Neurology. 2026 May 12;106(9):e214818. doi: 10.1212/WNL.0000000000214818. Epub 2026 Apr 10.
ABSTRACT
BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (CSVD) is a major cause of dementia and stroke, typically identified by lesions such as white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs), enlarged perivascular spaces, and brain atrophy. Biomarker-based biological age (BA), derived from routinely measured clinical indicators and largely reflecting vascular and metabolic physiologic burden, may provide complementary information beyond chronological age. The aim of this study was to investigate the associations between BA residual and both the presence and progression of CSVD and its neuroimaging manifestations.
METHODS: In the population-based Polyvascular Evaluation for Cognitive Impairment and Vascular Events cohort, participants underwent brain magnetic resonance imaging (MRI) at baseline (2017-2019) and at follow-up (2022-2024). BA was estimated using 3 established methods: PhenoAge, Klemera-Doubal method, and homeostatic dysregulation. Progression of CSVD and its imaging markers, including new lacunes, new CMBs, progression of enlarged perivascular spaces in the basal ganglia (BG-EPVS), and progression of WMHs, was assessed. Associations between BA residual and progression of CSVD were analyzed using logistic or ordinal logistic regression models, as appropriate.
RESULTS: A total of 3,050 participants were included at baseline (mean age 61.22 ± 6.67 years; 53.51% female); 2,662 completed follow-up MRI over a median of 4.7 years, and 388 were lost to follow-up. Higher BA residual, particularly KDMAge and PhenoAge residual, was associated with greater CSVD burden at baseline and follow-up. Moreover, KDMAge residual was positively associated with the progression of total CSVD burden (odds ratio [OR] = 1.18, 95% CI 1.08-1.30; p = 0.001), new lacunes (OR = 1.31, 95% CI 1.13-1.51, p < 0.001), and new CMBs (OR = 1.13, 95% CI 1.01-1.25; p = 0.028), but not with progression of BG-EPVS or WMHs at follow-up. PhenoAge residual showed results consistent with those of KDMAge residual, whereas HDAge residual showed no significant association with progression of CSVD or its imaging markers.
DISCUSSION: This community-based cohort study demonstrated that BA residuals, particularly KDMAge and PhenoAge, were associated with higher odds of CSVD progression, especially with development of new lacunes and new CMBs. Biomarker-based BA residual may help identify individuals at higher risk of clinically relevant CSVD progression. Future studies with longer follow-up periods and more diverse cohorts are warranted to validate these findings.
PMID:41962120 | DOI:10.1212/WNL.0000000000214818