Neurovascular Effects of Dopamine Replacement Therapy in Parkinson's Disease

多巴胺替代疗法对帕金森病的神经血管作用

基本信息

批准号：
10200914
负责人：
DAVID EIDELBERG
金额：
$ 59万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-16 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200914
关键词：
Air Animals Area Basal Ganglia Behavioral Blood - brain barrier anatomy Blood capillaries Blood flow Carbidopa Carbon Dioxide Chronic Clinical assessments Collaborations Core-Binding Factor Data Denervation Development Disease model Dissociation Dose Dyskinetic syndrome Evolution Functional disorder Goals Gold Human Image Individual Inflammatory Response Infusion procedures L-DOPA induced dyskinesia Levodopa Maps Measures Mediating Metabolic Metabolism Modeling Neurons Oxidopamine Parkinson Disease Patients Pharmaceutical Preparations Pharmacology Positron-Emission Tomography Rattus Reaction Refractory Regional Blood Flow Research Rodent Rodent Model Scanning Severities Sweden Synapses System Time Tracer Vascular Proliferation Vasomotor advanced disease angiogenesis base blood-brain barrier permeabilization density dopamine replacement therapy glucose metabolism imaging study indexing microPET nerve supply neuroinflammation neurovascular neurovascular unit prevent putamen recruit response side effect standard care

项目摘要

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.

项目概要该修订项目的总体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) 金标准治疗的一种致残和难治性副作用。几乎所有 PD 患者将在开始用药后 10 年内患上 LID。一旦 LID 开始，通常会随着进展这种疾病需要更高剂量的左旋多巴，PD 变得极难治疗。大多数关于 LID 的研究重点关注神经元水平，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 LID 过渡之间的关系仍然难以捉摸。因此我们有在人类 PD 患者和 LID 啮齿动物模型中采用了系统级方法。使用多重追踪器 PET 成像测量葡萄糖代谢和局部血流量，我们发现左旋多巴给药与显着的神经血管失调有关：血管舒缩和代谢对左旋多巴的反应相互分离，血流量增加，新陈代谢减弱多巴胺能去神经支配区域。这种分离在壳核中最为明显，在壳核中尤为突出。患有 LID 的受试者，其感觉运动皮层 (SMC) 的代谢活动也升高。服药状态。我们随后发现，在未接受药物治疗的状态下进行扫描时，LID 受试者显示壳核分离中高碳酸血管反应性（毛细血管密度指数）异常增加地区。假设长期左旋多巴治疗会增强解离区域的血管生成，我们与 Angela Cenci 博士（瑞典隆德）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通透性，与运动障碍的严重程度和组织病理学相关同一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是否也是与局部胶质血管反应（例如神经炎症）相关的仍不清楚，时间也是如此导致 LID 发生的变化过程。鉴于如果我们要放慢速度，这些信息将是必要的或预防 LID 的发展，我们建议：（1）追踪局部神经血管的进化 PD 患者过渡到 LID 时功能障碍； (2) 描绘神经血管单元的纵向变化在解偶联区域发挥作用； (3) 确定大鼠模型中神经血管变化的机制的 LID。