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.

项目摘要 /摘要 标题项目：“阐明脑淀粉样血管病中的微型出血机制； 人类的MRI在小鼠中进行体内光学元件” 脑淀粉样血管病（CAA）的特征是淀粉样β（Aβ）在小的壁中积累 大脑中的血管，经常在阿尔茨海默氏病（AD）患者的大脑中尸检时观察到。 CAA通过发生宽度的出血性病变在临床上表现出来，包括灾难性的病变 大量出血性中风。此外，CAA和与CAA相关的微型诊所 - 在没有主要的情况下 出血 - 被认为是认知障碍和痴呆症的重要贡献者。 最后，最近认为CAA增加了抗淀粉样蛋白中微生物的风险 免疫疗法，这是目前在AD患者中唯一的承诺治疗方法。但是，基础 出血形成的机制是完全未知的。拟议的研究对紧急的回应 需要研究小血管疾病与AD之间的相互作用，AD是一个快速增长的研究区域 由NIH推荐以特别重视。初步观察表明缺乏血管Aβ 在发生出血的地点的沉积物。这表明Aβ和 血管破裂，表明Aβ可能不会直接危害血管，而是间接导致出血。 申请人将确定在个体水平上涉及哪些结构和功能变化 通过结合最先进的神经影像学技术和人类神经病理检查的血管 带有尖端的光学成像工具的脑组织在活小鼠中。该提案建立在申请人的 Ex Vivo MRI和组织病理学的良好背景以及她目前在多光子方面不断增长的技能 小鼠的显微镜。出色的科学环境和大量资源 马萨诸塞州综合医院和哈佛医学院以及国际认可 申请人导师的领导以及与该领域专家的现有合作将是 成功完成拟议的研究。该K99奖项将对适用的 增强她的技能，进一步的科学和专业品质，并采取下一步 成为独立研究员。拟议的多模式方法将允许回答非常需要的 有关出血形成的潜在机制的问题，其长期目标是找到 预防抗淀粉样蛋白疗法中微生物的靶标。

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