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Microvascular changes in Parkinson´s Disease: Correlations to levodopa induced dyskinesia and grip froce control

帕金森病的微血管变化：与左旋多巴引起的运动障碍和握力冻结控制的相关性

基本信息

批准号：
219279688
负责人：
Professor Dr. Florian Holtbernd
金额：
--
依托单位：
Klinik für Neurologie
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/219279688?language=en
关键词：
Microvascular changes Parkinson Disease Correlations

项目摘要

Levodopa is the most effective medication for the treatment of Parkinson´s disease (PD), but long term treatment causes disruptive motor side effects in the vast majority of patients, i.e. levodopa induced dyskinesias (LID). The mechanisms underlying LID are complex and not fully understood. Recent studies suggest that large, transient increases in striatal levels of dopamine following levodopa (LD) administration may be a key promoter in the pathogenesis of LID. Moreover, LD has opposing effects on cerebral blood flow and metabolism (flow-metabolism-dissociation) that appear to be significantly more pronounced in LID-patients. It is therefore hypothesized that the observed alterations of striatal dopamine levels, at least in part, depend on functional and structural alterations of the brain microvasculature. Impaired hand function is a common symptom in PD. PD patients show a distinct pattern of alterations of the prehensile forces. In particular, PD patients exhibit excessive grip forces (GF). This phenomenon seems to be significantly more pronounced in LID patients. Whether this increase is an intrinsic feature of PD, is caused by dopaminergic treatment, or shares pathophysiological mechanisms with LID, is unknown. We will employ a longitudinal PET-imaging approach to determine whether the hemodynamic and metabolic effects of dopamine are relevant to the pathophysiology of LID. We will investigate whether the overshoot of GF is a reproducible feature of PD or exclusively occurs in LID patients. Lastly, we will determine whether abnormalities in GF control correlate to alterations of the cerebral microvasculature. For this purpose we will assess PET-data as well as GF data in drug naïve patients at baseline and after one year of dopaminergic treatment. The proposed project shall provide a deeper insight into the pathophysiology of LID and should open new avenues for treating this troubling side effect.

左旋多巴是治疗帕金森病（PD）最有效的药物，但长期治疗会导致绝大多数患者出现破坏性运动副作用，即左旋多巴诱导的运动障碍（LID）。LID背后的机制很复杂，尚未完全了解。最近的研究表明，大量的，短暂的增加纹状体多巴胺水平的左旋多巴（LD）管理可能是一个关键的启动子LID的发病机制。此外，LD对脑血流量和代谢（流量-代谢-解离）具有相反的影响，这在LID患者中似乎更明显。因此，假设观察到的纹状体多巴胺水平的改变，至少部分地，取决于脑微血管的功能和结构的改变。手功能受损是PD的常见症状。PD患者表现出明显的张力改变模式。特别是，PD患者表现出过度的握力（GF）。这种现象似乎在LID患者中更明显。这种增加是否是PD的内在特征，是由多巴胺能治疗引起的，还是与LID共享病理生理机制尚不清楚。我们将采用纵向PET成像方法来确定多巴胺的血流动力学和代谢效应是否与LID的病理生理学相关。我们将研究GF的过冲是否是PD的可再现特征或仅发生在LID患者中。最后，我们将确定是否异常的GF控制相关的脑微血管系统的改变。为此，我们将评估基线时和多巴胺能治疗一年后药物初治患者的PET数据以及GF数据。拟议的项目将提供更深入的了解LID的病理生理学，并为治疗这种令人不安的副作用开辟新的途径。