Differential Tractography As a Dynamic Imaging Biomarker: A Methodological Pilot Study for Huntington's Disease

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. Due to its diverse manifestations, the scientific community has long recognized the need for sensitive, objective, individualized, and dynamic disease assessment tools. We examined the feasibility of Differential Tractography as a biomarker to evaluate correlation of symptom severity and of HD progression at the individual level. Differential tractography is a novel tractography modality that maps pathways with axonal injury characterized by a decrease of anisotropic diffusion pattern. We recruited sixteen patients scanned at 0-, 6-, and 12-month intervals by diffusion MRI scans for differential tractography assessment and correlated its volumetric findings with the Unified Huntington's Disease Rating Scale (UHDRS). Deterministic fiber tracking algorithm was applied. Longitudinal data was modeled using the generalized estimating equation (GEE) model and correlated with UHDRS scores, in addition to Spearman correlation for cross-sectional data. Our results show that volumes of affected pathways revealed by differential tractography significantly correlated with UHDRS scores in longitudinal data (p-value < 0.001), and chronological changes in differential tractography also correlated with the changes in UHDRS (p-value < 0.001). This technique opens new clinical avenues as a clinical translational tool to evaluate presymptomatic and symptomatic gene positive individuals. Our results provide support that differential tractography has the potential to be used as a dynamic imaging biomarker to assess at the individual level in a non-invasive manner, disease progression in HD. Critically important, differential tractography proves to be a quantitative tool for following degeneration in presymptomatic patients, with potential applications in clinical trials.