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

MRC 过渡支持奖：NET-PDD 研究 - 定义神经炎症和 Tau 蛋白聚集在帕金森病痴呆中的作用

基本信息

批准号：
MR/W029235/1
负责人：
Caroline Williams-Gray
金额：
$ 45.51万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW029235%2F1
关键词：
MRC Transition Support Award NET

项目摘要

Parkinson's disease (PD) causes problems with movement and walking, but half of patients also develop dementia within the first 10 years after diagnosis. This is very difficult to treat and has a major impact on quality of life and care needs. The goal of my fellowship is investigate early biological changes that predict and drive dementia in PD. We already know that abnormal protein deposits (alpha-synuclein and tau) are found in the brain in PD at post-mortem and seem to be linked to dementia, but precisely how they cause dementia is unclear. I am exploring the theory that small clumps of these proteins form early in the disease and cause inflammation in the brain which leads to an earlier dementia. Protein clumps may also leak out of the brain into the blood and activate the body's immune system - which can further drive brain inflammation. To investigate this, I am measuring inflammation and protein deposits in the brain in PD patients using PET scans, as well as measuring immune markers and protein clumps in the fluid that bathes the brain and spinal cord (cerebrospinal fluid), and in the blood. In order to determine whether these processes predict and drive dementia, I am studying newly-diagnosed PD patients who have not yet developed dementia, and comparing a group at high dementia risk with a group at low dementia risk (with risk determined by thinking and genetic tests), and a group of healthy volunteers ('controls') of similar age. 40 patients (20 high risk, 20 low risk) and 40 controls have been recruited as planned. PET scanning has shown that there is more inflammation in certain brain regions in PD patients at higher dementia risk, and that inflammation and deposition of tau protein is linked across the brain in high risk cases. I have also found evidence of activation of immune cells in the blood in PD, particularly in those at high dementia risk. Furthermore, my results show more infiltration of immune cells from blood into the cerebrospinal fluid in PD compared to controls. I have also been working in collaboration with my colleagues in Chemistry to develop new techniques to visualise very small protein clumps in fluid samples. We have found differences in the composition of these small protein clumps in blood samples from PD patients compared to controls, and shown that similar-sized protein clumps extracted from PD brain samples cause inflammation when mixed with immune cells in the lab. A critical part of my project involves following study participants over time with repeated assessments at 18 months and 3 years to look at whether early markers of immune activation and protein clumping predict memory decline and dementia, and to see how these markers change alongside changes in thinking and memory. However, my study has encountered delays due to technical problems with PET scanning, availability of certain test kits, and the COVID pandemic and so I will not be able to complete the 3 year assessments by the end of my fellowship. During the delays, I have set up other studies to help answer my research question, including a clinical trial to test whether an immunosuppressant drug azathioprine) has any impact on the progression of early PD. Extending my fellowship with a 2 year transition award would ensure that I can complete the long-term assessments planned in my original project, and thereby identify the immune and protein markers which are most closely related to developing dementia in PD. These markers are critical for future clinical trials. By the end of the 2 years, I will also have completed the clinical trial of azathioprine in PD, which, if successful, will provide the first evidence that immune suppression can alter disease course in PD. I will also be able to complete my work investigating precisely how protein clumps interact with immune cells in the lab. This will help identify molecules to target with new treatments in future trials aiming to slow progression to dementia in PD.

帕金森病 (PD) 会导致运动和行走问题，但一半患者在诊断后的前 10 年内还会出现痴呆症。这是非常难以治疗的，并且对生活质量和护理需求产生重大影响。我的奖学金目标是研究预测和驱动帕金森病痴呆的早期生物学变化。我们已经知道，帕金森病死后大脑中发现了异常蛋白质沉积物（α-突触核蛋白和 tau 蛋白），并且似乎与痴呆有关，但它们到底是如何导致痴呆的尚不清楚。我正在探索这样一种理论，即这些蛋白质的小团块在疾病早期形成，并引起大脑炎症，从而导致早期痴呆。蛋白质团块也可能从大脑渗漏到血液中，激活人体的免疫系统，从而进一步加剧大脑炎症。为了研究这一点，我使用 PET 扫描测量 PD 患者大脑中的炎症和蛋白质沉积，并测量沐浴大脑和脊髓的液体（脑脊液）以及血液中的免疫标记物和蛋白质团块。为了确定这些过程是否预测并驱动痴呆症，我正在研究尚未发展为痴呆症的新诊断 PD 患者，并将痴呆症高风险组与痴呆症低风险组（风险由思维和遗传决定）进行比较。测试）和一组年龄相似的健康志愿者（“对照”）。已按计划招募 40 名患者（20 名高风险，20 名低风险）和 40 名对照。 PET 扫描显示，痴呆风险较高的 PD 患者的某些大脑区域存在更多炎症，并且在高风险病例中，炎症和 tau 蛋白沉积与整个大脑有关。我还发现了帕金森病患者血液中免疫细胞被激活的证据，特别是那些患有痴呆症的高风险人群。此外，我的结果显示，与对照组相比，PD 患者的血液中免疫细胞更多地渗透到脑脊液中。我还一直与化学领域的同事合作开发新技术，以可视化流体样品中非常小的蛋白质团块。我们发现，与对照组相比，PD患者血液样本中这些小蛋白质团块的成分存在差异，并表明从PD脑样本中提取的类似大小的蛋白质团块在实验室与免疫细胞混合时会引起炎症。我的项目的一个关键部分涉及长期跟踪研究参与者，并在 18 个月和 3 年内进行重复评估，以观察免疫激活和蛋白质聚集的早期标记是否可以预测记忆力下降和痴呆，并了解这些标记如何随着思维的变化而变化和记忆。然而，由于 PET 扫描的技术问题、某些测试套件的可用性以及新冠病毒大流行，我的研究遇到了延误，因此我将无法在奖学金结束时完成 3 年评估。在拖延期间，我开展了其他研究来帮助回答我的研究问题，包括一项临床试验，以测试免疫抑制剂药物硫唑嘌呤是否对早期 PD 的进展有影响。通过为期 2 年的过渡奖延长我的研究金期限，将确保我能够完成原始项目中计划的长期评估，从而确定与 PD 痴呆症最密切相关的免疫和蛋白质标记。这些标志物对于未来的临床试验至关重要。到两年结束时，我还将完成硫唑嘌呤治疗帕金森病的临床试验，如果成功，将提供第一个证据证明免疫抑制可以改变帕金森病的病程。我还将能够在实验室中完成精确研究蛋白质团块如何与免疫细胞相互作用的工作。这将有助于确定未来试验中新疗法的目标分子，旨在减缓帕金森病痴呆的进展。