Chou Kelvin L, Kanel Prabesh, van Emde Boas Miriam, Roytman Stiven, Carli Giulia, Albin Roger L, Bohnen Nicolaas I
Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
Functional Neuroimaging, Cognitive, and Mobility Laboratory, Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA.
Mov Disord. 2025 Apr 11. doi: 10.1002/mds.30196.
Freezing of gait (FoG) is a debilitating mobility disturbance that becomes increasingly resistant to dopaminergic pharmacotherapies with advancing Parkinson's disease (PD). The pathophysiology underlying the response of FoG to dopaminergic treatment is poorly understood. Prior vesicular acetylcholine transporter positron emission tomography (VAChT PET) imaging studies implicate the degeneration of cholinergic pathways, including bilateral striatal and limbic archicortex deficits, as significant contributors to FoG.
We aim to investigate whether specific cholinergic system changes are associated with FoG responsiveness to levodopa treatment in PD patients.
Thirty six PD subjects (31M/5F) completed [F]-fluoroethoxybenzovesamicol ([F]FEOBV) vesicular acetylcholine transporter positron emission tomography (VAChT PET) and underwent videotaped clinical assessments for FoG on and off levodopa.
Sixteen subjects had l-dopa-unresponsive FoG. Whole brain voxel-based analyses of [F]FEOBV PET (false discovery rate-corrected at P < 0.05 and adjusted for levodopa-equivalent dose) showed that those with l-dopa-unresponsive FoG had more severe cholinergic terminal deficits in the bilateral insula, hippocampi, fimbria, and lateral geniculate nuclei; left mid-temporal, putamen, and posterior cingulate regions; and the right mid-frontal region and anterior ventral nucleus of the thalamus compared to those with l-dopa-responsive FoG.
FoG unresponsive to levodopa is associated with bilateral cholinergic terminal reductions, mostly in extra-striatal regions involved in multisensory and cognitive integration of gait and postural control as well as spatial navigation. The lack of specific striatal involvement points to the disruption of widespread cerebral network functions underlying l-dopa-unresponsive FoG in PD and may explain the treatment-resistant nature of FoG to levodopa. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
冻结步态（FoG）是一种使人衰弱的运动障碍，随着帕金森病（PD）的进展，它对多巴胺能药物治疗的抵抗性越来越强。FoG对多巴胺能治疗反应的潜在病理生理学机制尚不清楚。先前的囊泡乙酰胆碱转运体正电子发射断层扫描（VAChT PET）成像研究表明，胆碱能通路的退化，包括双侧纹状体和边缘古皮质缺陷，是FoG的重要促成因素。
我们旨在研究特定胆碱能系统变化是否与PD患者FoG对左旋多巴治疗的反应性相关。
36名PD受试者（31名男性/5名女性）完成了[F] - 氟乙氧基苯甲酰甲基溴（[F]FEOBV）囊泡乙酰胆碱转运体正电子发射断层扫描（VAChT PET），并接受了左旋多巴开启和关闭状态下FoG的录像临床评估。
16名受试者的FoG对左旋多巴无反应。基于体素的全脑[F]FEOBV PET分析（在P < 0.05时进行错误发现率校正，并根据左旋多巴等效剂量进行调整）显示，与左旋多巴反应性FoG患者相比，左旋多巴无反应性FoG患者在双侧岛叶、海马、海马伞和外侧膝状体核；左侧颞中回、壳核和后扣带回区域；以及右侧额中回和丘脑前腹核有更严重的胆碱能终末缺陷。
对左旋多巴无反应的FoG与双侧胆碱能终末减少有关，主要发生在参与步态和姿势控制以及空间导航的多感觉和认知整合的纹外区域。缺乏特定的纹状体受累表明PD中左旋多巴无反应性FoG背后广泛脑网络功能的破坏，并可能解释FoG对左旋多巴的治疗抵抗性质。© 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。
