Research ArticleHuntington’s Disease

Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington’s disease

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Science Translational Medicine  16 Dec 2020:
Vol. 12, Issue 574, eabc2888
DOI: 10.1126/scitranslmed.abc2888

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Protein dynamics in HD

Huntington’s disease (HD) is a neurodegenerative disorder caused by mutations in the huntingtin (HTT) gene. Previous studies have shown that mutant HTT (mHTT) and neurofilament light (NfL) concentrations are increased in cerebrospinal fluid (CSF) of patients with HD. However, the longitudinal dynamics of mHTT and NfL remain unclear. Here, Rodrigues et al. measured mHTT and NfL in CSF of patients with HD over the course of 2 years and showed that baseline concentrations were good predictors of clinical progression and brain atrophy. The results can increase our understanding of HD pathophysiology and help design and evaluation of clinical trials.

Abstract

The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington’s disease (HD)—mutant huntingtin (mHTT) and neurofilament light (NfL)—are incompletely defined. Characterizing changes in these candidates during disease progression could increase our understanding of disease pathophysiology and help the identification of effective therapies. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), as well as NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status, subsequent clinical progression, and brain atrophy, better than did the rate of change in analytes. Overall, NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT has prognostic value and might be a valuable pharmacodynamic marker for huntingtin-lowering trials.

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