Cerebrospinal Fluid Proenkephalin Predicts Striatal Atrophy Decades before Clinical Motor Diagnosis in Huntington's Disease

Background Huntington's disease (HD) is characterized by early, selective, progressive vulnerability of striatal medium spiny neurons (MSNs). Proenkephalin (PENK), a precursor of opioid peptides abundantly expressed in MSNs, is a promising biomarker of striatal integrity, but region‐specific associations and its potential for early‐stage discrimination have not been characterized. Objectives We investigated cross‐sectional and longitudinal associations between baseline cerebrospinal fluid (CSF) PENK concentration and regional brain atrophy, compared identified patterns with CSF neurofilament light (NfL), and evaluated PENK and NfL for discriminating between HD Integrated Staging System (HD‐ISS) stage 0 versus 1 in a far‐from‐onset HD gene‐expanded (HDGE) cohort. Methods Whole‐brain voxel‐based morphometry was performed in 149 participants (72 HDGE, 77 controls) cross‐sectionally and 88 participants (54 HDGE, 34 controls) longitudinally over a mean interval of 4.8 years. Voxel‐wise linear regression tested associations between baseline biofluid biomarkers and gray/white matter volume, adjusting for age, sex and CAG‐Age Product score, with false discovery rate correction. Logistic regression and receiver operating characteristic analyses assessed stage discrimination. Results Lower baseline CSF PENK predicted longitudinal gray and white matter loss, predominantly in the striatum bilaterally. Higher baseline CSF NfL predicted widespread longitudinal white matter loss. For stage discrimination, PENK (area under curve [AUC], 0.706; P = 0.0002) outperformed NfL (AUC, 0.661; P = 0.1596) with minimal gain from combining both (AUC, 0.714; joint P = 0.0007). Conclusions Lower baseline CSF PENK concentration predicted longitudinal striatal atrophy and CSF PENK outperformed CSF NfL in distinguishing HD‐ISS stages 0 and 1, supporting its role as a striatum‐specific biomarker with potential to enrich early‐stage HD trial cohorts.