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This study aimed to conduct an unbiased discovery analysis and a targeted examination of proteomic biomarkers scrutinized by clinical validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cerebrospinal fluid was obtained from PREDICT\u2010HD and ancillary studies. Cohorts included HD family members who were gene\u2010tested and considered prodromal following neuroexam. An initial unbiased mass spectrometry proteomics analysis identified candidate disease biomarkers that were then added to a targeted mass spectrometry assay including 100+ proteins associated with other neurodegenerative diseases. This assay determined relative quantifications of proteins in a single analysis. Significant biomarkers were examined against genetic and clinical measures of disease onset and progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Two overlapping targeted analyses using 180 samples from 125 participants (61% female, 89% White, average age of 42\u2009\u00b1\u200914) were performed; longitudinal duration was 1\u20134\u2009years. Based on participants' clinical data, 25 proteins correlated significantly with CAG\u2010age\u2010product (CAP) score and Unified HD Rating Scale (UHDRS) motor and cognitive measures. While most proteins increase in abundance with disease progression, proenkephalin and prodynorphin were downregulated before CMD. Power was low for longitudinal analysis. However, the reliability of HD family normal controls indicates that each individual's proteome remains relatively stable over time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>Findings replicate and extend the verification of HD biomarkers. Monitoring proenkephalin and prodynorphin levels in persons with HD may facilitate early detection and disease\u2010tracking. These disease\u2010specific biomarkers may improve the rigor of therapeutic intervention before clinical motor diagnosis. Further studies emphasizing longitudinal changes are needed to assess disease\u2010monitoring.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                      identifier: NCT00051324\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70272","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T13:38:19Z","timestamp":1765287499000},"page":"911-923","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discovery and Targeted Proteomic Studies Reveal Striatal Markers Validated for Huntington's Disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Daniel","family":"Chelsky","sequence":"first","affiliation":[{"name":"CellCarta, Inc.  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cara","family":"Joyce","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Center for Translational Research and Education, Loyola University Chicago  Maywood Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Jeremy","family":"Bockholt","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":"Paul A.","family":"Rudnick","sequence":"additional","affiliation":[{"name":"Spectragen Informatics, LLC  Bainbridge Island Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William H.","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Center for Translational Research and Education, Loyola University Chicago  Maywood Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"McAllister","sequence":"additional","affiliation":[{"name":"CellCarta, Inc.  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