A 14-year longitudinal study of neurofilament light chain dynamics in premanifest and transitional Huntington’s disease

Background: Growing evidence supports the value of neurofilament light (NfL) as a prognostic biomarker in premanifest Huntington’s disease (HD). To date, however, there has been no longitudinal study exceeding 3 years examining either its serial dynamics or predictive power in HD. We aimed to conduct the first such study. Methods: Serum NfL was sampled using ultrasensitive immunoassay at four timepoints across a 14-year period in a cohort of HD gene carriers (n = 21) and controls (n = 14). Gene carriers were premanifest at baseline. Clinical features of HD were evaluated by Unified Huntington’s Disease Rating Scale (UHDRS TMS), Montreal Cognitive Assessment (MoCA), Trail A/B task, Symbol Digit Modalities Task and semantic/phonemic fluency tasks. Results: 14/21 HD gene carriers converted to prodromal or manifest disease by the final timepoint (“converters”). At baseline and each subsequent timepoint, NfL levels were higher in converters than in non-converters and controls (p = < 0.001–0.03, η _p ² = 0.25–0.66). The estimated rate of change in NfL was higher in converters than in non-converters (p = 0.03) and controls (p = 0.001). Baseline NfL was able to discriminate converters from non-converters (area under curve = 1.000, p = 0.003). A higher rate of change in NfL was predictive of more severe motor (UHDRS-TMS p = 0.007, β = 0.711, R ² = 0.468) and cognitive deficits (MoCA p = 0.007, β = − 0.798, R ² = 0.604; Trail B, p = 0.007, β = 0.772, R ² = 0.567; phonemic fluency p = 0.035, β = − 0.632, R ² = 0.345). Conclusions: Our data suggest that (1) NfL longitudinal dynamics in premanifest/transitional HD are non-constant; rising faster in those closer to disease onset, and (2) NfL can identify individuals at risk of conversion to manifest disease and predict clinical trajectory, > 10 years from disease onset.