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Publication Detail
Longitudinal Evaluation of Mutant Huntingtin and Neurofilament Light as Biomarkers for Huntington’s Disease: The HD-CSF Study 24-month Analysis
  • Publication Type:
    Conference presentation
  • Publication Sub Type:
  • Authors:
    Byrne LM, Brogueira Rodrigues F, Tortelli R, Johnson E, Wijeratne P, Wylezinska-Arridge M, De Vita E, Alexander D, Schobel S, Scahill R, Heslegrave A, Zetterberg H, Wild E
  • Date:
  • Status:
  • Name of Conference:
    Huntington Study Group 2019
  • Conference place:
  • Conference start date:
  • Conference finish date:
Background: There is a pressing need for sensitive biomarkers in Huntington’s disease (HD). Mutant huntingtin (mHTT) and neurofilament light (NfL) have been proposed as potential biofluid biomarkers for application in clinical trials. However, little is known about their longitudinal dynamics during the natural history of HD. Aims: We aimed to characterize the longitudinal trajectories of mHTT in CSF and NfL in CSF and blood plasma. Methods: We used 24-month longitudinal data from the HD-CSF study. CSF mHTT, CSF NfL and plasma NfL were measured using immunoassays. Participants underwent standardized clinical assessments, CSF and blood collections, and optional brain MRI. Data were modeled using mixed effects models, and associations with clinical and imaging outcomes was studied with Pearson’s partial correlations. Receiver operating characteristics curves were used to test discriminative ability, and samples size calculations to assess feasibility for clinical trials. Results: 93% of the participants completed the 24-month follow-up. CSF mHTT, CSF NfL and plasma NfL increased over time in HD mutation carriers and had trajectories distinct from healthy controls. A single measurement at baseline of each analyte significantly predicted subsequent brain atrophy and change in clinical outcomes, including the composite UHDRS. Rate of change in the analytes showed weak associations with change in clinical or imaging outcomes. Baseline measurements for each analyte had better accuracy than rate of change in analyte for distinguishing between controls and HD mutation carriers, and between premanifest and manifest HD. Sample size calculations provide participant numbers needed to incorporate these biomarkers into clinical trials. Conclusion: This longitudinal study provides the first characterization of how mHTT and NfL fluctuate with time in HD mutation carriers. These data will facilitate the interpretation of drug-related alterations in mHTT and NfL in current and future clinical trials. Lay Summary: Having sensitive biomarkers that respond when a drug is working could help make clinical trials run faster and with smaller numbers of people. In order to understand drug related changes in biomarkers we need to know how they alter in HD mutation carriers without a drug. This study will help us do this.
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Neurodegenerative Diseases
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