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

Abstract

SummaryBackgroundBlood 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.MethodsWe 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.FindingsBaseline 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).InterpretationNfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington's disease.FundingMedical Research Council, GlaxoSmithKline, CHDI Foundation, Swedish Research Council, European Research Council, Wallenberg Foundation, and Wolfson Foundation.

Current state of Alzheimer’s fluid biomarkers

“…Recently, there has been great interest in the potential utility of NF-L in blood as a biomarker for several neurodegenerative diseases including AD, MS, progressive supranuclear palsy (PSP), ALS, and Huntington’s disease [43, 71, 228, 240, 302, 385, 408], as well as a marker of traumatic brain injury [224, 324]. In AD, plasma or serum levels of NF-L have been shown to be elevated compared with controls in presymptomatic individuals known to be carriers of AD-causing gene mutations [385] and subjects with MCI or AD [240, 408].…”

Inhibition of Drp1 hyperactivation reduces neuropathology and behavioral deficits in zQ175 knock-in mouse model of Huntington's disease

“…4). Also, the zQ175 mice showed a decrease in immunodensity of neurofilament, a biomarker of HD [33,34], which was partially corrected after P110 treatment (Fig. 4).…”

Potential biomarker breakthrough for Huntington's disease

“…In summary, the study reported by Byrne and colleagues 4 represents a major advance in the field of Huntington's disease and neurodegeneration in general, and it seems likely to presage further advances in disease biology and, most importantly, in experimental therapeutics.…”

“…2 It shows that plasma concentrations of neurofilament light (NfL) chain are substantially increased in Huntington's disease and correlate well with age and CAG repeat length. 4 NfL concentrations were as much as 3·6 times greater in patients with manifest Huntington's disease compared with controls, and there was a very clear gradient from controls to early premanifest (far from expected motor onset), late premanifest (close to expected motor onset), and then to manifest Huntington's disease. The NfL increases in manifest Huntington's disease were similar to those in multiple sclerosis relapses, 5 and were at least as great as in other neurodegenerative diseases including progressive supranuclear palsy, 6 multiple system atrophy, 7 and corticobasal syndrome.…”

“…The large number of participants and great depth of phenotype information in the TRACK-HD study 2 made possible the intriguing correlations with clinical variables, as extensively described in the Article by Byrne and colleagues. 4 The investigators were also able to show that NfL concentrations have prognostic value for subsequent conversion from the premanifest to the manifest state, and to enable a number of other predictions of subsequent clinical variables during the 3 year follow-up.…”