Objective: Evaluate clinical utility of candidate biomarker assays for HD studies.

Background: Multiple clinical trials targeting the lowering of huntingtin (HTT) are underway or planned. Biomarker assays have been developed to detect changes in mHTT, tHTT, and neurofilament light chain (NFL). Due to the analytical inaccessibility of brain tissue, protein concentrations in cerebrospinal fluid (CSF) are investigated for their ability to represent changes in HTT expression and resultant pathology in the brain. In this study we use a large, prospectively collected dataset that includes bioanalytical and phenotypic data (HD-Clarity) to evaluate the reliability, sensitivity to change, and assay metrics.

Method: Quantification of mHTT, tHTT, NFL in 280 CSF samples from HDClarity (also hemoglobin [Hb], total protein [tProt]). Samples were collected from HD gene expansion carriers (HDGE carriers) and controls. HDGE carriers include early and late pre-manifest, early, moderate, and advanced manifest HD. Technical replicate consistency of repeated analysis of the same samples is determined. Reliability of each assay within a study participant is evaluated with samples collected a month apart. Hb and tProt are analyzed as possible confounders. All available data -including outliers – are used.

Results: NFL: Excellent reliability within technical replicates and between repeated visits. Trends of NFL align well with the literature.
mHTT: Very good technical replicate reliability, good repeated visit reliability. The lower portion of the range observed in premanifest and early manifest HD is near the lower level of quantification (LLoQ) of the assay.
tHTT: Very good technical replicate reliability. Poor repeated visit consistency.
Hb: No confounding impact on biomarker assay results. However, samples were selected on strict criteria for low Hb.
Modest effect of tProt on tHTT and NFL results.

Conclusion: NFL: Good confidence in data interpretation from high-quality samples.
Baseline mHTT levels in HDGE carriers in the early phase of the disease before clinical motor diagnosis are typically near the LLoQ: Differences are difficult to detect, in particular on an individual level.
The tHTT data have limitations. Currently, this assay cannot be recommended for the detection of treatment effects or temporal changes at an individual level.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evaluation-of-csf-assay-usability-for-huntingtons-disease-hd-clinical-studies-mhtt-thtt-and-nfl-in-hdclarity/