Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis

Abstract

Background: Blood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington's disease. We investigated whether neurofilament light protein NfL (also known as NF-L) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington's disease.

Methods: We did a retrospective analysis of healthy controls and carriers of CAG expansion mutations in HTT participating in the 3-year international TRACK-HD study. We studied associations between NfL concentrations in plasma and clinical and MRI neuroimaging findings, namely cognitive function, motor function, and brain volume (global and regional). We used random effects models to analyse cross-sectional associations at each study visit and to assess changes from baseline, with and without adjustment for age and CAG repeat count. In an independent London-based cohort of 37 participants (23 HTT mutation carriers and 14 controls), we further assessed whether concentrations of NfL in plasma correlated with those in CSF.

Findings: Baseline and follow-up plasma samples were available from 97 controls and 201 individuals carrying HTT mutations. Mean concentrations of NfL in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3·63 [SD 0·54] log pg/mL vs 2·68 [0·52] log pg/mL, p<0·0001) and the difference increased from one disease stage to the next. At any given timepoint, NfL concentrations in plasma correlated with clinical and MRI findings. In longitudinal analyses, baseline NfL concentration in plasma also correlated significantly with subsequent decline in cognition (symbol-digit modality test r=-0·374, p<0·0001; Stroop word reading r=-0·248, p=0·0033), total functional capacity (r=-0·289, p=0·0264), and brain atrophy (caudate r=0·178, p=0·0087; whole-brain r=0·602, p<0·0001; grey matter r=0·518, p<0·0001; white matter r=0·588, p<0·0001; and ventricular expansion r=-0·589, p<0·0001). All changes except Stroop word reading and total functional capacity remained significant after adjustment for age and CAG repeat count. In 104 individuals with premanifest Huntington's disease, NfL concentration in plasma at baseline was associated with subsequent clinical onset during the 3-year follow-up period (hazard ratio 3·29 per log pg/mL, 95% CI 1·48-7·34, p=0·0036). Concentrations of NfL in CSF and plasma were correlated in mutation carriers (r=0·868, p<0·0001).

Interpretation: NfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease.

Funding: Medical Research Council, GlaxoSmithKline, CHDI Foundation, Swedish Research Council, European Research Council, Wallenberg Foundation, and Wolfson Foundation.

Figure 1

Associations between NfL concentrations in plasma and disease stage, age, and CAG triplet repeat count (A) Baseline NfL concentrations in plasma, by disease stage. Boxes show first and third quartiles, the central band shows the median, and the whiskers show data within 1·5 IQR of the median. The dots represent outliers. Data were log transformed for comparisons. (B) Associations between NfL concentration in plasma, age, and CAG repeat count, modelled with a polynomial function of age, CAG repeat counts, their squares, and their interactions in 201 HTT mutation carriers and 97 controls. The lines show quadratic fit for all participants with a given CAG repeat count or all controls. Each increase in CAG repeat count was associated with higher and more steeply rising NfL concentrations in plasma. Predicted values are truncated at the vertical inflection point of the parabola. Datapoints for each individual CAG repeat count and for controls are provided in the appendix. HD=Huntington's disease mutation carriers. CAG=mutation carriers' CAG repeat counts.

Figure 2

Associations between NfL concentrations in plasma at baseline and cross-sectional measures of cognitive function, motor impairment, and brain volume on MRI (A, B) Association with cognitive scores. (C) Association with motor function. (D–H) Associations with global and regional brain volumes, expressed as percentages of total intracranial volume. UHDRS=Unified Huntington's Disease Rating Scale.

Figure 3

Association between baseline NfL concentration in plasma and progression to manifest Huntington's disease in HTT mutation carriers who were premanifest at baseline (A) NfL concentration in plasma at baseline by disease progression status at 3 years. Boxes show first and third quartiles, the central band shows the median, and the whiskers show data within 1·5 IQR of the median. The dots represent outliers. (B) Kaplan-Meier plot showing longitudinal survival in the premanifest state among HTT mutation carriers with NfL concentrations in plasma greater or less than the median. The Cox proportional hazards model is the more sensitive of the two models presented here.

Figure 4

Associations between baseline NfL concentration in plasma and longitudinal change in cognitive, motor, and functional decline and brain atrophy (A, B) Associations with cognitive scores. (C) Association with functional capacity. (D–H) Associations with global and regional brain volumes, expressed as percentages of total intracranial volume. By convention, negative values for change in lateral ventricle volumes indicate ventricular expansion (ie, brain atrophy). SDMT=Symbol-Digit Modality Test Score. SWR=Stroop Word Reading score. UHDRS TFC=Unified Huntington's Disease Rating Scale Total Functional Capacity score. HD=Huntington's disease mutation carriers.

Figure 5

NfL concentrations in paired CSF and plasma samples Concentrations in CSF (A) and plasma (B) in HTT mutation carriers and controls. Boxes show first and third quartiles, the central band shows the median, and the whiskers show data within 1·5 IQR of the median. The dots represent outliers. (C) Correlation between NfL concentration in CSF and plasma. HD=Huntington's disease mutation carriers.