bluuebunny/crossref_metadata_2025_split huggingface dataset:
Data‐driven Cognitive Composites and APOE ε4 Carriage Predict Progression to Mild Cognitive Impairment in Cognitively Unimpaired Older Adults
Authors: Tallapragada Bhargav , Galna Brook , Shishegar Rosita , Markovic Shaun J. , Brown Belinda M. , Dore Vincent , Laws Simon M. , O’Brien Eleanor K. , Porter Tenielle , Burnham Samantha C. , Weiner Michael S. W. , Morris John C. , Hassenstab Jason J. , Rowe Christopher C. , Jin Liang , Fripp Jurgen , Lim Yen Ying , Doecke James D. , Masters Colin L. , Maruff Paul , Sohrabi Hamid R. ,   the ADOPIC Consortium
Published: January 2025

AbstractBackgroundIn cognitively unimpaired (CU) individuals, the PACC is widely used as a cognitive outcome measure and endpoint in observational studies and clinical trials. However, it has drawn criticism for being heavily weighted towards memory. Increasing evidence indicates a decline spanning multiple cognitive domains in CU individuals. Therefore, using principal component analysis (PCA), we derived data‐driven domain‐specific cognitive composites. And subsequently, compared them against their summed z‐score counterparts in predicting progression to mild cognitive impairment (MCI).MethodBaseline cognitive, demographic, and genotype data of 2,853 CU older adults (aged 41.6 to 98.3) was obtained from the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) Consortium. Using varimax‐rotated PCA, tests significantly loading (≥ 0.5) onto each principal component were extracted to derive domain‐specific cognitive composites. The resulting domain scores were normalised to a mean of 0 and SD of 1, with a higher score indicating better cognition. Cox regression was used to assess the association between progression to MCI and baseline demographics, cognition, and APOE ε4 carriage. Akaike information criteria (AIC) was used to compare the fitness of PCA‐derived composites against the zPACC and z‐score domain‐specific composites.ResultBaseline cohort characteristics are described in Table 1. PCA explained 68% of the variance and resulted in four independent cognitive composites (Figure 1): memory; executive function; attention and processing speed; and global cognition. At 15 years from baseline, 309 participants progressed to MCI, while 2,544 remained CU. Cox regression showed that the four cognitive composites, age and APOE genotype significantly predicted progression to MCI (Concordance = 77%, p < 0.001, AIC = 4105, Table 1). Additionally, the PCA‐derived composites performed comparably, if not better than the summed z‐score counterparts, the PACC (Concordance = 74%, p < 0.001, AIC = 4163) and domain‐specific composites (Concordance = 75%, p < 0.001, AIC = 4142). Baseline older age, APOE ε4 carriage in a dose‐dependent manner (Figure 2) and poorer cognition for each PCA‐composite were independently associated with progression to MCI.ConclusionTogether with APOE ε4 carriage, our PCA‐derived domain‐specific composites performed better than their summed z‐score counterparts at predicting progression to MCI 15 years before symptom onset.
The relationship between amyloid‐b and cognition in young‐onset Mild Cognitive Impairment: the influence of disease duration
Authors: Carbone Chiara , Balboni Erica , Beltrami Daniela , Tondelli Manuela , Gallingani Chiara , Gasparini Federico , Salvatori Davide , Salemme Simone , Vinceti Giulia , Fraternali Alessandro , Marti Alessandro , Chiari Annalisa , Zamboni Giovanna 
Published: January 2025

AbstractBackgroundThe effect of amyloid‐b brain deposition on cognition is still debated, since it has been shown that its accumulation begins almost 15 years before cognitive symptoms' onset, then reaches a plateau while cognition continues to decline. We studied if there is a parallel between amyloid‐b deposition and cognitive performances in young‐onset Mild Cognitive Impairment (MCI) patients, and if it is associated to symptoms’ duration.MethodSubjects with a diagnosis of MCI and symptoms’ onset ≤ 65 years underwent neuropsychological assessment, Magnetic Resonance Imaging, and (18F)Flutemetamol‐PET (amy‐PET). FMRIB Software Library was used to assess voxel‐wise correlations between amyloid‐b deposition and cognitive performances, adjusted for age, sex, education, and degree of grey matter atrophy. Correlations were repeated grouping patients depending on whether the duration of their cognitive symptoms had been shorter or longer than the median of the entire group (34 months).ResultAmong the 30 recruited individuals we found a statistically significant correlation between amyloid‐b burden and performance in attentional‐executive (i.e., Trail Making Test [TMT]‐A/B and Stroop Test) and memory (i.e., Free and Cued Selective Reminding Test [FCSRT]‐immediate and delayed free recall, Corsi Supraspan, and Rey‐Osterrieth Complex Figure‐delayed recall) tests.Patients with short disease duration (n = 15) had even more significant associations relative to patients with longer duration. More precisely, they showed significant linear correlations in widespread brain regions between amyloid‐b burden and cognition in attentional‐executive (i.e., Attentional Matrices, Raven’s Coloured Progressive Matrices, TMT‐A/B) and memory (i.e., Babcock Short Tale‐immediate/delayed recall, FCSRT‐immediate free recall, and Corsi Supraspan) tests.ConclusionIn young‐onset MCI we found a linear relationship between amyloid‐b deposition and cognitive performance, which is more evident in patients with shorter disease duration. Our results contribute to identifying which cognitive tests are most sensitive to amyloid‐b deposition in the initial stages of dementing diseases.
Cortical Structure of left superior parietal cortex is associated with cognition and dual tasking: a cross‐sectional study of mild cognitive impairment
Authors: Zhang Siyun 
Published: January 2025

AbstractBackgroundIndividuals with mild cognitive impairment (MCI) commonly exhibit alterations in cortical structures accompanied by a mild decline in cognitive function. While the dual‐task paradigm is utilized for MCI detection, its cortical mechanism remains incompletely understood. This study seeks to explore cortical structural changes and cognitive decline using the dual‐task paradigm in individuals with MCI.MethodThirty participants with MCI and thirty healthy controls (HC) were recruited. Magnetic resonance imaging (MRI), cognitive assessments and dual‐task Timed Up and Go (TUG) test were performed. Cortical morphological parameters of cerebral cortical thickness and surface area were computed using Freesurfer software. Correlations analyses were then performed to assessment the relationship between cognitive, motor performance and morphological measures.ResultThe execution time of the dual‐task TUG significantly increased in MCI group, and was negatively correlate with the WAIS Digit Span Forward and Backwards test, total Montreal cognitive assessment (MoCA) score, and its delayed recall subdomain. At the whole brain level, the surface area in left superior parietal cortex (SPC) was significantly reduced in MCI group. No between‐group significant variation was found in cortical thickness was observed. The surface area of the left SPC was positively correlated with total score of the MoCA and its delayed recall subdomain. In the HC group, the cortical thickness was positively correlated with total score and its attention subdomain. Negative correlation between cortical thickness and dual‐task TUG test was also observed.ConclusionIndividuals with MCI showed decline in attention, short‐term memory, inhibitory control ability and dual‐task performance. The observed structural alterations in the left SPC suggested potential distinctions in this region, which may be associated with cognitive processes and the cognitive demands related to locomotion. This study provides additional evidence supporting the role of the left superior parietal cortex in cognitive and locomotor function in individuals with MCI.
Elevated iron levels in Alzheimer’s disease brain was partially due to increased cytosolic expression of hemoglobin in neurons
Authors: Roberts Blaine Russell , Mukherjee Soumya , Roberts Anne M , Platt Madison E , MacLean Catriona , Bush Ashley I. , Birchall Ian , Masters Colin L. 
Published: January 2025

AbstractBackgroundA better understanding of the molecular process that drive Alzheimer’s disease(AD) are required to develop effective biomarkers and therapies. This includes determining how essential elements like Fe, Cu and Zn are involved in the disease. In the literature there is debate over the role of iron in AD and there are reports of increased, decreased and unchanged levels of Fe in AD brain. Most of the studies have use a standard bulk analysis of Fe in brain tissue. However, this does not yield the necessary molecular information required to determine how the metalloenzymes that utilize Fe are affected in the disease.MethodWe used a combination of biochemical fraction and size exclusion inductively coupled plasma mass spectrometry to conduct a metalloproteomics analysis of post mortem human brain tissue from control and Alzheimer’s Disease cases.ResultWe observed a significant increase in a single iron containing protein. We used bottom up proteomics and purification to determine the protein was hemoglobin. We further confirmed increase expression of hemoglobin and the binding partner haptoglobin in neurons using immunoshitochemistry. We also use RNAscope to show that neurons express the MRNA for both hemoglobin and haptoglobin which was surprising as these are classic blood proteins.ConclusionThese results clarify that changes in iron proteins do occur in AD brain and open up a new area of research to understand the role of hemoglobin and haptoglobin in neuronal function.
A CAN‐PROTECT study: The effect of self‐reported and study partner‐reported mild behavioral impairment on quality of life in older adults without dementia
Authors: Warring Ibadat , Guan Dylan X. , Ismail Zahinoor , Smith Eric E. 
Published: January 2025

AbstractBackgroundMild behavioral impairment (MBI) is a syndrome that leverages neuropsychiatric symptoms that emerge in later‐life, and which persist, to identify individuals at high‐risk for incident dementia. Attendant with MBI are changes in quality of life (QoL), which can present concurrent with the onset of cognitive decline or even before. Obtaining information from participants and study partners can provide a broader overview of health and QoL. We investigated the relationship between MBI and QoL in dementia‐free older adults, incorporating both self‐ and study partner reports.MethodsData (n = 608) are from the CAN‐PROTECT study. MBI status (±) was determined with a MBI Checklist cut‐off score ≥8 based on self‐ or study‐partner report, resulting in a four‐level categorical variable of MBI positivity/negativity (S‐/SP‐[concordant MBI‐], S+/SP‐[discordant MBI S+], S‐/SP+[discordant MBI SP+], S+/SP+[concordant MBI+]). QoL was assessed using the self‐ and study‐partner‐reported EQ‐5D (higher scores reflecting poorer QoL). Linear regression modelled associations between MBI status (exposure) and EQ‐5D total score (outcome), adjusted for age, cognition, sex, education, ethnocultural origin, marital status, employment status, high blood pressure, diabetes, and heart disease. A sensitivity analysis removed EQ‐5D affective symptoms.ResultsParticipants (mean age = 64.8±7.1, 77.0% female) had mean self‐reported scores of 4.6±6.7 for MBI and 6.7±1.8 for EQ‐5D. Study partners reported mean scores of 3.7±5.8 for MBI and 1.4±0.4 for EQ‐5D. Distribution of MBI status was 71.9% for concordant MBI‐, 13.3% for discordant S+, 8.3% for discordant SP+ and 6.6% for concordant MBI+. QoL was poorer in the concordant MBI+ group for self‐reported (b = 2.48, 95% confidence interval [95%CI]: 1.96–3.00, p<.001) (Table 1) and study‐partner reported EQ‐5D (b = 2.63, 95%CI: 2.00‐3.27, p<.001) (Table 2), compared to concordant MBI‐ group. There was a significant association with discordant MBI S+ (p<.001) but not discordant MBI SP+ (p<.81) with self‐reported EQ‐5D. Both discordant groups were significant with study‐partner reported EQ‐5D.ConclusionIn a mostly cognitively unimpaired community dwelling sample, MBI associations with self‐ and study‐partner‐reported QoL were strongest when MBI symptoms were endorsed by both participants and their study partners. These findings underscore the importance of including study partners brain aging research across the cognitive continuum.
Peripheral Inflammation subgroups in Alzheimer’s disease and related dementias
Authors: Lima Bruna Seixas , Rosa‐Neto Pedro , Phillips Natalie , Borrie Michael , Roncero Carlos Tyler , Lahiri Durjoy , Dori Dvir , Chertkow Howard 
Published: January 2025

AbstractBackgroundA growing body of research has focused on inflammation as both a potential biomarker and a risk factor for Alzheimer’s disease (AD). The cytokine Interleukin‐6 (IL‐6) is involved in the pathogenesis of inflammatory disorders and in the physiological homeostasis of neural tissue. AD has been associated with increased IL‐6 expression in brain, however, increased levels of IL‐6 have also been linked to conditions such as diabetes and hypertension. We examined groups of individuals with AD and related disorders (ADRD) as well as healthy controls to check if elevated levels of IL‐6 (above 1.9 ng/L) were related to the presence of comorbidities.MethodsWe investigated individuals with AD (n = 58); mild cognitive impairment (MCI; n = 139); subjective cognitive impairment (SCI; n = 28); and cognitively unimpaired age matched controls (CU; n = 53). We considered four possible subgroups: Group 0 (defined as individuals with normal IL‐6 levels and without comorbidities that could be linked to elevated IL‐6); Group 1 (individuals with normal levels of IL‐6, despite having comorbidities); Group 2 (individuals with elevated IL‐6 without comorbidities), and Group 3 (individuals with elevated IL‐6 and comorbidities). The comorbidities investigated were hypertension, diabetes, peripheral vascular disease, history of cerebrovascular accident, and rheumatoid arthritis. Logistic regression was used to investigate the relationship between the occurrence of elevated IL‐6, age, sex, history of smoking, body mass index (BMI), Montreal Cognitive Assessment scores (MoCA), nutrition and sleep.ResultsWe found individuals with and without elevated IL‐6, and with and without comorbidities in all cohorts (Table 1). We found a significant relationship between elevated IL‐6 and aging in all cohorts (Figure 1a). A significant relationship was also found between elevated IL‐6 and greater BMI (MCI group only; Figure 1b), lower nutrition scores (SCI group only, Figure 1c), history of smoking (AD group only; Figure 2a) and sex, whereby males had more elevated IL‐6 (MCI group; Figure 2b).ConclusionsWe found variation in patterns of peripheral inflammation and other common conditions in aging and ADRD. These variations may reflect different mechanistic groups which might help the understanding of variation in clinical features of ADRD, disease progression and response to different therapeutic interventions.
Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease‐related Aβ pathology
Authors: Mancuso Renzo 
Published: January 2025

AbstractBackgroundMicroglia are central players in Alzheimer’s Disease (AD) pathology, but analyzing microglia states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies.MethodTo circumvent these issues, here we collected 138,577 single cell expression profiles of human stem cell derived‐microglia from a xenotransplantation model of AD.ResultXenografted human microglia adopt a disease‐associated (DAM) profile similar to that seen in mouse microglia, but display a more pronounced HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro‐inflammatory cytokine/chemokine CRM response to oligomeric Aβo. Expression of AD risk genes is distributed over this multi‐pronged response to amyloid pathology. Genetic deletion of TREM2 or APOE, as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially.ConclusionWe have identified multiple transcriptomic cell states adopted by microglia in response to AD‐related pathology, which should be taken into account in translational studies.
Tracing senescence in the Alzheimer’s brain through an eigengene‐based analysis of snRNA‐Seq data
Authors: Dehkordi Shiva Kazempour , Zare Habil , Orr Miranda E. 
Published: January 2025

AbstractBackgroundCellular senescence, which can cause significant changes in morphology, metabolism, and function, is a key contributor to aging and diseases including Alzheimer’s Disease (AD). Accurate biomarker identification is essential for detecting senescent cells. Our research aims at defining gene signatures that encapsulate senescence complexity in the brain. Our previous study, highlighted CDKN2D/p19 as a reliable senescence marker in tau neuropathology. This study advances our approach using a new snRNA‐Seq dataset.MethodWe evaluated snRNA‐Seq data from 92 postmortem brains (PMID: 37774680) to validate senescent cell types, utilizing the transcriptional profiles of around 414,000 cells. We used an eigengene‐based approach, where an eigengene is a weighted average expression of genes that summarizes biological signatures with minimal loss of information (PMID: 28298217). Using established weightings from our prior research (PMID: 35531351), we inferred eigengenes indicative of senescence in this dataset. We also recalculated eigengenes for key senescence pathways ‐ the canonical senescence pathway (CSP) which reflects cell cycle arrest, the senescence initiator pathway (SIP) indicating cellular damage and stress, and the senescence response pathway (SRP) representing the toxic senescence‐associated secretory phenotype (SASP) ‐ and assessed the overlap of senescent cells using statistical tests.ResultUsing eigengenes inferred from our previous study, we confirmed that excitatory neurons significantly expressed CSP and SIP signatures in the new dataset. Additionally, microglia and vascular cells in CSP, inhibitory neurons in SIP, and astrocytes and vascular cells in SRP showed significant enrichment (Fig. 1a‐c). Recalculation of eigengenes supported these findings by returning the enrichment of exact cell types within each pathway, demonstrating the method’s robustness in identifying senescent cell types. Furthermore, a substantial number of cells showed overlapping senescence signatures across the CSP, SIP, and SRP (Fig. 2), confirming consistency between inference and recalculated eigengenes.ConclusionOur findings validate a computational strategy for detecting senescent cells via eigengene analysis. Consistent identification of senescent cell signatures between inferred and recalculated eigengenes across neural and vascular cells confirms the accuracy of our methods. This approach may direct AD therapeutic development by pinpointing precise senescent cell targets, and uncover new biomarkers of brain cell senescence.
Plasma Aβ42/Aβ40 and phospho‐tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer’s disease
Authors: Rissman Robert A 
Published: January 2025

AbstractBackgroundOur data from several clinical trials of individuals with asymptomatic AD demonstrates that plasma Aβ42/40 quantification by mass spectrometry can serve as a reliable biomarker for predicting elevated brain amyloid as detected by PET. We investigated how adding plasma p‐tau measures to our plasma Aβ42/40 algorithm to streamline identification of eligible participants and reduce burden and trial cost. To determine if the addition of plasma p‐tau181 and/or p‐tau217 concentrations can improve plasma Aβ42/40 algorithms to correctly identify participants with amyloid burden of >20 centiloids with the NAV4694 tracer among individuals screening for participation in the AHEAD preclinical AD trial.MethodPlasma amyloid and tau were measured using C2N Diagnostics mass spectrometry. Participant samples (N = 1085) collected prior to the incorporation of plasma Aβ42/40 testing during screening were used. Plasma samples consisted of those with adequate amyloid PET levels (n = 364; 33%) to be eligible for AHEAD and those who did not and screen failed (n = 747; 67%). We quantified Aβ (Aβ42/40) and tau species, including the phosphorylated (p‐tau) and non‐phosphorylated (np‐tau) forms of tau181 and tau217. A ratio of p‐tau to np‐tau was calculated (p‐tau181r and p‐tau217r) to normalize inter‐individual differences in np‐tau. We conducted Receiver Operating Characteristic (ROC) curve analyses fagainst amyloid PET status (>20 centiloids). We fit a Mixture of Experts model and included p‐tau181r and p‐tau217r in the predictive algorithm (Aβ42/40, Age and APOE) for amyloid PET status.ResultPlasma samples from N = 1085 composed of 67% Female, 13.5% Hispanic, 3.7% Black or African American with a mean age of 67.6 (SD = 6.1) years. 45% of participants had at least one APOE4 allele. The Area Under the Curve (AUC) for Aβ42/40 was 0.87 (95% CI; 0.84, 0.89), consistent with prior reports. For plasma tau, we found AUCs of 0.74 (95% CI; 0.71, 0.77) with p‐tau181, to 0.91 (95% CI; 0.90, 0.93) with p‐tau217r. The model including covariates p‐tau217r, Aβ42/40, Age and APOE improved AUC to 0.95 (95% CI; 0.93, 0.96).ConclusionOur data suggests that plasma p‐tau217r in addition to Aβ42/40 ratio can significantly improve anti‐amyloid clinical trial screening burden and timelines for recruitment.
C9orf72 repeat expansions increase risk for secondary symptom development in amyotrophic lateral sclerosis and behavioral‐variant frontotemporal degeneration
Authors: Spencer Barbara E , Xie Sharon X , Elman Lauren , Quinn Colin , Amado Defne A , Baer Michael , Lee Eddie B , Van Deerlin Vivianna M , Dratch Laynie , Massimo Lauren , Irwin David J , McMillan Corey T 
Published: January 2025

AbstractBackgroundIn amyotrophic lateral sclerosis and behavioral‐variant frontotemporal degeneration, the presence of secondary cognitive‐behavioral or motor symptoms, respectively, is associated with shorter survival. However, factors influencing the risk of secondary symptom development remain largely unexplored and time‐to‐event characterization for developing secondary symptoms is important for prognostic clinical decision‐making.MethodWe performed a retrospective evaluation of the entire disease course of individuals in the Penn Integrated Neurodegenerative Disease Database with a primary clinical phenotype of amyotrophic lateral sclerosis (n = 173) or behavioral‐variant frontotemporal degeneration (n = 69). All individuals were evaluated for C9orf72 expansions (>30 repeats). Only individuals who had neuropathological confirmation of a TDP‐43 proteinopathy at autopsy or had a C9orf72 repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether they were modified by the presence of a C9orf72 repeat expansion or primary clinical phenotype.ResultBinary logistic regression and Cox proportional hazard analyses revealed increased odds (odds ratio = 4.26 [1.98‐9.18]; p<0.001) and an increased hazard (hazard ratio = 4.79 [2.33‐ 9.82], p<0.001) for developing secondary symptoms in C9orf72 expansion carriers compared to noncarriers. Primary phenotype, age at symptom onset, and sex were not associated with risk for secondary symptom development.ConclusionThese findings highlight the need for clinician vigilance to detect the onset of secondary cognitive‐behavioral and motor symptoms in patients carrying a C9orf72 repeat expansion, regardless of primary phenotype, and may warrant dual referrals between cognitive and neuromuscular clinics in these cases.