bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating stress hormones and multimodal measures of brain and cognition in older adults: Cross‐sectional findings from the AGE‐WELL cohort
Authors: Liebscher Maxie , White Silke , Touron Edelweiss , Mézenge Florence , Chocat Anne , Coulbaut Laurent , Vivien Denis , la Sayette Vincent De , Marchant Natalie L , Chételat Gael , Klimecki Olga M. , Poisnel Géraldine , Wirth Miranka ,   Medit‐Ageing Research Group
Published: January 2025

AbstractBackgroundIncreased stress, a proposed risk factor for Alzheimer’s disease (AD), is associated with increased brain and cognitive vulnerabilities in older populations, which may be different in women and men.ObjectiveTo examine cross‐sectional associations between circulating stress hormones (epinephrine, norepinephrine, cortisol, dehydroepiandrosterone sulfate (DHEAS), and DHEAS/cortisol ratio) and multimodal measures of brain health and cognition sensitive to AD.Method132 cognitively unimpaired older participants without clinical depression (age = 74.0 ± 4 years, females: n = 80) were included from the Age‐Well baseline dataset. Stress hormones were measured in overnight fasting blood serum (cortisol, DHEAS) and plasma (epinephrine, norepinephrine). The association of stress hormone levels with glucose metabolism and perfusion in AD sensitive brain regions, including the anterior and posterior cingulate cortex (ACC, PCC), insula and, precuneus, along with neocortical amyloid deposition and cognitive markers, including memory and Preclinical Alzheimer's Cognitive Composite‐5 (PACC5), was assessed. Linear regression models with and without stratification by sex adjusting for covariates of age, sex, education, subclinical anxiety, and depression were conducted.ResultIn the total cohort, higher epinephrine was associated with lower glucose metabolism (Figure 1) in the ACC (adj.‐β = ‐0.26, p = .027), PCC (adj.‐β = ‐0.32, p = .006), and precuneus (adj.‐β = ‐0.27, p = .021) and lower perfusion in the PCC (adj.‐β = ‐0.23, p = .013). Sex‐stratified analyses showed interactions (all p’s < .1): In males (but not in females), higher cortisol was associated with lower episodic memory (adj.‐β = ‐0.33, p = .02), short‐term memory (adj.‐β = ‐0.32, p = .014) and PACC5 scores (adj.‐β = ‐0.28, p =.04), suggesting a stress‐related vulnerability in the cognitive system of men. Stress biomarkers were not associated with neocortical amyloid deposition (all p’s ≥ .1).ConclusionOur results demonstrate the involvement of stress hormones, particularly epinephrine and cortisol, in increased vulnerability of the brain and cognition in older adults and the manifestation of sex specificities in this context. The role of stress on brain and cognitive health and related sex differences needs to be considered in intervention programs.
Enhancing Dementia Care: A Digitally Supported Care Management Program for Informal Caregivers ‐ A Cluster‐Randomized Controlled Trial
Authors: Boekholt Melanie , Klein Olga A. , Blotenberg Iris , Teipel Stefan , Michalowsky Bernhard , Kilimann Ingo , Hoffmann Wolfgang , Thyrian Jochen René 
Published: January 2025

AbstractBackgroundApproximately 1.8 million individuals in Germany live with dementia, imposing a substantial burden on family caregivers who provide most care and often experience health issues, social isolation, and diminished quality of life. Recognizing and addressing the diverse needs of these caregivers is vital for their well‐being and the stability of care arrangements.MethodThis study employed a longitudinal, cluster‐randomized controlled trial in Mecklenburg‐Western Pomerania, Germany, with 192 informal caregivers of people living with dementia. Participants were randomly assigned to either the control (n = 96) or intervention (n = 96) group. The intervention involved a digitally supported care management program delivered by trained care managers, specifically tailored to address the unmet needs of caregivers.ResultPrimary outcomes after 6 months included the number of unmet needs and the health‐related quality of life of caregivers. Secondary outcomes comprised caregiver burden and social network/support. While the intervention did not significantly reduce overall unmet needs in multivariate models, it demonstrated a notable effect in the subgroup of younger family caregivers. No statistically significant impacts were observed on other outcomes.ConclusionIndividualized care management, as delivered through this program, effectively addresses the specific support needs of informal caregivers. The study emphasizes the importance of tailoring interventions to sustain preferred caregiving arrangements and underscores the necessity of investigating nuanced needs for effective support. Although the program did not show a universal reduction in unmet needs, its positive impact on younger caregivers suggests potential benefits for specific demographic groups.
Longitudinal interplay between cerebral glucose metabolism, subclinical atherosclerosis and cardiovascular risk factors in midlife: the PESA study
Authors: Tristão‐Pereira Catarina , Fuster Valentin , Garcia‐Lunar Ines , Schöll Michael , Suarez‐Calvet Marc , Moro Maria Angeles , Garcia‐Alvarez Ana , Sanchez‐Gonzalez Javier , Zetterberg Henrik , Blennow Kaj , Ibañez Borja , Gispert Juan Domingo , Cortes‐Canteli Marta 
Published: January 2025

AbstractBackgroundCardiovascular disease and dementia often co‐exist at advanced stages. Yet, midlife longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health are scarce. We aimed to determine the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis and cardiovascular risk factors in middle‐aged asymptomatic individuals.MethodThe Progression of Early Subclinical Atherosclerosis (PESA) is a longitudinal observational cohort study of 4184 asymptomatic individuals aged 40‐54. Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose (FDG)‐PET (outcomes). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with 3D vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess outcome‐exposure associations through region‐of‐interest and voxelwise approaches. Additionally, blood‐based biomarkers of neuropathology were quantified and mediation analyses performed.ResultThis longitudinal study included 370 participants (median age: 49·8 [IQR=46·1‐52·2] years; 84% men; follow‐up: 4·7 [4·2‐5·2] years). Persistent high‐risk of cardiovascular disease was associated with an accelerated decline of cortical FDG uptake compared to low‐risk (β=‐0·008 [95% CI ‐0·013 to ‐0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; pFDR=0·050) (Figure 1). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in FDG uptake in Alzheimer’s disease brain regions, not explained by cardiovascular risk (β=‐0·269 [95% CI ‐0·509 to ‐0·027]; p=0·029) (Figure 2).ConclusionMiddle‐aged asymptomatic individuals with sustained cardiovascular risk and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintaining cardiovascular health during midlife may be key to reducing neurodegenerative disease burden later in life.
The MRI signature of alpha‐synuclein pathology in preclinical stages and in a memory clinic population
Authors: Wisse Laura E.M. , Spotorno Nicola , Strandberg Olof , van Westen Danielle , Mattsson‐Carlgren Niklas , Palmqvist Sebastian , Stomrud Erik , Parchi Piero , Hansson Oskar 
Published: January 2025

AbstractBackgroundAlpha‐synuclein pathology underlies Lewy body diseases and can also occur comorbid to other neurodegenerative pathologies. The lack of an in vivo measure for alpha‐synuclein pathology until recently has limited thorough characterization of its brain atrophy pattern, especially during early disease stages. We therefore aimed to assess the association of alpha‐synuclein pathology in cerebrospinal fluid (CSF) with magnetic resonance image (MRI) structural measures in three independent cohorts, and separately in clinically unimpaired (CU) and cognitively impaired (CI) individuals, the latter reflecting a memory clinic population.MethodIndividuals from BioFINDER‐1 (N=752), BioFINDER‐2 (N=1388) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI; N=823) with CSF alpha‐synuclein seed amplification assay results were included. T1‐weighted MRIs were processed with voxel‐based morphometry (VBM) and for region of interest (ROI) analyses with FreeSurfer 6.0 and an automated pipeline for basal forebrain nuclei CH1/2/3 and CH4/4p (=nucleus basalis of Meynert). All analyses were corrected for age, sex, intracranial volume (volumetric measures), CSF Aβ42/40 (ADNI: Aβ42), phospho‐tau181 and cognitive status (only whole cohort). Executive functioning was assessed with the symbol digit modalities test (BioFINDER‐1&2) or the harmonized composite executive function score (ADNI).ResultIn BioFINDER‐2, VBM analyses in the whole cohort revealed a specific association between alpha‐synuclein pathology and the cholinergic CH4/4p nuclei (Figure 1). Next, ROI‐based analyses, focused on regions involved in the cholinergic system, revealed that alpha‐synuclein pathology was indeed associated with smaller CH4/4p volumes, and with smaller CH1/2/3 volumes in BioFINDER‐2. Even in CU individuals, alpha‐synuclein pathology was associated with smaller CH4/4p volumes and entorhinal cortex thickness; only the former association was found in CI individuals (Figure 2). Overall, the association between alpha‐synuclein pathology and CH4/4p volume was replicated in BioFINDER‐1 and ADNI. In CI individuals, CH4/4p volumes partially mediated the association of alpha‐synuclein pathology with executive functioning in all cohorts (Figure 3).ConclusionThe findings suggest that atrophy in relation to alpha‐synuclein pathology is restricted and clearly affects the nucleus basalis of Meynert already during preclinical stages. Further, in memory clinic populations with cognitive impairment, alpha‐synuclein pathology is also associated with nucleus basalis of Meynert atrophy, which seems to partially mediate alpha‐synuclein‐induced executive impairment.
Synuclein Aggregate Assay Performance in Autopsy‐Confirmed Lewy Body Dementia: Results from the U.S. Dementia with Lewy Bodies Consortium
Authors: Leverenz James B , Patel Purvi , Formica Shane , Bekris Lynn M. , Tsuang Debby W , Zabetian Cyrus P , Litvan Irene , Fleisher Jori E , Berman Sarah , Irwin David J , Bozoki Andrea , Lippa Carol , Lopez Oscar L. , Galasko Douglas R. ,   Dementia with Lewy Bodies Consortium
Published: January 2025

AbstractBackgroundSynuclein Aggregate Assays (SAA) in cerebrospinal fluid (CSF) and in skin biopsy have been shown to successfully identify underlying synuclein (Lewy body) pathology in patients with Parkinson's disease. Data in Lewy Body Dementia (LBD) is limited, particularly with pathologic confirmation and staging of underlying Lewy body pathology, and other co‐pathologies.MethodUtilizing data and biofluids from participants in the U.S. based Dementia with Lewy Bodies Consortium (DLBC) who have donated CSF to the study and come to autopsy, we examined the performance of CSF‐based SAA and AD biomarkers during life to post‐mortem presence and staging of Lewy body pathology (LBP) and Alzheimer's disease Neuropathologic Change (ADNC). SAA testing was performed on CSF by Amprion (SynTap).ResultCurrently, the DLBC has enrolled over 160 participants, of which 31 cases have come to autopsy and been staged for LBP, ADNC, and TDP‐43 pathology. Twenty‐eight cases had CSF available from study participation. Three cases did not have LBP at autopsy and CSF SAA testing was negative in all three. Of the remaining 25 cases, two additional cases were CSF SAA indeterminate or negative and had anatomically limited LBP (brainstem and amygdala predominant respectively). One amygdala predominant LBP case had a positive CSF SAA. The remaining 22 limbic or neocortical stage LBP cases were CSF SAA positive ("detected"). SAA testing was positive in three cases with limbic or neocortical LBP and high stage ADNC co‐pathology.ConclusionCSF‐based SAA testing performed well in Lewy body dementia with autopsy‐confirmed limbic or neocortical stage LBP. Detection of LBP when in more limited anatomic locations, brainstem or amygdala, was less reliable. False positive CSF SAA was not observed in this autopsy confirmed sample of LBD.
Epigenomic assessment of differential pathological and clinical presentation in the Lewy body dementias
Authors: Harvey Joshua , Imm Jennifer , Creese Byron , Chouliaras Leonidas , Dempster Emma , Ballard Clive G , O'Brien John T , Aarsland Dag , Mill Jonathan , Pihlström Lasse , Pishva Ehsan , Lunnon Katie 
Published: January 2025

AbstractBackgroundThe Lewy body dementias are a class of neurodegenerative disease encompassing Parkinson’s disease dementia (PDD) and Dementia with Lewy bodies (DLB). Despite similar clinical and neuropathological profiles, the principal differentiating feature is the sequence in which symptoms develop. A question still remains as to a biological basis of this difference and a potential explanation is epigenetic mechanisms, molecular processes which alter the way in which the underlying genetic sequence is expressed.MethodDNA methylation was quantified using the Illumina EPIC array for 932 samples from the anterior cingulate cortex (ACC, n = 462) and the prefrontal cortex (PFC, n = 470), sourced from 481 unique donors. Samples were defined based on antemortem records as neurological controls (n = 103), PD (n = 123), PDD (n = 101), DLB (n = 95) and Alzheimer’s Disease (AD, n = 59). Weighted gene correlation network analysis (WGCNA) was conducted, controlling for confounders to define co‐methylated networks with evidence of association to pathological (Braak NFT and LB) outcomes and clinical subgroups, including presentation of neuropsychiatric symptoms. Significantly associated modules were tested using gene ontology analysis (GO, missMethyl) and expression enrichment in publically available single nucleus RNA sequencing datasets (Expression Weighted Cell Type Enrichment Analysis, EWCE).Result11 co‐methylation modules (ACC = 9, PFC = 2) showed FDR corrected significant association to either a pathological or clinical outcome. The most significantly associated module was observed in the ACC (Figure A & B), with association with both Braak LB stage (P = 1.49 x 10‐5) and PDD presentation stratification (P = 1.41 x 10‐6). The module showed significant GO term enrichment relevant to inflammation (Figure C) and EWCE analysis confirmed expression of genes annotated to this module were significantly enriched in microglial cell types. The module contained epigenetic loci annotated to C1QB, PLA2G15 and ERGIC1, all of which showed nominal clinical groupwise association in a clinical EWAS analysis of the same cohort.ConclusionEpigenetic alterations show evidence of insight into brain region specific pathological processes with differential stratification between DLB and PDD. Ongoing analysis in this cohort looks to resolve sex specific stratified analyses.
Alzheimer’s disease and microbiota: The MICMALZ cohort
Authors: Bennys Karim 
Published: January 2025

AbstractBackgroundMicrobiota is modulated by normal aging, but also by Alzheimer’s disease (AD) risk factors as poor diet or alteration of sleep patterns. Patients with AD exhibit a dysbiosis characterized by changes in the relative proportions of specific bacterial phyla. Eventually, fecal microbiota transplants (FMT) can improve cognitive deficits and reduce amyloid‐ß deposition, at least in mouse models of AD.MethodWe generated a cohort of AD patients, with control participants matching on age, sex, body mass index, Mini Nutritional Assessment® and education, to sample and compare microbiota composition in the stool and blood compartments. This metagenomic study will be completed by targeted and non‐targeted metabolomic analysis to inform about microbiota impact on the host. We precisely evaluated cognition, sleep parameters and dietary habits of the subjects. Moreover, stool samples from 19 patients were pooled by 4, with similar age and sex, from each group, and were transplanted in a mouse model of AD (5XFAD, n = 94) or their control littermates (n = 113) to evaluate the consequences on gut microbiota composition, memory‐related behaviors and molecular and cellular biomarkers of AD physiopathology.ResultWe generated a cohort of well characterized patients representative of mild to moderate AD patients with 45 AD patients [age 75 (SD 0.9), 51% women, minimental state examination (MMSE) 22 (interquartile range, IQR, 17‐25)] and 37 controls [age 72 (SD 1.5), 62% women, MMSE 29 (IQR 27‐30)]. Our preliminary results indicate i) a potential dysbiosis in AD patients that translates to mouse microbiota composition following FMT. A specific bacterial genus is increased both in 5XFAD and control mice potentially indicating over‐representation in AD patients relative to the controls; ii) an impact of microbiota transplanted from AD patients to mouse model on memory and behavior, with an alteration of novel object recognition but also on biomarkers of AD pathology including an increase in mouse Aß1‐42 expression level.ConclusionOur results suggest that gut microbiota dysbiosis is associated with AD status and point to a specific bacterial genus. Moreover, FMT from AD patients in an AD mouse model recapitulates important features of the disease, with memory impairment and Aß1‐42 accumulations.
Single‐cell transcriptomic landscapes of neurodegenerative diseases: towards mapping shared and distinct mechanisms
Authors: Shwab Elliot Keats , Man Zhaohui , Gingerich Daniel , Garrett Melanie E , Crawford Gregory , Ashley‐Koch Allison , Chiba‐Falek Ornit 
Published: January 2025

AbstractBackgroundAge‐related neurodegenerative disorders (NDDs) continuum includes late‐onset Alzheimer’s disease (LOAD), Dementia with Lewy bodies (DLB), and Parkinson’s disease (PD) exhibit shared and distinct clinicopathological characteristics. Each of the different NDDs is characterized by a complex genetic etiology and although numerous loci have been identified via GWAS, and the causal genes and the specific neuronal and glial cell subtypes through which they exert their pathogenic effects are yet to be fully elucidated. We aimed to untangle the genetic complexity of NDDs, and to identify shared and distinct biological pathways and disease driver cell‐subtypes across NDDs.MethodSingle‐cell transcriptomic profiling was performed using LOAD, DLB, PD and normal brains (12/group). Differential expression was analyzed using the single‐nucleus (sn)RNA‐seq datasets by Nebula. To investigate shared biological pathways, we analyzed the common DEGs across NDD pathologies for each cell‐type using Metascape and aPEAR. To identify distinct DEGs and biological pathways we comparted directly between each two pathologies. The vulnerable and disease driver cell‐subtypes were characterized by beta‐regression and AUCell analyses, respectively.ResultWe identified cell‐subtype specific differential expressed genes (DEGs) for each NDD compared to control. A catalogue of common DEGs across NDDs in each cell type showed the largest number of upregulated‐DEGs in inhibitory neurons (∼700). Pathway analysis using the shared DEGs indicated enrichment for biological pathways including, neurodegeneration, stress response, RNA and protein metabolism, and mitochondria dysfunction. Noteworthy, we observed overlap with pathways detected for NPS comorbidity. Differential gene expression analysis between LOAD vs PD identified >5000 upregulated‐DEGs in microglia followed by Astrocytes and OPC and found enrichment for pathways including oligodendrocytes maturation and myelination, while the majority of upregulated‐DEGs in PD compared to LOAD were identified in oligodendrocytes and enriched in biological terms related to protein biosynthesis and energy metabolism. We showed that microglia and oligodendrocytes cell‐subtypes are drivers of LOAD pathology whereas PD pathogenic effect is driven by excitatory neurons.ConclusionThis study represents the most comprehensive a systematic interrogation of gene dysregulation in a spectrum of NDDs in an unprecedented cell‐subtype resolution. The results enhance our understanding of the shared and distinct genetic factors and biological processes underlying age related NDDs.
Time window for early intervention in tauopathy mouse model
Authors: Maffei Benito , O'Neill Nathaneal , Dyson Chiara , Padmasola Guru , Moreira Francisco , Leite Marco , Magloire Vincent , Kullmann Dimitri Michael , Lignani Gabriele 
Published: January 2025

AbstractBackgroundEarly changes in network activity serve as distinctive hallmarks in tauopathies such as Alzheimer’s Disease and Frontotemporal Dementia. Decades before the onset of cognitive decline, many patients experience seizures which exacerbate the condition. Despite the recognised etiological overlaps between tauopathies and epilepsies, the relationship between tau and the development of circuit hyperexcitability is unclear and needs further investigation.MethodUsing wireless EEG to record intrahippocampal local field potentials (LFP), we characterised early biophysical alterations within the hippocampus of tauopathy mice.ResultWe identified a novel transient time window where hippocampal function is disrupted before the onset of tau pathology and cognitive declineConclusionA precise and robust targeting of this circuit prior to the manifestation of the disease would advance our understanding of the role of circuit excitability in tau pathology. This could serve as an early therapeutic target, offering a novel strategic approach to deter the progression of the disease.