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Updated: Jan 15, 2026
Whole-brain Segmentation and Change-point Analysis of Anatomical Brain MRI—Application in Premanifest Huntington's Disease
Published on: June 9, 2018
Systematic Review with Meta-Analysis of Biofluid Markers for Huntington's Disease
Jane S Paulsen1, Natalie A Bovin1,2, Jordan D Clemsen3
1Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
Insights
Huntington
Area of Science:
- Neuroscience
- Biomarkers
- Clinical Trials
Background:
- Huntington's disease (HD) requires long-term therapy before motor diagnosis.
- Early intervention necessitates sensitive biomarkers reflecting disease progression.
- Current early-stage HD diagnosis relies on MRI-detected structural decline.
Purpose of the Study:
- To systematically review and meta-analyze biofluid markers for Huntington's disease.
- To identify validated biomarkers for pre-symptomatic, early-stage, and mid-stage HD.
- To address limitations in current HD biomarker research and improve clinical trial methodology.
Main Methods:
- Systematic literature search identifying 804 records.
- Meta-analysis of 55 studies with reproducible findings.
- Evaluation of biofluid markers including NfL, hydroxycholesterols, tau, cortisol, HDL, and mHTT.
Main Results:
- Neurofilament light (NfL) is a validated prognostic biomarker for pre-symptomatic HD.
- Four markers (24-OHC, 27-OHC, NfL, T-tau) are validated for early-stage HD.
- Four markers (cortisol, HDL, mHTT, HTT) are validated for mid-stage HD.
Conclusions:
- Eight biofluid markers are supported for validation across HD stages.
- Improved reporting and rigor are needed to advance HD clinical trial methodology.
- Validated biomarkers are crucial for effective Huntington's disease therapeutic strategies.
Abstract:
Primary therapeutic objectives for Huntington's disease (HD) necessitate continued therapy for a long period before clinical motor diagnosis and its concurrent functional incapacities. Therefore, the need is paramount for alternative biomarkers that are not only highly sensitive but also clearly reflect the disease progression. Current trials increasingly rely upon biological definitions of disease to initiate intervention before significant decline. The primary biological measure of early-stage HD is volumetric evidence of structural decline on magnetic resonance imaging. This comprehensive review of biofluid markers is a systematic review documenting 804 records identified in a literature search. Updating a previous comprehensive review from 2018, we summarize effect sizes and conduct meta-analyses for 55 studies with reproducible findings. Evidence for neurofilament light (NfL) is sufficient to meet evidentiary guidelines as a prognostic biomarker in preHD (ie, before clinical motor diagnosis). Significant meta-analyses are found for 24-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), NfL, and T-tau (total tau) in early-stage HD and for cortisol, high-density lipoprotein (HDL), mutant huntingtin (mHTT), and HTT in mid-stage HD after clinical motor diagnosis. Despite over 800 published studies of biomarkers in HD and over 200 reviews of those efforts, the current state of the literature is limited by inconsistent reporting of necessary detail in existing reports. This is compounded by an inability to effectively compare outcomes and by continued publication when rigor is compromised, revealing a significant knowledge gap for HD clinical trial methodology improvements. Findings support validation for eight biofluid markers in HD: one in preHD, four in early-stage HD, and four in mid-stage HD after clinical motor diagnosis. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
