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.

帕金森氏症(PD)会导致运动和行走方面的问题，但有一半的患者在确诊后的头10年内也会患上痴呆症。这很难治疗，并对生活质量和护理需求产生重大影响。我的研究目标是研究预测和推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患者死后大脑中发现异常蛋白质沉积(α-突触核蛋白和tau)，似乎与痴呆症有关，但它们究竟是如何导致痴呆症的尚不清楚。我正在探索一种理论，即这些蛋白质的小块在疾病早期形成，并在大脑中引起炎症，从而导致更早的痴呆症。蛋白质团块也可能从大脑泄漏到血液中，激活身体的免疫系统，这可能会进一步推动脑部炎症。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)以及血液中的免疫标记物和蛋白质块。为了确定这些过程是否可以预测和驱动痴呆症，我正在研究新诊断的尚未发展为痴呆症的帕金森氏症患者，并将高痴呆症风险组与低痴呆症风险组(风险由思维和基因测试确定)以及一组年龄相似的健康志愿者(“对照组”)进行比较。按计划招募了40名患者(20名高风险患者，20名低风险患者)和40名对照组。PET扫描显示，痴呆风险较高的帕金森病患者的某些脑区有更多的炎症，在高危病例中，炎症和tau蛋白的沉积在整个大脑中都是相关的。我还发现了帕金森病患者血液中免疫细胞激活的证据，特别是在那些痴呆症高危人群中。此外，我的结果显示，与对照组相比，帕金森病患者血液中的免疫细胞更多地渗透到脑脊液中。我还一直在与我在化学方面的同事合作，开发新的技术来可视化流体样本中非常小的蛋白质块。我们发现PD患者血液样本中这些小蛋白质块的组成与对照组相比有所不同，并表明从PD脑样本中提取的类似大小的蛋白质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是，随着时间的推移，对研究参与者进行18个月和3年的重复评估，看看免疫激活和蛋白质聚集的早期标记物是否预示着记忆衰退和痴呆症，并看看这些标记物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冠状病毒大流行，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年的评估。在拖延期间，我还进行了其他研究来帮助回答我的研究问题，包括一项临床试验，以测试免疫抑制药物硫唑嘌呤(硫唑嘌呤)是否对早期帕金森病的进展有任何影响。延长我的两年过渡期奖金将确保我能够完成我最初项目中计划的长期评估，从而确定与帕金森氏症痴呆症发展最密切相关的免疫和蛋白质标记物。这些标记物对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我的工作，准确地研究蛋白质块如何与免疫细胞相互作用。这将有助于在未来的试验中确定新的治疗目标分子，旨在减缓帕金森病向痴呆的进展。

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

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

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