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

Z J Voysey; N E Owen; J A Holbrook; M Malpetti; C Le Draoulec; L R B Spindler; A O G Goodman; A S Lazar; R A Barker

doi:10.1007/s00415-024-12700-x

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

J Neurol. 2024 Oct 3. doi: 10.1007/s00415-024-12700-x. Online ahead of print.

Authors

Z J Voysey^#¹, N E Owen^#², J A Holbrook², M Malpetti³, C Le Draoulec², L R B Spindler², A O G Goodman², A S Lazar⁴, R A Barker^{2

5}

Affiliations

¹ Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK. zv214@cam.ac.uk.
² Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
³ Department of Clinical Neurosciences, Cambridge Centre for Frontotemporal Dementia and Related Disorders, University of Cambridge, Cambridge, UK.
⁴ Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK.
⁵ Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.

^# Contributed equally.

PMID: 39361164
DOI: 10.1007/s00415-024-12700-x

Abstract

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_p² = 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, R² = 0.468) and cognitive deficits (MoCA p = 0.007, β = - 0.798, R² = 0.604; Trail B, p = 0.007, β = 0.772, R² = 0.567; phonemic fluency p = 0.035, β = - 0.632, R² = 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.

Keywords: Biomarker; Dementia; Huntington’s disease; Longitudinal; Neurodegeneration; Neurofilament light chain.