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

• 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

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.

帕金森氏病（PD）会引起运动和步行问题，但一半的患者在诊断后的头10年内也患有痴呆症。这很难治疗，并对生活质量和护理需求产生重大影响。我的团契的目标是研究预测和推动PD痴呆症的早期生物学变化。我们已经知道，在验尸后的PD中，在PD的大脑中发现了异常的蛋白沉积物（α-突触核蛋白和tau），并且似乎与痴呆症有关，但正是它们如何引起痴呆症。我正在探索这样的理论，即这些蛋白质的小团块在疾病早期形成，并引起大脑炎症，从而导致早期痴呆症。蛋白质团块也可能从大脑中泄漏到血液中并激活人体的免疫系统 - 这可能会进一步驱动脑部炎症。为了调查这一点，我正在使用PET扫描测量PD患者中大脑中的炎症和蛋白质沉积物，并测量沐浴脑和脊髓（脑脊液）以及血液中的液体中的免疫标记和蛋白质团。为了确定这些过程是否预测和驱动痴呆症，我正在研究尚未患上痴呆症的新诊断的PD患者，并将高痴呆症风险的一组与低痴呆症风险（通过思维和基因测试确定的风险）以及一组健康志愿者（“对照者”）的痴呆症风险（通过思维和基因测试确定的风险）进行比较。按计划招募了40名患者（20个高风险，20个低风险）和40例对照。 PET扫描表明，某些大脑区域的炎症患者的炎症较高，并且痴呆症风险较高，并且在高风险病例中，tau蛋白的炎症和沉积在整个大脑中连接。我还发现了PD血液中免疫细胞激活的证据，特别是在痴呆症高风险的人中。此外，与对照组相比，我的结果表明，从血液中的免疫细胞更多地浸润到PD中的脑脊液。我还一直与我的化学同事合作，以开发新技术，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患者的血液样本中这些小蛋白质团的组成差异，并表明从PD脑样品中提取的相似大小的蛋白质团会在实验室中与免疫细胞混合时会引起炎症。我项目的关键部分涉及随着时间的推移研究参与者在18个月零3年的重复评估中，以研究免疫激活和蛋白质结块的早期标记是否可以预测记忆的下降和痴呆症，并查看这些标记如何随着思维和记忆的变化而变化。但是，由于PET扫描，某些测试套件的可用性以及Covid Pandemic的技术问题，我的研究遇到了延迟，因此我将在奖学金结束时无法完成3年评估。在延迟期间，我已经进行了其他研究，以帮助回答我的研究问题，包括一项临床试验，以测试免疫抑制剂硫唑嘌呤是否对早期PD的进展有任何影响。将我的奖学金扩大为2年过渡奖，将确保我可以完成原始项目中计划的长期评估，从而确定与PD发展痴呆症最密切相关的免疫和蛋白质标记。这些标记对于将来的临床试验至关重要。到2年结束时，我还将完成PD中硫唑嘌呤的临床试验，如果成功，该试验将提供第一个证据，证明免疫抑制可以改变PD中的疾病病程。我还将能够完成我的工作，以精确地研究蛋白质团与实验室中的免疫细胞相互作用。这将有助于确定以后的试验中靶向新疗法的分子，旨在减缓PD痴呆症的进展。

项目成果

Neuroinflammation is linked to dementia risk in Parkinson's disease.

神经炎症与帕金森病的痴呆风险有关。

• DOI: 10.1093/brain/awad322
• 发表时间: 2024
• 期刊: a journal of neurology
• 作者: Kouli A

Imaging Protein Aggregates in Parkinson's Disease Serum Using Aptamer-Assisted Single-Molecule Pull-Down.

• DOI: 10.1021/acs.analchem.3c02515
• 发表时间: 2023-10-17
• 期刊: ANALYTICAL CHEMISTRY
• 影响因子: 7.4
• 作者: Zhang, Yu P.;Lobanova, Evgeniia;Emin, Derya;Lobanov, Sergey V.;Kouli, Antonina;Williams-Gray, Caroline H.;Klenerman, David
• 通讯作者: Klenerman, David

B lymphocyte responses in Parkinson's disease and their possible significance in disease progression.

• DOI: 10.1093/braincomms/fcad060
• 发表时间: 2023
• 期刊: Brain communications
• 影响因子: 4.8

Natural killer cells have an activated profile in early Parkinson's disease

• DOI: 10.1016/j.jneuroim.2023.578154
• 发表时间: 2023-07
• 期刊: Journal of Neuroimmunology
• 影响因子: 3.3
• 作者: J. Holbrook;B. Patel;M. Camacho;L. Kahanawita;J. Greenland;C. Williams-Gray

Cognitive and Motor Decline in Dementia with Lewy Bodies and Parkinson's Disease Dementia.

路易体痴呆和帕金森病痴呆的认知和运动下降。

• DOI: 10.1002/mdc3.13752
• 发表时间: 2023
• 期刊: Movement disorders clinical practice
• 影响因子: 4
• 作者: Gonzalez MC