Mapping neurodegeneration across the Huntington's disease spectrum: a five-year longitudinal analysis of plasma neurofilament light

Abstract

Background: Neurofilament light (NfL) has previously been highlighted as a potential biomarker for Huntington's Disease (HD) using cross-sectional analyses. Our study aim was to investigate how longitudinal trajectories of plasma NfL relate to HD disease stage.

Methods: 108 participants [78 individuals with the HD mutation, and 30 healthy controls (HC)] were included in this study. Individuals with the HD mutation were categorised separately by both HD-Integrated Staging System (HD-ISS) (Study 1) and PIN score-Approximated Staging System (PASS) (Study 2) criteria. Plasma NfL trajectories were examined using Mixed Linear Modeling (MLM); associations with symptom presentation were assessed using Spearman's rho correlations.

Findings: The MLM coefficients for disease stage (HD-ISS β = 32.73, p < 0.0001; PASS β = 33.00, p < 0.0001) and disease stage∗time (HD-ISS β = 7.85, p = 0.004; PASS β = 6.58, p = 0.0047) suggest these are significant contributors to plasma NfL levels. In addition, the plasma NfL rate of change varied significantly across time (HD-ISS β = 3.14, p = 0.04; PASS β = 2.94, p = 0.050). The annualised rate of change was 8.32% for HC; 10.55%, 12.75% and 15.62% for HD-ISS Stage ≤1, Stage 2, and Stage 3, respectively; and 12.13%, 10.46%, 10.33%, 17.52%, for PASS Stage 0, Stage 1, Stage 2, and Stage 3, respectively. Plasma NfL levels correlated with the Symbol Digit Modalities Test (SDMT) in HD-ISS Stage ≤1, and both SDMT and Total Motor Score in Stage 3 (ps < 0.01).

Interpretation: Our findings suggest that plasma NfL levels increase linearly across earlier disease stages, correlating with the cognitive SDMT measure. Thereafter, an increase or surge in plasma NfL levels, paired with correlations with both cognitive and motor measures, suggest a late acceleration in clinical and pathological progression.

Funding: NIH (NS111655); the UCSD HDSA CoE; the UCSD ADRC (NIH-NIA P30 AG062429).

Keywords: Biomarkers; Huntington's disease; Neurofilament light; Plasma.

Fig. 1

A presentation of longitudinal NfL values by HD-ISS category (Stage ≤1 n = 37, Stage 2 n = 14, Stage 3 n = 27), determined at each participant's baseline visit (a), and the corresponding predicted years to clinical motor diagnosis (pCMD) values (b). Longitudinal plasma NfL values in healthy controls (n = 30) are presented in (Panel c). Symbols represent the median, and shaded areas represent the interquartile range. Percentage values provided represent the percentage of participants who contributed a value at that time-point (all time 0s = 100%). In (a) and (c), the coloured linear regression line corresponds to the linear regression equation below each graph. All biological measurements conducted with two technical replicates.

Fig. 2

Graphical presentation of associations between plasma NfL and clinical scores—Symbol Digit Modalities Test (SDMT) (a), Total Motor Score (TMS) (b), and composite Unified Huntington's Disease Rating Scale (cUHDRS) (c)–that passed Bonferroni p value correction. Data is grouped into HD-ISS Stage ≤1 (blue; n = 37), Stage 2 (purple; n = 14) and Stage 3 (green; n = 27). Values presented are Spearman's rho correlations and associated p values. All biological measurements conducted with two technical replicates.

Fig. 3

A presentation of longitudinal NfL values by PASS category (Stage 0 n = 15, Stage 1 n = 25, Stage 2 n = 19, Stage 3 n = 19), determined at each participant's baseline visit (a), and the corresponding predicted years to clinical motor diagnosis (pCMD) values (b). Symbols represent the median, and shaded areas represent the interquartile range. Percentage values provided represent the percentage of participants who contributed a value at that time-point (all time 0s = 100%). In (a) and (c), the coloured linear regression line corresponds to the linear regression equation below each graph. All biological measurements conducted with two technical replicates.