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：《解开脑淀粉样血管病中微出血的机制；来自体外 从人体核磁共振到小鼠体内光学 脑淀粉样血管病的特征是淀粉样蛋白β(Aβ)在小脑室壁中积聚。 大脑中的血管，经常在阿尔茨海默病(AD)患者的大脑尸检中观察到。 CAA的临床表现为广泛的出血性损害，包括灾难性的 大面积出血性中风。此外，CAA和CAA相关的微出血-在没有重大 出血--越来越多地被认为是认知障碍和痴呆症的重要因素。 最后，CAA最近被认为增加了在抗淀粉样蛋白中发生微出血的风险。 免疫疗法，这是目前唯一有希望治疗AD患者的方法。然而，潜在的 出血的形成机制完全不清楚。这项拟议的研究回应了一项紧急的 需要研究小血管疾病和阿尔茨海默病之间的相互作用，这是一个快速增长的研究领域 由美国国立卫生研究院推荐，特别强调。初步观察显示血管Aβ缺失 出血部位的沉淀物。这表明β和AFP之间存在复杂的相互作用 血管破裂，表明Aβ可能对血管没有直接伤害，但间接导致出血。这个 申请人将决定在个人层面上涉及哪些结构和功能改变 结合最先进的神经成像技术和人类神经病理检查的血管 在活着的小鼠身上使用尖端光学成像工具的脑组织。这项建议是建立在申请人的 在体外磁共振成像和组织病理学方面有很强的背景，目前她在多光子领域的技能正在增长 小鼠的显微镜检查。该中心提供的优良科学环境和众多资源 马萨诸塞州综合医院和哈佛医学院，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 圆满完成了拟议的研究。这项K99奖项将有助于申请者 增强她的技能，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使人们能够回答急需的问题 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出血的目标。

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