Topographic reference modelling of white matter hyperintensities across the adult lifespan

White matter hyperintensities (WMH) are among the most common MRI findings in older adults. They are widely regarded as markers of brain aging and cerebral small-vessel disease, and associated with risk for cognitive decline, Alzheimers disease and related dementias (ADRD), and stroke. White matter hyperintensities (WMH) are typically interpreted by total lesion burden, but lesions with similar volumes can occupy different anatomical locations, potentially reflecting distinct pathological processes. Here we present voxelwise topographic reference modelling (vTRM), a framework for characterizing individual WMH masks against age- and sex-stratified frequency maps derived from cognitively unimpaired individuals. Using 42,469 FLAIR-derived lesion masks from twelve adult cohorts, we mapped population-level WMH spatial vulnerability, characterized age-related changes in its distribution across periventricular, lobar and arterial-territory compartments, and constructed paired percentile charts for lesion burden and spatial typicality. A quadrant-based classification defined by these two percentile dimensions revealed graded relationships with ADRD pathophysiology, neurodegeneration, and cognitive impairment, while identifying WMH patterns differentially associated with ageing-related, vascular and neurodegenerative processes among individuals with similar lesion volumes. These reference charts establish a benchmark for normative WMH ageing, enabling quantification of individual deviations from typical age-, sex- and burden-related patterns and identification of WMH phenotypes associated with vascular, neurodegenerative or mixed etiologies. The framework, together with a deployable 3D U-Net model trained on these data for automated WMH segmentation, is available through the Brain Lesion Analytics platform (https://brainlesionanalytics.org/).

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-11-03
DOI
https://doi.org/10.64898/2026.10.28.760476
Primary Topic
Cerebrovascular and genetic disorders
Type
preprint
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preprint

Topographic reference modelling of white matter hyperintensities across the adult lifespan

Reisa Anne Sperling, Timothy J. Hohman, Adam M. Brickman, Jennifer Manly et al.
bioRxiv (Cold Spring Harbor Laboratory)
Cerebrovascular and genetic disorders
preprint

Topographic reference modelling of white matter hyperintensities across the adult lifespan

Reisa Anne Sperling, Timothy J. Hohman, Adam M. Brickman, Jennifer Manly, Sarah Biber, Shannon L. Risacher, Julie A. Schneider, Andrew J. Saykin, Derek B. Archer, Güray Erus, Patrick J. Lao, Christos A. Davatzikos, Robert C. Barber, Clarissa D. Morales, Rafael V. Lippert, Michael L. Cuccaro, Carlos C Cruchaga, Natalie M. Morel, Paul K. Crane, Shubhabrata Mukherjee, Jeffrey D. Pyne, Sid E. O’Bryant, Walter A. Kukull, Mohamad J. Alshikho, Dahyun Yi, Annie Lee, Richard P Mayeux, Sterling C. Johnson, Michaël E. Belloy, Jesse B Mez, Dong Yeong Kim, Arthur W. Toga, David A. A Bennett, Christiane Hale, Alzheimer's Disease Sequencing Project, Alzheimer's Disease Neuroimaging Initiative (ADNI), HABS-HD Study Team, Mohamad Habes, Natalie C. Edwards, Tammie Lee Smith Benzinger, Dejania Cotton Samuel, Lisa L. Barnes, A4 Study team
preprint en

Abstract

White matter hyperintensities (WMH) are among the most common MRI findings in older adults. They are widely regarded as markers of brain aging and cerebral small-vessel disease, and associated with risk for cognitive decline, Alzheimers disease and related dementias (ADRD), and stroke. White matter hyperintensities (WMH) are typically interpreted by total lesion burden, but lesions with similar volumes can occupy different anatomical locations, potentially reflecting distinct pathological processes. Here we present voxelwise topographic reference modelling (vTRM), a framework for characterizing individual WMH masks against age- and sex-stratified frequency maps derived from cognitively unimpaired individuals. Using 42,469 FLAIR-derived lesion masks from twelve adult cohorts, we mapped population-level WMH spatial vulnerability, characterized age-related changes in its distribution across periventricular, lobar and arterial-territory compartments, and constructed paired percentile charts for lesion burden and spatial typicality. A quadrant-based classification defined by these two percentile dimensions revealed graded relationships with ADRD pathophysiology, neurodegeneration, and cognitive impairment, while identifying WMH patterns differentially associated with ageing-related, vascular and neurodegenerative processes among individuals with similar lesion volumes. These reference charts establish a benchmark for normative WMH ageing, enabling quantification of individual deviations from typical age-, sex- and burden-related patterns and identification of WMH phenotypes associated with vascular, neurodegenerative or mixed etiologies. The framework, together with a deployable 3D U-Net model trained on these data for automated WMH segmentation, is available through the Brain Lesion Analytics platform (https://brainlesionanalytics.org/).

bioRxiv (Cold Spring Harbor Laboratory)
Boston University (US), University of Southern California (US), Rush University Medical Center (US), University of Wisconsin–Madison (US), Harvard University (US), Seoul National University (KR), University of Miami (US), University of North Texas Health Science Center (US), University of Washington (US), Washington University in St. Louis (US), Indiana University School of Medicine (US), The University of Texas at San Antonio (US), Indiana University (US), Columbia University (US), University of Pennsylvania (US), Vanderbilt University Medical Center (US)
Cerebrovascular and genetic disorders
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