Characterizing spatiotemporal white matter hyperintensity pathophysiology in vivo to disentangle vascular and neurodegenerative contributions

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 helps parsing vascular and neurodegenerative contributions of WMHs in vivo, which could alter the course of treatment strategies and provide nuanced interpretations of research findings.

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Publication Details

Journal
Nature Communications
Published
2026-03-31
DOI
https://doi.org/10.1038/s41467-026-70832-2
Primary Topic
Dementia and Cognitive Impairment Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Characterizing spatiotemporal white matter hyperintensity pathophysiology in vivo to disentangle vascular and neurodegenerative contributions

Alfonso Fajardo-Valdez, Josefina Maranzano, Alexa Pichet-Binette, Aurélie Bussy et al.
Nature Communications
Dementia and Cognitive Impairment Research
article

Characterizing spatiotemporal white matter hyperintensity pathophysiology in vivo to disentangle vascular and neurodegenerative contributions

Alfonso Fajardo-Valdez, Josefina Maranzano, Alexa Pichet-Binette, Aurélie Bussy, Sophia Osborne, Manuela Costantino, Christopher J. Steele, Sylvia Villeneuve, Adeline Bernier, Jérémie P. Fouquet, Zaki Alasmar, Olivier Parent, Daniela Quesada, Ann McQuarrie, Mahsa Dadar, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), M. Mallar Chakravarty, Gabriel A. Devenyi
article en

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 helps parsing vascular and neurodegenerative contributions of WMHs in vivo, which could alter the course of treatment strategies and provide nuanced interpretations of research findings.

Nature Communications
Montreal Neurological Institute and Hospital (CA), Douglas Mental Health University Institute (CA), Institut Universitaire de Gériatrie de Montréal (CA), Max Planck Institute for Human Cognitive and Brain Sciences (DE), Canadian Sleep & Circadian Network (CA), McGill University (CA), Concordia University (CA), Université du Québec à Trois-Rivières (CA), Université de Montréal (CA)
Pfizer, McGill University, Fondation Brain Canada, Canadian Bee Research Fund, Government of Canada, Alzheimer Society, Canada First Research Excellence Fund, Alliance de recherche numérique du Canada, Pfizer Canada, Canadian Institutes of Health Research, Fonds de Recherche du Québec - Santé
Openalex Percentile: Top 33%
Dementia and Cognitive Impairment Research
DOIOpen Access PDFOpenAlex
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