bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic overlap between cortical brain morphometry and frontotemporal dementia risk
Authors: Diaz‐Torres Santiago , Ogonowski Natalia , García‐Marín Luis M , Bonham Luke W. , Duran‐Aniotz Claudia , Yokoyama Jennifer S. , Renteria Miguel E. 
Published: December 2023

AbstractBackgroundFrontotemporal dementia (FTD) has a complex genetic aetiology, where the precise mechanisms underlying the selective vulnerability of brain regions remain unknown.MethodWe leveraged summary‐based data from genome‐wide association studies (GWASs) and performed LD‐score regression to estimate pairwise genetic correlations between FTD risk and cortical brain imaging. Then, we isolate specific genomic loci with a shared aetiology between FTD and brain structure. We also performed functional annotation, summary‐based‐data Mendelian randomisation for eQTL using human peripheral blood and brain tissue data and evaluated the gene expression in mice targeted brain regions to better understand the dynamics of the FTD candidate genes.ResultPairwise genetic correlation estimates between FTD and brain morphology measures were high but not statistically significant. We identified five brain regions with a strong genetic correlation (rg > 0.45) with FTD risk. Functional annotation identified eight protein‐coding genes. Building upon these findings, we show in a mouse model of FTD that cortical NSF expression decreases with age.ConclusionOur results highlight the molecular and genetic overlap between brain morphology and higher risk for FTD, specifically for the right inferior parietal surface area and right medial orbitofrontal cortical thickness. In addition, our findings implicate NSF gene expression in the aetiology of FTD.
Towards the Biomechanics of Alzheimer’s Disease: Computational Models
Authors: Saeidi Saeideh , Terzano Michele , Holzapfel Gerhard A. 
Published: December 2023

AbstractBackgroundPhysical changes in the brain microenvironment are highly associated with changes in mechanosensitivity of neuronal cells and mechanical properties of brain tissue. The progression of amyloid plaques and neurofibrillary tangles in the brain network significantly affects brain microstructure in Alzheimer’s disease (AD). To better understand the underlying mechanisms of AD, it is crucial to explore the effect of neuropathologies that cause brain tissue softening.MethodWe propose a microstructural model of brain white matter characterized by axons embedded in an extracellular matrix (ECM). The microscale is described by a representative volume element and includes features such as mechanical properties of axons and ECM, distribution of axon diameters, and axon tortuosity from experimental observations. The aim of this work is to investigate how the presence of β‐amyloid as hard senile plaques in the ECM and neurofibrillary tangles leads to softer mechanical properties of the brain during AD. The model is validated by simulating healthy brain tissue and comparing the homogenized response with existing experimental data.ResultPreliminary analyses to validate the model have shown tissue behavior similar to that seen in the mechanical experiments. In the case of AD, as expected, changes in the mechanical properties of the ECM due to the presence of hard senile plaques, demyelination due to the detachment of hyperphosphorylated tau proteins and neuronal death significantly affect the material properties at the macroscale.ConclusionThe combination of computational mechanical models with experimental observations opens a window to assess the structure‐function relationship of brain tissues in neuropathological disorders, which may be particularly useful to precisely design biomarkers for early detection or more informed therapeutic strategies.References• Schäfer, J. Weickenmeier, and E. Kuhl, “The interplay of biochemical and biomechanical degeneration in Alzheimer’s disease”, Comput. Methods Appl. Mech. Eng., vol. 352, pp. 369‐388, 2019.• M. Hall, E. Moeendarbary, and G.K. Sheridan, “Mechanobiology of the brain in ageing and Alzheimer’s disease”, Eur. J. Neurosci., pp. 1‐28, 2020.• Budday, G. Sommer, C. Birkl, C. Langkammer, J. Haybaeck, J. Kohnert, M. Bauer, F. Paulsen, P. Steinmann, E. Kuhl, G.A. Holzapfel, “Mechanical characterization of human brain tissue”, Acta Biomater., pp. 319‐340, 2017.
Integrative omics studies to discover genetic determinants of brain cell type proportions
Authors: Reddy Joseph S. , Allen Mariet , Patel Tulsi , Quicksall Zachary , Wang Xue , Carnwath Troy , Min Yuhao , Golde Todd E , Ertekin‐Taner Nilufer 
Published: December 2023

AbstractBackgroundNeurodegenerative disorders affect different brain regions at different time points and to varying degrees, although the underlying reasons for this variability in regional susceptibility is unknown. Brain regions have different proportions of cell types. This cell proportion variability may be further influenced by presence and degree of brain disorders, including neurodegenerative diseases. We postulate that genetic and other factors that influence brain cell type proportions may also provide insights into brain regional susceptibility to neurodegenerative diseases.MethodsUtilizing bulk transcriptomics data from 7 brain regions obtained from 3 cohorts and corresponding whole genome sequencing (WGS) data, genetic variants were evaluated for association with cell type proportions across brain regions. Utilizing cell type specific marker genes for deconvolution provided by McKenzie et.al, we estimated surrogate variables for proportion (SVP) of various cell types using BRETIGEA. We then evaluated relationship between SVP and AD as well as Age, Sex, APOE ε4 and neuropathology measures. Genetic variants from WGS were then tested for association with SVP to identify distinct and conserved patterns across 6 cell types and 7 brain regions.ResultsAnalysis of SVP by diagnosis, sex, age, APOE ε4 and neuropathology measures identified significant differences in cell proportions in various cell types and brain regions. GWAS of SVP identified 134 loci that reached genome‐wide significance (5e‐8). After conservative adjustment for multiple testing (6 cell types and 7 brain regions; 42 tests), variants proximal to SYNPR and VENTXP7 remained significant (p‐value<1.19E‐09). Variants proximal to SYNPR were associated with increased proportion of oligodendrocytes in cerebellum whereas variants near VENTXP7 were associated with reduced proportion of astrocytes in DLPFC. Variants in SYNPR have previously been associated with neurofibrillary tangles and diffuse plaque measurements while variants in VENTXP7 have been associated with measurement of neurofibrillary tangles, cognitive decline, unipolar depression, and bipolar disorder.ConclusionsIt is likely that there are genetic variants associated with cell proportion in brain, may vary by cell type and brain region, while others may act more broadly. Identification of genetic variants associated with cell proportions in different brain regions may provide insights into affected cells and regional vulnerabilities.
New in vitro tools to investigate the role of microglia in neurodegeneration
Authors: Erlebach Lena , Welzer Marc , Bühler Anika , Miely Daniela , Schwarz Niklas , Panagiotakopoulou Vasiliki , Haesler Lisa M. , Lambert Marius , Obermüller Ulrike , Beschorner Natalie , Koch Henner , Neher Jonas J. , Wuttke Thomas , Hedrich‐Klimosch Ulrike , Jucker Mathias , Kronenberg‐Versteeg Deborah 
Published: December 2023

AbstractBackgroundHuman induced pluripotent stem cells (iPSCs) have transpired as an attractive tool to investigate neurological diseases. And while immune cells, and in particular microglia, have emerged as important players in many neurological and in particular in neurodegenerative diseases, it remains a challenge to fully recapitulate an in vivo‐like phenotype ex vivo. This is due to the fact that microglial identity is shaped by the neural tissue environment.MethodWe have now developed a chimeric brain slice culture system, where we engraft iPSC‐derived microglia onto mouse (and human) organotypic brain slice cultures. Brain slice cultures offer the advantage that many aspects of the complex cytoarchitecture of the mature/aged living brain, including cortical layering, columnar organization and electrophysiological properties can be preserved over several weeks.ResultWe found that iPSC‐derived microglial precursors integrate and differentiate well in the brain slice cultures, with morphology, network characteristics and functional responses reminiscent of human microglia. Gene expression profiling of iPSC‐derived microglia revealed enhanced maturation over time. Upon induction of neurodegenerative disease pathology in these slice cultures, the iPSC‐derived microglia show transcriptional changes converging towards those observed in patients with neurodegenerative disease pathology.ConclusionThis system is a novel cellularly complex tool allowing to dissect the dynamics and molecular mechanisms of microglial genetic risk factors of many neurological diseases, while preserving experimental amenability to test therapeutic approaches in a human(ized) system.
Integrative gene expression studies on the path to precision medicine in Alzheimer’s and related disorders
Authors: Ertekin‐Taner Nilufer 
Published: December 2023

AbstractBackgroundGenetic studies in Alzheimer’s disease and related disorders (ADRD) revealed numerous disease risk loci many of which reside in noncoding regions. To translate these discoveries to precision medicine therapies and biomarkers, integrative multi‐omics studies especially combining gene expression and disease phenotypes are necessary.MethodIn this presentation, we will review existing and emerging approaches in the discovery of functional disease risk variants, pathways and key disease molecules in ADRD via integrating multi‐omics and disease phenotypic data using computational systems biology followed by experimental validation.ResultsIntegrative genome‐wide association studies (GWAS) of ADRD risk, ADRD‐related phenotypes, gene expression and epigenetic factors such as methylation nominate disease variants and pinpoint risk mechanisms. Large scale differential gene and co‐expression network analyses discovered novel disease pathways unique to or shared between different ADRD. Experimental validations of these findings in model systems yielded high confidence molecular perturbations in ADRD.ConclusionADRD is characterized by molecular perturbations in myriad pathways including vascular, synaptic, immune, myelination and many others that are revealed through integrative multi‐omics studies in well‐characterized human cohorts and prioritized through experimental model systems. These molecules serve as candidate precision medicine therapeutic targets and biomarkers.
APOE‐dependent and ‐independent polygenic pathways determining early Alzheimer’s Disease pathological changes in CSF and MRI
Authors: Lorenzini Luigi , Collij Lyduine E. , Tesi Niccoló , Ingala Silvia , Sudre Carole H , Wolz Robin , Haller Sven , Blennow Kaj , Frisoni Giovanni B , Payoux Pierre , Martinez‐Lage Pablo , Ewers Michael , Chetelat Gael , Ritchie Craig W , Gispert Juan Domingo , Mutsaerts Henk‐Jan , Altmann Andre , Tijms Betty M. , Wink Alle Meije , Visser Pieter Jelle , Barkhof Frederik 
Published: December 2023

AbstractBackgroundLittle is known about the genetic factors and downstream molecular pathways determining individual variability in fluid and imaging biomarkers associated with Alzheimer’s disease(AD). We studied polygenic risk scores (PRS) and pathway‐specific PRS in relationship with AD fluid and imaging biomarkers, in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort.MethodEPAD inclusion criteria were age>50 and Clinical Dementia Rating = 0.5 (n = 1886, Table 1). AD‐PRS was based on 85 previously identified loci, including and excluding APOE (PRSAPOE, PRSnoAPOE)[1]. Using gene‐variant and variant‐pathway mapping[2], six pathway‐specific PRSnoAPOE were identified:1) immune‐activation, 2) signal‐transduction, 3) inflammatory‐response, 4) migration, 5) amyloid‐production, and 6) clearance. Linear models were used to assess the relationship of all PRS with fluid AD biomarkers, including Aß1‐42, p‐Tau181, and t‐tau; and several imaging biomarkers, including hippocampal volume, global and lobar white matter hyperintensities (WMH) volumes, fractional anisotropy (FA) in 14 regions of interest from diffusion tensor imaging, and 10 resting‐state network connectivity from functional MRI. Models were adjusted for age, sex, site, and multiple comparisons.ResultModels’ coefficients are reported in Table 2. PRSAPOE was significantly associated with decreased Aß1‐42, and increased p‐Tau181 and t‐Tau. PRSnoAPOE showed a weaker, but still significant, negative association with Aß1‐42 levels, and a significant positive association with p‐Tau181 and t‐Tau. Aß1‐42 was only significantly associated with the migration, amyloid, and clearance pathways, while all pathways were significantly positively associated with p‐Tau181 and t‐Tau. Hippocampal volume was only significantly associated with PRSAPOE. Regarding WMH load, PRSAPOE showed a positive association with global, frontal periventricular, and parietal deep lobes. Furthermore, the clearance pathway was related to WMH load in all regions, most strongly in periventricular areas. Only the migration pathway was related to increases in FA in the splenium, body, and genu of the corpus callosum. Only the PRSAPOE was related to reduced functional connectivity (FC) in the default mode, control, and visual networks.ConclusionWe show that genetic risk beyond APOE facilitates the manifestation of AD related pathologies. Moreover, clearance and migration pathways were associated with neuroimaging measures of white matter integrity, while FC and hippocampal volume were associated with overall AD genetic risk.
Novel CSF tau biomarkers can be used for disease staging of sporadic Alzheimer’s
Authors: Salvadó Gemma , Horie Kanta , Barthélemy Nicolas R. , Vogel Jacob W , Binette Alexa Pichet , Chen Charles D. , Gordon Brian A. , Benzinger Tammie L.S. , Holtzman David M. , Morris John C , Palmqvist Sebastian , Stomrud Erik , Janelidze Shorena , Ossenkoppele Rik , Schindler Suzanne E. , Bateman Randall J. , Hansson Oskar 
Published: December 2023

AbstractBackgroundStaging Alzheimer’s disease (AD) allows for the identification of key milestones and inflection points in the disease course. However, most current in vivo disease staging methods rely on costly and low‐accessible measures such as PET. Our objective was to generate and evaluate a staging model based on multiple cerebrospinal fluid (CSF) biomarkers.MethodWe created a staging model using the Subtype and Stage Inference (SuStaIn) algorithm in 426 participants covering the whole AD spectrum (Table 1) by evaluating CSF Ab42/40 and 5 CSF tau markers: the proportion of tau phosphorylated at three threonine residues (pT205/T205, pT217/T217, and pT231/T231), and the concentrations of microtubule‐binding region of tau at residue 243 [MTBR‐tau243] and total‐tau [mid‐domain containing T212‐221]). We investigated associations between CSF stages and cross‐sectional and longitudinal changes in amyloid and tau pathologies, neurodegeneration and cognition using linear regression models. ROC curves were used to identify the optimal stage for predicting positivity in imaging biomarkers and to separate AD vs non‐AD cognitive symptoms. We also tested the relative risk of progression from cognitively unimpaired or MCI to AD‐type dementia using Kaplan‐Meier curves and Cox‐proportional Hazard models. Creation of the model and cross‐sectional analyses were replicated in an independent cohort (n = 222, Table 1).ResultSuStaIn revealed that only one subtype was present and that five CSF biomarkers (ordered: Ab42/40, pT217/T217, pT205/T205, MTBR‐tau243, T212‐221) were sufficient to create an accurate disease staging model (Fig.1A‐B). Increasing stages (0‐5) were associated with increased abnormality in other AD‐related biomarkers (Fig.1C). In both cohorts, stage = 2 accurately predicted amyloid‐PET positivity (AUC = 0.89), stage = 4 predicted tau‐PET (AUC = 0.94) and neurodegeneration positivity (AUC = 0.81). In the main cohort, stage = 2 separated non‐AD from AD‐related cognitive impairment (AUC = 0.96). Longitudinal changes for several AD‐biomarkers by stages are presented in (Fig.2A). Higher stages (4‐5) at baseline were associated with higher hazard ratios (HR) of progressing to AD‐type dementia (CU&MCI: HR = 4.6[2.0,10.9], MCI: HR = 3.5[1.5,8.1], Fig.2B‐C).ConclusionOur results suggest that the AD continuum can be accurately staged with a single CSF sample, which may be useful in the clinical setting for patient management but also as a tool in clinical trials for selection and monitoring of study participants.
Discerning neurodegenerative and aging genetic influences on hippocampal subfields trajectories in the Alzheimer’s disease continuum
Authors: Vilor‐Tejedor Natalia , Evans Tavia E , Genius Patricia , Rodríguez‐Fernández Blanca , Rodrigo Albert , Navarro Arcadi , Gispert Juan Domingo , Adams Hieab H.H. 
Published: December 2023

AbstractBackgroundHippocampal atrophy is one of the most characteristic biomarkers of Alzheimer’s disease (AD), and its genetic basis, as well as that of its distinct subfields, is of current interest. However, hippocampal subfields have so far only been assessed largely unrelated to brain atrophy, and the majority of studies were focused on general population samples, explicitly excluding diagnosed patients. In this study, we evaluated whether hippocampal subfields trajectories are a suitable endophenotype to discern between neurodegenerative and aging genetic influences in the Alzheimer’s continuum.MethodThe dataset includes AD patients (N = 113), mild cognitive impairment (N = 426), and control normal (CN) (N = 272) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Individuals were evaluated with 3T MRI at baseline and every 6 months for a total of 96 months. Hippocampal subfields were extracted using longitudinal processing within FreeSurfer(6.0). We used longitudinal mixed‐effect models with random intercept for individuals to investigated the association between hippocampal subfields volumetric changes and genetic predisposition to AD, Parkinson’s disease, frontotemporal dementia (neurodegeneration), as well as intrinsic and extrinsic epigenetic clock acceleration and telomere length (biological aging). Models were adjusted by age, sex, AD‐stage and total hippocampal volume. Disease status‐specific trajectories were also assessed.ResultGenetic predisposition to biological aging (driven by genetic predisposition to telomere length) was significantly associated with subfield changes in presubiculum (β = ‐11.2, p = 4.1e‐04), parasubiculum (β = ‐4.4, padj = 4.4e‐04), molecular layer (β = 5.9, padj = 2.0e‐04), dentate gyrus (DG) (β = 5.79, padj = 4.4e‐04), CA4 (β = 7.2, padj = 4.4e‐05), and HATA (β = ‐1.7, padj = 0.027). Genetic predisposition to neurodegeneration (driven by predisposition to AD) was associated with volumetric changes in CA3 (β = 4.4, p = 0.047). In stratified models, we observed significant volumetric changes due to genetic predisposition to neurodegeneration in controls (CA1, CA4, DG, parasubiculum, molecular layer). In MCI (subiculum regions and CA4) and AD (hippocampal fissure, molecular layer and DG), volumetric changes were mostly associated with genetic predisposition to biological aging processes.ConclusionWe showed differential genetic mechanisms associated with hippocampal subfield trajectories that were specific to Alzheimer’s disease stage. These results may help elucidate new biological mechanisms in the course of the disease as well as discern additional molecular mechanisms related to neurodegeneration and aging.
Brain MRI diffusion abnormalities associated with arteriolosclerosis pathology
Authors: Tomash Ana , Tazwar Mahir , Yasar Md Tahmid , Zhang Shengwei , Evia Arnold M , Schneider Julie A , Arfanakis Konstantinos 
Published: December 2023

AbstractBackgroundBrain arteriolosclerosis is one of the main pathologies of cerebral small vessel disease. It involves the thickening of the vessel wall and stenosis of arterioles causing lower cognitive and motor function, and higher odds of dementia. This work intends to explore the independent association of brain arteriolosclerosis with diffusion abnormalities in the white matter (WM) of community‐based older adults.MethodParticipants comprised community‐dwelling older adults (N = 175) from four studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Fig.1A). Whole brain 3D T1w MPRAGE, T2w FLAIR, and diffusion‐weighted MRI (2×2×2mm3, b = 1,000s/mm2 for 40 diffusion gradient directions, and 6 b = 0s/mm2 volumes) data were acquired in‐vivo using 3T MRI scanners. The fractional anisotropy (FA) and trace maps were transformed to the space of the IIT Human Brain Atlas v.5.0 and projected onto the WM skeleton of the IIT atlas. Following a participant’s death, the extracted brain underwent a detailed evaluation by a neuropathologist. Assessed neuropathologies included arteriolosclerosis, Alzheimer’s pathology, LATE‐NC, gross and microscopic infarcts, atherosclerosis, and cerebral amyloid angiopathy (Fig.1B). Linear regression was used in voxels of the WM skeleton to test the association of FA or trace with the severity of arteriolosclerosis controlling for all other neuropathologies, white matter hyperintensities (WMH), demographic variables (age at scan, sex, years of education), antemortem interval to imaging, and scanner. The statistical analyses were carried out using FSL’s PALM tool with 5,000 permutations and threshold‐free cluster enhancement. The significance level was set at p<0.05, after family‐wise error rate (FWER) correction for multiple testing.ResultArteriolosclerosis score was associated with lower FA (Fig.2) and higher trace (Fig.3) of the diffusion tensor throughout the brain in multiple WM regions, even in areas typically free of WMH. Other neuropathologies or the effects of WMH on diffusion characteristics had no impact on these relationships.ConclusionThe current study showed that, regardless of the impact of other neuropathologies or visible WMH, brain arteriolosclerosis in older persons is associated with diffusion abnormalities that extend throughout the WM.