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

• 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
• 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

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.

项目总结