Threshold Effects, Cognitive Decline, and Longitudinal Changes in White Matter Hyperintensity Volume

Background: Changes in Ischemic White matter hyperintensities volume (WMH) on MRI over time are associated with cognitive decline. We investigated whether changes in WMH volume over time exhibit WMH-normalized volume threshold effects on declining cognitive performance and whether these effects on cognition differ between deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVWMH). Methods: We followed 339 participants longitudinally from GeneSTAR with brain MRI and neuropsychological testing at baseline and at 13-years (62% female, and 33% Black, mean baseline age 49.7±9.6). WMH were classified as PVWMH (within 2mm of ventricles) or DWMH. Two-segment linear spline regression models using adjusted mixed linear regression identified test-specific thresholds longitudinally beyond which cognitive decline accelerated. Cognitive scores from both timepoints were treated as repeated measures, with WMH included as a time-varying predictor. Results: Declines in motor function and processing speed accelerated beyond thresholds of changing PVWMH and DWMH volumes. For Grooved Pegboard tests, changes in volume were associated with minimal effects below a threshold of changing volume (log-transformed ratio of lesion volume to intracranial volume for: PVWMH -9.42 to -9.29; and DWMH -11.8 to -11.7). Substantial declines in cognitive performance were observed above thresholds of increases in volume (slope differences: PVWMH; 14.5-15.1 seconds per log-unit, p