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.
Highlights
Huntington’s disease is a slowly progressive neuro degenerative disorder for which no proven diseasemodifying treatments yet exist
Knowledge of its genetic cause, CAG repeat expansions in the HTT gene leading to the formation of mutant huntingtin, has enabled focused study of the disease and the development of advanced therapeutics targeting known aspects of its pathobiology.[1]
We found a strong association between increased NfL concentration and CAG repeat count, which suggests a firm link between this factor and the genetic basis of Huntington’s disease
Summary
Huntington’s disease is a slowly progressive neuro degenerative disorder for which no proven diseasemodifying treatments yet exist. Knowledge of its genetic cause, CAG repeat expansions in the HTT gene leading to the formation of mutant huntingtin (mHTT), has enabled focused study of the disease and the development of advanced therapeutics targeting known aspects of its pathobiology.[1]. Extensive efforts have established well char acterised clinical, cognitive, and neuroimaging biom arkers of progression,[2,3,4,5] few biochemical markers have been identified that enable direct assessment of relevant aspects of pathology.[6,7] No prognostic biomarkers for assessing neuronal damage, disease progression, or therapeutic response have been validated, which limits the ability to test novel therapeutics, especially in mutation carriers with premanifest Huntington’s disease for whom treatment is most likely to result in long-term meaningful benefits. Accessible, reliable, biochemical markers would greatly facilitate the development of novel therapeutics for Huntington’s disease.[1]. Many potential markers in CSF have been proposed, but only a few (eg, mHTT itself, microtubule-associated protein tau, and chitinase-3-like protein 1) have shown associations with clinical phenotype beyond established
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