Spatial and signal features of white matter integrity and associations with clinical factors: A CARDIA brain MRI study

White matter hyperintensities (WMH) may be indicative of age-related cerebrovascular diseases and contribute to cognitive and functional decline. Normal appearing WM (NAWM) adjacent to WMH, termed “penumbra,” is known to be vulnerable to future WMH pathology. WM integrity can be evaluated using multiple magnetic resonance imaging (MRI) modalities. We aimed to identify MRI features predictive of WMH growth and to compare the implications of these features based on spatial proximity to existing WMH versus signal features in baseline NAWM. We used baseline and 5-year follow-up MRI scans in 485 middle-aged participants form the Coronary Artery Risk Development in Young Adults (CARDIA). Multimodal MRI at baseline, including fluid attenuated inversion recovery (FLAIR), diffusion tensor imaging (DTI), and cerebral blood flow (CBF), was measured within WM ROIs including baseline WMH and regions that later developed into new WMH, within and external to the baseline penumbra. Overall, we found that 80% of new WMH appeared within the baseline penumbra. We also found lower fractional anisotropy (FA) and CBF and higher FLAIR and median diffusivity (MD) in NAWM at baseline in regions with subsequent WMH growth compared to those without WMH growth. For NAWM regions defined by signal features, subthreshold FA and suprathreshold MD and FLAIR abnormality at baseline were the most robust predictors of WMH growth. Baseline systolic blood pressure had significant associations with baseline abnormalities in NAWM and subsequently with cognitive decline, particularly for FA and MD measures. The findings support the use of DTI as the predictor of WMH growth, which is correlated with subtle, adverse WM alterations and cognitive function years before developing to WMH. The results may contribute to future clinical trials aimed at preserving WM integrity.