Discovery and Targeted Proteomic Studies Reveal Striatal Markers Validated for Huntington's Disease

Daniel Chelsky; Cara Joyce; H Jeremy Bockholt; Paul A Rudnick; William H Adams; Fiona McAllister; Justin W Smock; Michael A Newton; Jane S Paulsen

doi:10.1002/acn3.70272

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Discovery and Targeted Proteomic Studies Reveal Striatal Markers Validated for Huntington's Disease

Journal article

Open access

Peer reviewed

Discovery and Targeted Proteomic Studies Reveal Striatal Markers Validated for Huntington's Disease

Daniel Chelsky, Cara Joyce, H Jeremy Bockholt, Paul A Rudnick, William H Adams, Fiona McAllister, Justin W Smock, Michael A Newton and Jane S Paulsen

Annals of clinical and translational neurology, Vol.13(5), pp.911-923

05/2026

DOI: 10.1002/acn3.70272

PMCID: PMC13161869

PMID: 41363816

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Abstract

Clinical trials for Huntington's disease (HD) enrolling persons before clinical motor diagnosis (CMD) lack validated biomarkers. This study aimed to conduct an unbiased discovery analysis and a targeted examination of proteomic biomarkers scrutinized by clinical validation. Cerebrospinal fluid was obtained from PREDICT-HD and ancillary studies. Cohorts included HD family members who were gene-tested 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. Two overlapping targeted analyses using 180 samples from 125 participants (61% female, 89% White, average age of 42 ± 14) were performed; longitudinal duration was 1-4 years. Based on participants' clinical data, 25 proteins correlated significantly with CAG-age-product (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. Findings replicate and extend the verification of HD biomarkers. Monitoring proenkephalin and prodynorphin levels in persons with HD may facilitate early detection and disease-tracking. These disease-specific biomarkers may improve the rigor of therapeutic intervention before clinical motor diagnosis. Further studies emphasizing longitudinal changes are needed to assess disease-monitoring. ClinicalTrials.gov identifier: NCT00051324.

Biomarkers

Proteomics

qualification

striatum

Huntington's disease

Details

Title: Subtitle: Discovery and Targeted Proteomic Studies Reveal Striatal Markers Validated for Huntington's Disease
Creators: Daniel Chelsky - CellCarta, Inc., Montreal, Quebec, Canada
Cara Joyce - Loyola University Chicago
H Jeremy Bockholt - Center for Translational Research in Neuroimaging and Data Science
Paul A Rudnick - Spectragen Informatics, LLC, Bainbridge Island, Washington, USA
William H Adams - Loyola University Chicago
Fiona McAllister - CellCarta, Inc., Montreal, Quebec, Canada
Justin W Smock - University of Iowa
Michael A Newton - University of Wisconsin–Madison
Jane S Paulsen - University of Wisconsin–Madison
Resource Type: Journal article
Publication Details: Annals of clinical and translational neurology, Vol.13(5), pp.911-923
DOI: 10.1002/acn3.70272
PMID: 41363816
PMCID: PMC13161869
NLM abbreviation: Ann Clin Transl Neurol
ISSN: 2328-9503
eISSN: 2328-9503
Publisher: Wiley
Grant note: NS105509 / NIH HHS NS103475 / NIH HHS NS082089 / NIH HHS NS040068 / NIH HHS
Language: English
Electronic publication date: 12/09/2025
Date published: 05/2026
Academic Unit: Psychiatry; General Internal Medicine; Internal Medicine
Record Identifier: 9985091806202771

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