Cholinergic degeneration in prodromal and early Parkinson's: a link to present and future disease states.

IF 10.6 1区医学 Q1 CLINICAL NEUROLOGY

Brain Pub Date : 2025-05-06 DOI:10.1093/brain/awaf168

Tamir Eisenstein,Karolien Groenewald,Ludo van Hillegondsberg,Falah Al Hajraf,Tanja Zerenner,Michael A Lawton,Yoav Ben-Shlomo,Ludovica Griffanti,Michele T Hu,Johannes C Klein

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引用次数: 0

Abstract

The neuropathological process in Parkinson's disease (PD) and Lewy body disorders has been shown to extend well beyond the degeneration of the dopaminergic system, affecting other neuromodulatory systems in the brain which play crucial roles in the clinical expression and progression of these disorders. Here, we investigate the role of the macrostructural integrity of the nucleus basalis of Meynert (NbM), the main source of cholinergic input to the cerebral cortex, in cognitive function, clinical manifestation, and disease progression in non-demented subjects with PD and individuals with isolated REM sleep behaviour disorder (iRBD). Using structural MRI data from 393 early PD patients, 128 iRBD patients, and 186 controls from two longitudinal cohorts, we found significantly lower NbM grey matter volume in both PD (β=-12.56, p=0.003) and iRBD (β=-16.41, p=0.004) compared to controls. In PD, higher NbM volume was associated with better higher-order cognitive function (β=0.10, p=0.045), decreased non-motor (β=-0.66, p=0.026) and motor (β=-1.44, p=0.023) symptom burden, and lower risk of future conversion to dementia (Hazard ratio (HR)<0.400, p<0.004). Higher NbM volume in iRBD was associated with decreased future risk of phenoconversion to PD or dementia with Lewy bodies (DLB) (HR<0.490, p<0.016). However, despite similar NbM volume deficits to those seen in PD, associations between NbM structural deficits and current disease burden or clinical state were less pronounced in iRBD. These findings identify NbM volume as a potential biomarker with dual utility: predicting cognitive decline and disease progression in early PD, while also serving as an early indicator of phenoconversion risk in prodromal disease. The presence of structural deficits before clear clinical correlates in iRBD suggests complex compensatory mechanisms may initially mask cholinergic dysfunction, with subsequent failure of these mechanisms potentially contributing to clinical conversion.

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前驱和早期帕金森病的胆碱能变性：与现在和未来疾病状态的联系

帕金森病（PD）和路易体疾病的神经病理过程已被证明远远超出了多巴胺能系统的退化，影响了大脑中其他在这些疾病的临床表现和进展中起关键作用的神经调节系统。在这里，我们研究了Meynert基底核（NbM）的宏观结构完整性在非痴呆PD患者和孤立性REM睡眠行为障碍（iRBD）患者的认知功能、临床表现和疾病进展中的作用，NbM是大脑皮层胆碱能输入的主要来源。利用来自两个纵向队列的393名早期PD患者、128名iRBD患者和186名对照者的结构MRI数据，我们发现PD （β=-12.56, p=0.003）和iRBD （β=-16.41, p=0.004）的NbM灰质体积均显著低于对照组。在PD中，较高的NbM体积与更好的高阶认知功能（β=0.10, p=0.045），减少非运动（β=-0.66, p=0.026）和运动（β=-1.44, p=0.023）症状负担以及降低未来转化为痴呆的风险相关（风险比(HR)<0.400, p<0.004）。iRBD中较高的NbM体积与未来表型转化为PD或路易体痴呆（DLB）的风险降低相关（HR<0.490, p<0.016）。然而，尽管与PD相似的NbM体积缺陷，但iRBD中NbM结构缺陷与当前疾病负担或临床状态之间的关联不太明显。这些发现确定了NbM体积作为一种潜在的生物标志物具有双重用途：预测早期PD的认知能力下降和疾病进展，同时也作为前驱疾病表型转化风险的早期指标。在明确的临床相关性之前，iRBD中存在结构缺陷，这表明复杂的代偿机制最初可能掩盖了胆碱能功能障碍，随后这些机制的失败可能导致临床转化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain 医学-临床神经学

CiteScore

20.30

自引率

4.10%

发文量

458

审稿时长

3-6 weeks

期刊介绍： Brain, a journal focused on clinical neurology and translational neuroscience, has been publishing landmark papers since 1878. The journal aims to expand its scope by including studies that shed light on disease mechanisms and conducting innovative clinical trials for brain disorders. With a wide range of topics covered, the Editorial Board represents the international readership and diverse coverage of the journal. Accepted articles are promptly posted online, typically within a few weeks of acceptance. As of 2022, Brain holds an impressive impact factor of 14.5, according to the Journal Citation Reports.