Microglia in Early Dementia with Lewy Bodies

AimsThe的目的是这个项目是确定一个新的治疗目标与Lewy body.BackgroundDementia早期阶段的痴呆症影响一个人的思维能力，记忆力和能力，进行他们的日常活动。英国约有100万人患有痴呆症。这些人中有5-10%患有一种称为路易体痴呆症（DLB）的痴呆症。除了思维能力的问题，DLB还与其他症状有关，包括幻视和帕金森病的症状。这些症状会给DLB患者及其亲人带来严重的痛苦。目前，没有治疗方法可以减缓疾病的进展。小胶质细胞是大脑中的专门细胞，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使用称为TSPO PET成像的专门大脑扫描来测量。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。小胶质细胞和Toll样受体可以在DLB患者死后的脑组织中测量。本研究的目的是证明Toll样受体是否是旨在减缓DLB进展的药物的良好靶点。目标1.使用TSPO PET成像：量化早期DLB中的小胶质细胞，并评估增加的小胶质细胞与更快的疾病进展相关的程度2。使用脑组织：量化早期DLB患者脑中的小胶质细胞和Toll样受体，并检查小胶质细胞Toll样受体与DLB疾病过程之间的关联设计目标1：脑成像我们将招募50名早期DLB参与者，沿着20名健康人。所有参与者将进行全面的临床评估，包括在基线、12个月和24个月时测量痴呆的严重程度。将在基线和24个月时采集所有参与者的血液样本，沿着进行可选的腰椎穿刺以获得脑脊液（大脑和脊髓周围的液体）。参与者将进行TSPO PET扫描。这将使我们能够看到早期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的更快进展有关。我们将在24个月后对DLB参与者重复TSPO PET扫描。这将使我们能够看到小胶质细胞的数量是否随着时间的推移在DLB的变化。目标2：脑组织分析我们将使用脑组织捐赠的30人谁死于早期DLB和30人谁没有任何脑部疾病死亡。特殊的染料将用于在显微镜下观察小胶质细胞和toll样受体。还将测量脑组织中的化学物质，以了解Toll样受体和小胶质细胞如何与其他疾病过程相关。这将使我们能够了解影响Toll样受体是否可能减缓DLB的疾病进展。患者/服务使用者，护理人员和公众参与在2020年4月制定这项建议时咨询了一个患者和公众参与（PPI）小组。一个PPI参考小组将在整个奖学金期间开会，PPI成员将被邀请参加项目指导小组。应用和益处本研究的结果可能会迅速导致早期DLB中基于Toll样受体的治疗的早期临床试验。这项研究还可能导致使用TSPO PET成像来识别适当的参与者并测量此类试验中的治疗反应。

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.