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

Abstract

Huntington's disease (HD) is a genetic progressive neurodegenerative disorder, caused by a mutation in the 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.

Cerebrospinal fluid flow dynamics in Huntington's disease evaluated by phase contrast MRI

“…We conducted a prospective cross‐sectional pilot study named “Phase1‐HD” involving participants enrolled simultaneously in the Enroll‐HD study (CHDI Foundation, ) an international multicentre, prospective registry, and in the HD‐CSF study (Byrne, Rodrigues, Johnson, De Vita, et al., ; Byrne, Rodrigues, Johnson, Wijeratne, et al., ), a single‐centre prospective cohort based at the UCL Huntington's Disease Centre, London, UK.…”

Huntingtin Lowering Strategies

“…Thus, this study provided decisive preclinical evidence for the concept of "huntingtin holidays" as the basic principle of a disease-modifying strategy for HD patients [24]. Sensitive and standardized immunoassays, which allow the quantification of mutated htt protein in cerebrospinal fluid [25,26], have become available as biomarkers [27].…”

Neurofilaments: The C-Reactive Protein of Neurology

“…In HD, biomarkers have the potential role of assessing therapeutic efficacy, and most recently NF has been tested in both CSF and plasma [35,36,130,131] ( Table 1). A recent study investigated the correlation between mutant huntingtin (mHTT) and CSF and plasma NF-L levels in HD patients, revealing NF-L to be a clinically stronger marker than mHTT, even within the study's limitations [33]. ELISA showed that NF-L levels in CSF of HD patients were significantly higher than those in matched controls [36], while plasma levels of NF-H, using ELISA, excluded this NF subunit as a potential biomarker [130].…”