PET Imaging of Damaging Neuroinflammation in Alzheimer's Disease

阿尔茨海默病损伤性神经炎症的 PET 成像

• 批准号: 10547472
• 负责人: Andrew Christian Larson
• 金额: $ 49.76万
• 依托单位: EINSENCA INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547472
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Anti-Inflammatory Agents; Axon; Blood - brain barrier anatomy; Brain; Cells; Clinical Trials; Cyclic GMP; Demyelinations; Development; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Event; Evolution; Functional disorder; Goals; Human; Image; Imaging technology; Immune; Inflammation; Inflammatory; Mediating; Mediator of activation protein; Monitor; Mus; Neurons; Output; Oxidative Stress; Patients; Peroxidases; Phase; Positron-Emission Tomography; Prognosis; Progressive Disease; Proteins; Rattus; Reporting; Technology; Testing; Time; Toxicology; Validation; age related; clinical imaging; clinical translation; first-in-human; fluorodeoxyglucose; glucose metabolism; imaging agent; imaging modality; immunoreactivity; inhibitor; innovation; neuroinflammation; non-invasive imaging; non-invasive monitor; novel marker; response; tau Proteins; treatment response

Alzheimer's disease (AD) is a devastating and progressive disease without a cure. Neuroinflammation is now recognized as a key early event in the development of AD. Aberrant neuroinflammatory response activates immune cells that can increase oxidative stress, and oxidative stress can directly damage neurons and axons, cause demyelination, and break down the blood-brain barrier (BBB). Thus, damaging neuroinflammation is emerging to be a potential treatment target. A non-invasive imaging method to detect and assess early damaging neuroinflammation would be able to detect disease before irreversible damage occurs, and enable monitoring of disease progression and treatment response of current and emerging therapies. However, current clinical imaging technologies do not distinguish between damaging and reparative inflammation. The goal of this proposal is to develop an imaging method to detect and monitor oxidative stress and consequent damaging neuroinflammation in AD. We hypothesize that such an imaging technology will allow early detection of damaging neuroinflammation in AD patients, enable timely treatment decisions, predict progression, and allow non-invasive monitoring of treatment response, particularly for emerging anti-inflammatory therapies. We have found that myeloperoxidase (MPO) is highly expressed by pro-inflammatory cells but not by reparative cells. MPO is a key mediator of oxidative inflammation and has been found to be associated with AD. An increased number of MPO immunoreactive cells have been found in the brains of early AD patients, but not in the brains of normal patients. We have developed an activatable MPO-PET imaging agent (18F-EH301) that can cross the BBB to enable imaging of MPO activity in AD. In Phase 1 we will establish that 18F-EH301 can specifically detect oxidative stress in the brain in the 5XFAD mouse AD model. In Phase 2 we will use 18F- EH301 PET imaging to a) longitudinally track the evolution of oxidative stress in the brain in different AD models, b) compare and correlate with other AD imaging agents: 18F-FDG (glucose metabolism), 18F-florbetapir (β-amyloid), 18F-flortaucipir (tau), 11C-PBR28 (translocator protein), and c) monitor treatment changes using an MPO inhibitor (verdiperstat) with and without donezepil. Finally, to enable clinical translation of this technology, we will synthesize 18F-EH301 under cGMP conditions and perform GLP toxicology studies in rats. This proposal addresses the NIA priority of development and validation of innovative diagnostic tests and novel biomarkers to identify or predict age-related decline, dysfunction, diseases, and conditions, including Alzheimer's disease and AD-related dementias. The output of this proposal will be a translational MPO- targeting PET imaging method with demonstrated efficacy to report damaging neuroinflammation in AD for diagnosis, prognosis, and treatment monitoring. This project will directly enable first-in-man clinical trials to test MPO imaging in human AD and potentially other diseases in which MPO is implicated.

阿尔茨海默病（AD）是一种破坏性的、进行性的疾病，无法治愈。现在是神经炎症 被认为是 AD 发展的关键早期事件。异常的神经炎症反应激活 免疫细胞可以增加氧化应激，而氧化应激可以直接损害神经元和轴突， 导致脱髓鞘，破坏血脑屏障（BBB）。因此，破坏性神经炎症是 正在成为潜在的治疗目标。一种早期检测和评估的非侵入性成像方法 破坏性神经炎症将能够在不可逆转的损害发生之前检测到疾病，并能够 监测疾病进展以及当前和新兴疗法的治疗反应。然而， 目前的临床成像技术无法区分破坏性炎症和修复性炎症。这 该提案的目标是开发一种成像方法来检测和监测氧化应激及其后果 AD 中的破坏性神经炎症。我们假设这种成像技术将允许早期检测 AD 患者的破坏性神经炎症，能够及时做出治疗决策，预测进展，并 允许对治疗反应进行非侵入性监测，特别是对于新兴的抗炎疗法。我们 发现髓过氧化物酶（MPO）在促炎细胞中高度表达，但在修复细胞中不表达 细胞。 MPO 是氧化炎症的关键介质，已被发现与 AD 相关。一个 在早期 AD 患者的大脑中发现 MPO 免疫反应细胞数量增加，但在 正常患者的大脑。我们开发了一种可激活的 MPO-PET 显像剂 (18F-EH301) 可以穿过 BBB 以实现 AD 中 MPO 活性的成像。在第一阶段，我们将确定 18F-EH301 可以 专门检测 5XFAD 小鼠 AD 模型中大脑中的氧化应激。在第 2 阶段，我们将使用 18F- EH301 PET 成像 a) 纵向追踪不同 AD 患者大脑中氧化应激的演变 模型，b) 与其他 AD 显像剂进行比较和关联：18F-FDG（葡萄糖代谢）、18F-florbetapir （β-淀粉样蛋白）、18F-flortaucipir (tau)、11C-PBR28（易位蛋白），以及 c) 使用 MPO 抑制剂 (verdiperstat) 联合或不联合多奈匹尔。最后，为了实现这项技术的临床转化， 我们将在cGMP条件下合成18F-EH301并在大鼠中进行GLP毒理学研究。这 该提案涉及 NIA 开发和验证创新诊断测试和新颖药物的优先事项 用于识别或预测与年龄相关的衰退、功能障碍、疾病和状况的生物标志物，包括 阿尔茨海默病和 AD 相关痴呆症。该提案的输出将是一个翻译性的 MPO- 靶向 PET 成像方法已被证明能够有效报告 AD 中的破坏性神经炎症 诊断、预后和治疗监测。该项目将直接启用首次人体临床试验来测试 人类 AD 以及与 MPO 相关的其他潜在疾病的 MPO 成像。