The NET-PDD study: defining the roles of NEuroinflammation and Tau aggregation in Parkinson's Disease Dementia

帕金森氏症（PD）会导致行走和运动方面的问题，但大约一半的患者也会在发病的前10年内患上痴呆症。这项研究的主要目标是更好地了解大脑中导致PD患者记忆问题和痴呆的最早变化。这些早期变化将是预防或减缓痴呆症的新疗法的最佳目标，而且可能不仅与PD痴呆症有关，而且与其他形式的痴呆症（包括阿尔茨海默病）有关，因为在死后对大脑进行检查时，许多这些疾病具有相似的特征。在大多数涉及痴呆症的情况下，很难在症状出现之前研究最早的大脑变化，但这在PD中是可能的，因为痴呆症比运动问题晚出现。此外，我之前的工作已经确定了一种方法，可以确定早期PD患者在未来几年内发展为痴呆症的风险是高还是低（基于思维测试和基因变异的表现）。这意味着我们可以在痴呆症变得明显之前，专门研究高危痴呆症患者的大脑发生了什么变化。我之前的研究为以下理论做出了贡献：两种过程——一种叫做tau的蛋白质的积累和大脑内的炎症——可能在PD痴呆的发展中特别重要。本研究的主要目的是通过比较两组患者中这些过程的标志物来研究这一理论：痴呆高风险组和痴呆低风险组（每组20人）。年龄相近的健康志愿者也将被纳入比较。炎症和tau沉积将使用一种特殊的脑部扫描（PET成像），以及浸泡在大脑和脊髓的液体（脑脊液）和血液中进行测量。在研究开始时，参与者将接受PET扫描，腰椎穿刺收集脑脊液样本，血液检查，临床和记忆评估。他们将在18个月大时再次接受检查，以评估他们的临床状况和记忆力的变化，并进行血液检查。扫描、腰椎穿刺和血液测试将在3年后重复进行，以观察炎症和tau蛋白的积累是如何变化的，以及它们与记忆问题和痴呆的发展有何关系。除了测量扫描和液体样本中的炎症和tau标记物外，还将从血液中提取免疫细胞，并将其用于实验室的实验中，以观察它们对tau和其他关键蛋白质的反应。最后，在脑脊液和血液中发现的最有希望的炎症和tau相关标记物将在大约200名患者和100名健康个体的单独大组中进行测量，以确认它们在跟踪痴呆症进展方面的价值。该研究将具体解决这些关键问题：1。炎症和tau沉积在帕金森氏症发展过程中是重要的早期事件吗？2. 我们能否在痴呆症高风险的帕金森患者的脊髓液和血液中测量tau蛋白和其他相关蛋白（如α突触核蛋白）的小团块（“寡聚物”），这是否是帮助预测和跟踪痴呆症发展的有用工具？3. 这些异常的tau蛋白团块是否会在患者的免疫细胞中引发炎症反应？回答这些问题将使我们更接近于开发新的治疗方法，以预防或减缓痴呆症的发作，痴呆症对帕金森病患者有着毁灭性的后果。它还将使我们能够找出我们正在研究的工具（脑成像、血液和脊髓液测试）的哪种组合对追踪痴呆症的进展和治疗的效果最有用，这将对这些治疗的未来临床试验至关重要。

Parkinson's disease (PD) causes problems with walking and movement, but around half of patients will also develop dementia within the first 10 years of their disease course. The primary goal of this study is to better understand the earliest changes in the brain that lead to memory problems and dementia in PD. These early changes would be the best targets for new treatments to prevent or slow dementia, and may be relevant not just to PD dementia but to other forms of dementia (including Alzheimer's disease), because a number of these conditions share similar features when brains are examined after death. In most conditions involving dementia, it is difficult to study the earliest brain changes before symptoms emerge, but this is possible in PD because the dementia comes later than the movement problems. In addition, my previous work has identified a method of determining whether an individual with early PD is at high risk or low risk of going on to develop a dementia within the next few years (based on performance on thinking tests and genetic variation). This means that we can look specifically at what brain changes are occurring in high dementia risk patients before the dementia actually becomes apparent.My previous research has contributed to the theory that 2 processes - build-up of a protein called tau, and inflammation within the brain - might be particularly important in the development of PD dementia. The main aim of this study is to investigate this theory by comparing markers of these processes in 2 groups of patients: a group at high dementia risk, and a group at low dementia risk (20 per group). Healthy volunteers of similar age will also be included for comparison. Inflammation and tau deposits will be measured using a special type of brain scanning (PET imaging), as well as in the fluid that bathes the brain and spinal cord (cerebrospinal fluid), and in the blood. Participants will undergo PET scanning at the beginning of the study, as well as a lumbar puncture to collect a cerebrospinal fluid sample, a blood test, and clinical and memory assessments. They will be seen again at 18 months to assess changes in their clinical condition and memory, and have a blood test. Scans, lumbar punctures and blood tests will then be repeated at 3 years to look at how measures of inflammation and build-up of tau protein have changed, and how they relate to the development of memory problems and dementia. As well as measuring markers of inflammation and tau on the scans and in the fluid samples, immune cells will be extracted from blood and used in experiments in the laboratory to look at how they respond to tau and other key proteins. Finally, the most promising of the inflammation and tau-related markers identified in cerebrospinal fluid and blood will be measured in a separate large group of approximately 200 patients and 100 healthy individuals to confirm their value in tracking progression to dementia. The research will specifically address these key questions:1. Are inflammation and tau deposition important early events in the brain as Parkinson's dementia is developing? 2. Can we measure small clumps ('oligomers') of tau and other related proteins (such as alpha synuclein) in the spinal fluid and blood of Parkinson's patients at high risk of dementia, and is this a useful tool to help predict and track development of dementia? 3. Do these abnormal clumps of tau protein drive an inflammatory response in patients' immune cells? Answering these questions will bring us much closer to developing new treatments to prevent or slow the onset of the dementia which has such devastating consequences for patients with PD. It will also allow us to work out which combination of the tools we are studying (brain imaging, blood and spinal fluid tests) is most useful for tracking progression to dementia and the effect of treatments on this over time, which will be critical for future clinical trials of these treatments.