{"doi":"10.1101/2025.06.10.25329342","title":"Characterizing spatiotemporal white matter hyperintensity pathophysiology in vivo to disentangle vascular and neurodegenerative contributions","abstract":"Abstract White matter hyperintensities (WMHs) are neuroimaging markers widely interpreted as caused by cerebral small vessel disease, yet emerging evidence suggests that a subset may have a neurodegenerative etiology. Current imaging methods have lacked the specificity to disentangle biological processes underlying WMHs in vivo . Here, we used voxel-level normative modeling and seven microstructural MRI markers with complementary biophysical sensitivities to generate single-subject high-resolution WMH pathophysiology maps in a large cohort ( n =32,526). We calculated data-driven spatial patterns of similar WMHs, revealing distinct periventricular, posterior, and anterior clusters. We identified a reproducible WMH signature linked to dementia and Alzheimer’s disease, characterized by a posterior predominance and a pathophysiological pattern indicative of selective fiber degeneration. Posterior WMHs connected cortical regions vulnerable to tau pathology. Our framework distinguishes vascular and neurodegenerative contributions of WMHs in vivo , which could alter the course of treatment strategies and provide nuanced interpretations of research findings.","journal":"medRxiv","year":2025,"id":556444,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.886,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1381669,"name":"Zaki Alasmar","orcid":"0009-0002-1164-6950","position":1,"is_corresponding":false},{"id":1456114,"name":"Sophia Osborne","orcid":null,"position":2,"is_corresponding":false},{"id":683913,"name":"Aurélie Bussy","orcid":"0000-0001-6695-9941","position":3,"is_corresponding":false},{"id":804411,"name":"Manuela Costantino","orcid":"0000-0003-1886-3173","position":4,"is_corresponding":false},{"id":1455688,"name":"Jérémie P. Fouquet","orcid":"0000-0001-6815-7037","position":5,"is_corresponding":false},{"id":1456115,"name":"Daniela Quesada","orcid":null,"position":6,"is_corresponding":false},{"id":820024,"name":"Alexandre Pastor‐Bernier","orcid":"0000-0002-8865-6551","position":7,"is_corresponding":false},{"id":1456116,"name":"Alfonso Fajardo-Valdez","orcid":null,"position":8,"is_corresponding":false},{"id":561487,"name":"Alexa Pichet Binette","orcid":"0000-0001-5218-3337","position":9,"is_corresponding":false},{"id":1456117,"name":"Ann McQuarrie","orcid":null,"position":10,"is_corresponding":false},{"id":316576,"name":"Josefina Maranzano","orcid":"0000-0002-9696-5522","position":11,"is_corresponding":false},{"id":353192,"name":"Gabriel A. Devenyi","orcid":"0000-0002-7766-1187","position":12,"is_corresponding":false},{"id":564696,"name":"Christopher J. Steele","orcid":"0000-0003-1656-7928","position":13,"is_corresponding":false},{"id":351879,"name":"Sylvia Villeneuve","orcid":"0000-0003-2338-0467","position":14,"is_corresponding":false},{"id":244090,"name":"The Alzheimer’s Disease Neuroimaging Initiative (ADNI)","orcid":null,"position":15,"is_corresponding":false},{"id":301640,"name":"Mahsa Dadar","orcid":"0000-0003-4008-2672","position":16,"is_corresponding":false},{"id":107785,"name":"M. Mallar Chakravarty","orcid":"0000-0002-0759-5508","position":17,"is_corresponding":false},{"id":570879,"name":"Olivier Parent","orcid":"0000-0002-3177-0353","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:08.896385Z","pmid":"40585093","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}