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

项目摘要/摘要 重新提交的以患者为导向的导师研究职业发展奖(K23)来自 专门研究运动障碍的神经科医生。综合的职业发展和研究计划是 重点关注帕金森氏病(PD)认知能力下降易感性标记物的发展和 利用它们来预测帕金森病深部脑刺激(DBS)后的认知功能下降，使用认知 结合α4β2-烟碱型乙酰胆碱受体(α4β2-AChR)的正电子发射计算机断层扫描。这个 主要假设是认知功能障碍局限于特定的皮质区域，并降低了α-4-β-2- Achr在这些地区的可用性将预测DBS手术后的认知障碍。这项研究 该项目的动机是越来越多的人意识到认知障碍是帕金森氏症的一种致残症状 随着治疗方法的进步，运动症状可以更早地得到治疗。缺乏可靠的临床标记物 手术决策中迫在眉睫的认知障碍使一些患者暴露在过度的认知 风险“接受星展银行手术，而允许其他优秀的候选人不接受星展银行的治疗。为此， 本研究的目的是：1)测量PD患者和对照组中与PD相关的认知区域的α-4、β、2-AChR 损害，2)测量α-4，β，2-乙酰胆碱受体与帕金森病患者认知损害的相关性，以及3)测量 基线α-4、β-2-AChR与星形细胞瘤手术后认知功能下降之间的关系。 研究计划与职业发展计划相辅相成，具体的短期计划如下 培训目标集中在：1)PET成像的应用、分析和解释；2)选择、分析、 以及对认知评价的解读，3)对认知变化的全面理解 DBS，4)生物静力学方面的高级培训，以及5)将多学科合作作为翻译 研究员。应聘者将由具有病理生理学专业知识的资深教师直接指导。 神经退行性疾病与帕金森病、运动与非运动的帕金森病、分子影像及认知研究 DBS在PD和生物统计学方面的作用，并将参加补充的正规课程和外部 培训计划。 完成研究和培训目标将推动初级调查员的职业生涯迈向 开发一个独立的研究计划，专注于发展神经心理学和分子 帕金森病患者功能性神经外科术后认知功能下降的影像危险因素 常见的程序和流行的疾病。了解烟碱型胆碱能神经的作用机制 侵入性脑手术后认知功能快速变化的系统将为设计 R01建议验证这些标记物在预测帕金森病患者即将出现的认知功能下降中的使用 在进行侵入性脑部手术后。研究结果也将对未来的发展产生影响。 基于烟碱型胆碱能系统的缓解帕金森病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.