Di Vico Ilaria Antonella, Moretto Manuela, Tamanti Agnese, Tomelleri Giovanni, Burati Giulia, Martins Daniel, Dipasquale Ottavia, Veronese Mattia, Bertoldo Alessandra, Menini Elisa, Sandri Angela, Ottaviani Sarah, Pizzini Francesca Benedetta, Tinazzi Michele, Castellaro Marco
Neurology Unit, Department of Neurosciences, Biomedicine and Movement Sciences, Policlinico Borgo Roma, University of Verona, Verona, Italy.
Department of Information Engineering, University of Padova, Padova, Italy.
Mov Disord. 2025 Aug;40(8):1561-1571. doi: 10.1002/mds.30214. Epub 2025 Apr 22.
Fatigue in Parkinson's disease (PD) is a prevalent and debilitating non-motor symptom. Despite its significant impact on quality of life, the underlying neurochemical and network-based mechanisms remain poorly understood.
This observational study applied a multimodal imaging approach to explore potential links between the functional connectivity of neurotransmitter-specific circuits and fatigue in a sample of patients with PD.
We acquired resting-state functional magnetic resonance imaging data in 35 patients with PD including 18 with clinically significant fatigue and 17 without. We applied the receptor-enriched analysis of functional connectivity by targets (REACT) pipeline to derive patients' specific molecularly enriched networks informed by the spatial distribution of the dopamine, noradrenaline, serotonin transporters, and metabotropic glutamate 5 receptors as assessed using molecular imaging data in independent samples of healthy controls. We then conducted whole-brain analyses inspecting both categorical differences between groups of patients with and without clinically significant fatigue, and associations exploring the full within-sample variation in symptom ratings.
We found a significant decrease in noradrenaline-enriched and glutamate-enriched functional connectivity in key regions, belonging to the sensorimotor, salience, and default mode network, with increasing fatigue severity. Notably, noradrenaline-enriched functional connectivity reductions were widespread, while glutamate-enriched functional connectivity reductions were more restricted to the supplementary motor area. No significant relationships between fatigue and dopamine or serotonin-enriched functional connectivity were found.
These findings offer supportive evidence for the putative involvement of the noradrenaline and glutamate systems in the genesis of fatigue in PD, opening new directions for treatment development exploring these neurochemical systems. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
帕金森病（PD）中的疲劳是一种常见且使人衰弱的非运动症状。尽管其对生活质量有重大影响，但其潜在的神经化学和基于网络的机制仍知之甚少。
本观察性研究采用多模态成像方法，在一组帕金森病患者样本中探索神经递质特异性回路的功能连接与疲劳之间的潜在联系。
我们获取了35例帕金森病患者的静息态功能磁共振成像数据，其中18例有临床显著疲劳，17例无。我们应用基于靶点的功能连接受体富集分析（REACT）流程，根据多巴胺、去甲肾上腺素、5-羟色胺转运体以及代谢型谷氨酸5受体的空间分布，利用健康对照独立样本中的分子成像数据，得出患者特定的分子富集网络。然后我们进行全脑分析，检查有和无临床显著疲劳的患者组之间的分类差异，以及探索症状评分在整个样本中的全部变化的相关性。
我们发现，随着疲劳严重程度增加，属于感觉运动、突显和默认模式网络的关键区域中，去甲肾上腺素富集和谷氨酸富集的功能连接显著降低。值得注意的是，去甲肾上腺素富集的功能连接减少广泛存在，而谷氨酸富集的功能连接减少更多局限于辅助运动区。未发现疲劳与多巴胺或5-羟色胺富集的功能连接之间存在显著关系。
这些发现为去甲肾上腺素和谷氨酸系统可能参与帕金森病疲劳发生提供了支持性证据，为探索这些神经化学系统的治疗开发开辟了新方向。© 2025作者。《运动障碍》由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版。
