Molecular Imaging of the Nicotinic Cholinergic Receptor in Parkinson's disease (PD): Implication of for understanding the neurobiology of cognitive impairment

项目总结/摘要 这一重新提交的指导病人为导向的研究职业发展奖（K23）是从一个 专门研究运动障碍的神经学家。综合职业发展和研究计划是 专注于开发帕金森病（PD）认知能力下降的脆弱性标志物， 使用他们的使用来预测PD患者脑深部电刺激（DBS）后的认知下降， 与α4β2-烟碱乙酰胆碱受体（α4β2-AChR）的PET成像相结合的性能。的 总体假设是，认知功能障碍定位于特定的皮质区域，α4β2- 这些地区的AChR可用性将预测DBS手术后的认知障碍。研究 该项目的动机是越来越多的认识到认知障碍是PD的一种致残症状， 随着治疗方法的进步，运动症状得到了更早的治疗。缺乏可靠的临床标志物 手术决策中即将发生的认知障碍使一些患者暴露于过度的“认知障碍”， 通过接受DBS手术，同时允许其他良好的候选人接受DBS治疗。为此，委员会建议， 目的是：1）测量PD患者和对照组中涉及PD相关认知功能区域的α4β2-AChR， 损害，2）测量α4β2-AChR与PD认知损害之间的关联，以及3）测量 基线α4β2-AChR与DBS手术后认知功能下降之间的相关性。 该研究计划由职业发展计划补充，其中包括以下具体的短期 培训目标集中在：1）PET成像的应用、分析和解释，2）选择、分析， 认知评价的解释; 3）全面了解与 DBS，4）生物静力学高级培训，以及5）发展多学科合作作为翻译 研究员候选人将直接由具有病理生理学专业知识的高级教师指导 帕金森病、神经退行性疾病的分子成像和认知研究以及帕金森病、运动和非运动 DBS在PD和生物统计学中的作用，并将参加补充的正式课程和外部 培训项目。 完成研究和培训目标将推动初级研究者的职业生涯， 发展一个独立的研究计划，重点是发展神经心理学和分子生物学。 帕金森病患者功能性神经外科手术后认知功能下降的影像学危险因素， 常见程序和流行病。理解烟碱胆碱能神经的机制作用 系统在侵入性脑手术后认知功能的快速变化将为设计一个 R 01建议验证这些标志物在预测PD中即将发生的认知下降中的用途 在侵入性脑部手术之后研究结果也将对未来的发展产生影响 基于烟碱胆碱能系统减轻PD认知功能障碍的治疗。

Project Summary/Abstract This resubmission for a Mentored Patient-Oriented Research Career Development Award (K23) is from a neurologist specializing in movement disorders. The integrated career development and research plan are focused on the development of markers of vulnerability to cognitive decline in Parkinson’s disease (PD) and use their use to predict cognitive decline following Deep Brain Stimulation (DBS) in PD, using cognitive performance combined with PET imaging of the α4β2-nicotinic acetylcholine receptor (α4β2-AChR). The overarching hypothesis is that cognitive dysfunction localizing to specific cortical regions, and decreased α4β2- AChR availability in these regions, will predict cognitive impairment following DBS surgery. The research project is motivated by the increasing awareness of cognitive impairment as a disabling symptom of PD as motor symptoms are treated earlier with advances in therapies. The lack of reliable clinical markers for impending cognitive impairment in surgical decision-making exposes some patients to excessive “cognitive risk” by undergoing DBS surgery while allowing other good candidates to go untreated with DBS. To this end, the aims are to 1) measure α4β2-AChR in PD patients and controls in regions involved in PD-related cognitive impairment, 2) measure associations between α4β2-AChR and cognitive impairment in PD, and 3) measure associations between baseline α4β2-AChR and subsequent cognitive decline following DBS surgery. The research plan is complemented by a career development plan with the following specific short-term training goals focused on: 1) the application, analysis and interpretation of PET imaging, 2) selection, analysis, and interpretation of cognitive evaluations, 3) a comprehensive understanding of cognitive changes related to DBS, 4) advanced training in biostatics, and 5) developing multidisciplinary collaboration as a translational researcher. The candidate will be mentored directly by senior faculty with expertise in pathophysiology research in PD, molecular imaging and cognition in neurodegenerative disease and PD, motor and non-motor effects of DBS in PD and biostatistics and will participate in complementary formal coursework and external training programs. Completion of the research and training objectives will advance the career of a junior investigator toward developing an independent research program focused on developing neuropsychological and molecular imaging risk factors for cognitive decline following functional neurosurgery in PD patients, an increasingly common procedure and prevalent disease. Understanding the mechanistic role of the nicotinic cholinergic system in rapid changes in cognitive function following invasive brain procedures will inform the design of an R01 proposal to validate the use of these markers in the prediction of impending cognitive decline in PD following invasive brain procedures. The results will also have implications for the development of future therapies to mitigate cognitive dysfunction in PD based on the nicotinic cholinergic system.