Neurovascular Effects of Dopamine Replacement Therapy in Parkinson's Disease

项目总结 这一修订项目的首要目标是了解左旋多巴诱发的运动障碍的演变。 (LID)，这是帕金森病(PD)黄金标准治疗的一种无效和难治性副作用。差一点 所有帕金森病患者都将在开始服药后10年内获得眼皮。一旦盖上，通常作为前进 疾病需要更高剂量的左旋多巴，帕金森病变得极其难以管理。关于盖子的研究最多 专注于神经元水平，在那里LID与各种突触前和突触后的变化有关[1]。 然而，这些变化与向LID过渡的关系仍然难以捉摸。因此，我们有 在人类帕金森病患者和LID啮齿动物模型中进行了系统水平的方法。使用多重示踪剂 PET成像测量葡萄糖代谢和局部血流时，我们发现左旋多巴 给药与严重的神经血管失调有关：血管运动和代谢 左旋多巴的反应彼此分离，血流量增加，代谢减弱。 多巴胺能失神经的区域。这种解离在壳核中最严重，在 患有LID的受试者，在睡眠期间感觉运动皮质(SMC)的代谢活动也升高- 用药状态。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的异常增加，这是毛细血管密度的一个指标。 区域。假设慢性左旋多巴治疗增强了离解区的血管生成，我们 与Angela Cenci博士(瑞典隆德)合作，在啮齿类动物的眼睑模型中使用了微型PET。我们发现 左旋多巴介导的神经血管调节失调和血脑屏障改变的证据 基底节的通透性与运动障碍的严重程度和组织病理学相关 同样的动物有血管生成的证据。因此，来自人类患者和啮齿动物的数据都表明盖子- 相关的神经血管改变发生在系统水平上，并随着时间的推移逐渐发展。盖子是否也 与神经炎症等局部神经血管反应有关的时间和时间尚不清楚 导致LID发病的变化过程。考虑到如果我们要放慢速度，这些信息是必要的 为了防止LID的发展，我们建议：(1)追踪局部神经血管的演变 帕金森病患者过渡到LID时的功能障碍；(2)描述神经血管单位的纵向变化 非偶联区域的功能；以及(3)确定大鼠模型中神经血管变化的机制 盖上盖子。

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.