bluuebunny/crossref_metadata_2025_split huggingface dataset:
Norming and standardization of Hong Kong Brief Cognitive Test and diagnostic study on the effectiveness of screening patients with cognitive impairment
Authors: Zheng Yaonan , Chan Helen Y. L. , Li Nan , Zhu Jiahui , Pei Minyue , Yu Xin , Shi Chuan , Wang Huali 
Published: January 2025

AbstractBackgroundThe Hong Kong Brief Cognitive Test (HKBC) has solved the problems of limited population, insufficient coverage of cognitive domains and copyright limitation of previously used cognitive function test tools, which has a preliminary research basis for promotion. To make HKBC more widely used, it is necessary to collect normative data from different regions to make it have reference standards.MethodFrom September 2019 to December 2021, 2312 aged 40 years and older people were recruited from different regions of China as norm construction participants. The diagnostic study included 93 normal elderly patients and 224 patients with cognitive impairment (including 156 patients with mild cognitive impairment and 68 patients with Alzheimer’s disease). Multinomial regression model was used to analyze the correlation between HKBC score and age, sex, living area and education level. The norm of HKBC total score and T score (HKBC‐T) were constructed. Based on the receiver operating characteristic curve, the AUC, sensitivity, specificity and Youden index of HKBC‐T were calculated to determine the optimal cutoff value of cognitive impairment.ResultThe results showed that HKBC score was negatively correlated with age (SE = 0.007, β = ‐0.067, P < 0.001) and positive correlation with education (SE = 0.016, β = 0.280, P < 0.001), no significant association with gender and living area (p > 0.05). According to different ages and education levels, norm of HKBC total score and HKBC‐T were constructed, and the conversion equation of HKBC‐T was calculated. The results of HKBC‐T showed a good AUC value of 0.85 in distinguishing patients with cognitive impairment from normal elderly people. The optimal cutoff value for the diagnosis of cognitive impairment by the HKBC‐T was 46 points (sensitivity = 0.914, specificity = 0.667).ConclusionThe HKBC score is influenced by age, living area and education level, which provides a scientific basis for the development of HKBC norm model. The results of the diagnostic study showed that the optimal cutoff value of the HKBC‐T was 46 when distinguishing patients with cognitive impairment from the normal elderly.
Genome‐wide investigation of a neuropathological cohort offers novel insights in the genetic risk underlying hallmark and co‐morbid lesions implicated in Alzheimer’s disease
Authors: Laureyssen Celeste , Gawor Klara , Van Dongen Jasper , Küçükali Fahri , Koper Marta J , Ronisz Alicja , Otto Markus , von Arnim Christine , Van Damme Philip , Vandenberghe Rik , Thal Dietmar Rudolf , Sleegers Kristel 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a heterogenous disease with a strong heritability. Genetic studies are of irreplaceable value in elucidating the mechanisms that underly this disease. The classical genome‐wide association studies (GWAS) rely on ever‐increasing sample sizes and utilize clinical AD diagnosis to investigate genetic risk. Here, we aim to eliminate phenotypic heterogeneity by performing GWAS on a deeply phenotyped neuropathological cohort.MethodPhenotypic data regarding hallmark and co‐morbid AD lesions was collected on 721 individuals. DNA was extracted from frozen or paraffin‐fixed cerebellar tissue. Subsequently, genetic data was generated using low‐coverage whole‐genome sequencing (lcWGS) followed by imputation based on 1000 Genomes Project reference panel using GLIMPSE. Linear or logistic regression was performed in PLINK correcting for age, gender and the first 3 PCs for every phenotype. Investigated phenotypes include but are not limited to: Amyloid phases, Braak‐NFT stage, cerebral amyloid angiopathy (CAA) severity and type, pTDP presence in CA1 and dentate gyrus, alpha‐synuclein spread/presence, age‐related tau‐astrogliopathy (ARTAG) and Hirano bodies.ResultWe discovered genome‐wide significant hits for well‐established AD lesions such as tau tangles, amyloid plaques and CAA. Furthermore, significant hits for co‐morbid lesions like alpha‐synuclein stages, granulovacuolar degeneration and Hirano bodies (extracellular actin aggregates in the CA1) were found. Suggestive associations were discovered for pTDP and ARTAG. Associated loci included proof‐of‐concept findings such as strong relations between amyloid and CAA with APOE SNPs, but also included several loci that have not been previously linked to the specific phenotype or AD in general.ConclusionImplementing phenotypic information on neuropathological lesions in a hypothesis‐free genome‐wide investigation as a preliminary screening rendered genome‐wide significant and suggestive loci which can contribute to a deeper understanding of the individual lesions observed in AD. From our preliminary results we observe the benefits of accurate phenotyping on GWAS power. Despite small sample size, we managed to detect genome‐wide significant associations for AD‐related lesions by eliminating phenotypic heterogeneity. Associated loci will be subjected to gene prioritization and functional validation analysis to determine the causal risk genes. For more commonly investigated hallmark lesions, replication analysis will be performed in publicly available cohorts.
Regional microglial activation differs across the cortex of patients in the Alzheimer’s disease trajectory: A cross‐sectional study
Authors: Tuil Marie Emilie , Calsolaro Valeria , Crook Harry , Femminella Grazia Daniela , Pasqualetti Giuseppe , Buckley Christopher , Trigg William , Gentleman Steve , Brooks David J , Jogaudaite Simona , Abarrategui Javier Alegre , Hinz Rainer , Edison Paul 
Published: January 2025

AbstractBackgroundMicroglial reactivity and neuroinflammation are crucial pathological processes in Alzheimer’s Disease (AD). Several attempts to develop a treatment by supressing the immune response in AD have been made, yet these yielded very limited results. Recent studies suggest contrasting effects of microglial reactivity, indicating a biphasic response with both beneficial and deleterious effects at distinct stages of AD.We evaluated the regional differential influence of microglial reactivity on neuropathological processes across AD trajectory.Method48 patients were divided by diagnosis into control (11), Mild Cognitive Impairment (MCI, 14), and AD (23) groups. They underwent TSPO‐PET imaging, magnetic resonance imaging (MRI), and neuropsychological testing. The spectral analysis generated a TSPO‐PET impulse response function at 90 minutes (IRF90), reflecting its volume of distribution. Region of interest and voxel‐level analyses were performed, and grey matter (GM) volume was calculated using FreeSurfer and voxel‐based morphometric analysis. Additionally, post mortem brain tissue from 27 patients at Braak Stages IV‐VI was stained for CD32a and CD163, markers of pro and anti‐inflammatory activation respectively.ResultThe AD group showed increased microglial reactivity in the temporal, parietal, occipital, and medio‐temporal lobes, and the cingulate cortex compared to controls. Voxel‐wide analyses of AD and MCI patients yielded similar results across the cortex.The voxel‐wise analysis revealed both positive and negative clusters of association between tracer uptake and GM volume, with negative associations more often found in regions affected earlier in AD trajectory. This dual effect is further denoted by the presence of both CD32a‐positive and CD164‐positive microglia within the same regions in post mortem tissue.ConclusionThe contrasting effects of reactive microglia on different pathological processes show regional disparities, with deleterious effects more closely associated with regions affected in the early stages of AD. This suggests a diverging response driven by both anti‐ and pro‐inflammatory reactivity profiles. The former, neuroprotective, would emerge locally alongside early pathology, while the later, neurotoxic, would only appear with more advanced pathology.Consequently, potential treatments should promote anti‐inflammatory polarization and supress pro‐inflammatory activation in microglia for an effective therapeutic strategy.
Association of Neuropsychiatric Symptoms and General Psychopathology with Markers of Neurodegeneration in the General Population
Authors: Etteldorf Rika , de Vries Folgerdiena M. , Ettinger Ulrich , Breteler Monique M.B. 
Published: January 2025

AbstractBackgroundMental disorders have been linked to an increased risk of developing dementia including Alzheimer’s disease. However, previous studies have typically focused on individuals who meet diagnostic criteria for a given psychiatric disorder. The goal of our study was to examine whether diverse neuropsychiatric symptoms are related to early markers of neurodegeneration in the general population.MethodThe analysis was based on 8,318 participants (aged 30‐95) from the population‐based Rhineland Study. Neuropsychiatric symptoms (perceived stress, depressive symptoms, anxiety symptoms, attention deficit hyperactivity (ADHD) symptoms, obsessive‐compulsive disorder (OCD) symptoms) were measured using self‐report questionnaires. A general psychopathology factor was generated using principal component analysis (PCA). Cognitive performance was measured across different cognitive domains. Whole‐brain and regional brain volumes as well as white matter hyperintensities (WMH) were obtained from magnetic resonance images (3T Siemens MAGNETOM Prisma). Plasma neurofilament light chain (NfL) levels were assessed using Quanterix’s Simoa NF‐light™ assay. Relations of symptom scores with markers of neurodegeneration were quantified using multivariable linear regression models. We performed a sensitivity analysis by excluding participants reporting a neurodegenerative or psychiatric disease (n = 1,784).ResultParticipants with more severe neuropsychiatric symptoms and higher scores on the psychopathology factor performed significantly worse in all fluid cognitive domains (standardized beta coefficients (β) range between ‐0.01 and ‐0.06). The strength of association between neuropsychiatric symptoms and cognitive performance increased with age. Furthermore, neuropsychiatric symptoms (except for ADHD symptoms) and general psychopathology were associated with smaller grey matter volume (β between ‐0.00 and ‐0.02). Perceived stress, depressive symptoms, and anxiety were additionally associated with higher WMH load (β between 0.02 and 0.04), while OCD symptoms were associated with thinner cerebral cortex (β = ‐0.05 [‐0.07, ‐0.02]). Sensitivity analysis showed robustness of the associations. We found no associations between neuropsychiatric symptoms and NfL levels.ConclusionVarious neuropsychiatric symptoms and a generally higher level of psychopathology are associated with poorer cognitive performance, grey matter atrophy, and WMH burden, even in adults without a psychiatric diagnosis. However, we did not find direct evidence of neuroaxonal injury, as indicated by the absence of an association with NfL.
Exploring Ancestry‐dependent Regulation of Alzheimer’s disease‐associated genetic risk factors in iOligodendroglia
Authors: Ramirez Aura M , Shepherd Jihanne J , Coombs Lauren , Simon Shaina A. , Moura Sofia , Rajabli Farid , DeRosa Brooke A. , Whitehead Patrice L. , Adams Larry D. , Starks Takiyah D. , Illanes‐Manrique Maryenela Z. , Tejada Sergio J. , Byrd Goldie S. , Cornejo‐Olivas Mario , Feliciano‐Astacio Briseida E. , Wang Liyong , Jin Fulai , Dykxhoorn Derek M. , Griswold Anthony J. , Young Juan I , Vance Jeffery M. 
Published: January 2025

AbstractBackgroundGenome‐wide association studies (GWAS) in Alzheimer’s disease (AD) are consistently discovering genetic variants linked to the risk of developing this neurodegenerative condition. However, the effect size of the shared associated loci varies across populations as well as each population can have unique associations. This phenomenon could be explained by ancestry‐dependent changes in the genomic regulatory architecture (GRA) influencing the expression of these genes, similar to the effect of different local ancestry on the risk of AD in APOE4 carriers. Thus, understanding of GRA in the context of AD is imperative but currently most GRA data available is predominantly European, limiting our ability to comprehensively interpret the variability associated with AD risk genes across populations. For this study we focused on oligodendroglia, a cell lineage that has been historically overlooked but that is emerging as key players in AD due to their involvement in various pathological processes, including neuroinflammation, oxidative stress, and synaptic dysfunction. Here, we report ancestry‐dependent differences in the GRA of iPSC derived oligodendroglia with African, Amerindian, or European global ancestry.MethodWe obtained PBMCs from individuals with Alzheimer’s disease (AD) or without cognitive impairment, each with over 85% global ancestry of a specific ancestral background. These cells were then transformed into induced pluripotent stem cells (iPSC) and subsequently differentiated into oligodendroglia‐containing 3D neural cultures. On the 76th day of differentiation, we harvested and lysed the cells to isolate nuclei for Multiomic profiling including Single Cell ATAC and Single Cell RNA‐seq, we analyzed the chromatin accessibility and transcriptomes to identify ancestry‐dependent changes genome‐wide and in AD GWAS hits.ResultWe found several AD GWAS hits differentially expressed between ancestries in OPCs and in the more mature oligodendrocyte population (including APP and CLU) and some differentially accessible peaks associated to some of these genes (predominantly PRDM7). Nevertheless, OPCs showed more ancestry‐specific regulation than the more mature oligodendrocytes.ConclusionOur findings offer ancestry‐specific understanding of oligodendroglia chromatin changes and gene regulation in the context of AD. These results present a comprehensive perspective on the genetic regulatory architecture of oligodendroglia and constitute a resource for gene identification studies in the African American and Hispanic populations.
Exploring how genetic variation within Aquaporin‐4, influences the relationship between sleep and amyloid beta
Authors: Porter Tenielle , Armstrong Ayeisha Milligan , Dore Vincent , O’Brien Eleanor K. , Bourgeat Pierrick , Maruff Paul , Rowe Christopher C. , Smith Stephanie Rainey , Villemagne Victor L , Laws Simon M. ,   The AIBL Research Group
Published: January 2025

AbstractBackgroundThe glymphatic system has been suggested as an important clearance mechanism for amyloid‐β (Aβ) during sleep. Animal and cellular models have suggested this clearance mechanism involves the water‐channel protein, Aquaporin‐4 (encoded by the AQP4 gene), located primarily in the astrocytic end‐feet. We have previously reported on the interaction between genetic variants within AQP4, sleep and cross‐sectional cortical amyloid‐β (Aβ) burden. This study investigated how the relationship between AQP4 genetic variants and sleep may further influence changes in cortical Aβ levels.MethodsThe current study assessed cognitively unimpaired individuals enrolled in the Australian Imaging, Biomarker and Lifestyle (AIBL) Study of Ageing, who were considered Aβ accumulators (n = 319). Aβ accumulators were defined as those who had a high baseline level of cortical Aβ (centiloid ³20), or a positive rate of change in cortical Aβ, calculated using a minimum of 3 study time‐points. 13 AQP4 gene variants were selected for analysis based on fine mapping of the gene region, and sleep was assessed using measures calculated from the Pittsburgh Sleep Quality Index (PSQI) questionnaire. The relationship between AQP4 gene variants and rate of Aβ accumulation was investigated using linear regressions. Additional linear regression models with AQP4 variant x sleep measure interaction terms and post‐hoc simple slopes were analysed to assess how these relationships may influence Aβ accumulation.ResultsAQP4‐rs68006382 was associated with Aβ accumulation, where minor allele carriers/homozygotes were observed to have a higher rate of accumulation when compared to major allele homozygotes. Linear regressions with AQP4 variant x sleep measure interaction terms revealed that in AQP4‐rs68006382 minor allele carriers there was a significant relationship between Aβ accumulation and sleep quality. Additionally, interaction analysis revealed a relationship between Aβ accumulation and sleep latency in AQP4‐rs3875089 minor allele carriers.ConclusionThe results of this study confirm our previous findings and suggests that interactions between AQP4 genotypes and sleep measures are also associated with the rate of Aβ accumulation.
Astrocyte reactivity and cerebral glucose hypermetabolism in early Alzheimer’s: insights from a longitudinal study in the TgF344‐AD rat model
Authors: de Lima Amanda Muliterno DominguesLourenço , da Rocha Andreia Silva , Machado Luiza Santos , Soares Carolina , Ferreira Pamela C.L. , Bellaver Bruna , da Silva Patrícia Eduarda Carvalho , Venturin Gianina Teribele , Greggio Samuel , Lazzarotto Gabriela , Vidor Pedro , Kunach Peter , Green Kim N. , da Costa Jaderson Costa , Souza Diogo O. , Rosa‐Neto Pedro , Zimmer Eduardo R. , AD MODEL 
Published: January 2025

AbstractBackgroundRecent studies have suggested a transient glucose hypermetabolism in early phases of Alzheimer’s Disease (AD), which is followed by a characteristic glucose hypometabolism in dementia stages. This phenomenon desveres further investigation and it is suggested to be associated to glial/inflammatory or compensatory neuronal responses. Here, we aimed to longitudinally investigate brain glucose metabolism in an AD animal model and explore associated cellular and inflammatory changes.MethodLongitudinal assessments, including cerebral glucose metabolism (18F]FDG‐PET), behavioral tasks and cerebrospinal fluid (CSF) sample collection were performed at 3, 6, 9, and 12 months of age (mo) in wild type (WT) and TgF344‐AD rats (Tg). Glial and inflammatory markers were evaluated in the CSF via ELISA multiplex. A cross‐sectional cohort was used to follow the spatial distribution of Aβ plaques (IHC), to assess the brain content of glial and neuronal proteins (western blot), and to analyze the cortical glutamate uptake (ex‐vivo slices) at the same time points.ResultAt 9mo, three months after the initial appearance of Aβ plaque deposits, Tg animals exhibited cortical glucose hypermetabolism (Figure 1A‐C). At the same age, astrocytic glutamate uptake was increased in the cortex and hippocampus (Figure 2). Declines in performance on the Y‐maze and Novel Object Recognition tasks were observed at 9 and 12mo (Figure 1D). CSF analysis revealed elevated GFAP levels at 6, 9 and 12mo, and reduced S100B at 9mo (Figure 1E e F). Tissue GFAP immunocontent increased in the temporoparietal cortex at 6 and 9mo, in the hippocampus at 9mo, and was reduced in the frontal and temporoparietal cortices at 12mo (Figure 3).ConclusionOur findings suggest the presence of an early, transient phase of brain glucose hypermetabolism in TgF344‐AD rats, consistent with observations in recent animal and human studies. This phenomenon seems to be closely linked to the astrocyte response, reflected in variations of crucial astrocyte proteins such as GFAP and S100B, along with an increase in the glutamate uptake by these cells. In contrast, neuronal, microglial and inflammatory markers did not exhibit changes during this timeframe.
Using Remote, Automated Verbal Paired Associates for Learning Over Repeated Exposure: Six Learning Bursts Over Six Months
Authors: Kaula Alexander J , McCoy Bronagh , Taptiklis Nick , Cormack Francesca K 
Published: January 2025

AbstractBackgroundLearning over repeated exposures (LORE) is an emerging paradigm that has shown sensitivity to AD biomarkers in apparently cognitively unimpaired (CU) samples using visual stimuli. We present results of a six‐month study in a CU sample that explored brief (<2 minute) assessment of verbal LORE alongside other measures of memory and sleep.MethodThe Prolific platform was used to recruit 190 participants. In a baseline session we obtained a measure of sleepiness (Karolinska Sleepiness Scale), and visual and verbal measures of memory using paired associates learning (PAL) and verbal paired associates (VPA). Five‐day bursts of VPA‐LORE were then carried out once‐monthly for six months, with participants learning a new set of word‐pairs each burst. One month after the final burst, delayed recall for all 48 associates was tested in a single session.The first session of a burst comprised presentation of the month’s associates, followed by a test of immediate recall. In subsequent sessions, cued‐recall was tested first, after which the set was presented again. A measure of LORE was created by integrating recall scores over the burst. We used linear mixed‐effects modelling to explore relationships among 1) age and baseline memory measures, measures of immediate recall and LORE and 2) between day‐by‐day scores, age and sleepiness.ResultTest‐retest correlations of LORE scores from burst‐to‐burst over the six bursts were strong (rp = .69 ‐ .75). At baseline, sleepiness did not affect PAL‐errors or VPA‐errors. PAL‐errors were positively associated with age (β = 0.391, p<.001) and VPA‐errors, but VPA‐errors were not associated with age. LORE scores were not significantly associated with age or PAL‐errors. However, day‐to‐day learning within a burst was impacted by daily sleepiness (β = ‐0.122, p<.001). In contrast to LORE, delayed‐recall after the final burst was significantly impacted by age (β = ‐0.010, p = .043).ConclusionReliability of VPA‐LORE was found to be good between bursts over six months. The association of LORE with PAL but not with age suggests VPA‐LORE measures a stable form of memory different from PAL. Additionally, the sensitivity the task to sleepiness may be relevant for use in AD‐related research given the impact of AD pathology on sleep.
Genome‐Wide Association Studies of Cognitive Progression in Alzheimer’s Disease
Authors: Shi Ruyu , Fan Kang‐Hsien , Lopez Oscar L. , Feingold Eleanor , Liu Menghan , Gorijala Priyanka , Cruchaga Carlos , Kamboh M. Ilyas 
Published: January 2025

AbstractBackgroundCognitive decline represents a significant and gradual clinical manifestation in individuals affected by Alzheimer’s disease (AD). Currently, there is a lack of effective treatments to delay its progression. Quantitative genome‐wide association studies (GWAS) have yielded limited insights into progression traits. The primary objective of this study was to identify underlying genetic variants in AD patients using longitudinal Mini‐Mental State Examination (MMSE) measures.MethodA total of 1,089 AD patients, including 410 with available whole genome‐sequencing (WGS) data from the University of Pittsburgh Alzheimer’s Disease Research Center (ADRC), and 1,117 AD patients from the Washington University in St. Louis were recruited and genotyped. GWAS were executed on four MMSE‐based cognitive decline phenotypes. Subsequently, a meta‐analysis was performed, followed by a functional exploratory analysis of identified top variants.ResultDistinct genetic variants were associated with each progression phenotype. Notably, a genome‐wide significant association was identified on chromosome 4 near the TAPT1 (top SNP = rs79296051; MAF = 0.017; p = 3.47E‐08; z = ‐5.52) gene, linked explicitly to the annual MMSE percentage changes. Additionally, several suggestive associations (p < 1E‐05) were observed in the other decline phenotypes.ConclusionWe identified one genome‐wide significant association and multiple suggestive associations with MMSE‐based cognitive progression in AD patients. Replications of these results in independent larger cohorts are needed.