Lesion-Level Subtypes of White Matter Hyperintensity Evolution Beyond Spatial Location.
Lesion-Level Subtypes of White Matter Hyperintensity Evolution Beyond Spatial Location.
Where did the research take place?
Possible study sites were matched from the text; these need review.
Normal, US · Possible study site
METHODS: We conducted a longitudinal observational study analyzing 3224 MRI scans from 403 participants spanning cognitively normal aging, mild cognitive impairment, Alzheimer, and Parkinson disease.Location evidence
Montréal, CA · Author affiliation
Neuroinformatics for Personalized Medicine Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Quebec, Canada.Location evidence
Québec, CA · Author affiliation
Neuroinformatics for Personalized Medicine Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Quebec, Canada.Location evidence
Buenos Aires, AR · Author affiliation
Departamento de Física, Universidad de Buenos Aires, Argentina.Location evidence
Santiago, CL · Author affiliation
Latin American Brain Health Institute (BrainLat), Universidad Adolfo Ibañez, Santiago, Chile.Location evidence
Victoria, AR · Author affiliation
Cognitive Neuroscience Center, Universidad de San Andrés, Victoria, Buenos Aires, Argentina.Location evidence
São Paulo, BR · Author affiliation
Instituto de Assistência Médica ao Servidor Público Estadual, São Paulo, Brazil; and.Location evidence
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Original abstract
BACKGROUND AND OBJECTIVES: White matter hyperintensities (WMHs) are common neuroimaging markers of cerebrovascular pathology in aging and neurodegeneration. Despite their clinical relevance, WMH are typically quantified using global burden measures that assume a relatively homogeneous pathologic process. However, growing evidence suggests substantial biological heterogeneity across lesions. We aimed to identify lesion-level WMH subtypes beyond anatomic location and evaluate their associations with neurodegeneration and vascular risk. METHODS: We conducted a longitudinal observational study analyzing 3224 MRI scans from 403 participants spanning cognitively normal aging, mild cognitive impairment, Alzheimer, and Parkinson disease. Imaging at baseline and 2-year follow-up included structural, diffusion, and resting-state MRI. A total of 2107 WMH lesions were identified, and lesion-wise longitudinal changes were used to derive subtypes using unsupervised clustering. Associations with neurodegeneration and vascular risk factors were assessed using multivariable models with false discovery rate correction. RESULTS: Three lesion subtypes (L1-L3) were identified, frequently coexisting within the same individual. L1 lesions were the most prevalent (48.1%), predominated in cognitively normal individuals, and exhibited relatively stable trajectories without association with brain atrophy. L2 lesions represented a less frequent (11.3%) unstable subtype associated with weight gain (odds ratio [OR] 1.33, 95% CI 1.22-1.45; pFDR ≤ 0.001), suggesting metabolic vulnerability. L3 lesions (40.6%) represented an unstable subtype associated with brain atrophy (β = -0.11, 95% CI -0.16 to -0.05; pFDR < 0.001), older age (OR 1.15, 95% CI 1.07-1.23; pFDR < 0.001), and vascular risk reflected by pulse pressure changes (OR 1.09, 95% CI 1.03-1.15; pFDR = 0.006). Global WMH burden was no longer associated with brain atrophy after accounting for L3 lesion burden. Clustering robustness was supported by sensitivity analyses excluding anatomical location and by external validation in an independent cohort reproducing the main atrophy-related findings. DISCUSSION: WMH are not a homogeneous entity but comprise biologically distinct lesion subtypes with differential neurobiological and clinical significance. Lesion composition may therefore offer a more informative framework than global WMH burden for understanding cerebrovascular contributions to aging and neurodegeneration, with potential implications for risk stratification, clinical interpretation, and targeted interventions.