INVESTIGATIONS OF DEMENTIA IN PARKINSON DISEASE

帕金森病痴呆症的研究

• 批准号: 8261671
• 负责人: JOEL Synes PERLMUTTER
• 金额: $ 60.1万
• 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/8261671
• 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. PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) is a progressive neurologic degenerative disease affecting nearly one million people in North America. These people have very high risk for development of dementia that adds substantial morbidity, mortality and economic burden to patients, families and society. This proposal will investigate the clinical manifestations of different forms of dementia, clarify the underlying causes and develop biomarkers that herald the onset of dementia. These steps are critical for development of effective treatment of dementia associated with 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，并大幅增加这些患者的发病率、死亡率和护理成本。事实上，这可能是最重要的因素，导致住宿照顾安置。然而，PD中痴呆症的治疗仍然几乎不存在，这使得这成为北美近100万受PD影响的人的巨大未满足需求之一。开发和测试PD痴呆症新疗法的一个主要障碍是确定给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PD中是一个特别的挑战，因为痴呆可能是由潜在的皮质α-突触核蛋白（α-syn）病理学或共存的阿尔茨海默病（AD）病理学（包括A？和tau蛋白的异常沉积）引起的。我们最近的研究表明，这可能过于简单化了。阿乌可能是一个独立的因素，不一定与PD中的tau蛋白病相关，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A <$异常，3）较少见的皮质突触核蛋白病伴A <$异常和tau蛋白病。我们将测试行为、PET、MRI、遗传和CSF生物标志物将允许识别这些原因并帮助预测PD痴呆发作的假设。我们建议对PD伴痴呆和不伴痴呆的患者以及匹配的健康对照进行纵向随访，以检验这些假设。多学科团队将进行评估，包括标准临床评估，临床痴呆评级，神经心理学测试，基于体积MRI的局部萎缩测量，脑网络的静息状态功能连接MR，淀粉样蛋白的PET PIB体内测量，相关蛋白质（a-syn，A 42和tau）的CSF测量，死后神经病理学和选定脑区域中a-syn，A 42和tau的定量分析。大脑的死后分析将允许生物标志物的验证。这也将提供机会，使成像结果，行为和大脑中的区域蛋白质表达之间的联系。这项研究将验证PD痴呆症的特定病理学生物标志物，并预测痴呆症的发作。我们的方法大量借鉴了AD研究，将为测试待开发的措施提供框架，如新的CSF蛋白，成像方法或遗传特征，以确定它们是否是PD痴呆的更可靠或更早的生物标志物。最终目标是使用这些生物标志物来测试预防PD痴呆的新疗法的疗效。 公共卫生相关性：帕金森病（PD）是一种进行性神经退行性疾病，影响北美近100万人。这些人患痴呆症的风险很高，增加了患者、家庭和社会的发病率、死亡率和经济负担。该提案将调查不同形式痴呆症的临床表现，阐明根本原因，并开发预示痴呆症发作的生物标志物。这些步骤对于开发与PD相关的痴呆的有效治疗至关重要。