Cerebrospinal Fluid Proenkephalin Predicts Striatal Atrophy Decades before Clinical Motor Diagnosis in Huntington's Disease
Year: 2025
Type: article
Study design: Observational Study
Abstract: 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. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Source: Movement Disorders
DOI: 10.1002/mds.70062
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Funders: Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Myotonic Dystrophy Foundation, Pfizer, Sanofi, CHDI Foundation, Alnylam Pharmaceuticals, Familjen Erling-Perssons Stiftelse, Cure Alzheimer's Fund, Wellcome Trust, Stiftelsen för Gamla Tjänarinnor, Vertex Pharmaceuticals, PTC Therapeutics, EU Joint Programme – Neurodegenerative Disease Research, Ionis Pharmaceuticals, Sage Therapeutics, Sarepta Therapeutics, European Huntington's Disease Network, Apellis Pharmaceuticals, National Institute for Health and Care Research, University College London, European Commission, Eisai, Hjärnfonden, Vetenskapsrådet, Göteborgs Universitet, Alzheimerfonden, Ministry of Minority Affairs, Science for Life Laboratory, UK Dementia Research Institute, HORIZON EUROPE Framework Programme, Medical Research Council, Sahlgrenska Akademin, National Institute of Neurological Disorders and Stroke
Awards: G1057200632, G1088883541, G1307999793, G1343867371, G1346957673, G1451607819, G150733400, G1546555014, G1551449788, G1588116593, G1710774808, G1771944843, G1802301745, G1833008592, G1928552717, G1938858119, G196098375, G201353144, G2057385626, G2081597990, G2224941001, G2237966762, G2256555670, G237833635, G2434909840, G2475953241, G2543812357, G2799940023, G2804859505, G292763017, G3241251457, Fluid biomarkers for neurodegenerative dementias, G3509189227, G3809224024, G3842727039, G3903502641, G3914690605, G4166693258, G4228906844, G4234328627, G4244943609, G4260843567, G432431387, G434337789, G4377393254, G4786159458, TREAT-HD: Delivering therapies to prevent neurodegeneration in Huntington’s disease, G4960203590, G5040492720, G506008078, G516766298, G5264190596, Fluid biomarkers for neurodegenerative dementias, G5576250680, G5712520100, G5778058681, CASCADE: CAuSe or Consequence in Alzheimer DiseasE?, G6158734006, G6207287561, G6252389079, G6289970089, G6361952146, G6544145387, Multi-omics Interdisciplinary Research Integration to Address DEmentia diagnosis, G6701856265, G6745400708, G691317373, G7075164165, G7293611571, G7359277818, G7907773732, G7972240148, G839602194, G861818073, G8782684654, G8906644882
OpenAlex ID: W4414545210