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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\u2010stage 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\u2010analyses 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\u2010analyses are found for 24\u2010hydroxycholesterol (24\u2010OHC), 27\u2010hydroxycholesterol (27\u2010OHC), NfL, and T\u2010tau (total tau) in early\u2010stage HD and for cortisol, high\u2010density lipoprotein (HDL), mutant huntingtin (mHTT), and HTT in mid\u2010stage 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\u2010stage HD, and four in mid\u2010stage HD after clinical motor diagnosis. \u00a9 2025 The Author(s).\n                    <jats:italic>Movement Disorders<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.\n                  <\/jats:p>","DOI":"10.1002\/mds.70067","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T01:52:03Z","timestamp":1760406723000},"page":"2578-2595","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Systematic Review with Meta\u2010Analysis of Biofluid Markers for Huntington's Disease"],"prefix":"10.1002","volume":"40","author":[{"given":"Jane S.","family":"Paulsen","sequence":"first","affiliation":[{"name":"Department of Neurology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie A.","family":"Bovin","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"},{"name":"Department of Neurology University of Colorado Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan D.","family":"Clemsen","sequence":"additional","affiliation":[{"name":"Tri\u2010institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Weiss","sequence":"additional","affiliation":[{"name":"Evotec SE  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail M.","family":"Key","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica L.","family":"Janz","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5200-9678","authenticated-orcid":false,"given":"Deven K.","family":"Burks","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg  M\u00f6lndal Sweden"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital  M\u00f6lndal Sweden"},{"name":"Department of Neurodegenerative Disease UCL Institute of Neurology  London UK"},{"name":"UK Dementia Research Institute at University College London  London UK"},{"name":"Hong Kong Center for Neurodegenerative Diseases  Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Shannon","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Wisconsin School of Medicine and Public Health  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-323-85654-6.00042-3"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlae022"},{"key":"e_1_2_11_4_1","unstructured":"Wave Life Sciences.Wave Life Sciences Announces Positive Results from Phase 1b\/2a SELECT\u2010HD Trial with First Clinical Demonstration of Allele\u2010Selective Mutant Huntingtin Lowering in Huntington's Disease [Press Release]. 2024."},{"key":"e_1_2_11_5_1","unstructured":"BEST (Biomarkers EndpointS and other Tools) Resource. 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