Cerebrovascular Reactivity in the Presence of Cerebral Amyloid and Cerebrovascular Disease: A novel multi-modal imaging measure of vascular reserve in cognitively normal elderly

存在脑淀粉样蛋白和脑血管疾病时的脑血管反应性：认知正常老年人血管储备的新型多模态成像测量

• 批准号: 9125707
• 负责人: Eric Martin McDade
• 金额: $ 15.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9125707
• 关键词: Accounting; Affect; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Anisotropy; Area; Attenuated; Biological Markers; Biology; Blood Vessels; Brain; Brain imaging; Carbon Dioxide; Cardiovascular Diseases; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Chronic; Clinical; Clinical Research; Cognition; Cognitive; Cognitive aging; Cohort Studies; Complex; Correlation Studies; Data; Dementia; Deposition; Development Plans; Diffuse; Diffusion; Dilatation - action; Disease; Doctor of Philosophy; Elderly; Epidemiology; Evaluation; Failure; Foundations; Functional disorder; Funding; Goals; Health; Hypercapnia; Hypertension; Image; Imaging Techniques; Impaired cognition; Impairment; Indium; Individual; International; Investigation; Lead; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mentors; Mentorship; Metabolic; Methodology; Modeling; Multimodal Imaging; Neurodegenerative Disorders; Neurons; Outcome Study; Participant; Pathologic; Pathology; Perfusion; Perfusion Weighted MRI; Physiological; Pilot Projects; Population; Positioning Attribute; Positron-Emission Tomography; Prevalence; Prevention; Preventive treatment; Process; Property; Proteins; Publications; Qualifying; Recording of previous events; Recruitment Activity; Research; Resources; Rest; Risk; Site; Stimulus; Stress; Stroke; Structure; Study of magnetics; Symptoms; System; Time; Tracer; Translational Research; Tweens; Universities; Vascular Diseases; White Matter Hyperintensity; Work; amyloid imaging; arterial stiffness; base; brain health; cardiovascular risk factor; career; career development; cerebral amyloidosis; cerebral microvasculature; cerebrovascular; cerebrovascular amyloid; cerebrovascular health; cerebrovascular imaging; cofactor; cognitive function; cognitive performance; cognitive reserve; cognitive testing; cross reactivity; hypoperfusion; imaging biomarker; improved; in vivo; innovation; knowledge base; meetings; microvascular pathology; mild cognitive impairment; neuroimaging; neurological pathology; neurovascular; neurovascular unit; novel; prevent; programs; response; skills; statistics; tau Proteins; theories; treatment strategy; vascular contributions; white matter

 DESCRIPTION (provided by applicant): The overall goal of this project is to employ magnetic resonance imaging (MRI) in a novel manner to study the integrity and dynamics of the microvascular cerebral blood vessels in elderly subjects at risk for developing AD. Specifically, I will evaluate the affect that brain amyloid, a major pathologic component of AD, has on the reactive capacity of the cerebral microvasculature (i.e. cerebrovascular reserve) - a fundamental process in brain health, brain reserve and cognitive efficiency. Furthermore, I will evaluate the affect that co-existing cardiovascular risk factors, a major cause of health problems worldwide, have on the relationship between brain amyloid and cerebrovascular health. I hypothesize that cerebral amyloid will attenuate the ability of the cerebral microvessels to react appropriately to stimulus. This results in a chronic state of functional, neuronal hypoperfusion and contributes to cognitive failure. Furthermore, I hypothesize that differences in cerebrovascular reactivity between individuals will manifest as differences in cognitive performance. Lastly, I postulate that the relationship between cerebrovascular reactivity and brain amyloid will be partially modified by the presence of cardiovascular and cerebrovascular disease. This work will advance our understanding of two highly prevalent disorders, cerebrovascular and cardiovascular disease, and how these could be targeted in the treatment and prevention of AD and progressive cognitive decline in aging. The objective of this application is to evaluate a surrogate of small vessel cerebrovascular disease and cerebrovascular compliance, CVR, in the presence of cerebral amyloid using magnetic resonance imaging (MRI) in a population of cognitively normal and mild cognitive impaired subjects with cerebral amyloidosis. I will fulfill this by studying a unique population that have cognitive tests, amyloid PET scans and markers of cardio and cerebrovascular disease by employing a CO2 -hypercapnia measure of CVR. I will assess the independent contribution of cardio-and cerebrovascular disease, and cerebral amyloid on CVR. I will plan to recruit 50 subjects from two existing, federally funded projects, of ongoing longitudinal studies focusing on predictors of cognitive decline. Additionally, I will utilize a noel post-mortem pathologic- MRI/PET scan study to better explore the underlying relationship of microvascular pathology to the alterations identified with MRI measures of CVR. With the use of pilot funding we have completed 10 subjects thus far demonstrating feasibility as well as providing preliminary data to support the aims of this study. My long term goal is to identify critical elements in the relationship between cerebrovascular disease, cerebral amyloid and cognitive decline in order to improve the understanding of this complex, yet vital, connection and improve strategies for treatment and prevention of AD. This K23 investigation will help me to develop the skills, methodologies, and theories needed to pursue a career in clinical translational research investigating cerebrovascular cofactors associated with the expression of AD, particularly using multimodal brain imaging. By leveraging the resources at the University of Pittsburgh to acquire this critical knowledge base, I will be well positioned to gain the necessary expertise in brain imaging, pathology and vascular biology to move to the next step of independent research in vascular contributions to cognitive aging and AD. I am uniquely qualified to succeed in clinical research based on my clinical expertise, affiliation with the Alzheimer Disease Research Center (ADRC), recent publications and as site PI of an international, multisite biomarker study of familial Alzheimer Dementia. I will build on this promising early career through the five year career development plan proposed in this application. Mentors include Oscar Lopez MD, Co-Director of the ADRC and leader in research on cognitive aging; William Klunk MD, PhD, co-Director of the Alzheimer Disease Research Center and co-inventor of the amyloid tracer PiB; Milos Ikonomovic MD, leader in amyloid PET to pathology correlations; Alberto Vazquez, PhD, and expert in neuro-vascular and neuro- metabolic imaging of normal brain function with extensions to neurological pathologies, especially Alzheimer's disease; John Detre MD (consultant) co-inventor of ASL-MRI; as well as local ASL imaging expert, Tae Kim PhD, vascular biologists Jeffrey Isenberg, MD, MPH, and imaging biostatistician Dana Tudorascu, PhD. Through a combination of close mentorship, utilization of a unique cohort of study participants, specialized weekly lab meetings, and advanced imaging programs here, as well as structured didactic courses in neuroimaging and multivariate statistics, I will pursue expertise in multimodal neuroimaging. By the completion of this study I will possess the necessary expertise in multi-modal imaging focusing on vascular interactions in AD and cognitive aging. This work will serve as the foundation to move forward in independent research focusing on identifying mechanisms of neurovascular unit dysfunction in AD and related neurodegenerative disorders.

 描述（由申请人提供）：该项目的总体目标是以一种新颖的方式利用磁共振成像（MRI）来研究有患AD风险的老年受试者脑微血管的完整性和动力学。我特别 将评估脑淀粉样蛋白（AD的主要病理成分）对脑微血管反应能力（即脑血管储备）的影响-脑健康，脑储备和认知效率的基本过程。此外，我将评估共存的心血管危险因素对脑淀粉样蛋白和脑血管健康之间关系的影响，心血管危险因素是全球健康问题的主要原因。我假设大脑淀粉样蛋白会减弱大脑微血管对刺激做出适当反应的能力。这导致功能性神经元灌注不足的慢性状态，并导致认知障碍。此外，我假设个体之间脑血管反应性的差异将表现为认知能力的差异。最后，我假设， 脑血管反应性和脑淀粉样蛋白之间的关系将因心血管和脑血管疾病的存在而部分改变。这项工作将促进我们对两种高度流行的疾病，脑血管和心血管疾病的理解，以及如何将这些疾病作为治疗和预防AD和老年进行性认知下降的目标。本申请的目的是在认知正常和轻度认知障碍的脑淀粉样变性受试者人群中，使用磁共振成像（MRI）评价存在脑淀粉样蛋白的情况下小血管脑血管疾病和脑血管顺应性（CVR）的替代指标。我将通过采用CVR的CO2 -高碳酸血症指标来研究一个独特的人群来实现这一目标，该人群进行了认知测试、淀粉样蛋白PET扫描以及心血管和脑血管疾病的标志物。我将评估心脑血管疾病和脑淀粉样蛋白对CVR的独立贡献。我将计划从两个现有的联邦资助项目中招募50名受试者，这些项目是正在进行的纵向研究，重点是认知能力下降的预测因素。此外，我将利用一项诺埃尔的尸检病理- MRI/PET扫描研究，以更好地探索微血管病理学与CVR MRI测量确定的改变的潜在关系。通过使用试点资金，我们迄今已完成了10个主题，证明了可行性，并提供了初步数据，以支持这项研究的目标。我的长期目标是确定脑血管疾病，脑淀粉样蛋白和认知能力下降之间关系的关键因素，以提高对这种复杂而重要的联系的理解，并改善AD的治疗和预防策略。这项K23研究将帮助我发展所需的技能，方法和理论，以从事临床转化研究，研究与AD表达相关的脑血管辅助因子，特别是使用多模态脑成像。通过利用匹兹堡大学的资源来获得这一关键的知识基础，我将能够很好地获得必要的 在脑成像，病理学和血管生物学的专业知识，移动到血管的认知老化和AD的贡献独立研究的下一步。基于我的临床专业知识，与阿尔茨海默病研究中心（ADRC）的联系，最近的出版物以及作为家族性阿尔茨海默病的国际多位点生物标志物研究的研究中心PI，我唯一有资格在临床研究中取得成功。我将在这个有前途的早期职业生涯的基础上，通过本申请中提出的五年职业发展计划。导师包括Oscar洛佩斯医学博士，ADRC的联合主任和认知衰老研究的领导者; William Klunk医学博士，博士，阿尔茨海默病研究中心的联合主任和淀粉样蛋白示踪剂PiB的共同发明者; Milos Ikonomovic医学博士，淀粉样蛋白PET与病理学相关性的领导者; Alberto Vazquez博士是正常脑功能神经血管和神经代谢成像以及神经病理学扩展的专家，特别是阿尔茨海默病; John Detre医学博士（顾问）ASL-MRI的共同发明者;以及当地ASL成像专家Tae Kim博士，血管生物学家Jeffrey Isenberg医学博士，公共卫生硕士和成像生物统计学家Dana Tudorascu博士。通过密切的指导，利用独特的研究参与者队列，专门的每周实验室会议，先进的成像程序，以及神经成像和多元统计的结构化教学课程的结合，我将追求多模态神经成像的专业知识。通过这项研究的完成，我将拥有必要的专业知识，在多模态成像重点血管相互作用的AD和认知老化。这项工作将作为推进独立研究的基础，重点是确定AD和相关神经退行性疾病中神经血管单位功能障碍的机制。