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

帕金森病 (PD) 烟碱胆碱能受体的分子成像：对于理解认知障碍的神经生物学的意义

• 批准号: 9555054
• 负责人: Kelly Alexander Mills
• 金额: $ 20万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9555054
• 关键词: Affinity; Age; Anterior; Area; Attention; Awareness; Binding; Binding Proteins; Biometry; Brain; Brain imaging; Brain region; Cholinergic Receptors; Clinical Markers; Cognition; Cognitive; Cognitive deficits; Complement; Data; Data Analyses; Decision Making; Deep Brain Stimulation; Dementia; Detection; Development; Development Plans; Disease; Elderly; Evaluation; Exhibits; Functional disorder; Future; Gender; Goals; Growth; Hippocampus (Brain); Image; Imaging Techniques; Impaired cognition; Interdisciplinary Study; Measures; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Methodology; Motor; Movement; Movement Disorders; Neurobiology; Neurodegenerative Disorders; Neurologist; Neuropsychology; Newly Diagnosed; Nicotinic Receptors; North America; Operative Surgical Procedures; Outcome; Parkinson Disease; Parkinson' s Dementia; Patients; Persons; Positron-Emission Tomography; Postoperative Period; Prefrontal Cortex; Procedures; Process; Psychometrics; Randomized; Research; Research Personnel; Research Project Grants; Research Training; Risk; Risk Factors; Role; Short-Term Memory; Signal Transduction; Statistical Methods; Symptoms; System; Temporal Lobe; Training; Training Programs; Tremor; Verbal Learning; Visuospatial; base; career; career development; cholinergic; cognitive change; cognitive disability; cognitive function; cognitive performance; design; disability; disabling symptom; executive function; illness length; meetings; mild cognitive impairment; molecular imaging; motor symptom; neurochemistry; neurosurgery; non-demented; prevent; programs; radiotracer; receptor; receptor binding; research and development; senior faculty; symptom treatment; translational scientist

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.

项目摘要/摘要 这项重新提交受过指导的注重患者研究职业发展奖（K23）的重新提交来自 神经科医生专门研究运动障碍。综合职业发展和研究计划是 专注于发展帕金森氏病认知能力下降（PD）和 使用认知，使用它们的用途来预测PD深脑刺激（DB）的认知能力下降 性能与α4β2-NICOTINIC乙酰胆碱受体（α4β2-ACHR）的PET成像结合。这 总体假设是，在特定皮质区域定位的认知功能障碍，并改善了α4β2- 这些区域的ACHR可用性将预测DBS手术后的认知障碍。研究 项目的动机是由于对认知障碍的认识越来越多，作为PD的残疾症状 运动症状以疗法的进展为早期治疗。缺乏可靠的临床标记 手术决策中即将来临的认知障碍使某些患者暴露于过多的“认知” 风险”通过接受DBS手术，同时允许其他优秀候选人接受DBS的治疗。为此， 目的是1）在PD患者中测量α4β2-ACHR和与PD相关认知的区域的对照 损伤，2）测量α4β2-ACHR与PD中认知障碍之间的关联，3）测量 DBS手术后基线α4β2-ACHR与随后的认知下降之间的关联。 研究计划由职业发展计划完成，并具有以下特定的短期 培训目标的重点是：1）PET成像的应用，分析和解释，2）选择，分析， 和对认知评估的解释，3）对与 DBS，4）生物统计学的高级培训，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专业知识的高级教师考虑 PD研究，神经退行性疾病和PD，运动和非运动的分子成像和认知 DB在PD和生物统计学中的影响，将参加完整的正式课程和外部 培训计划。 完成研究和培训目标的完成将使初级调查员的职业发展 制定一个专注于开发神经心理学和分子的独立研究计划 PD患者功能性神经外科手术后认知下降的危险因素，越来越多 常见的程序和普遍疾病。了解烟碱胆碱能的机械作用 在侵入性大脑程序之后，认知功能快速变化的系统将为设计提供信息 R01提议在预测PD的认知能力下降时验证这些标记的使用 遵循侵入性的大脑程序。结果也将对未来的发展产生影响 基于烟碱能系统的PD减轻认知功能障碍的疗法。