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：
10631133
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10631133
关键词：
Air Animals Area Basal Ganglia Behavioral Blood Vessels Blood brain barrier dysfunction Blood capillaries Blood flow Breathing Carbidopa Carbon Dioxide Chronic Clinical assessments Collaborations Core-Binding Factor Data Denervation Development Disease model Dissociation Dose Dyskinetic syndrome Evolution Functional disorder Goals 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 Positron-Emission Tomography Rattus Reaction Refractory Regional Blood Flow Research Rodent Rodent Model Scanning Severities Sweden System Time Tracer Vascular Proliferation Vasomotor advanced disease angiogenesis blood-brain barrier permeabilization density dopamine replacement therapy glial activation glucose metabolism imaging study indexing microPET nerve supply neuroinflammation neurovascular neurovascular unit pharmacologic postsynaptic presynaptic 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.

项目摘要这个修订的项目的总体目标是了解左旋多巴引起的运动障碍的演变（盖），是帕金森氏病金标准治疗（PD）的残疾和难治性副作用。几乎所有PD患者将在开始药物后的10年内获得盖子。一旦盖子开始，通常作为前进疾病需要更高剂量的左旋多巴，PD变得极为困难。大多数关于盖子的研究已经集中在神经元水平上，其中盖子与多种突触前和突触后变化有关[1]。但是，这些变化与向盖子的过渡的关系仍然难以捉摸。因此，我们有在人类PD患者和啮齿动物模型中采取了系统级方法。使用多跟踪器宠物成像以测量葡萄糖代谢和区域血流，我们发现左旋多巴给药与明显的神经血管失调相关：血管舒张子和代谢对左旋多巴的反应彼此解离，血流增加，代谢减少多巴胺能神经区域。这种分离在壳中最大，在具有盖子的受试者，他们在异性观念皮层（SMC）中的代谢活性也升高用药状态。随后，我们发现，当在未经物体状态进行扫描时，盖子会显示壳质解离时，过度capnic caplic血管反应性异常（毛细血管密度的指数）异常增加地区。假设慢性左旋多巴治疗增强了分离区域的血管生成，我们与Angela Cenci博士（瑞典隆德）合作，在啮齿动物盖模型中使用Micropet。我们发现左旋多巴介导的神经血管功能障碍和血脑屏障（BBB）的证据基底神经节中的渗透性，这与运动障碍的严重程度和组织病理学有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都表明盖子相关的神经血管变化在系统级别发生，并随着时间的推移逐渐发展。盖子是否也是与诸如神经炎症之类的局部神经血管反应有关的时间仍然未知，时间也是如此导致盖子发作的变化过程。鉴于如果我们要放慢脚步，则需要此信息或防止盖子的发展，我们建议：（1）追踪局部神经血管的演变 PD患者过渡到盖子时的功能障碍；（2）划定神经血管单元的纵向变化在解偶联区域的功能；（3）确定大鼠模型中神经血管变化的机制盖子。