Jane Paulsen1, Alex Pinto1, Natalie Bovin1, Maria Rudrud1, Esha Mahalingam1, Monica Janz1, William Adams2, Michael Newton1, H. Bockholt3, Kathleen Shannon1
1University of Wisconsin–Madison, 2Loyola University Chicago, 3Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, and Emory University
Objective:
This systematic review aims to quantify Huntington’s disease (HD) biofluid biomarkers by their effects sizes to distinguish HD from healthy controls and evaluate their quality and level of evidence.
Background:
Sensitive and specific biomarkers are needed to monitor disease progression and treatment response in HD. However, studies have been limited by sample size and design heterogeneity.
Design/Methods:
A systematic literature review in PubMed from 2/18/17 to 7/24/23 was performed to review literature regarding candidate saliva, urine, blood, and cerebrospinal fluid biomarkers for HD. Study selection and assessment of quality were conducted by three independent reviewers. The search yielded 621 results, 191 of which met review inclusion criteria. Study-specific sample sizes, means, and standard deviations were extracted from all identified publications and assessed via the standardized mean difference between HD and healthy controls. Standardized mean differences were estimated by Hedges’ g.
Results:
A majority of publications failed to report sufficient summary statistics for a comparison across studies to be conducted. Only 24 of 621 publications met analysis inclusion criteria. We focused on biomarkers that have been validated in at least two independent cohorts. The following biomarkers showed potential for distinguishing between healthy controls and stages of HD: BDNF; IL-6; NfL; T-tau; tHtt; YKL-40. Effect sizes for mHTT were included even though it was only represented in one article.
Conclusions:
Numerous published biomarkers encompass inflammatory, metabolic, and oxidative stress pathways, with emphasis on markers of neuronal degeneration. Neurofilament light chain is the most consistent biomarker in the literature in addition to BDNF, IL-6, T-tau, tHtt, and YKL-40, which show the most robust differentiation between healthy controls and the stages of HD. Unfortunately, publication bias in biomarker research is widespread given (1) the lack of reporting regarding non-significant findings and (2) the absence of information necessary to sufficiently evaluate potential biomarkers for qualification and context of use.