bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying the Severity of Dementia Based on Cognitive Performance and Index of Independence in Basic Activities of Daily Living
Authors: Huynh Duong , Ghomi Reza Hosseini , Huang Bin , Patterson Mary 
Published: January 2025

AbstractBackgroundAlzheimer’s disease and related dementias (ADRD) are characterized by impairments in an individual’s cognitive and functional abilities. Computerized cognitive tests have been shown to be effective in detecting mild cognitive impairment and ADRD but whether they can stage the ADRD disease remains to be studied.MethodRetrospective analysis was performed on a BrainCheck dataset containing 1,749 ADRD patients with different cognitive and functional assessments completed for cognitive care planning, including the Dementia Severity Rating Scale (DSRS), the Katz Index of Independence in Activities of Daily Living (ADL), and the BrainCheck cognitive assessment battery (BC‐Assess). The patients were staged according to their DSRS total score (DSRS‐TS): 971 mild‐stage (DSRS‐TS: 10‐18), 664 moderate‐stage (19‐26), and 114 severe‐stage (37‐54) patients. Pearson correlation was calculated to assess the strength of associations between BC‐Assess overall score (BC‐OS), ADL total score (ADL‐TS), and DSRS‐TS. A three‐way Multivariate‐Analysis‐of‐Variance (MANOVA) was used to examine how the ADL‐TS and the BC‐OS combined differ across stages after controlling for age group and gender. Multinomial logistic regression was used to evaluate the possibility of using patients’ ADL‐TS and/or BC‐OS to predict their condition.ResultCorrelations between scores are moderate. A stronger correlation was found between the DSRS‐TS and the ADL‐TS (r = ‐0.58) than that between the DSRS‐TS and the BC‐OS (r = ‐0.54) and between the ADL‐TS and the BC‐OS (r = 0.38). The ADL‐TS and BC‐OS vary significantly across ADRD stages. ROC analysis of the logistic regression shows that, although either ADL‐TS or BC‐OS can effectively predict ADRD stage, highest accuracy is when both scores are included in the model (ROC‐AUC: mild = 0.94; moderate = 0.77; severe = 0.9; micro‐average = 0.93). Except a low sensitivity in identifying the moderate group, a sensitivity/specificity of at least 76% was observed for all models and stages.ConclusionOur results suggest a progressive decline in both cognitive and functional abilities as patients move through the stages of ADRD. Among ADRD patients, performance in a cognitive assessment (BC‐Assess) or in basic activities of daily living (ADL) is informative of severity diagnosis. However, combining both measures generates highest accuracy.
Analysis of genetic variants TREM2 and plasma gingipain K and R level in patients with Alzheimer’s disease
Authors: Hurla Mikolaj , Banaszek Natalia , Florczak‐Wyspianska Jolanta , Michalczyszyn Olivia , Owecki Wojciech , Kozubski Wojciech , Dorszewska Jolanta 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by an acquired, progressive impairment of cognitive functions. The pathogenesis of this disease remains unknown. It is explained based on the following theories: amyloid cascade, inflammation, vascular, and infection hypothesis. Recently hypothesized that Porphyromonas gingivalis may be a unifying factor linking the different hypotheses related to AD pathogenesis. P. gingivalis produces cysteine proteinases called gingipain K and gingipain R, which are virulence factors. P. gingivalis plays a significant role in periodontitis. Periodontitis is provoked by bacterial lipopolysaccharide, which then leads to an immune response. The TREM2 gene is involved in the immune response. P. gingivalis may be responsible for reducing the expression of the TREM2 gene and TREM2 protein. TREM2 protein deficiency may impair Aß degradation, which may significantly increase the risk of AD. It has been showed a tendency for earlier onset of symptoms and faster progression of AD in people who were carriers of the potentially pathogenic TREM2 (rs143332484) CT variant of this gene. The study aimed to analyze plasma gingipain K and R concentration and TREM2 (rs143332484) genetic variants in AD patients, control subjects related to AD cases (CR), and control subjects without a family history of AD (CU).MethodThe studies were conducted on 74 subjects (AD and controls). The TREM2 genotype was determined by HRM and sequencing. The gingipain K and R concentrations were determined by the ELISA method.ResultsThe highest concentration of gingipain K (p = 0.0820) and R (p = 0.0740) was found in AD compared to CR, and CU. The TREM2 CT genotype was most common in AD patients. Patients with this genotype had the highest concentration of gingipain K. However, AD patients with the TREM2 CC genotype showed statistically significantly higher concentrations of gingipain R (p<0.05) compared to CR and CU.ConclusionIt seems that both gingipains K and R may be involved in the pathogenesis of AD.
Longitudinal variability in resting heart rate associates with empathy decline in pre‐symptomatic and symptomatic familial frontotemporal degeneration
Authors: Rhodes Emma , Massimo Lauren , Dratch Laynie , Irwin David J , Boeve Brad F. , Heuer Hilary W. , Boxer Adam L. , Rosen Howard J. , Rankin Katherine P. , Sturm Virginia , McMillan Corey T ,   ARTFL‐LEFFTDS (ALLFTD)
Published: January 2025

AbstractBackgroundAutonomic dysfunction has been linked to empathy deficits in symptomatic frontotemporal degeneration (FTD), but less is known about pre‐symptomatic FTD mutation carriers (preFTD+). Our prior work found that increasing resting heart rate (RHR) over time predicts decline in emotional empathy in preFTD+. Here, we replicate previous findings in a large, multi‐site consortium sample and assess relationships between RHR and empathy loss across disease stages.MethodRHR and Interpersonal Reactivity Index (IRI) were obtained serially for up to 7 years in 348 preFTD+, 202 symptomatic FTD mutation carriers (FTD+), and 311 non‐carrier family members (FTD‐) enrolled in ALLFTD. IRI Perspective Taking (IRI‐PT) and Empathic Concern (IRI‐EC) subscales measured cognitive and emotional empathy, respectively. Separate multiple linear regressions related mutation status and annualized change in RHR to annualized change in IRI subscales and assessed interactions between RHR change and phenoconversion status among mutation carriers. Logistic regression was used to assess the association between change in RHR and phenoconversion among mutation carriers, and Wilcoxon signed‐rank tests were used to examine differences in change in RHR between all study groups.ResultIn asymptomatic participants (preFTD+ and FTD‐), increase in RHR over time was associated with greater decline in IRI‐EC (ß = ‐0.07, p<.001) and IRI‐PT (ß = ‐0.03, p = .011), regardless of mutation status. Among mutation carriers (preFTD+ and FTD+), increase in RHR was associated with greater decline in IRI‐EC (ß = ‐0.04, p = .041), and this effect was stronger in FTD+ compared to PreFTD+ (ß = ‐0.07, p = .038), while an increase in RHR was associated with decline in IRI‐PT only in FTD+ (ß = ‐0.07, p = .046). Change in RHR did not predict phenoconversion in mutation carriers (PreFTD+ and FTD+), but PreFTD+ showed less change in RHR over time relative to FTD+.ConclusionChanges in empathy in asymptomatic preFTD+ and FTD‐ are linked to variability in RHR regardless of genetic status, likely reflecting a non‐specific impact of autonomic functioning on empathy and prosocial behavior. In contrast, increasing RHR predicts decline in cognitive and emotional empathy in FTD mutation carriers but primarily after phenoconversion, suggesting that autonomic contributions to empathy in familial FTD increase with disease progression and could be an early marker of manifest disease.
Investigating heterogeneity of cognitive and functional decline using Subtype and Stage Inference machine learning
Authors: Petersen Kellen K. , Nallapu Bhargav Teja , Demirsoy Idris , Lipton Richard B. , Grober Ellen , Rabin Laura , Ghanbarian Elham , Ezzati Ali 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a heterogeneous disease with different clinical phenotypes and pathophysiological subtypes. Identifying cognitive/functional subtypes in AD could elucidate the diverse clinical progression patterns. The Cognitive Function Index (CFI), a 15‐item questionnaire completed by participants and study partners, captures aspects of cognitive and functional decline. We investigated participant heterogeneity using the CFI and compared differences between subtypes based on participant or study partner reports.MethodsParticipants were 4486 cognitively unimpaired older adults from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study. All participants and study partners completed the CFI. Participants had baseline demographics, neuropsychological test scores, and amyloid PET measures available. The Staging and Subtype Inference (SuStaIn) algorithm was independently applied to participant (PT) and study partner (SP) CFI reports to identify subtypes. Differences between subtypes were assessed using Analysis for Variance (ANOVA) with post hoc analysis.ResultsTable 1 summarizes participant characteristics. Analysis of PT and SP CFI responses independently identified three subtypes with distinct progression patterns. Notably, 35.2% and 57.5% of participants showed no progression based on PT and SP reports, respectively. All subtypes, except SP‐2, had CFI items related to difficulties with recall, needing written reminders, and misplacing items as the first items of suspected decline (Figure 1). Clusters PT‐1 (66.5%) and SP‐1 (45.8%) were the subtypes with most frequent progression pattern (Figure 1). Subtypes PT‐2 and SP‐2 had the highest scores on Digit Symbol Substitution test, walked the most, and for SP‐2 lowest Geriatric Depression Scores (p<0.05 for all; Figure 3). Subtypes PT‐3 and SP‐3 scored lowest on the participant Activities of Daily Living (ADL; p<0.05). Additionally, PT‐3 scored lowest on the Study Partner ADL.ConclusionWe identified distinct subtypes from both participant and study partner CFI reports. Post hoc analysis indicated consistency within subtypes identified from the two sources of information. Subjective reports on cognitive decline could serve as a valuable tool for classifying participants into different risk groups.
Irisin attenuates astrocyte activation and rescues memory in Alzheimer model mice
Authors: Heimfarth Luana , Ribeiro Felipe C , Fortuna Juliana , Ferreira Sergio T 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by synapse and memory failure, and severe cognitive impairment. Physical exercise stimulates neuroprotective pathways, has pro‐cognitive actions, and has been reported to alleviate memory impairment in AD. Irisin, an exercise‐induced hormone, is secreted following proteolytic cleavage of fibronectin type‐III‐domain‐containing 5 (FNDC5). Irisin regulates peripheral metabolism, and has been found to protect synapses and rescue memory in mouse models of AD. The aim of the current study was to evaluate the possible role of irisin in astrocytes within the framework of AD pathophysiology.MethodsWe exposed primary cortical astrocyte cultures to irisin (25 nM), and the expression of neurotrophic factors and/or MAPK activity were determined by RT‐PCR or western blot, respectively. Cognitive impairment was investigated in C57BL/6 mice that received an intracerebroventricular (i.c.v.) infusion of AβOs in the presence or absence of irisin.ResultWe demonstrate that irisin promotes the expression of brain‐derived neurotrophic factor (BDNF) and glial cell line‐derived neurotrophic factor (GDNF) in astrocytes, and stimulates transient activation of extracellular signal‐regulated kinase 1/2 (ERK 1/2). We further show that irisin attenuates memory impairments in an AD mouse model, and modulates GDNF and insulin‐like growth factor‐1 (IGF1) signaling in vivo.ConclusionOur findings support the idea that physiological protection by irisin against synaptotoxic AβOs can be mediated by modulation of astrocyte‐derived factors.
Differential Protein Expression in Alzheimer’s Disease Prefrontal Cortex
Authors: Gholampour Maryam , Basu Malay , Swerdlow Russell H , Haeri Mohammad 
Published: January 2025

AbstractBackgroundUnderstanding the proteomes of specific cell types within the brain is crucial for elucidating the mechanisms underlying Alzheimer’s disease (AD). However, the isolation and analysis of these diverse and low‐abundance cell populations remain significant challenges. This study aims to assess GeoMxTM Digital Spatial Profiler (DSP) by NanoString Technologies (NanoString, Seattle, USA) capable of spatially resolving protein expression profile of AD brains extracted from formalin‐fixed paraffin‐embedded (FFPE) specimens.MethodWe analyzed protein expression profile of prefrontal cortices in post‐mortem AD brains (n = 4) and age‐matched controls (n = 4) using DSP. Regions of interest (ROIs) were targeted at gray matter and the DSP panel recorded the spatial expression of 76 proteins alongside three cell specific markers (GFAP for astrocytes, Iba1 for microglia, NeuN for neurons, and nuclear stain for DNA/nuclei). Protein expression was normalized to spiked‐in ERCC RNA controls and background‐corrected using IgG controls. Group‐wise comparisons employed linear mixed models, and pairwise comparisons used t‐tests with Benjamini‐Hochberg (BH) adjustment.ResultsIn each ROI, an average of 774 cells were counted, consisting of 61 GFAP, 74 microglia, and 370 neurons for each case. As expected, levels of amyloid‐β (Aβ) 1‐42, phospho‐tau (S396), and phospho‐tau (S214) were significantly elevated in AD, as confirmed by immunohistochemistry (IHC). Interestingly, Neprilysin (NEP), a key regulator of Aβ levels that catalyzes its proteolysis and prevents plaque formation, exhibited increased expression in all cell types (astrocytes, microglia, and neurons). Additionally, CD40, a crucial protein for Aβ‐induced microglial activation, showed higher levels in AD neurons, specifically.ConclusionWhile there are still some limitations, DSP technology demonstrates a potential for analyzing the brain proteome in post‐mortem tissues. Screening protein expression in larger cohorts using DSP could hold promise for identifying tissue‐based biomarkers.
Tau is required for pneumonia‐induced cerebrovascular dysfunction
Authors: Chaney Samantha D , McAdams Lauren H , Gwin Meredith S , Stevens Troy T , Lin Mike , Nelson Amy R. 
Published: January 2025

AbstractBackgroundMany survivors of lung injury, including those with bacterial pneumonia and COVID‐19, suffer from incident dementia. Patients who have had pneumonia and other infections are at a higher risk for developing Alzheimer’s disease and related dementias (ADRD) (Chu et al., BBI, 2022, Sipila et al., Lancet Infec Dis, 2021, Girard et al., J Gen Intern Med, 2018). Previous experimental studies have shown that tau is required for pneumonia‐elicited deficits in long‐term potentiation (Balczon et al., FASEB J, 2021). Neurovascular unit dysfunction, including breakdown of the blood‐brain barrier (BBB) and gliosis, occurs early in the ADRD pathophysiological cascade. We have shown that bacterial pneumonia causes BBB breakdown, gliosis, and increased tau phosphorylation in the brain. Here, we investigated whether tau is required for pneumonia‐induced cerebrovascular dysfunction.MethodC57BL/6J or tau knockout (KO) adult mice (1‐3 months old, both male and female) were intratracheally infected with P. aeruginosa (PA103, ExoU and ExoT competent, 105 CFU) for 24 hours. Next, we performed immunofluorescence staining for CD13 (pericytes), lectin (endothelial cells), IgG (BBB leakage), GFAP (reactive astrocytes), and Iba1 (microglia) on serially sectioned brain slices, and imaged and analyzed hippocampus and cortex.ResultBBB leakage and reactive astrocytes and microglia were increased in the hippocampus and cortex 24 hours post‐infection with PA103 compared to saline in C57BL/6J mice. Pericyte coverage of capillaries was reduced in the hippocampus 24 hours post‐infection with PA103 compared to saline in C57BL/6J mice. There was no significant difference in BBB leakage, pericyte coverage or gliosis 24 hours post‐infection with PA103 compared to saline in tau KO mice.ConclusionTau is required for bacterial pneumonia‐induced BBB breakdown and gliosis, revealing a novel immune role for this pathological hallmark of ADRD. Future studies should focus on 1) mechanism(s) by which pneumonia‐induced tau causes neurovascular unit dysfunction, 2) whether cytotoxic tau produced by the lungs during infection contributes to ADRD, 3) how the tau generated in pneumonia compares to ADRD tau variants and phosphorylation states, and 4) the applicability and benefit of therapeutics targeting tau, such as anti‐tau antibodies, on incident dementia associated with pneumonia and/or on cerebrovascular dysfunction in mild‐cognitive impairment and ADRD.
Neuropathological and cell type‐specific effects of Kv1.3 blockers in a pre‐clinical AD mouse model
Authors: Srivastava Upasna , Bowen Christine A , Kumar Prateek , Sampson Maureen , Xiao Hailian , Zeng Hollis , Sing Anson , Sojka Caitlin , Bhatia Tarun , Wulff Heike , Sloan Steven A , Rangaraju Srikant ,   Department of Neurology
Published: January 2025

AbstractBackgroundKv1.3 channels are promising therapeutic targets to modulate neuroinflammatory responses in neurodegenerative disease including Alzheimer’s disease (AD). Although the ability of Kv1.3 blockers to reduce neuropathology in AD mouse models has been demonstrated, the cellular mechanisms remain unclear.Method5xFAD mice aged 6 months were treated with PAP‐1 (a small molecule Kv1.3 blocker, chow), ShK‐223 (peptide blocker, intra‐peritoneal twice‐weekly), control chow, or vehicle injections until 9 months age. We assessed neurobehavior, Aβ burden neuropathology and single‐nuclei transcriptomics (10x Chromium 3’). For Sn‐RNA‐seq, 137,375 cortical nuclei from n = 4 mice/group passed QC after alignment, data integration (Seurat) and batch effects removal (Harmony), followed by cell‐type annotation using a reference and its prediction score, pseudo‐bulk analysis was performed using cell‐type subsets based on the contrast PAP‐1 versus Control. DEGs were identified using (glmGamPoi) based on log2FC > < 0.25 and adjP <0.05, and magnitude of drug effect was compared across cell types. Utilized GSEA with ClusterProfiler and enrichGO to investigate Kv1.3 blockade effects on diverse cell populations.ResultWhile both Kv1.3 blockers (PAP‐1 and ShK‐223) reduced Ab plaque burden in 5xFAD mice, lower Ab42 ELISA‐measured levels and improved fear conditioning behavior were only observed in the PAP‐1 group. snRNAseq revealed distinct cell type clusters, with consistent cell type proportions across all treatment groups. 5xFAD mice exhibited increased disease‐associated microglia compared to WT mice. In pseudo‐bulk analyses, PAP‐1 had the most significant impact on microglia compared to other cell types, evident from the proportion of DEGs in the sampled transcriptome. In microglia, PAP‐1 upregulated complement genes (C1qa, C1qb, C1qc), induced glial cell differentiation, transmembrane transport and voltage‐gated potassium channel. PAP‐1 treatment enhanced myelination (Plp1), oligodendrocyte differentiation and neuronal ensheathment in oligodendrocytes. These aligned with heightened activity of cognition and synapse‐related genes in astrocytes, glutamatergic and GABAergic neurons.ConclusionOur studies re‐affirm beneficial neuropathological effects of pharmacological Kv1.3 blockade in Ab models, and additionally reveal differential effects and mechanisms of membrane permeable and brain penetrant versus non‐permeant Kv1.3 blockers. PAP‐1 prominently affects microglia and oligodendrocytes, suggesting they may be potential targets of Kv1.3 blockade. Additionally, evidence indicates pro‐myelination and synaptic‐protective effects of Kv1.3 blockade.
Higher Cerebrovascular Reactivity Predicts Better Memory Function in Older Adults Without Dementia
Authors: Kapoor Arunima , Engstrom Allison C , Dutt Shubir , Gaubert Aimée , Alitin John Paul M , Sible Isabel , Marshall Anisa J , Shenasa Fatemah , Shao Xingfeng , Wang Danny JJ , Nation Daniel A. 
Published: January 2025

AbstractBackgroundOptimal cerebral blood flow is crucial to maintaining cognitive function. Cerebrovascular reactivity (CVR) is a dynamic measure of cerebrovascular function which represents the ability of cerebral blood vessels to regulate blood flow in response to vasoactive stimuli. Prior studies have demonstrated an association between impaired CVR and cognitive function in cerebrovascular and neurodegenerative conditions, including cerebral amyloid angiopathy and Alzheimer disease. However, few studies have examined the association between cerebrovascular reactivity and cognitive function in older adults prior to the onset of cognitive decline.MethodIndependently living older adults (N = 111, mean age = 69.2 years; SD = 7.1; age range 55‐89 years; 29.7% male, mean education = 16.5 years; SD = 2.4) free of dementia or clinical stroke were recruited from the community and underwent brain MRI and neuropsychological assessment. Pseudo‐continuous arterial spin labeling MRI quantified whole brain cerebral perfusion during CVR to hypercapnia (vasodilation) induced by visually guided breathing exercises (15s breath holds) and indexed by capnography. We specifically examined verbal and visual memory, assessed using the RAVLT word list learning and memory, WMS‐R Logical Memory I and II, and WMS‐IV Visual Reproduction I and II.ResultAdjusting for age, sex and education, multiple regression analyses revealed a significant positive association between CVR to hypercapnia and RAVLT word list delayed recall (B = .084, 95% CI (.001, .167), p = .048), Logical Memory II (B = .240, 95% CI (.012, .468), p = .039) and Visual Reproduction II (B = .280, 95% CI (.097, .464), p = .003).ConclusionIn older adults without stroke or dementia, higher cerebrovascular reactivity is associated with better memory function. Cerebrovascular dysfunction is known to precede and contribute to the development of cognitive impairment. These findings suggest that cerebrovascular dysfunction influences cognitive performance even in preclinical stages. Future longitudinal may elucidate whether early cerebrovascular reactivity changes can predict long‐term development of dementia.