Longitudinal diffusion changes in prodromal and early HD : Evidence of white‐matter tract deterioration

Huntington's disease (HD) is a genetic neurodegenerative disorder that primarily affects striatal neurons. Striatal volume loss is present years before clinical diagnosis; however, white matter degradation may also occur prior to diagnosis. Diffusion‐weighted imaging (DWI) can measure microstructural changes associated with degeneration that precede macrostructural changes. DWI derived measures enhance understanding of degeneration in prodromal HD (pre‐HD). Methods As part of the PREDICT‐HD study, N  = 191 pre‐HD individuals and 70 healthy controls underwent two or more (baseline and 1–5 year follow‐up) DWI, with n  = 649 total sessions. Images were processed using cutting‐edge DWI analysis methods for large multicenter studies. Diffusion tensor imaging (DTI) metrics were computed in selected tracts connecting the primary motor, primary somato‐sensory, and premotor areas of the cortex with the subcortical caudate and putamen. Pre‐HD participants were divided into three CAG‐Age Product (CAP) score groups reflecting clinical diagnosis probability (low, medium, or high probabilities). Baseline and longitudinal group differences were examined using linear mixed models. Results Cross‐sectional and longitudinal differences in DTI measures were present in all three CAP groups compared with controls. The high CAP group was most affected. Conclusions This is the largest longitudinal DWI study of pre‐HD to date. Findings showed DTI differences, consistent with white matter degeneration, were present up to a decade before predicted HD diagnosis. Our findings indicate a unique role for disrupted connectivity between the premotor area and the putamen, which may be closely tied to the onset of motor symptoms in HD. Hum Brain Mapp 38:1460–1477, 2017 . © 2017 Wiley Periodicals, Inc.