Associations of Baseline Clinical Phenotypes With White Matter Hyperintensity Volume Change: A Study of 4,329 UK...

White matter hyperintensities (WMHs) relate to cognitive and physical impairment. Although WMHs typically progress over time, regression has also been observed. Our aim was to explore baseline clinical phenotypes associated with subsequent WMH volume change in the UK Biobank (UKB).

We included participants with total volume of WMHs at first and follow-up brain MRI. We assessed 107 preselected clinical phenotypes measured at baseline and preprocessed using the Phenome Scan Analysis Tool (PHESANT). We derived a measure of WMH change as the residual from a linear regression of follow-up WMH volumes on baseline WMH volumes to account for baseline WMH burden. We ran (1) linear regressions for continuous WMH change as the outcome and (2) multinomial logistic regressions comparing progression, regression, and stable groups after categorizing WMH volume change using an established percentile-based approach. Models were unadjusted, partially adjusted (age, sex, total brain tissue volume, follow-up time), or fully adjusted (further adding blood pressure; BP). We corrected p values using false discovery rate (FDR) correction.

We included 4,329 participants (median age 52; interquartile range 12), 54.6% female, with a median follow-up of 2.3 years (range 1-7 years). Across follow-up, total brain volume decreased (mean decrease 16,058 mm³) and WMH volume increased (median increase 293 mm³; both p < 0.001). WMHs progressed in 53.9% of participants, regressed in 26.01%, and remained stable in 20%. In fully adjusted linear models, higher diastolic BP was the only baseline phenotype associated with greater WMH progression (0.10 SD higher WMH change per 1 SD higher inverse-rank normal transformed diastolic BP; 95% CI 0.05-0.15, FDR p < 0.05). In multinomial models, hip pain lasting more than 3 months (odds ratio [OR] 0.25, 95% CI 0.11-0.58) and faster walking pace (OR 0.79, 95% CI 0.66-0.95) were inversely associated with WMH progression, whereas hip pain was also inversely associated with WMH regression vs stability (OR 0.31, 95% CI 0.12-0.79; all FDR p < 0.05).

We established vascular risk factors associated with subsequent WMH volume change in the studied cohort. Distinct clinical and demographic profiles characterized WMH progression, regression, and stable groups. Results suggest that vascular factors relate to WMH change but are sensitive to covariate control. Further studies should establish factors differentially and causally related to WMH progression, regression, and stability.