Longitudinal and combined assessment of 24(S)-hydroxycholesterol and Neurofilament light chain in the early stages of Huntington's disease

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder. Recent clinical research has focused on neurofilament light chain protein (NfL), and cholesterol metabolites as potential fluid biomarkers related to disease progression.Our aim was to explore whether the combined longitudinal assessment of NfL and cholesterol-derived metabolites would improve the characterization of early HD stages.We enrolled 96 HD individuals and 63 healthy controls. Disease stage of HD participants was determined using both the system based on Total Motor Score (TMS), and the new HD-Integrated Staging System (HD-ISS). Concentrations of plasma NfL, and cholesterol precursors and metabolites, were measured at baseline and 2-year follow-up.In premanifest individuals, classified according to TMS, we found significantly reduced 24(S)-hydroxycholesterol (24S-OHC), a metabolite entirely derived from brain cholesterol catabolism, and normal level of NfL. When applying the HD-ISS, 24S-OHC was significantly reduced in HD-ISS-1 (25.6 ± 7.6 ng/ml) and HD-ISS-3 (30.5 ± 15.7) compared with controls (39.5 ± 14.1). NfL was increased in HD-ISS-1 (16.1 ± 6.5 pg/ml), HD-ISS-2 (16.1 ± 6.5) and HD-ISS-3 (27.0 ± 6.9) compared with controls (5.5 ± 1.7 pg/ml). In HD-ISS-0, all biomarker concentrations were similar to those of controls. At follow-up, NfL increased in HD-ISS-1 (+20%; p < 0.005). ROC analyses showed that NfL discriminated HD-ISS-0 and HD-ISS-1 from controls. 24S-OHC distinguished HD-ISS-1 from controls.Plasma NfL and 24S-OHC concentrations provide complementary insights into early biological changes in HD, and holds the potential to characterize the transition phase from the pre-symptomatic to the early symptomatic stage.