Neurovascular Effects of Dopamine Replacement Therapy in Parkinson's Disease

项目摘要 这个修订项目的首要目标是了解左旋多巴引起的运动障碍的演变 (LID)帕金森病（PD）的金标准治疗的致残性和难治性副作用。近 所有PD患者将在开始用药后10年内获得LID。一旦LID设置，通常作为推进 疾病需要更高剂量的左旋多巴，PD变得非常难以管理。关于LID的大多数研究 已经集中在神经元水平，其中LID与各种突触前和突触后变化相关[1]。 然而，这些变化与向LID过渡的关系仍然难以捉摸。我们因此 在人类PD患者和LID的啮齿动物模型中进行了系统水平的方法。使用多示踪剂 PET成像测量葡萄糖代谢和局部血流，我们发现左旋多巴 给药与显著的神经血管失调有关：血管和代谢紊乱， 对左旋多巴的反应彼此分离，血流量增加，代谢减少， 多巴胺能去神经支配区这种解离在壳核中最大，在 患有LID的受试者，他们在离体的感觉运动皮层（SMC）中也具有升高的代谢活性， 药物状态。我们随后发现，当在未用药状态下扫描时，LID受试者显示 壳核分离时高碳酸血症血管反应性（毛细血管密度指数）异常增加 地区假设慢性左旋多巴治疗增强了解离区的血管生成，我们 与Angela Cenci博士（隆德，瑞典）合作，在啮齿动物LID模型中使用microPET。我们发现 左旋多巴介导的神经血管失调和血脑屏障（BBB）改变的证据 基底神经节的渗透性，这与运动障碍的严重程度和组织病理学相关 在相同的动物中血管生成的证据。因此，来自人类患者和啮齿动物的数据表明LID- 相关的神经血管变化发生在系统水平，并随着时间的推移逐渐发展。LID是否也是 与局部神经胶质血管反应如神经炎症相关的疾病仍然未知， 导致LID发作的变化过程。如果我们想放慢速度 或阻止LID的发展，我们建议：（1）追踪局部神经血管的演变 PD患者过渡到LID时功能障碍;（2）描绘神经血管单位的纵向变化 在解偶联区域的功能;和（3）确定大鼠模型中神经血管变化的潜在机制 的LID。

PROJECT SUMMARY The overarching goal of this revised project is to understand the evolution of levodopa-induced dyskinesias (LID), a disabling and refractory side-effect of the gold standard treatment for Parkinson's disease (PD). Nearly all PD patients will acquire LID within 10 years of beginning the drug. Once LID sets in, usually as advancing disease requires higher doses of levodopa, PD becomes extremely difficult to manage. Most research on LID has focused on the neuronal level, where LID is associated with a variety of pre- and post-synaptic changes [1]. The relationship of these changes to the transition to LID, however, remains elusive. We have therefore undertaken a systems-level approach in human PD patients and in a rodent model of LID. Using multi-tracer PET imaging to measure both glucose metabolism and regional blood flow, we discovered that levodopa administration is associated with significant neurovascular dysregulation: the vasomotor and metabolic responses to levodopa dissociate from one another, with blood flow increasing and metabolism diminishing in areas of dopaminergic denervation. This dissociation is greatest in the putamen and particularly prominent in subjects with LID, who also have elevated metabolic activity in the sensorimotor cortex (SMC) in the off- medication state. We subsequently found that, when scanned in the unmedicated state, LID subjects show abnormal increases in hypercapnic vasoreactivity, an index of capillary density, in the putamen dissociation region. Hypothesizing that chronic levodopa treatment potentiates angiogenesis in dissociation regions, we collaborated with Dr. Angela Cenci (Lund, Sweden) to use microPET in the rodent LID model. We found evidence of levodopa-mediated neurovascular dysregulation and altered blood-brain-barrier (BBB) permeability in the basal ganglia, which correlates with the severity of dyskinesia and with histopathological evidence of angiogenesis in the same animals. Thus, data from both human patients and rodents suggest LID- related neurovascular changes occur at the systems level and develop gradually over time. Whether LID is also associated with local gliovascular reactions such as neuroinflammation remains unknown, as does the time course of changes leading up to the onset of LID. Given that this information will be necessary if we are to slow or prevent the development of LID, we propose to: (1) trace the evolution of localized neurovascular dysfunction in PD patients as they transition to LID; (2) delineate longitudinal changes in neurovascular unit function in uncoupling regions; and (3) identify mechanisms underlying neurovascular changes in a rat model of LID.