INVESTIGATIONS OF DEMENTIA IN PARKINSON DISEASE

描述(申请人提供)：痴呆症发生在高达80%的特发性帕金森病(PD)患者中，并大大增加了这些人的发病率、死亡率和护理费用。事实上，这可能是导致住宿照顾安置的最重要因素。然而，帕金森病的痴呆症治疗仍然几乎不存在，这使这成为北美近100万受帕金森病影响的人尚未得到满足的巨大需求之一。开发和测试帕金森病痴呆新疗法的一个主要障碍是确定特定个体的痴呆症原因-这对于在相对同质的组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，这可能过于简单化了。A？可能是一个独立因素，与帕金森病无必然关系，可产生3组PD痴呆：1)原发皮质联核性痴呆，2)原发A异常的皮质联核症，3)较少见的皮质联核病A异常组和变异组。我们将测试行为、PET、MRI、遗传和脑脊液生物标记物将有助于识别这些原因并帮助预测帕金森病患者痴呆发病的假设。我们建议通过对患有和不患有痴呆症的帕金森病患者和匹配的健康对照组的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、临床痴呆症分级、神经心理测试、基于体积MRI的区域萎缩测量、大脑网络的静息状态功能连接MR、体内淀粉样蛋白的PET PIB测量、脑脊液相关蛋白质(a-syn、A？42和tau)的测量、死后神经病理学以及选定大脑区域的a-syn、A？和tau的量化分析。对大脑的尸检分析将允许对生物标记物的验证。这也将提供在成像结果、行为和大脑中局部蛋白质表达之间建立联系的机会。这项研究将验证帕金森病患者痴呆潜在的特定病理生物标志物以及预测痴呆发病的生物标志物。我们的方法大量借鉴了AD的研究，将为测试有待开发的指标提供框架，如新的脑脊液蛋白、成像方法或遗传特征，以确定它们是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帕金森氏症痴呆的新疗法的疗效。

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.