Biology subjects

Debette, S.

Publications and source records attributed to Debette, S..

10 recordsLinked to original sources

bioRxiv2026

A mitochondrial program encodes brain vascular reserve

Brain resilience depends on collateral vessels whose geometries preserve blood flow when primary arteries are perturbed. How these protective vascular architectures are developmentally established remains unknown. Using longitudinal in vivo imaging in zebrafish, we show that mitochondrial state in embryonic angiogenic tip cells encodes the topology of basal and surface brain collateral networks. Mechanistically, microRNA-125a establishes the bioenergetic and redox balance of endothelial tip-cell mitochondria through conserved repression of the metabolic regulator PGC1a. Disruption of the microRNA-125a-PGC1a axis uncouples mitochondrial capacity from redox buffering in developing brain tip cells, redirecting their migration toward sparse, incompletely connected collateral network topologies and increasing adult cerebrovascular vulnerability. Consistent with this mechanism, humans with subclinical cerebrovascular injury exhibit reduced circulating microRNA-125a levels associated with incomplete basal collateral configurations. Together, these findings identify mitochondrial state as an instructive and conserved developmental program that encodes brain vascular reserve.

developmental biology↗

bioRxiv2026

Characterization of variants associated with Cerebral Small Vessel Disease identifies a functional SNV in Versican

BackgroundSingle nucleotide variants in the non-coding genome can significantly alter disease risk, but identifying the function of SNVs is a challenge. Increasing numbers of variants of unknown significance have been associated with the risk of Stroke, Cerebral Small Vessel Disease and burden of White Matter Hyperintensities, but without biological validation, the significance of these findings is uncertain. MethodsWe use a Multiplexed Parallel Reporter Assay (MPRA) to assay the function of 44 SNVs associated with Cerebral Small Vessel Disease and stroke in EFEMP1, FOXF2, HAAO, KCNK3, NMT1, OPA1, RASL12, STAT3 and VCAN. A functional SNV in versican was further probed using transcriptional reporter and Chromatin Immunoprecipitation assays. ResultsWe identify 26 allele-specific enhancers in where the SNV either increases or decreases transcriptional activity. We validate rs13176921 as an SNV that significantly modulates an intronic enhancer in the matrisome protein Versican and show it affects mRNA levels of the gene. We identify that the transcription factor NKX3.1 binds to the region of this SNV. ConclusionsThus, using MRPA we were able to gain mechanistic insight into which GWAS-identified SNVs modulate transcriptional activity, and validate a functionally important SNV in Versican and provide a mechanism by which it controls its transcription.

genetics↗

bioRxiv2024

Cerebral Small Vessel Disease genetic determinant TRIM47 controls brain homeostasis via the NRF2 antioxidant system

Cerebral small vessel disease (cSVD) is a leading cause of stroke, cognitive decline and dementia, for which no specific mechanism-based treatments are available to date. Genome-wide and whole-exome association studies previously identified robust associations of common variants at chr17q25 with cSVD features on magnetic resonance imaging, with converging bioinformatic and experimental data for a causal involvement of TRIM47. Preliminary functional evaluation of TRIM47, an ubiquitin ligase enriched in brain endothelial cells (ECs), suggested its potential role in blood brain barrier (BBB) integrity. Here, we show that TRIM47 regulates brain EC resilience and adaptive responses to oxidative stress by binding to KEAP1, stabilizing NRF2 protein levels and promoting the NRF2 antioxidant signaling pathway. In vivo, Trim47-deficient mice exhibit downregulation of NRF2 target genes, BBB dysfunction, astrogliosis and cognitive impairments. Endothelial-specific deletion of Trim47 recapitulates these phenotypes. Treatment with the NRF2 activator tert- butylhydroquinone normalized BBB integrity and cognitive function in Trim47-deficient mice, highlighting the role of endothelial TRIM47 in driving brain homeostasis through NRF2 pathway activation. This work indicates that loss of the protective TRIM47/NRF2 axis may increase the susceptibility to developing human cSVD and that targeting the TRIM47/NRF2 axis could be a promising therapeutic approach for vascular cognitive impairment and dementia.

neuroscience↗

bioRxiv2023

Early detection of white matter hyperintensities using SHIVA-WMH detector

White matter hyperintensities (WMH) are well-established markers of cerebral small vessel disease (cSVD), and are associated with an increased risk of stroke, dementia, and mortality. Although their prevalence increases with age, small and punctate WMHs have been reported with surprisingly high frequency even in young, neurologically asymptomatic adults. However, most automated methods to segment WMH published to date are not optimized for detecting small and sparse WMH. Here we present the SHIVA-WMH tool, a deep-learning (DL)-based automatic WMH segmentation tool that has been trained with manual segmentations of WMH in a wide range of WMH severity. We show that it is able to detect WMH with high efficiency in subjects with only small punctate WMH as well as in subjects with large WMHs (i.e. with confluency) in evaluation datasets from three distinct databases: MRi-Share consisting of young university students, MICCAI 2017 WMH challenge dataset consisting of older patients from memory clinics, and UK Biobank with community-dwelling middle-aged and older adults. Across these three cohorts with a wide-ranging WMH load, our tool achieved voxel-level and individual lesion cluster-level Dice scores of 0.66 and 0.71, respectively, which were higher than for three reference tools tested: the lesion prediction algorithm implemented in the lesion segmentation toolbox (LST-LPA: Schmidt, 2017), PGS tool, a DL-based algorithm and the current winner of the MICCAI 2017 WMH challenge (Park et al, 2021), and HyperMapper tool (HPM: Mojiri Forooshani et al., 2022), another DL-based method with high reported performance in subjects with mild WMH burden. Our tool is publicly and openly available to the research community to facilitate investigations of WMH across a wide range of severity in other cohorts, and to contribute to our understanding of the emergence and progression of WMH. HighlightsO_LIWe propose a novel 3D Unet-based model, SHIVA-WMH detector, with much improved detection of small WMH across subjects with a wide range of WMH burden compared to existing methods C_LIO_LIWe characterize microstructural properties of small white matter hyperintensities in young adults from MRi-Share study C_LI

neuroscience↗

bioRxiv2022

A meta-analysis of genome-wide association studies identifies new genetic loci associated with all-cause and vascular dementia

Dementia is multifactorial with Alzheimer (AD) and vascular (VaD) pathologies making the largest contributions. Genome-wide association studies (GWAS) have identified over 70 genetic risk loci for AD but the genomic determinants of other dementias, including VaD remain understudied. We hypothesize that common forms of dementia will share genetic risk factors and conducted the largest GWAS to date of "all-cause dementia" (ACD) and examined the genetic overlap with VaD. Our dataset includes 809,299 individuals from European, African, Asian, and Hispanic ancestries with 46,902 and 8,702 cases of ACD and VaD, respectively. We replicated known AD loci at genome-wide significance for both ACD and VaD and conducted bioinformatic analyses to prioritize genes that are likely functionally relevant, and shared with closely related traits and risk factors. For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and MRI markers of small vessel disease (HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). Our study identified genetic risks underlying all-cause dementia, demonstrating overlap with neurodegenerative processes, vascular risk factors (Type-II diabetes, blood pressure, lipid) and cerebral small vessel disease. These novel insights could lead to new prevention and treatment strategies for all dementias.

genetics↗

bioRxiv2021

Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer's disease

Brain perfusion and normal blood brain barrier integrity are reduced early in Alzheimers disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and control brains to characterise pathological transcriptional signatures. We found that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. EC transcriptional signatures identified mechanisms for impaired {beta}-amyloid clearance. Evidence for immune activation was found with upregulation of interferon signalling genes in EC and in pericytes (PC). Transcriptional signatures suggested dysregulation of vascular homeostasis and angiogenesis with upregulation of pro-angiogenic signals (HIF1A) and metabolism in EC, but downregulation of homeostatic growth factor pathways (VEGF, EGF, insulin) in EC and PC and of extracellular matrix genes in fibroblasts (FB). Our genomic dissection of vascular cell risk gene enrichment suggests a potentially causal role for EC and defines transcriptional signatures associated with microvascular dysfunction in AD.

neuroscience↗

bioRxiv2021

Changes in regional white matter volumetry and microstructure during the post-adolescence period: a cross-sectional study of a cohort of 1,713 university students

Human brain white matter undergoes a protracted maturation that continues well into adulthood. Recent advances in diffusion-weighted imaging (DWI) methods allow detailed characterizations of the microstructural architecture of white matter, and they are increasingly utilised to study white matter changes during development and ageing. However, relatively little is known about the late maturational changes in the microstructural architecture of white matter during post-adolescence. Here we report on regional changes in white matter volume and microstructure in young adults undergoing university-level education. As part of the MRi-Share multi-modal brain MRI database, multi-shell, high angular resolution DWI data were acquired in a unique sample of 1,713 university students aged 18 to 26. We assessed the age and sex dependence, as well as hemispheric asymmetry of diffusion metrics derived from diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), in the white matter regions as defined in the John Hopkins University (JHU) white matter labels atlas. We demonstrate that while regional white matter volume is relatively stable over the age range of our sample, the white matter microstructural properties show clear age-related variations. Globally, it is characterised by a robust increase in neurite density index (NDI), and to a lesser extent, orientation dispersion index (ODI). These changes are accompanied by a decrease in diffusivity. In contrast, there is minimal age-related variation in fractional anisotropy. There are regional variations in these microstructural changes: some tracts, most notably cingulum bundles, show a strong age-related increase in NDI coupled with decreases in radial and mean diffusivity, while others, mainly cortico-spinal projection tracts, primarily show an ODI increase and axial diffusivity decrease. These age-related variations are not different between males and females, but males show higher NDI and ODI and lower diffusivity than females across many tracts. We also report a robust hemispheric asymmetry in both the volume and microstructural properties in many regions. These findings emphasise the complexity of changes in white matter structure occurring in this critical period of late maturation in early adulthood.

neuroscience↗

bioRxiv2020

The MRi-Share database: brain imaging in a cross-sectional cohort of 1,870 university students

We report on MRi-Share, a multi-modal brain MRI database acquired in a unique sample of 1,870 young healthy adults, aged 18 to 35 years, while undergoing university-level education. MRi-Share contains structural (T1 and FLAIR), diffusion (multispectral), susceptibility weighted (SWI), and resting-state functional imaging modalities. Here, we described the contents of these different neuroimaging datasets and the processing pipelines used to derive brain phenotypes, as well as how quality control was assessed. In addition, we present preliminary results on associations of some of these brain image-derived phenotypes at the whole brain level with both age and sex, in the subsample of 1,722 individuals aged less than 26 years. We demonstrate that the post-adolescence period is characterized by changes in both structural and microstructural brain phenotypes. Grey matter cortical thickness, surface area and volume were found to decrease with age, while white matter volume shows increase. Diffusivity, either radial or axial, was found to robustly decrease with age whereas fractional anisotropy only slightly increased. As for the neurite orientation dispersion and densities, both were found to increase with age. The isotropic volume fraction also showed a slight increase with age. These preliminary findings emphasize the complexity of changes in brain structure and function occurring in this critical period at the interface of late maturation and early aging.

neuroscience↗

bioRxiv2018

Genetic determinants of risk and survival in pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a rare disorder leading to premature death. Rare genetic variants contribute to disease etiology but the contribution of common genetic variation to disease risk and outcome remains poorly characterized.\n\nMethodsWe performed two separate genome-wide association studies of PAH using data across 11,744 European-ancestry individuals (including 2,085 patients), one with genotypes from 5,895 whole genome sequences and another with genotyping array data from 5,849 further samples. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. We functionally annotated associated variants and tested associations with duration of survival.\n\nFindingsA locus at HLA-DPA1/DPB1 within the class II major histocompatibility (MHC) region and a second near SOX17 were significantly associated with PAH. The SOX17 locus contained two independent signals associated with PAH. Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. PAH risk variants determined haplotype-specific enhancer activity and CRISPR-inhibition of the enhancer reduced SOX17 expression. Analysis of median survival showed that PAH patients with two copies of the HLA-DPA1/DPB1 risk variant had a two-fold difference (>16 years versus 8 years), compared to patients homozygous for the alternative allele.\n\nInterpretationWe have found that common genetic variation at loci in HLA-DPA1/DPB1 and an enhancer near SOX17 are associated with PAH. Impairment of Sox17 function may be more common in PAH than suggested by rare mutations in SOX17. Allelic variation at HLA-DPB1 stratifies PAH patients for survival following diagnosis, with implications for future therapeutic trial design.\n\nFundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, Inserm, Universite Paris-Sud, and French ANR.

genetics↗

bioRxiv2017

Genetic analysis of over one million people identifies 535 novel loci for blood pressure.

High blood pressure is the foremost heritable global risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits to date (systolic, diastolic, pulse pressure) in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared loci influencing lifestyle exposures. Our findings offer the potential for a precision medicine strategy for future cardiovascular disease prevention.

genetics↗