Microglia in Early Dementia with Lewy Bodies

目的这个项目的目的是为路易体痴呆的早期阶段确定一个新的治疗目标。痴呆症会影响一个人的思维能力、记忆力和日常活动能力。英国大约有100万人患有痴呆症。这些人中有5-10%患有一种叫做路易体痴呆（DLB）的痴呆症。除了思维能力问题外，DLB还与其他症状有关，包括视幻觉和帕金森病的症状。这些症状给DLB患者和他们的亲人带来了巨大的痛苦。目前，没有任何治疗方法可以减缓这种疾病的进展。小胶质细胞是大脑中的特殊细胞，具有一系列作用，包括控制大脑炎症和清除脑细胞周围不需要的物质。先前的研究表明，小胶质细胞可能在DLB的早期阶段发挥作用。大脑中小胶质细胞的活动可以通过一种叫做TSPO PET成像的特殊脑部扫描来测量。这使我们能够显示小胶质细胞的数量是否在早期DLB中增加。toll样受体是位于小胶质细胞和其他细胞表面的蛋白质。它们可以影响小胶质细胞的活性。DLB患者死后脑组织中可检测到小胶质细胞和toll样受体。本研究的目的是证明toll样受体是否是减缓DLB进展的药物的良好靶点。Objectives1。使用TSPO PET成像：量化早期DLB的小胶质细胞，并评估小胶质细胞增加与疾病更快进展的关联程度2。使用脑组织：量化早期DLB患者大脑中的小胶质细胞和toll样受体，并检查小胶质toll样受体与dllb疾病过程之间的关系设计目的1：脑成像我们将招募50名早期DLB患者，以及20名健康人。所有参与者都将进行全面的临床评估，包括基线、12个月和24个月时痴呆严重程度的测量。将在基线和24个月时采集所有参与者的血液样本，同时可选择腰椎穿刺以获取脑脊液（包裹大脑和脊髓的液体）。参与者将进行TSPO PET扫描。这将使我们能够了解早期DLB患者的大脑中是否有更多的小胶质细胞，以及小胶质细胞是否与痴呆症的快速发展有关。我们将在24个月后对DLB患者进行TSPO PET扫描。这将使我们看到小胶质细胞数量是否随着时间的推移而变化。目的2：脑组织分析我们将使用30例早期DLB死亡患者和30例无任何脑部疾病死亡患者捐赠的脑组织。将使用特殊染料在显微镜下观察小胶质细胞和toll样受体。脑组织中的化学物质也将被测量，以了解toll样受体和小胶质细胞如何与其他疾病过程相关联。这将使我们了解影响toll样受体是否可能减缓DLB的疾病进展。患者/服务用户、护理人员和公众参与2020年4月，在制定该提案时咨询了患者和公众参与（PPI）小组。一个PPI参考小组将在奖学金期间召开会议，PPI成员将被邀请参加项目指导小组。应用和益处：这项研究的发现可能会迅速导致基于toll样受体的早期DLB治疗的早期临床试验。这项研究还可能导致在此类试验中使用TSPO PET成像来识别合适的参与者并测量治疗反应。

AimsThe aim of this project is to identify a new treatment target for the early stages of dementia with Lewy bodies.BackgroundDementia affects a person's thinking skills, memory and ability to carry out their day-to-day activities. Around one million people in the UK have dementia. 5-10% of these people have a type of dementia called dementia with Lewy bodies (DLB). In addition to problems with thinking skills, DLB is associated with other symptoms, including visual hallucinations and the symptoms of Parkinson's disease. These symptoms cause significant distress for people with DLB and their loved ones. At present, there is no treatment that can slow the progression of the disease. Microglia are specialised cells in the brain with a range of roles including controlling brain inflammation and removing unwanted material from around brain cells. Previous research has suggested that microglia may play a role in the early stages of DLB. The activity of microglia in the brain can be measured using a specialised brain scan called TSPO PET imaging. This allows us to show whether the number of microglia is increased in early DLB.Toll-like receptors are proteins that sit on the surface of microglia and other cells. They can influence the activity of microglial cells. Microglia and toll-like receptors can be measured in brain tissue from people with DLB after death. The aim of this study is to demonstrate whether toll-like receptors are a good target for drugs aiming to slow the progression of DLB. Objectives1. Using TSPO PET imaging: quantify microglia in early DLB and assess the degree to which increased microglia are associated with more rapid disease progression2. Using brain tissue: quantify microglial cells and toll-like receptors in the brains of people with early DLB and examine the association between microglial toll-like receptors and disease processes in DLBDesignObjective 1: Brain ImagingWe will recruit 50 participants with early DLB, along with 20 healthy people. All participants will have a thorough clinical assessment including measurements of the severity of dementia at baseline, 12 months and 24 months. Blood samples will be taken from all participants at baseline and 24 months, along with an optional lumbar puncture to obtain cerebrospinal fluid (the fluid that surrounds the brain and spinal cord).Participants will have a TSPO PET scan. This will allow us to see if there are more microglial cells in the brains of people with early DLB and if microglial cells are associated with faster progression of dementia.We will repeat the TSPO PET scan after 24 months in participants with DLB. This will allow us to see if microglial cell numbers change over time in DLB.Objective 2: Brain Tissue AnalysisWe will use brain tissue donated by 30 people who died with early DLB and 30 people who died without any brain disease. Special dyes will be used to look at microglial cells and toll-like receptors under a microscope. Chemicals in the brain tissue will also be measured to understand how toll-like receptors and microglia are associated with other disease processes. This will allow us to understand whether influencing toll-like receptors is likely to slow disease progression in DLB.Patient/service user, carer and public involvementA patient and public involvement (PPI) group was consulted in the development of this proposal in April 2020. A PPI Reference Group will meet throughout the Fellowship and PPI members will be invited to sit on the project steering group. Applications and benefitsThe findings of this study could rapidly lead to early-stage clinical trials of toll-like receptor-based treatments in early DLB. This study could also lead to the use of TSPO PET imaging to identify appropriate participants and measure treatment response in such trials.