INVESTIGATIONS OF DEMENTIA IN PARKINSON DISEASE

帕金森病痴呆症的研究

• 批准号: 8640769
• 负责人: JOEL Synes PERLMUTTER
• 金额: $ 55.64万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8640769
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid deposition; Area; Atrophic; Autopsy; Behavior; Biochemical; Biochemical Genetics; Biochemistry; Biological Markers; Brain; Caring; Clinical; Cognitive; Data; Dementia; Deposition; Development; Economic Burden; Etiology; Evaluation; Family; Future; Genetic; Genetic Markers; Genetic Status; Goals; Image; Impaired cognition; Individual; Investigation; Lewy Bodies; Life; Magnetic Resonance Imaging; Measures; Morbidity - disease rate; Neurites; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neuropsychological Tests; North America; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pathology; Patients; Pattern; Persons; Play; Positron-Emission Tomography; Proteins; Rest; Role; Sampling; Societies; Tauopathies; Testing; Time; Universities; Validation; Washington; alpha synuclein; base; brain tissue; cohort; cost; effective therapy; efficacy testing; follow-up; high risk; imaging modality; in vivo; mortality; multidisciplinary; neuropathology; prevent; protein expression; public health relevance; research clinical testing; synuclein; synucleinopathy; tau Proteins; tau mutation; therapy development; uptake

DESCRIPTION (provided by applicant): Dementia occurs in up to 80% of people with idiopathic Parkinson disease (PD) and substantially increases morbidity, mortality and cost of care for these individuals. In fact, it may be the most important factor leading to residential care placement. Yet, treatment of dementia in PD remains nearly non-existent, making this one of the great unmet needs for the nearly one million people affected by PD in North America. A major roadblock in developing and testing new treatments for dementia in PD is identification of the cause of dementia in a given individual - critically important to test therapies in relatively homogenous groups. This is a particular challenge in PD since dementia may be caused by either underlying cortical a-synuclein (a-syn) pathology or co-existing Alzheimer's (AD) pathology that includes abnormal deposition of A¿ and tau proteins. Our recent studies suggest that this may be an oversimplification. A¿ may be an independent factor, not necessarily related to tauopathy in PD, producing 3 groups of PD dementia: 1) primarily cortical synucleinopathy, 2) primarily cortical synucleinopathy with abnormal A¿ and 3) much less commonly cortical synucleinopathy with abnormal A¿ and tauopathy. We will test the hypotheses that behavior, PET, MRI, genetic and CSF biomarkers will permit identification of these causes and help predict onset of dementia in PD. We propose to test these hypotheses with a longitudinal follow up of people with PD with and without dementia and matched healthy controls. The multidisciplinary team will do evaluations including standard clinical evaluation, clinical dementia ratings, neuropsychological testing, volumetric MRI based measures of regional atrophy, resting state functional connectivity MR of brain networks, PET PIB in vivo measures of amyloid, CSF measures of relevant proteins (a-syn, A¿42 and tau), postmortem neuropathology and quantified analysis of a-syn, A¿ and tau in selected brain areas. The postmortem analyses of brains will permit validation of the biomarkers. This also will provide the opportunity to make connections between imaging findings, behavior and regional protein expression in the brain. This study will validate biomarkers of specific pathologies underlying dementia in PD and that predict dementia onset. Our approach, borrowed heavily from studies in AD, will provide the framework for testing to-be-developed measures such as new CSF proteins, imaging methods or genetic signatures to determine whether they are more reliable or earlier biomarkers of dementia in PD. The ultimate goal is to use these biomarkers to test the efficacy of new therapies that will prevent dementia in PD.

描述（由申请人提供）：高达80%的特发性帕金森病（PD）患者发生痴呆，并且大大增加了这些患者的发病率、死亡率和护理成本。事实上，这可能是导致寄宿护理安排的最重要因素。然而，PD患者的痴呆治疗仍然几乎不存在，这使得北美近100万PD患者的巨大需求未得到满足。开发和测试PD痴呆症新疗法的一个主要障碍是确定特定个体的痴呆症病因，这对于在相对同质的群体中测试疗法至关重要。这在帕金森病中是一个特别的挑战，因为痴呆症可能是由潜在的皮质a-突触核蛋白（a-syn）病理或共存的阿尔茨海默病（AD）病理引起的，其中包括a¿和tau蛋白的异常沉积。我们最近的研究表明，这可能是一种过度简化。A¿可能是一个独立的因素，不一定与PD中的tau病有关，产生3组PD痴呆：1)主要是皮质突触核蛋白病，2)主要是皮质突触核蛋白病伴异常A¿和3)不太常见的皮质突触核蛋白病伴异常A¿和tau病。我们将测试行为、PET、MRI、遗传和CSF生物标志物的假设，这些生物标志物将允许识别这些原因，并帮助预测PD中痴呆的发病。我们建议通过对PD患者（伴和不伴痴呆）和匹配的健康对照进行纵向随访来检验这些假设。多学科团队将进行评估，包括标准临床评估、临床痴呆评分、神经心理学测试、基于区域萎缩的体积MRI测量、静息状态脑网络功能连接MR、PET PIB体内淀粉样蛋白测量、脑脊液相关蛋白（A -syn、A - 42和tau）测量、死后神经病理学和选定脑区域A -syn、A - 42和tau的量化分析。大脑的死后分析将允许生物标记物的验证。这也将为在成像结果、行为和大脑区域蛋白表达之间建立联系提供机会。这项研究将验证帕金森病中痴呆的特定病理的生物标志物，并预测痴呆的发病。我们的方法从阿尔茨海默病的研究中大量借鉴，将为测试有待开发的措施提供框架，如新的CSF蛋白、成像方法或遗传标记，以确定它们是否更可靠或更早的PD痴呆症生物标志物。最终目标是使用这些生物标志物来测试新疗法的有效性，以预防帕金森病中的痴呆。