Parkinson disease and DBS: cognitive effects in GBA mutation carriers

帕金森病和 DBS：GBA 突变携带者的认知影响

• 批准号: 10227501
• 负责人: Gian D Pal
• 金额: $ 19.01万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227501
• 关键词: Academic Medical Centers; Affect; Aging; Anterior; Area; Basal Ganglia; Biometry; Body Burden; Clinical; Clinical Research; Clinical Trials Design; Clinical dementia rating scale; Cognition; Cognitive; Data; Data Analyses; Decision Making; Dementia; Diffuse; Doctor of Philosophy; Environment; Environment Design; Enzymes; Epidemiology; Ethical Issues; Fellowship; Functional disorder; Funding; Genes; Genetic; Genetic Diseases; Genotype; Globus Pallidus; Goals; Grant; Hippocampus (Brain); Impaired cognition; Impairment; Impulsivity; International; Intervention; Knowledge; Learning; Lewy Bodies; Lewy body pathology; Longitudinal Studies; Manuscripts; Measures; Medial; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Motor; Movement Disorders; Mutation; Neurobiology; Neurodegenerative Disorders; Neuropsychological Tests; Neuropsychology; Nursing Homes; Outcome; Parkinson Disease; Patients; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Postoperative Period; Predisposition; Publications; Research; Research Personnel; Risk; Scientist; Secondary to; Short-Term Memory; Structure of subthalamic nucleus; System; Techniques; Time; Training; Training Programs; United States; United States National Institutes of Health; Visual; Visual impairment; Work; base; career; cingulate cortex; cognitive function; cognitive impairment in Parkinson' s; deep brain stimulator; executive function; genetic testing; glucosylceramidase; high risk; improved; longitudinal analysis; mortality; mutation carrier; mutational status; nervous system disorder; neurogenetics; neurophysiology; patient subsets; prevent; programs; side effect; skills; visual memory

Parkinson disease (PD) is a neurodegenerative disease affecting at least 1 million people in the U.S. Each year, 9,000 PD patients undergo deep brain stimulator (DBS) placement into the subthalamic nucleus (STN- DBS), the most commonly used basal ganglia target. Despite motor improvement, up to 50% of patients have cognitive impairment after DBS. Cognitive impairment is associated with a 2-3 fold increase in mortality, progression to dementia, and nursing home placement. At present, subjects with cognitive impairment after DBS cannot be identified pre-operatively and the effects of DBS on cognitive function are not fully understood. A specific group of PD patients, carriers of mutations in the glucocerebrosidase (GBA) gene, are at particularly high risk for cognitive impairment. PD-GBA mutation carriers have dysfunction of the glucocerebrosidase (GCase) enzyme, resulting in more rapid accumulation and spread of Lewy bodies compared with non- mutation carriers. Clinically, PD-GBA mutation carriers have: (1) deficits in visual memory due to higher Lewy body burden in hippocampal and medial temporal regions, and (2) faster progression to dementia secondary to diffuse cortical Lewy body pathology. Approximately 12-17% of PD subjects with DBS carry GBA mutations, indicating that a substantial portion of the DBS population may be susceptible to cognitive problems. Importantly, STN-DBS itself can impair cognition through modulation of the striato-anterior cingulate cortex circuit, resulting in impulsivity and more errors when faced with tasks that rely on executive functions. Therefore, my central hypothesis is that PD-GBA mutation carriers have greater global cognitive decline after STN-DBS compared with PD-GBA mutation carriers without STN-DBS, and compared with non-mutation carriers with and without STN-DBS. This is a critical area of research because if an association between GBA and STN-DBS is detected, clinicians will be able to identify subjects at risk for worsened cognitive dysfunction through genetic testing and prevent harm by: (1) recommending that PD-GBA mutation carriers avoid STN- DBS, or (2) considering an alternative DBS target such as the globus pallidus interna (GPi) that may have less cognitive side effects. This training grant will provide skills in PD cognition, PD genetics, longitudinal data analysis, clinical trial design, manuscript publication and grantsmanship. The following aims are proposed: Aim 1: Determine the longitudinal changes in global cognitive function in PD-GBA mutation carriers and non- mutation carriers with and without STN-DBS; Aim 2: Determine the specific pattern of cognitive dysfunction in PD-GBA mutation carriers and non-mutation carriers with and without STN-DBS; Aim 3: Determine the differential effects of DBS on cognitive function in the ON-stimulation state vs. OFF-stimulation state, comparing PD-GBA mutation and non-mutation carriers. The PI is fellowship trained in movement disorders, completed a Masters in clinical research, and has a growing number of original first-author publications, demonstrating his commitment to a career in clinical research. Rush University Medical Center is the ideal environment for this proposed research since this program, established in 1980, is one of the oldest movement disorders training programs in the United States and has a long track record of training clinician-researchers. The primary mentor for this proposal, Deborah Hall, MD, PhD, is an internationally recognized clinician-scientist with expertise in neurogenetics and epidemiology. The co-mentors include Robert Wilson, PhD an expert in studies that determine longitudinal cognitive trajectories in aging and repeated measures analysis; Glenn Stebbins, PhD an expert in biostatistics who has served as the chief statistician to numerous clinical studies in PD and other movement disorders; and Christopher Goetz, MD, an internationally recognized expert in PD and clinical trial design. Successful funding and implementation of this proposal will allow the PI to pursue the following career goals: 1) Acquire further knowledge in PD cognition with a focus on neurobiology, systems neurophysiology of DBS, and methods of neuropsychological assessment. 2) Master methods in analysis of longitudinal data, repeated measures analysis, and clinical trial design. 3) Learn basic techniques in interpretation of genetic data and ethical issues related to genetic testing. The candidate's background and goals, the research and mentoring environment, and the design of the proposed study, positions the PI as an ideal candidate for the K23 mechanism.

帕金森病(PD)是一种神经退行性疾病，在美国每个人至少有100万人受到影响。 年，9000名帕金森病患者接受深部脑刺激器(DBS)植入丘脑底核(STN- 星展银行(DBS)，最常用的基底节靶点。尽管运动能力有所改善，但高达50%的患者 DBS后认知功能障碍。认知障碍与死亡率增加2-3倍有关， 进展为痴呆症和养老院安置。目前，有认知障碍的受试者 DBS不能在术前被识别，DBS对认知功能的影响也不完全清楚。 一组特殊的帕金森病患者，葡萄糖脑苷酶(GBA)基因突变的携带者，尤其是 认知障碍的高风险。PD-GBA突变携带者存在葡萄糖脑苷酶功能障碍 (GCase)酶，导致路易体比非路易体积累和扩散更快 突变携带者。临床上，PD-GBA突变携带者有：(1)高刘易斯引起的视觉记忆障碍 海马区和内侧颞区的身体负荷，以及(2)继发性痴呆的更快进展 弥漫性皮质路易体病理改变。大约12%-17%的患有DBS的PD患者携带GBA突变， 这表明星展银行人群中的很大一部分人可能容易受到认知问题的影响。 重要的是，STN-DBS本身可以通过调节纹状体前扣带回皮质来损害认知。 当面对依赖执行功能的任务时，会导致冲动和更多的错误。 因此，我的中心假设是PD-GBA突变携带者在 STN-DBS与无STN-DBS的PD-GBA突变携带者及非突变携带者的比较 有和没有STN-DBS的运营商。这是一个关键的研究领域，因为如果GBA与 和STN-DBS被检测到，临床医生将能够识别有恶化认知功能障碍风险的受试者 通过基因检测，预防危害：(1)建议PD-GBA突变携带者避免STN- DBS，或(2)考虑替代DBS目标，如苍白球(GPI) 认知副作用。这笔培训补助金将提供PD认知、PD遗传学、纵向数据方面的技能 分析，临床试验设计，手稿出版和格兰杰精神。建议的目标如下： 目的1：测定PD-GBA突变携带者和非PD-GBA突变携带者整体认知功能的纵向变化 突变携带者伴和不伴STN-DBS；目的2：确定儿童认知功能障碍的具体模式 PD-GBA突变携带者和非突变携带者有无STN-DBS；目的3：确定 DBS对有无刺激状态下认知功能的不同影响 PD-GBA突变携带者与非突变携带者的比较。PI是在运动障碍方面接受训练的团契， 获得临床研究硕士学位，并拥有越来越多的原创第一作者出版物， 表明了他对临床研究事业的承诺。拉什大学医学中心是理想的 这项拟议研究的环境，因为这项计划成立于1980年，是最古老的运动之一 美国的精神障碍培训计划，并在培训临床医生和研究人员方面有着长期的记录。 这项建议的主要导师，黛博拉·霍尔，医学博士，是国际公认的临床科学家 具有神经遗传学和流行病学方面的专业知识。共同导师包括罗伯特·威尔逊博士，一位 在衰老和重复测量分析中确定纵向认知轨迹的研究 Stebbins博士，生物统计学专家，曾担任多项临床研究的首席统计师 帕金森病和其他运动障碍；克里斯托弗·戈茨医学博士，国际公认的帕金森病和 临床试验设计。这项提议的成功资助和实施将使私人投资机构能够继续 以下职业目标：1)获得帕金森病认知方面的进一步知识，重点是神经生物学、系统 DBS的神经生理学和神经心理评估方法。2)掌握分析方法 纵向数据、重复测量分析和临床试验设计。3)学习基本技术 解释基因数据和与基因检测有关的伦理问题。候选人的背景和 目标、研究和指导环境以及拟议研究的设计，将PI定位为 K23机制的理想候选者。