , Wong Philip C 
Published: January 2025

AbstractBackgroundTDP‐43 proteinopathy, initially discovered in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, including Alzheimer’s Disease (AD). While such co‐pathology is strongly associated with worsened neurodegeneration and steeper cognitive decline, how these two pathologies influence each other to exacerbate neuron loss remains elusive. That loss of TDP‐43 splicing repression occurring in presymptomatic ALS‐FTD suggests that loss of TDP‐43 function could facilitate the pathological conversion of tau to accelerate tauopathy and neuron loss.MethodTo elucidate how loss of TDP‐43 function influence tauopathy, we used two complementary approaches to express a four‐repeat domain fragment of human tau (hTauRD) to seed tauopathy in CaMKII‐CreER;Tardbpf/f mice: 1) inducible transgenesis; and 2) intraparenchymal delivery of an adeno‐associated viral vector unilaterally in the hippocampus.ResultsHere, we found that depletion of TDP‐43 is sufficient to activate caspase 3‐dependent cleavage of tau and cell death of vulnerable neurons, such as those in CA3/2 of the hippocampus, in mice lacking TDP‐43 in their forebrains (CaMKII‐CreER;Tardbpf/f mice). To establish this mechanistic insight that the level of activated caspase 3‐dependent cleavage of tau may determine the vulnerability of neurons in AD cases harboring the co‐pathology of TDP‐43, we elevated levels of hTauRD in CaMKII‐CreER;Tardbpf/f mice to stimulate the activation of caspase 3. As compared to age‐matched controls, we show an additive impact of TDP‐43 loss‐of‐function and hTauRD to promote further increase of activated caspase 3 to elevate the cleavage of endogenous tau, thereby accelerating death of cells to also include neurons of the dentate gyrus and/or CA1.ConclusionTaken together with previous results documenting that activated caspase 3‐dependent cleavage of tau occurs in cases of AD and their mouse models, our findings strongly support the view that TDP‐43 loss‐of‐function accelerates tauopathy in vulnerable neurons by promoting caspase 3‐mediated endoproteolytic cleavage of tau, thereby exacerbating neuron loss in neurodegenerative disorders harboring co‐pathologies of tau and TDP‐43, and disclose for these human diseases a potential therapeutic target to attenuate neuron loss.
Neural correlates of emotion recognition in illiterate adults
Authors: Silva Vinicius Tinarelli , de Faria Rocha João Victor , Friedlaender Clarisse Vasconcelos , Antunes Augusto , Grinberg Lea T. , Maciel Francisca Izabel Pereira , Caramelli Paulo , de Paula França Resende Elisa 
Published: January 2025

AbstractBackgroundThe salience network (SN) functions as a dynamic switch between the default mode network (DMN) and the frontoparietal network (FPN), aligning with salience and cognitive demand. Dysfunctions in SN activity within the cognitive and affective domains are linked to a wide range of deficits and maladaptive behavioral patterns in various clinical disorders. Emotion recognition is pivotal in social interactions and can be affected in neurodegenerative disorders. The neural correlates of emotion recognition are well studied in adults with high levels of education, but few studies exist on neural correlates of emotion cognition in illiterate individuals.MethodCognitively healthy illiterate adults (with barely no formal education) underwent neuropsychological evaluation and brain MRI scans. Emotion recognition was assessed using the Ekman test. The CONN toolbox was used for functional brain connectivity analysis. We then correlated the Ekman total score with the salience network connectivity using a voxel threshold of p < 0.05 and a cluster threshold of p < 0.05.ResultA total of 108 participants aged 57.7 (±9.51) years, with 2.0 (±2.3) years of education, of which 72.6% were women were recruited, eight participants declined the MRI scan and five participants were excluded because of structural lesions found in the MRI leaving out 95 participants. Ekman total score was 19.9 ±4.3. There was a significant correlation between the Ekman total score and regions in the salience network, with the most prominent voxels at the Superior Parietal Lobule Left (407 voxels covering 28%); Frontal Pole Right (370 voxels covering 5%) and Cerebellum Crus2 Left (221 voxels covering 11%).ConclusionWe can see a correlation between the clusters of the salience network and the total score on the Eckman test in illiterate individuals. This suggests that the salience network is also related to social cognition in this particular group.
Distinct mouse models correspond to distinct AD molecular subtypes
Authors: Pandey Ravi S , Carter Gregory W , Howell Gareth R , Sasner Michael , Kotredes Kevin P , Oblak Adrian L , Lamb Bruce T. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a complex, multifactorial pathology with high heterogeneity in biological alterations. Our understanding of cellular and molecular mechanisms from disease risk variants to various phenotypes is still limited. Mouse models of AD serve as indispensable platforms for comprehensively characterizing AD pathology, disease progression, and biological mechanisms. However, selection of the right model in preclinical research and translation of findings to clinical populations are intricate processes that require identification of pathophysiological resemblance between model organisms and humans. Many existing clinical trials that showed promising efficacy in one particular mouse model later do not align with human trial results, assuming that study had consisted of a heterogeneous group of participants, and individual animal models may only recapitulate features of a subgroup of human cases. To improve interspecies translation, it is necessary to comprehensively compare molecular signatures in mouse models with subgroup of human AD cases with distinct molecular signatures.MethodWe performed transcriptomic and proteomics analysis on whole brain samples from mouse models carrying LOAD risk variants. To assess the human disease relevance of LOAD risk variants in mice, we determined the extent to which changes due to genetic perturbations in mice matched those observed in human AD subtypes and disease stages of AD in the ROS/MAP, Mayo and Mount Sinai Brain Bank cohorts. Genesets within these disease subtypes are highly co‐expressed and represent specific molecular pathways.ResultWe have identified that distinct mouse models match to distinct human AD subtypes in age‐dependent manner. Specifically, mouse models carrying human AD risk variants such as Abca7*A1527G showed strong correlation with inflammatory AD subtypes, while mouse models carrying risk variant such as Plcg2*M28L exhibited transcriptomics changes similar to non‐inflammatory AD subtypes.ConclusionIn this study, we highlighted that mouse model of AD may match to a particular subset of human AD subtypes but not all subtypes simultaneously, and that risk for these subtypes may be influenced by distinct AD genetic factors. Additional work toward validating and better understanding the role of each subtype key regulator in its matching mouse model will provide great value and have a great impact on future studies of AD.
The effect of VTA stimulation on hippocampal beta amyloid, tau protein accumulation and oxidative stress
Authors: Bakhtiarzadeh Fatemeh , Najafi_Zadeh Javad Mir , Shahpasand Koorosh 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a degenerative condition characterized by a progressive decline in cognitive function, predominantly affecting older individuals. AD is associated with a range of histopathological alterations, including the gradual demise of neuronal cells, the accumulation of amyloid plaques, and the formation of neurofibrillary tangles. Furthermore, research suggests that the brain tissue of AD patients is subject to oxidative stress, which manifests as the oxidation of proteins, lipids, DNA, and the process of glycoxidation, throughout the disease progression. Considering the potential effect of deep brain stimulation in the treatment of Alzheimer’s disease and the possible role of dopamine in this disease, in the present study the effect of the ventral tegmental area (VTA) stimulation was investigated in a mice model of Alzheimer‐like disease.MethodThis Alzheimer‐like model was created by bilateral injecting cis‐phospho‐tau into the dorsal hippocampus. A bipolar electrode was implanted in the VTA for stimulation at the frequency of 100 Hz. In Alzheimer‐like animals, the effect of electrical stimulation on the amount of tau protein and beta amyloid accumulation by immunohistochemistry and oxidative stress by ELISA test were investigated.ResultThe injection of cis‐phospho‐tau increased the phospho‐tau protein and beta‐amyloid accumulation. Applying VTA stimulation in Alzheimer‐like animals reduced tau and beta‐amyloid accumulation. In addition, it reduced some oxidative stress and inflammation indices, which were increased after the injection of cis‐phospho‐tau and increase anti‐oxidants.ConclusionIt seems that VTA stimulation reduce the accumulation of phosphor‐tau protein and amyloid beta, in addition factors involved in oxidative stress and inflammation. These ameliorative effects are at least partly through the activity of D1‐like dopamine receptors.
Variant‐gene pair in silico analyses and functional validation of LOAD GWAS loci in human brain‐relevant cell types identify EGFR as a target gene for potential drug repurposing
Authors: Leung Yuk Yee , Kuksa Pavel P. , Cifello Jeffrey , Greenfest‐Allen Emily , Boateng Louisa , Laub Shannon , Tulina Natalia , Schellenberg Gerard D. , Chesi Alessandra , Wang Li‐San 
Published: January 2025

AbstractBackgroundRecent studies suggest genome‐wide‐association‐studies (GWAS) loci confer their effects on microglia in late‐onset Alzheimer’s disease (LOAD) brains. Relatively fewer studies have investigated the effects of other genome‐wide significant loci (p<5e‐8) using human neurons.MethodGWAS itself cannot directly identify causal variant‐(effector)gene‐pairs as GWAS only reports the sentinel variant at a given locus. To map the physical interactions between GWAS‐implicated putative causal non‐coding variants and their corresponding effector genes in LOAD, we leveraged the post‐GWAS analytical framework, INFERNO, coupled with the largest harmonized functional genomics data catalog to date, FILER. Our goal was to unravel the effects of all 75 genome‐wide significant genetic loci reported in Bellenguez et al in human brain cell types. We searched for plausible evidence of causality for LOAD candidate variants in any brain‐specific variant‐gene pair through a total of 3,873 publicly curated datasets (123 enhancer, 3,153 epigenetics, 105 QTL) across 12 resources. We then validated the top variant‐gene pairs using high‐resolution promoter‐focused Capture C, ATAC‐seq and RNA‐seq datasets from several neuronal cell types and performed CRISPR interference.ResultThe computational variant‐gene analyses identified a novel candidate causal SNP, rs74504435 (r2 = 0.94 to sentinel SNP rs76928645) at the SEC61G locus, located between SEC61G/EGFR. With a CADD score of 15, it is predicted as “regulatory” by both ENSEMBL and regulomeDB2. rs74504435 is found in ChromHMM and EpiMAP brain enhancers, and perturbs the transcriptional factor OCT6, which controls Schwann cell myelination. The minor allele T is protective to LOAD and downregulates EGFR in GTEx brain cortex (p = 2.3e‐13), CommonMind (FDR p = 5.8e‐5), and ROSMAP DLPFC (FDR p = 8.6e‐9) datasets with the same effect direction. In our Capture C and ATAC‐seq datasets, the SNP resides in open chromatin and directly contacts EGFR in human iPSC‐derived cortical neurons and ES‐derived hypothalamic neurons. We further validated a regulatory role for the enhancer region containing rs74504435 on EGFR using CRISPR interference in human microglial cells.ConclusionTogether, we identified a novel LOAD‐associated neuronal enhancer that drives EGFR gene expression. Further research is needed to investigate if EGFR inhibitors approved as anti‐cancer drugs can serve as potential candidates for repurposing as LOAD therapeutics.
Revisiting the Wood Criteria for Frontotemporal Degeneration Pedigree Classification: 10 Years Later
Authors: Dratch Laynie , Kwiecinski Julia , Van Deerlin Vivianna M , Suh EunRan R , Hinks Allyson , Irwin David J , Massimo Lauren , Peskin Sara Manning , McMillan Corey T 
Published: January 2025

AbstractBackgroundPreviously, the Penn Frontotemporal Degeneration (FTD) Center developed and validated criteria to stratify pedigrees of patients with FTD by likelihood of identifying a genetic etiology (Wood, JAMA Neurol., 2013). Pedigrees were classified as high‐risk, medium‐risk, low‐risk, apparent sporadic, or unknown significance. Genetic testing for the three most common genes that cause FTD (C9orf72, MAPT, GRN) was completed to assess the detection rate of genetic cases per category. Given advances in FTD genetics, the current study aims to cross‐validate this pedigree classification criteria in an independent cohort and determine the extent to which consideration of newly identified disease‐associated genes increases the detection rate.MethodFirst, pedigrees in the initial cohort (n = 306) were reclassified when appropriate based on updated family history information. Next, we evaluated whether more comprehensive genetic analysis altered detection rates in the initial cohort. Then, we applied the Wood criteria to an independent cohort of pedigrees of probands with FTD‐spectrum disorders (n = 400) and assessed detection rate with testing for exclusively C9orf72, MAPT, and GRN, and then with broader sequencing.ResultIn the initial cohort, genetic analysis beyond C9orf72, MAPT, and GRN identified genetic etiologies in six additional pedigrees, five of which were in the high‐risk group, raising the overall cohort detection rate from 15% to 17%. In the independent cohort, when only C9orf72, MAPT, and GRN were analyzed detection rates were approximately 18% (72/400) overall, 67% (38/57) in the high‐risk group, 29% (15/51) in medium‐risk, 9% (6/70) in low‐risk, 3% (4/135) in apparent sporadic, and 10% (9/87) in unknown significance. Broader sequencing identified two additional genetic cases in the high‐risk group and one in the apparent sporadic group, increasing the overall cohort detection rate from 18% to 19%.ConclusionThese results reiterate the importance of gathering a detailed neurologic family history in genetic risk assessment for FTD. Given the emergence of gene‐specific clinical trials, we suggest that using this cross‐validated pedigree classification criteria provides an accurate first step in determining the likelihood of a genetic diagnosis. Genetic counseling and comprehensive testing should be routinely offered in clinical care for all patients with FTD, regardless of risk stratification.
Biological sex and multilingualism: The interaction of risk and reserve for dementia
Authors: Calvo Noelia , Siddiqui Rumsha , Phillips Natalie , Einstein Gillian 
Published: January 2025

AbstractBackgroundGlobally, females are at twice the risk of AD than males; in Canada, over 700,000 are living with Alzheimer’s disease and related dementia (ADRDs), with 72% being female. However, females maintain verbal memory in the face of more AD pathology than men. It is unclear how multilingualism, considered a resilience factor, might interact with the risk and resilience of sex. Thus, we wondered if female sex and multilingualism might interact to confer more resilience in individuals with Mild Cognitive Impairment (MCI) in a Canadian cohort: The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND).MethodNeuropsychology data from 270 female and male participants diagnosed with MCI were analyzed using female or male sex as a categorical variable with 2 levels: 116 women and 156 men. They self‐reported language use and history allowing a multilingualism score which identified 148 multilinguals, and 124 monolinguals. First univariate analysis was used to explore individual differences among the 4 groups: women, men, monolinguals, multilinguals. Then, different models using Path analysis and Structural Equation Modelling (SEM) were used to create a Cognitive Reserve index (CRI) which accounted for multilingualism and biological sex. Simple regressions were used to estimate cognitive performance in relation to the CRI.ResultFemales with MCI had higher scores than men in The Rey Auditory Verbal Learning Test (RAVLT); this effect was even stronger in those women who had ever used Hormone replacement therapy. Multilinguals outperformed monolinguals in the verbal fluency component of the Delis‐Kaplan Executive Function System (D‐KEFS) which was performed in English. Moreover, CRI significantly predicted increased performance in tasks measuring visuospatial memory and attention.ConclusionPrevious mixed‐sex studies have suggested that multilingualism may be a proxy for cognitive reserve delaying the onset of AD symptoms for approximately 4‐5 years. Other studies have indicated that women are more affected by AD than men but that verbal memory may be a form of reserve for them. Here, we show that multilingualism and biological sex together may associate with increased neuropsychological performance even in the presence of MCI.
The MR1/MAIT cell axis reduces phagocytosis and dystrophic neurites in Alzheimer’s disease
Authors: Johnson Season K , Ackley Samantha , Warren Jalyn , Brutkiewicz Randy R 
Published: January 2025

AbstractBackgroundPlaques are a hallmark feature of Alzheimer’s disease (AD). We found the loss of mucosal‐associated invariant T (MAIT) cells and its antigen‐presenting molecule MR1 caused a delay in plaque pathology development in AD mouse models. However, it remains unknown how this axis is impacting microglial response and dystrophic neurites. This study aims to understand the impact of MAIT cells and microglial MR1 in AD.MethodBrain tissue from various ages of 5XFAD mice and those that are MR1‐deficient (MR1KO), was analyzed for the presence of MAIT cells. Methoxy‐X04 was used to analyze the phagocytic capacity of microglia ± MR1. Immunofluorescent microscopic analysis of dystrophic neurites in the brain was performed with antibodies against microglia, Aβ, Lamp1, Ubiquitin, and nAPP.ResultInjection of Methoxy‐X04 in 5XFAD and 5XFAD/MR1KO mice revealed reduced levels of Methoxy‐X04 uptake in CD11b+CD45low cells in the MR1 KO group (P < 0.05). However, this remained unaltered in the CD11b+CD45high cells. In the 5XFAD/MR1 KO group there was reduced expression of LAMP1, Ubiquitin, and nAPP in the hippocampus at 8 months compared to 5XFAD mice (P < 0.001). In the cortex only nAPP remained reduced in the 5XFAD/MR1 KO mice (P < 0.001).ConclusionThe loss of MR1 and MAIT cells reduced the phagocytic capacity of microglia and dystrophic neurite formation in the hippocampus. Our data indicate a potential detrimental role for MR1 and/or MAIT cells in AD pathology. Understanding this axis of the innate immune system could provide new clues as to the overall role of innate immunity in AD and its potential as a therapeutic target in AD.