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

IF 7.6 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders Pub Date : 2025-09-26 DOI:10.1002/mds.70062

Mena Farag,Michael J Murphy,Nicola Z Hobbs,Michela Leocadi,Kate Fayer,Olivia Thackeray,Johan Gobom,Marc Ciosi,Amanda Heslegrave,Henrik Zetterberg,Douglas R Langbehn,Darren G Monckton,Edward J Wild,Sarah J Tabrizi,Rachael I Scahill

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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.

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脑脊液前脑啡肽在亨廷顿病的临床运动诊断前几十年预测纹状体萎缩。

背景：亨廷顿氏病（HD）的特点是纹状体中棘神经元（msn）的早期、选择性、进行性易感性。Proenkephalin （PENK）是一种在msn中大量表达的阿片肽的前体，是一种很有前途的纹状体完整性生物标志物，但区域特异性关联及其早期鉴别的潜力尚未被表征。目的：我们研究了基线脑脊液（CSF） PENK浓度与区域脑萎缩之间的横断面和纵向关联，比较了脑脊液神经丝光（NfL）的识别模式，并评估了PENK和NfL在远发病HD基因扩增（HDGE）队列中区分HD综合分期系统（HD- iss） 0期和1期的作用。方法在平均4.8年的时间间隔内，对149名参与者（72名HDGE， 77名对照）和88名参与者（54名HDGE， 34名对照）进行了横断面全脑体素形态学测量。体素线性回归测试了基线生物流体生物标志物与灰质/白质体积之间的关联，调整了年龄、性别和CAG-Age产品评分，并校正了错误发现率。逻辑回归和接受者工作特征分析评估了阶段歧视。结果低基线脑脊液PENK预测纵向灰质和白质损失，主要发生在双侧纹状体。较高的基线CSF NfL预示着广泛的纵向白质损失。在阶段识别方面，PENK（曲线下面积[AUC]， 0.706; P = 0.0002）优于NfL (AUC, 0.661; P = 0.1596)，两者结合获得的收益最小（AUC, 0.714；联合P = 0.0007）。结论较低的基线CSF PENK浓度预测纵向纹状体萎缩，并且CSF PENK在区分HD- iss 0期和1期方面优于CSF NfL，支持其作为纹状体特异性生物标志物的作用，具有丰富早期HD试验队列的潜力。©2025作者。Wiley期刊有限责任公司代表国际帕金森和运动障碍学会出版的《运动障碍》。

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.