bluuebunny/crossref_metadata_2025_split huggingface dataset:
Similarity of regional brain blood flow and glucose utilization imaging biomarkers in older adults
Authors: Lepping Rebecca J , Taylor Jasmine M , Honea Robyn A , Hess Benjamin J , Vidoni Eric D , Brooks William M , Burns Jeffrey M , Swerdlow Russell H 
Published: January 2025

AbstractBackgroundCerebral blood flow (CBF) and glucose utilization have both proven sensitive biomarkers of brain function in Alzheimer’s disease. However, while blood flow supplies glucose to cells to meet local demand, and therefore, are inter‐related, the two aspects are physiologically distinct. Our goal was to conduct a region‐to‐region correlation of magnetic resonance imaging (MRI) and 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) biomarkers of cerebral blood flow and glucose utilization to determine whether these physiologically distinct biomarkers yield functionally distinct information.Method108 older adults who were cognitively unimpaired (n = 71), or had mild cognitive impairment (n = 17) or dementia due to Alzheimer’s disease (n = 18), and who were enrolled in the KUMC Alzheimer’s Center Cohort completed both MRI T1‐weighted structural and pseudocontinuous arterial spin labelling (PCASL) and FDG‐PET scanning. Participant‐unique brain regions were created by segmentation of the T1‐weighted images with FreeSurfer, combined into large regions of interest for anterior/posterior cingulate, frontal, temporal, and parietal cortices. Preprocessing in SPM12 and AFNI were conducted for the PCASL and FDG‐PET data separately, and regional CBF and glucose utilization (specific uptake value ratio [SUVR]) were extracted. Correlation analysis was conducted in SPSS 29.ResultCBF and FDG‐PET SUVR were significantly positively correlated in the ACC‐PCC (r = .22, p = .02), Temporal (r = .26, p<.01), and Parietal (r = .37, p<.001) cortices, but not in the Frontal cortex (r = .13, p = .19). The correlations were modest, with the largest at .37 in Parietal cortex.ConclusionOur results indicate an expected, yet somewhat modest correlation in the majority compared regions. Additionally, the correlation was not identical across the brain, and non‐significant in frontal regions. This analysis revealed that CBF and FDG‐PET are complementary measures that provide non‐overlapping information. We conclude that these two biomarkers yield unique information and may have unique value in elucidating the relationship between blood flow and neuronal function, potentially more so for frontal rather than parietal regions.
KLOTHO‐VS heterozygosity ameliorates the effects of APOE ε4 on longitudinal hippocampal atrophy
Authors: Zhang Linda , Alfayate Eva , Calero Miguel , Medina Miguel , Grothe Michel J. , Sanchez‐Juan Pascual , Strange Bryan A. 
Published: January 2025

AbstractBackgroundKLOTHO‐VS heterozygosity (KL‐VShet+) has been posited to be a protective factor against age‐related disease and cognitive decline, having been associated with increased cortical volumes and brain connectivity, as well as improved cognition in healthy elderly individuals. Conversely, the APOE‐e4 allele is a primary risk factor for the development of Alzheimer’s disease (AD), with e4 carriers more likely to have greater ß‐amyloid burden, earlier age of AD onset, and accelerated rates of cognitive decline. Relatively few studies have investigated the interaction between these two genetic factors, with those that have presenting conflicting findings.Methods720 cognitively normal elderly participants (mean age: 74.7 years, range: 69‐87) with 3T T1‐weighted MRI, APOE and KL‐VS genotyping were selected for cross‐sectional analyses from the Vallecas Project cohort, a single‐centre 12‐year longitudinal study with annual follow‐ups. Of these participants, 443 had at least two visits and were included in longitudinal analyses (average follow‐up 4.7 years). Linear regression models were conducted to study the interaction between KL‐VS heterozygosity (KL‐VShet‐ vs. KL‐VShet+: n = 539 and 181, respectively) and APOE‐e4 (carrier vs. non‐carrier: n = 135 and 585, respectively) on FreeSurfer‐derived hippocampal volumes, neuropsychological test scores, and plasma AD biomarkers (available for a subset, n=186), controlling for age, sex, education (in models with neuropsychological outcomes), and total intracranial volume (when considering hippocampal volume). Linear mixed‐effects models were used for longitudinal analyses of the same variables.ResultsNo significant interactions between genotypes were found for any cross‐sectional comparisons. A significant KL‐VShet+ by APOE‐e4 interaction was observed in longitudinal right hippocampal volumes, where KL‐VShet+ e4‐carriers had similar rates of hippocampal atrophy compared to e4‐noncarriers, and slower rates compared to KL‐VShet‐ e4‐carriers (ß=52.94, SE=25.03, p=0.03). No significant interactions were found for neuropsychological scores or biomarker levels.ConclusionOur study provides additional evidence to suggest that KL‐VS heterozygosity attenuates the detrimental effects of APOE‐e4 on brain structure in healthy elderly adults, although the effects are not apparent in cognitive performance. Plasma AD biomarker levels did not vary significantly as a function of genotype, although this may be due to the smaller sample size. Further analyses will be conducted as more samples continue to be processed.
Clusters of modifiable risk factors provide resilience to the cognitive effects of β‐amyloid pathology in aging
Authors: Bhade Mohini , Pezzoli Stefania , Giorgio Joseph , Ward Tyler J. , Landau Susan M. , Jagust William J. 
Published: January 2025

AbstractBackgroundAlthough it has been estimated that modifiable risk factors account for around 40% of population variability in dementia risk, understanding how risk factors are related to one another and to brain pathology and cognition has been challenging. We used a clustering approach to examine patterns of risk factor interrelationships and to investigate how these patterns affect relationships between pathology and cognition.MethodWe collected risk factor data concerning health, lifestyle, sleep, and personality from 149 cognitively normal older adults (73±6.2 years), as well as PET‐measured amyloid (11C‐Pittsburgh compound‐B, PiB) and, in a subsample (n = 126), PET‐measured tau (18F‐Flortaucipir, FTP). All participants completed longitudinal neuropsychological testing (follow‐up 8.1±4.2 years). K‐means clustering was used to assign participants to different risk profiles that reflected how risk factors were interrelated. Linear mixed‐effects models were used to assess associations between decline in 1) episodic memory (EM) and 2) non‐memory (NM) cognition composite scores, with cluster assignment and PiB‐status (±) or entorhinal FTP uptake as predictors. Analyses were age and sex adjusted.ResultK‐means clustering generated 3 distinct risk‐related profiles, with more favorable profiles seen for participants in cluster 1 (physical/cognitive activity, education) and cluster 2 (sleep, depression, personality) than cluster 3 (Figure 1). In a model predicting NM decline with PiB‐status as a predictor, we observed a significant three‐way interaction between PiB‐status, cluster, and time (p<0.01) with an attenuated effect of Aß on NM decline in cluster 1 (ß = 3.7, p<0.01) and cluster 2 (ß = 3.7, p<0.01) compared to cluster 3. A model predicting EM revealed no significant interaction between cluster, PiB‐status and time (Figure 2). While a significant entorhinal tau x time effect was observed in a model predicting EM decline, cluster assignment did not modify this relationship. Results were similar when APOE4 status was included in the models.ConclusionFavorable risk profiles (cluster 1 and 2) attenuated the effect of Aß, but not tau, on cognitive decline. These findings suggest that different risk profiles moderate pathology‐cognition relationships, and demonstrate that different factors may operate together in reducing risk. This highlights the role of groups of modifiable resilience factors in mitigating the effects of Aß deposition.
Accelerated Temporal Cortex Tau Accumulation Mediates the Effects of Low Physical Activity on Faster Cognitive Decline in Preclinical Alzheimer's Disease
Authors: Yau Wai‐Ying Wendy , Kirn Dylan , Rabin Jennifer S , Properzi Michael J , Schultz Aaron P , Rentz Dorene M. , Johnson Keith A , Sperling Reisa A , Chhatwal Jasmeer P. 
Published: January 2025

AbstractBackgroundPhysically inactivity is associated with increased risk of dementia including Alzheimer’s disease (AD). Prior work from the Harvard Aging Brain Study (HABS) suggests that lower baseline physical activity in cognitively unimpaired individuals with elevated amyloid burden is associated with faster prospective cognitive decline. However, whether this detrimental effect on cognition in preclinical AD is mediated by accelerated tau pathology remains unclear.MethodWe examined 293 baseline cognitively unimpaired older adults from HABS (Table 1). Baseline physical activity (mean steps per day) was measured using a waistband‐mounted pedometer (HJ‐720ITC; Omron Healthcare) worn over 7 consecutive days during waking hours. Using linear mixed effects models, we examined the interactive effects of baseline physical activity and amyloid PET burden (Pittsburgh Compound‐B) on longitudinal cognitive decline (Preclinical Alzheimer Cognitive Composite‐5 [PACC5]), adjusting for age, sex and education (APOE not significant). In a subset of 169 participants, we examined the interactive effects on longitudinal tau pathology (Flortaucipir PET) in 36 whole‐brain FreeSurfer cortical and limbic ROIs (FDR‐correction). We further investigated if the physical activity effects on PACC5 decline in preclinical AD are mediated by changes in tau.ResultIn a larger sample of HABS participants with up to 13 years of cognitive follow‐up, we replicated the significant interaction between lower physical activity and elevated amyloid burden on faster prospective cognitive decline (ß=0.09, t=3.42, p<0.001; Figure 1A). We further demonstrated a novel interactive effect on tau pathology, where lower physical activity was associated with accelerated amyloid‐related tau accumulation in inferior temporal (ITC) and middle temporal (MTC) cortices (ITC: ß=‐0.10, t=‐3.36, FDR‐p=0.02; MTC: ß=‐0.09, t=‐3.27, FDR‐p=0.02; Figure 1B). Importantly, moderated mediation analyses revealed that accelerated tau accumulation fully mediated the effects of lower physical activity on faster cognitive decline in the setting of elevated amyloid (p<0.001, 100% mediated; Figure 2).ConclusionOur findings provide strong support for promoting physical activity as a lifestyle intervention, in conjunction with anti‐amyloid therapy, to slow the onset and/or progression of early neocortical tau pathology and cognitive decline in preclinical AD.
Alpha Synuclein co‐pathology is associated with faster Ab‐related tau accumulation in Alzheimer's disease
Authors: Roemer Sebastian Niclas , Dehsarvi Amir , Steward Anna , Dewenter Anna , Pescoller Julia , Wagner Fabian , Levin Johannes , Brendel Matthias , Höglinger Günter , Franzmeier Nicolai 
Published: January 2025

AbstractBackgroundLewy body pathology consisting of aggregated alpha‐Synuclein (a‐Syn) is the hallmark pathology in Parkinson’s disease, yet a‐Syn aggregates are also commonly observed post‐mortem as a co‐pathology in Alzheimer’s disease (AD) patients. Preclinical research has shown that a‐Syn can amplify Ab‐associated tau seeding and aggregation, hence a‐Syn co‐pathology may contribute to the Ab‐induced progression of tau pathology in AD. To address this, we combined a novel CSF‐based RT‐QuIC seed‐amplification assay to determine a‐Syn positivity, with PET‐neuroimaging in a large patient cohort ranging from cognitively normal to dementia, to determine whether a‐Syn co‐pathology accelerates Ab‐driven tau accumulation.MethodIn 261 Ab‐positive vs. 272 Ab‐negative subjects ranging from cognitively normal to dementia we employed amyloid‐PET, Flortaucipir tau‐PET and a CSF‐based a‐Syn RT‐QuIC assay for in vivo detection of abnormal a‐Syn aggregation. A subset of 136 Ab‐positive vs. 102 Ab‐negative subjects had longitudinal tau‐PET across ∼2.5years. Using linear regression, we tested whether a‐Syn positivity was linked to stronger Ab‐related tau aggregation (i.e. interaction a‐Syn x amyloid‐PET on tau‐PET).ResultPrevalence of a‐Syn positivity rose across increasing clinical severity and was particularly pronounced in Ab+ (i.e. CN/MCI/Dementia=20/23/47%) vs. Ab‐ subjects (i.e. CN/MCI/Dementia=15/10/29%), suggesting that a‐Syn co‐pathology is more common in clinically advanced AD (chi‐squared‐test, p<0.001). When testing the interaction between a‐Syn and global amyloid‐PET, we found that a‐Syn positivity was associated with stronger Ab‐related tau deposition (Figure 1A, p<0.001), and faster Ab‐related tau accumulation rates (Figure 1B, p=0.010) in typical tau vulnerable brain regions (i.e. temporal meta ROI), adjusting for age and sex. Regional analyses confirmed that higher regional amyloid‐PET was associated with stronger temporal‐lobe tau deposition (Figure 2A) and faster tau accumulation in downstream regions (Figure 2B) in a‐Syn positive individuals. In addition, there was an independent effect of a‐Syn positivity on faster temporal lobe tau accumulation rates controlling for age, sex and global amyloid, suggesting that a‐Syn may also independently contribute to tau aggregation (Figure 3).Conclusiona‐Syn co‐pathology as detected by CSF seed‐amplification assays is more common at clinically advanced AD and related to faster Ab‐related tau aggregation. This suggests that a‐Syn co‐pathology may actively contribute to AD‐related tau accumulation and therefore contribute to dementia development.
A single nucleotide polymorphism from a differentially‐expressed gene shared across four neurodegenerative diseases increases tau accumulation independently of amyloid
Authors: Ramos Vanessa G. , Carello‐Collar Giovanna , Schlickmann Thomas Hugentobler , Siebert Marina , Cristino Alexandre Santos , Bastiani Marco De , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundNeurodegenerative diseases (NDs), including Alzheimer's disease (AD), Huntington's disease (HD), Multiple Sclerosis (MS), and Parkinson's disease (PD) are characterized by the accumulation of misfolded proteins and progressive loss of neurons. However, whether a neurodegeneration transcriptomic signature exists remains uncertain. Thus, we aimed to explore differentially expressed genes (DEGs) in common to AD, HD, MS, and PD. We also seek to evaluate the effect of single nucleotide polymorphisms (SNPs) derived from the NDs‐shared DEGs on AD pathophysiology.MethodsWe obtained RNA‐sequencing and microarray datasets of vulnerable brain regions of AD, HD, MS, and PD individuals from the Gene Expression Omnibus. Differential gene expression analysis (adjusted p‐value < 0.05) was conducted to identify DEGs in common among these four NDs. Then, we examined the impact of shared DEG‐related SNPs on amyloid and tau burden in AD through a linear regression model adjusted for the covariates of age, sex, and ApoEe4 status. We obtained DEG‐related SNPs and amyloid‐ and tau‐PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI).ResultsWe identified 467 DEGs in common among AD, HD, MS, and PD vulnerable brain regions (Figure 1, p‐value < 0.05). From these DEGs, 15,574 SNPs were available in ADNI. Linear regression analysis revealed that IQGAP2 rs79679327 carriers had higher tau accumulation independently of amyloid burden (Figure 2, p‐value = 0.001; carriers: n = 21, mean age ± standard deviation (SD) = 72.76 ± 4.54; non‐carriers: n = 176, mean age ± SD = 71.64 ± 6.85).ConclusionHere, we show transcriptional similarities across four NDs. In AD, individuals carrying the IQGAP2 rs79679327 variant exhibited greater tau accumulation, regardless of amyloid. Our findings may provide insights into neurodegenerative traits, through a common signature of neurodegeneration.
Volumetric Characterization of Medial Temporal Lobe in Down Syndrome Along the Alzheimer's Disease Continuum
Authors: Zsadanyi Sara E , Buehner Bejamin J. , Morcillo‐Nieto Alejandra O. , Aranha Mateus Rozalem , Arriola‐Infante José Enrique , Vaqué‐Alcázar Lídia , Arranz Javier , Rodríguez‐Baz Íñigo , Maure‐Blesa Lucía , Videla Laura , Barroeta Isabel , Hoyo Laura Del , Benejam Bessy , Fernandez Susana , Hernandez Aida Sanjuan , Bargalló Núria , González‐Ortiz Sofía , Giménez Sandra , de Flores Robin , Alcolea Daniel , Belbin Olivia , Lleo Alberto , Carmona‐Iragui Maria , Fortea Juan , Bejanin Alexandre 
Published: January 2025

AbstractBackgroundIndividuals with Down Syndrome (DS) almost invariably develop Alzheimer's Disease (AD), but detecting early clinical changes is challenging due to comorbid intellectual disability, highlighting the importance of non‐invasive biomarkers. Neuroimaging of the medial temporal lobe (MTL), a key site of tau pathology, shows promise as an early AD biomarker. Here, we aimed to characterise volumetric patterns of the MTL in DS across the AD clinical continuum, and define associations with AD cerebrospinal fluid (CSF) biomarkers.Method253 adults with DS and 190 euploid controls from the Down Alzheimer Barcelona Neuroimaging Initiative underwent a 3T‐MRI protocol, and a comprehensive clinical assessment. T1‐weighted images were used to parse the medial temporal lobe using the Automated Segmentation of Hippocampal Subfields (ASHS) pipeline. Segmentation quality was visually inspected and W‐scores were computed for MTL subregions (anterior and posterior hippocampus, entorhinal cortex (ERC), parahippocampal cortex (PHC), and Brodmann areas Br35 and Br36) to adjust volumes for total intracranial volume, age and MRI scanner. Non‐parametric statistical tests were employed to assess volumes by AD clinical stage, age, and CSF biomarkers of AD.ResultHippocampal and Br36 volumes gradually decreased with AD clinical stage, and all subregions were decreased at the dementia stage (dDS) compared to asymptomatic (aDS) and prodromal (pDS) stages (Fig. 1). Surprisingly, significantly larger ERC, PHC and Br35 volumes were found at the asymptomatic DS stage compared to controls. All subregions had decreased volumes with age, with inflexion points around 40y for the hippocampus, ERC and Br36, 45y for Br35 and 50y for PHC (Fig. 2). Most subregions exhibited significant correlations with CSF Aß42/40 ratio, p‐tau‐181 and neurofilament light chain, and the strongest associations were found with anterior and posterior hippocampus (Fig. 3).ConclusionAD clinical stage and age are associated with progressive decreasing MTL volumes. Among all subregions, the hippocampus correlated best with CSF measures and appears particularly sensitive to detect early disease processes. These results indicate effectiveness of MTL volumes as a biomarker of early AD pathological changes in DS. Further studies are required to determine the pathological substrate of MTL atrophy and understand the increased volumes in some subregions.
A Study on the Expression Profile of Genes Coding for Secretory Proteins Using in vitro Model of Alzheimer's Disease
Authors: Singh Ravinder , Sunkaria Aditya 
Published: January 2025

AbstractBackgroundAge‐related neurological illness like Alzheimer's disease (AD) is steadily becoming more prevalent among the aged population in India and around the world. Cognitive deficits are caused by a progressive loss of normal brain functions. Increased production of amyloid (Aß) and the development of neurofibrillary tangles (NFTs) are the two most significant pathogenic events that take place during AD progression. Until today, many attempts have been made towards discovering novel targets which are more precise and could identify the progression of the disease at very early stage.MethodIn the present study the Human Protein Atlas (HPA) database was used to filter out total human secretome. Using single cell type proteome of the HPA database, neuronal proteins were compared with total human secretome to discover overlapping proteins and their respective genes. Further, Alzheimer's disease associated genes were extracted using DisGeNet database and ranked according to their gene‐disease association (gda) score. Further, different proteoforms of Aß were used to treat neuronal cells in vitro to mimic early stages of AD like pathology. The expression of secretory protein genes from in vitro model system has been analysed.ResultOut of 1678 genes, 24 neuronal genes were identified that were coding for secretory proteins. These genes were further categorized according to their proteins function. Specific primers for the top gda score genes were designed and expression analyses were conducted. Analyses revealed modulation in the expression of APOE, MAPT, NPY, NGF, and RELN genes.ConclusionThe aim of this study was to discover early‐stage biomarkers for Alzheimer's disease. In the present study we have tried to identify modulation in the genes coding for secretory proteins which might be reflected at protein levels also. Currently our lab is working on to fully understand the modulation of AD secretome which would enable us to identify AD specific early stage biomarkers.
A‐T+ PET participants in preclinical AD: Clinical progression and concordance with fluid markers
Authors: Yakoub Yara , St‐Onge Frédéric , Fajardo Alfonso , Mohammediyan Bery , Dery Christine , Sylvain Elisabeth , Tremblay‐Mercier Jennifer , Remz Jordana , Gonneaud Julie , Vogel Jacob W. , Soucy Jean‐Paul , Binette Alexa Pichet , Villeneuve Sylvia 
Published: January 2025

AbstractBackgroundAmyloid‐negative tau‐positive PET (A‐T+) participants have been reported in several studies. We assessed the prevalence and characteristics of A‐T+ participants in a cohort of cognitively unimpaired individuals with a first‐degree family history of Alzheimer’s disease (AD) dementia.MethodWe studied 252 participants from the longitudinal PREVENT‐AD cohort (mean cognitive follow‐up = 3.42 years, SD = 2.86) who received an amyloid (18F‐NAV4694) and a tau (18F‐Flortaucipir) PET‐scan. The amyloid‐positivity threshold was 18 centiloids (SUVR=1.27) and tau positive threshold was set as 2SD above the mean of A‐ participants in a temporal meta‐ROI (SUVR=1.29). Follow‐up PET scans were available for 109 participants. We characterized A‐T+ participants on clinical (age, sex, APOE4 status, education, depression, apathy, anxiety, sleep), cognitive (RBANS, MMSE, ECoG) and fluid (CSF, plasma) measurements.ResultIn the PREVENT‐AD cohort, only 3 (1.2 %) of all studied participants were classified as A‐T+ (see Table 1 for participants characteristics). Participants 1 and 2 were positive based on plasma Aß42/40 and they had relatively low levels of tau binding that could represent early pathology. Participant 3 was also positive based on CSF and plasma, her Aß‐PET scan was classified as positive on visual read and became quantitatively positive at follow‐up. Participant 3 had extensive unilateral tau binding at baseline that became bilateral at follow‐up (Figure 1). Figure 2 details the longitudinal cognitive trajectory of Participant 3. During the cognitive follow‐up, participants 1 developed mild cognitive impairment and participant 3 developed dementia.ConclusionA‐T+ individuals are rare in the PREVENT‐AD cohort and the 3 A‐T+ were classified as Aß positive based on fluid biomarkers. One of the 3 A‐T+ individuals showed a very fast clinical progression and a tau uptake pattern atypical of AD.