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

帕金森氏症（PD）会导致运动和行走方面的问题，但一半的患者在确诊后的前10年内也会患上痴呆症。这是非常难以治疗的，并对生活质量和护理需求产生重大影响。我的研究目标是研究预测和驱动帕金森痴呆症的早期生物学变化。我们已经知道，PD患者死后的大脑中发现了异常的蛋白质沉积（α -突触核蛋白和tau蛋白），似乎与痴呆症有关，但它们究竟是如何导致痴呆症的还不清楚。我正在探索一种理论，即这些蛋白质的小团块在疾病早期形成，并在大脑中引起炎症，从而导致早期痴呆。蛋白质团块也可能从大脑中泄漏到血液中，激活身体的免疫系统，从而进一步引发大脑炎症。为了研究这一点，我正在使用PET扫描测量PD患者大脑中的炎症和蛋白质沉积，以及测量大脑和脊髓（脑脊液）和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和驱动痴呆，我正在研究尚未发展为痴呆的新诊断的PD患者，并将痴呆高风险组与痴呆低风险组（通过思维和基因测试确定风险）和一组年龄相近的健康志愿者（“对照组”）进行比较。按计划招募患者40例（高危20例，低危20例），对照组40例。PET扫描显示，痴呆风险较高的PD患者的某些大脑区域有更多的炎症，在高风险病例中，炎症和tau蛋白的沉积在整个大脑中都有联系。我还发现了PD患者血液中免疫细胞活化的证据，特别是在那些高风险的痴呆症患者中。此外，我的结果显示，与对照组相比，PD患者有更多的免疫细胞从血液渗入脑脊液。我也一直在与我的化学同事合作，开发新的技术来可视化液体样品中非常小的蛋白质团块。我们发现PD患者血液样本中这些小蛋白团块的组成与对照组存在差异，并表明从PD脑样本中提取的类似大小的蛋白团块在实验室中与免疫细胞混合时会引起炎症。我的项目的一个关键部分是长期跟踪研究参与者，在18个月和3岁时进行反复评估，以观察免疫激活和蛋白质聚集的早期标记是否能预测记忆力下降和痴呆，并观察这些标记如何随着思维和记忆的变化而变化。然而，由于PET扫描的技术问题、某些检测试剂盒的可用性以及COVID大流行，我的研究遇到了延迟，因此我将无法在奖学金结束时完成3年的评估。在延迟期间，我已经建立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（azathioprine）是否对早期PD的进展有任何影响。延长我的奖学金2年的过渡奖将确保我能够完成我原项目中计划的长期评估，从而确定与PD中痴呆发展最密切相关的免疫和蛋白质标志物。这些标记物对未来的临床试验至关重要。在2年的时间里，我还将完成azathioprine在PD中的临床试验，如果试验成功，将首次提供免疫抑制可以改变PD病程的证据。我也将能够完成我的工作，精确地研究蛋白质团块如何在实验室中与免疫细胞相互作用。这将有助于在未来的试验中确定靶向分子，以减缓PD患者痴呆的进展。

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.