Background Although white matter (WM) abnormalities and subcortical iron accumulation are causal factors of neurodegeneration in Huntington’s disease (HD), their specific role is not clear yet. Aims: To understand the dynamics of the physiopathology process underlying in HD by using a multimodal temporo-spatial characterization of WM tracts (microstructural integrity and iron content).

Methods Thirty-one HD gene-expansion carriers (12 premanifest, 19 manifest) and 24 healthy controls participated in this study. DTI and T2*-relaxometry were employed to characterize the structural connectivity and the iron distribution of eighteen main WM tracts. Three approaches have been used for the statistical analysis: average measure, segmental measures based on anatomic division of the tracts, and measures along the tract considering multiple points.

Results Striatal medium spiny neurons are the most affected entailing basal ganglia atrophy with disruption of cortico-basal ganglia-thalamocortical circuits. Consequently, different WM tracts included in these circuits are presumed to be affected in presymptomatic stages as demonstrated in our study: motor function depending on putamino-pallidal connections (CST), limbic system depending on ventral striatum (cingulate), and executive function depending on caudate (ATR, forceps minor and forceps major). Associative tracts (uncinate, inferior longitudinal, superior longitudinal fronto-parietal and fronto-temporal fasciculus) are also altered in symptomatic stages, most probably as a consequence of transaxonal degeneration when the brain breaks down globally.

Conclusion This study has allowed to depict the temporo-spatial dynamics of WM tracts disintegration in HD. In particular, while all tracts showed widespread disintegration as the disease progress, motor-related tracts present higher iron levels than non-motor-related tracts.