Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, China.
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China.
J Neurol. 2022 Dec;269(12):6452-6466. doi: 10.1007/s00415-022-11294-6. Epub 2022 Aug 6.
Freezing of gait (FOG) is a common, disabling symptom of Parkinson's disease (PD), and its exact pathophysiological mechanism is still poorly understood. The control of gait is a complex process that may be influenced by emotions modulated by serotonergic networks. Therefore, this study aimed to determine factors associated with FOG in PD patients and to evaluate the importance of the dorsal raphe nucleus (DRN; central node in the serotoninergic system) in FOG pathophysiology.
We combined cross-sectional survey data from 453 PD patients. According to the Freezing of Gait Questionnaire (FOGQ), patients were divided into two groups: the "PD with frozen gait (PD-FOG)" and "PD without frozen gait (PD-nFOG)" groups. Demographic characteristics, clinical features, and motor and nonmotor symptoms (NMS) assessments of PD patients were recorded. Univariate statistical analysis was performed between the two groups, and then regression analysis was performed on related factors. We also acquired resting-state functional MRI (rs-fMRI) data from 20 PD-FOG, 21 PD-nFOG, and 22 healthy controls (HCs) who were randomly chosen. We defined seeds in the DRN to evaluate functional connectivity (FC) patterns.
The overall frequency of FOG was 11.9% patients in the PD-FOG group were older, had a longer disease duration, had a higher levodopa equivalent daily dose, had more severe motor symptoms and worse quality of life, had a higher proportion of dyskinesia, wearing-off and postural instability/gait difficulty (PIGD) clinical phenotype, and experienced more depression and impaired sleep function than those in the PD-nFOG group. Logistic regression analysis showed that H&Ystage ≥ 3, UPDRS-III scores, PIGD clinical phenotype and excessive daytime sleepiness were associated with FOG. In addition, there was significantly lower FC between the DRN and some cortical structures, including the supplementary motor area (SMA), left superior frontal gyrus (SFG), and left median cingulated cortex (MCC) in PD-FOG patients than HCs and PD-nFOG patients.
These results demonstrate that the severity of PD and PIGD clinical phenotype are associated factors for freezing and that DRN dysfunction may play a key role in PD-related NMS and FOG. An abnormal cortical and brainstem networks may contribute to the mechanisms underlying FOG.
冻结步态（FOG）是帕金森病（PD）的一种常见致残症状，但其确切的病理生理机制仍知之甚少。步态的控制是一个复杂的过程，可能受到 5-羟色胺能网络调节的情绪的影响。因此，本研究旨在确定与 PD 患者 FOG 相关的因素，并评估中缝背核（DRN；5-羟色胺能系统的中央节点）在 FOG 病理生理学中的重要性。
我们结合了 453 名 PD 患者的横断面调查数据。根据冻结步态问卷（FOGQ），患者分为两组：“PD 伴冻结步态（PD-FOG）”和“PD 无冻结步态（PD-nFOG）”组。记录 PD 患者的人口统计学特征、临床特征、运动和非运动症状（NMS）评估。对两组进行单变量统计分析，然后对相关因素进行回归分析。我们还从 20 名 PD-FOG、21 名 PD-nFOG 和 22 名随机选择的健康对照者（HCs）中获得了静息态功能磁共振成像（rs-fMRI）数据。我们在 DRN 中定义种子以评估功能连接（FC）模式。
PD-FOG 组中 FOG 的总发生率为 11.9%。PD-FOG 组患者年龄较大，病程较长，左旋多巴等效日剂量较高，运动症状和生活质量更严重，异动症、开-关现象和姿势不稳/步态困难（PIGD）临床表型的比例较高，且经历更多的抑郁和睡眠功能障碍。Logistic 回归分析表明，H&Y 分期≥3、UPDRS-III 评分、PIGD 临床表型和日间嗜睡与 FOG 相关。此外，与 HCs 和 PD-nFOG 患者相比，PD-FOG 患者的 DRN 与一些皮质结构之间的 FC 明显降低，包括辅助运动区（SMA）、左额上回（SFG）和左中央扣带皮层（MCC）。
这些结果表明，PD 的严重程度和 PIGD 临床表型是冻结的相关因素，而 DRN 功能障碍可能在与 PD 相关的 NMS 和 FOG 中起关键作用。异常的皮质和脑干网络可能有助于 FOG 机制。
