Unraveling the mechanisms of microhemorrhages in cerebral amyloid angiopathy

揭示脑淀粉样血管病微出血的机制

• 批准号: 10406382
• 负责人: Susanne Janneke Van Veluw
• 金额: $ 24.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406382
• 关键词: 3-Dimensional; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Animal Model; Anticoagulation; Area; Autopsy; Award; Blood Vessels; Brain; Brain hemorrhage; Brain imaging; Cerebral Amyloid Angiopathy; Cerebral hemisphere; Cerebrovascular Physiology; Clinical; Collaborations; Complex; Dementia; Deposition; Development; Disease; Environment; Excision; Exposure to; Fibrosis; General Hospitals; Goals; Hemorrhage; Histopathology; Human; Hypertension; Image; Imaging Device; Immunotherapy; Impaired cognition; Individual; Injury; International; Investigation; Leadership; Lesion; Life; Link; Magnetic Resonance Imaging; Massachusetts; Mentors; Microscopy; Microvascular Dysfunction; Mus; Optics; Outcome; Pathology; Patients; Pattern; Phase; Physiological; Prevention strategy; Property; Research; Research Personnel; Resources; Rest; Risk; Role; Rupture; Safety; Sampling; Site; Stroke; Structure; Techniques; Time; Tissues; Training Programs; United States National Institutes of Health; abeta accumulation; amyloid pathology; brain tissue; experimental study; hypertensive; immunotherapy trials; improved; in vivo; in vivo optical imaging; insight; medical schools; mortality; mouse model; multi-photon; multidisciplinary; multimodality; neuroimaging; neuropathology; novel; optical imaging; preclinical imaging; prevent; skills; temporal measurement; tool; translational research program; treatment strategy; β-amyloid burden

Project Summary / Abstract Title project: “Unraveling the mechanisms of microhemorrhages in cerebral amyloid angiopathy; from ex vivo MRI in humans to in vivo optics in mice” Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid β (Aβ) in the walls of small vessels in the brain, and is frequently observed at autopsy in the brains of Alzheimer’s disease (AD) patients. CAA manifests itself clinically by the occurrence of widespread hemorrhagic lesions, including catastrophic large hemorrhagic stroke. Moreover, CAA and CAA-related microhemorrhages - in the absence of major bleeding - have increasingly been recognized as important contributors to cognitive impairment and dementia. Finally, CAA has recently been assumed to increase the risk of developing microhemorrhages in anti-amyloid immunotherapy, which is currently the only promising treatment in patients with AD. Yet, the underlying mechanisms of hemorrhage formation are completely unknown. The proposed research responds to an urgent need to study the interaction between small vessel disease and AD, a rapidly growing research area recommended by the NIH for special emphasis. Preliminary observations suggest absence of vascular Aβ deposits at the sites where hemorrhages had occurred. This suggests a complex interplay between Aβ and vessel rupture and indicates that Aβ may not be directly harmful to vessels, but indirectly causes bleeding. The applicant will determine which structural and functional alterations are involved at the level of the individual vessels by combining state-of-the-art neuroimaging techniques and neuropathological examinations of human brain tissue with cutting-edge optical imaging tools in living mice. The proposal builds on the applicant’s strong background in ex vivo MRI and histopathology and her currently growing skills in multi-photon microscopy in mice. The excellent scientific environment and numerous resources provided by the Massachusetts General Hospital and Harvard Medical School, as well as the internationally recognized leadership of the applicant’s mentors, and existing collaborations with experts in the field will be key to the successful completion of the proposed research. This K99 award will be instrumental for the applicant to strengthen her skillset, further grow in her scientific and professional qualities, and take the next steps towards becoming an independent researcher. The proposed multi-modal approach will allow answering much needed questions regarding the underlying mechanisms of hemorrhage formation, with the long-term goal to find targets to prevent microhemorrhages in anti-amyloid therapies.

项目总结/摘要 标题项目：“揭示脑淀粉样血管病中微血管形成的机制;来自体外 从人类的MRI到小鼠的体内光学” 脑淀粉样血管病（CAA）的特征是淀粉样β蛋白（Aβ）在小血管壁的积聚， 在脑血管中，并且在阿尔茨海默病（AD）患者的脑中的尸检中经常观察到。 CAA在临床上表现为广泛出血性病变的发生，包括灾难性的 大出血性中风此外，CAA和CAA相关的微血管病变-在缺乏主要 出血-越来越被认为是认知障碍和痴呆的重要因素。 最后，CAA最近被认为会增加抗淀粉样蛋白治疗中发生微血管病变的风险。 免疫疗法，这是目前唯一有希望的治疗AD患者。然而， 出血形成的机制完全未知。这项研究是为了回应一项紧迫的 需要研究小血管疾病和AD之间的相互作用，这是一个快速发展的研究领域 这是NIH特别强调的。初步观察结果表明缺乏血管Aβ 沉积物在现场发生了破坏。这表明Aβ和 提示Aβ可能不直接损害血管，但间接引起出血。的 申请人将确定在个人水平上涉及哪些结构和功能改变 通过结合最先进的神经成像技术和人类神经病理学检查， 脑组织与先进的光学成像工具在活老鼠。该提案建立在申请人的 在离体MRI和组织病理学方面有很强的背景，目前她在多光子成像方面的技能不断提高， 显微镜在小鼠。良好的科学环境和众多的资源提供了 马萨诸塞州总医院和哈佛医学院，以及国际公认的 申请人导师的领导力，以及与该领域专家的现有合作将是 成功完成了所提出的研究。这个K99奖项将有助于申请人 加强她的技能，进一步提高她的科学和专业素质，并采取下一步行动， 成为一名独立研究人员。拟议的多模式方法将允许回答急需的问题， 关于出血形成的潜在机制的问题，长期目标是找到 在抗淀粉样蛋白治疗中预防微血管化的靶点。

项目成果

Deep learning assisted quantitative assessment of histopathological markers of Alzheimer's disease and cerebral amyloid angiopathy.

• DOI: 10.1186/s40478-021-01235-1
• 发表时间: 2021-08-21
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Perosa V;Scherlek AA;Kozberg MG;Smith L;Westerling-Bui T;Auger CA;Vasylechko S;Greenberg SM;van Veluw SJ
• 通讯作者: van Veluw SJ