Johansson Martin E, Toni Ivan, Bloem Bastiaan R, Helmich Rick C
Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Centre of Expertise for Parkinson & Movement Disorders, 6525 EN Nijmegen, The Netherlands.
Radboud University, Donders Institute for Brain, Cognition and Behaviour, 6525 EN Nijmegen, The Netherlands.
Brain. 2025 Aug 12. doi: 10.1093/brain/awaf302.
Parkinson's disease (PD) is a common and debilitating neurodegenerative disorder characterized by motor slowing (bradykinesia), which is thought to arise mainly due to nigro-striatal dopaminergic cell loss. Paradoxically, longitudinal changes in striatal dopamine relate poorly to the progression of bradykinesia, indicating that other pathophysiological mechanisms play a role. In line with this, cross-sectional studies have shown that more benign motor phenotypes of PD are characterized by increased activity in the parieto-premotor cortex, indicative of cerebral compensation. However, the role of cerebral compensation in disease progression remains unclear. Here, we used a longitudinal design to test the hypothesis that the clinical progression of bradykinesia in PD is related to a decline in compensatory parieto-premotor function, over and above worsening nigro-striatal cell loss. We used a validated action selection task in combination with functional MRI to measure motor- and selection-related brain activity relative to the most-affected hand in a large sample of 351 PD patients (≤5 years disease duration) and 60 healthy controls. In addition, we used diffusion-weighted MRI to obtain structural indices of substantia nigra and cerebral cortex integrity. These measurements were acquired at baseline and at two-year follow-up, enabling us to compare longitudinal changes in brain metrics between patients and controls, and to investigate their relationships with clinical metrics of bradykinesia progression. Consistent with our hypothesis, we observed that bradykinesia progression was inversely related to longitudinal changes in selection-related dorsal premotor cortex activity, suggesting that faster loss of cortical compensation contributes to faster symptom worsening. Importantly, this relationship remained after adjusting for longitudinal changes in the functional and structural integrity of the nigro-striatal system, indicating that bradykinesia progression is uniquely determined by loss of cortical compensation. In group comparisons of longitudinal change, PD patients showed an overall reduction in putamen activity, which did not decrease further over time, in combination with an acceleration of structural decline in the substantia nigra and the premotor cortex. Despite showing expected patterns of PD pathology, neither of these metrics correlated with bradykinesia progression. We conclude that the progression of bradykinesia in PD is determined by longitudinal changes in compensatory premotor cortex function. This presents opportunities to develop new progression-slowing interventions that focus on preserving and enhancing cortical compensation.
帕金森病（PD）是一种常见且使人衰弱的神经退行性疾病，其特征为运动迟缓（运动徐缓），人们认为这主要是由于黑质纹状体多巴胺能细胞丢失所致。矛盾的是，纹状体多巴胺的纵向变化与运动迟缓的进展关系不大，这表明其他病理生理机制也发挥了作用。与此相符的是，横断面研究表明，帕金森病较良性的运动表型的特征是顶叶-运动前皮质活动增加，这表明存在大脑代偿。然而，大脑代偿在疾病进展中的作用仍不清楚。在此，我们采用纵向研究设计来检验这一假设：帕金森病中运动迟缓的临床进展与代偿性顶叶-运动前功能的下降有关，且这种关系超出了黑质纹状体细胞丢失加剧的影响。我们在351名帕金森病患者（病程≤5年）和60名健康对照组成的大样本中，使用经过验证的动作选择任务并结合功能磁共振成像（fMRI），来测量相对于受影响最严重的手的运动和选择相关脑活动。此外，我们使用扩散加权磁共振成像来获取黑质和大脑皮质完整性的结构指标。这些测量在基线期和两年随访期进行，使我们能够比较患者和对照之间脑指标的纵向变化，并研究它们与运动迟缓进展的临床指标之间的关系。与我们的假设一致，我们观察到运动迟缓的进展与选择相关的背侧运动前皮质活动的纵向变化呈负相关，这表明皮质代偿更快丧失会导致症状更快恶化。重要的是，在对黑质纹状体系统功能和结构完整性的纵向变化进行校正后，这种关系仍然存在，这表明运动迟缓的进展是由皮质代偿丧失唯一决定的。在纵向变化的组间比较中，帕金森病患者壳核活动总体下降，且不会随时间进一步降低，同时黑质和运动前皮质的结构衰退加速。尽管呈现出帕金森病病理的预期模式，但这些指标均与运动迟缓的进展无关。我们得出结论，帕金森病中运动迟缓的进展是由代偿性运动前皮质功能的纵向变化决定的。这为开发专注于保留和增强皮质代偿的新型延缓疾病进展干预措施提供了机会。
