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

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

Loyola University Chicago

Research output: Contribution to journal › Article › peer-review

Abstract

OBJECTIVE: 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.

METHODS: 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.

RESULTS: 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.

INTERPRETATION: 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.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00051324.

Original language	English
Journal	Annals of clinical and translational neurology
DOIs	https://doi.org/10.1002/acn3.70272
State	E-pub ahead of print - Nov 9 2025

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10.1002/acn3.70272

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@article{ce59676b6ddd4f4f88550cd872a66e4b,

title = "Discovery and Targeted Proteomic Studies Reveal Striatal Markers Validated for Huntington's Disease",

abstract = "OBJECTIVE: 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.METHODS: 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.RESULTS: 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.INTERPRETATION: 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.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00051324.",

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

note = "{\textcopyright} 2025 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",

year = "2025",

month = nov,

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doi = "10.1002/acn3.70272",

language = "English",

journal = "Annals of clinical and translational neurology",

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T1 - Discovery and Targeted Proteomic Studies Reveal Striatal Markers Validated for Huntington's Disease

AU - Chelsky, Daniel

AU - Joyce, Cara

AU - Bockholt, H Jeremy

AU - Rudnick, Paul A

AU - Adams, William H

AU - McAllister, Fiona

AU - Smock, Justin W

AU - Newton, Michael A

AU - Paulsen, Jane S

PY - 2025/11/9

Y1 - 2025/11/9

N2 - OBJECTIVE: 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.METHODS: 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.RESULTS: 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.INTERPRETATION: 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.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00051324.

AB - OBJECTIVE: 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.METHODS: 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.RESULTS: 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.INTERPRETATION: 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.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00051324.

U2 - 10.1002/acn3.70272

DO - 10.1002/acn3.70272

M3 - Article

C2 - 41363816

SN - 2328-9503

JO - Annals of clinical and translational neurology

JF - Annals of clinical and translational neurology

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