Research ArticleHuntington’s Disease

Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington’s disease

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Science Translational Medicine  12 Sep 2018:
Vol. 10, Issue 458, eaat7108
DOI: 10.1126/scitranslmed.aat7108

Improving Huntington’s disease detection

Early detection of Huntington’s disease (HD) could help the development of effective therapeutic strategies to block or delay disease progression. Byrne and colleagues now show that in blood and cerebrospinal fluid, mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations correlated with disease severity in HD patients. Computational analysis further showed that alterations in circulating NfL and mHTT concentrations may be among the earliest detectable changes in HD. Thus, the results suggest that analysis of mHTT and NfL concentrations in biofluids might be used in combination with other clinical measures for improving the accuracy and efficiency of early HD detection.


Huntington’s disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the HTT gene, for which there is currently no cure. The identification of sensitive indicators of disease progression and therapeutic outcome could help the development of effective strategies for treating HD. We assessed mutant huntingtin (mHTT) and neurofilament light (NfL) protein concentrations in cerebrospinal fluid (CSF) and blood in parallel with clinical evaluation and magnetic resonance imaging in premanifest and manifest HD mutation carriers. Among HD mutation carriers, NfL concentrations in plasma and CSF correlated with all nonbiofluid measures more closely than did CSF mHTT concentration. Longitudinal analysis over 4 to 8 weeks showed that CSF mHTT, CSF NfL, and plasma NfL concentrations were highly stable within individuals. In our cohort, concentration of CSF mHTT accurately distinguished between controls and HD mutation carriers, whereas NfL concentration, in both CSF and plasma, was able to segregate premanifest from manifest HD. In silico modeling indicated that mHTT and NfL concentrations in biofluids might be among the earliest detectable alterations in HD, and sample size prediction suggested that low participant numbers would be needed to incorporate these measures into clinical trials. These findings provide evidence that biofluid concentrations of mHTT and NfL have potential for early and sensitive detection of alterations in HD and could be integrated into both clinical trials and the clinic.

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