Associations of Baseline Clinical Phenotypes with Subsequent White Matter Hyperintensity Volume Change - A Study of 4329 UK Biobank Participants

Background and ObjectivesWhite matter hyperintensities (WMHs) relate to cognitive and physical impairment. Although WMHs typically increase/progress with time, regression/decreasing has also been observed. We tested which baseline clinical phenotypes predict subsequent WMH volume change in UK Biobank (UKB). MethodsWe included participants with total volume of WMHs at first brain magnetic resonance imaging (MRI) and follow-up brain MRI. We assessed whether 107 pre-selected clinical phenotypes at baseline related to follow-up WMH volume change. We derived a measure of WMH change as the residual from a linear regression of follow-up WMH volume on baseline WMH volume. We pre-processed clinical phenotypes using PHESANT. We ran (i) linear regressions for continuous WMH change as the outcome and (ii) multinomial logistic regressions comparing progression, regression, and stable groups after categorising WMH volume change using a quintile-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 all P-values for multiple testing using false discovery rate (FDR) correction. ResultsWe included 4329 participants (median age=52; IQR=12), 54.6% female. Median follow-up was 2.3 years (range=1-7 years). On average, total brain volume decreased across follow-up (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%. Fully-adjusted associations with WMH increase included an increased risk of diabetes-related eye disease and higher diastolic BP (FDR-adjusted p<0.05). In group comparisons, progressors were older than regressors and stable individuals, on average. Regressors and progressors had higher BMI than the stable group. Regressors had the highest baseline WMH burden. In unadjusted models, progressors versus stable were more likely to have cataract and higher BP, while regressors had higher weight and systolic BP. These associations did not survive covariate adjustment. DiscussionWell-established vascular risk factors related to subsequent WMH volume change. 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 related to WMH progression, regression, and stability.