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Molecular and Physiological Mechanisms of Hypertensive Cerebral Microangiopathy

高血压脑微血管病的分子和生理机制

基本信息

批准号：
10631211
负责人：
Mahmut Edip Gurol
金额：
$ 80.18万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10631211
关键词：
Adult Age Years Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid Amyloid Proteins Amyloid beta-Protein Atrophic Basal Ganglia Blood Pressure Blood Vessels Brain Brain Diseases Brain Injuries Brain Ischemia Brain Pathology Brain hemorrhage Carbon Dioxide Cerebral small vessel disease Cerebrovascular Disorders Cerebrovascular system Cerebrum Cessation of life Clinical Trials Design Cognition Cognitive Dementia Deposition Diagnosis Elderly Exhibits Experimental Designs Foundations Functional Imaging Functional Magnetic Resonance Imaging Functional disorder Hemorrhage Hypertension Hypertensive Intracerebral Hemorrhage Impaired cognition Impairment Infarction Injury Ischemia Ischemic Stroke Lesion Link Magnetic Resonance Imaging Measures Mediating Mediator Methodology Methods Microvascular Dysfunction Molecular Multimodal Imaging National Institute of Neurological Disorders and Stroke Nerve Degeneration Pathologic Pathology Patients Physiological Physiology Pittsburgh Compound-B Population Positron-Emission Tomography Preventive Process Proteins Randomized, Controlled Trials Recommendation Research Research Priority Risk Factors Severities Severity of illness Source Stimulus Survivors Testing Therapeutic Therapeutic Studies United States United States National Institutes of Health Vascular Cognitive Impairment Vascular Dementia Vascular Diseases White Matter Hyperintensity aging population biomarker development brain tissue cerebrovascular cognitive change cohort dementia risk disability experimental study gray matter human model hypertensive imaging approach imaging biomarker innovation magnetic resonance imaging biomarker multidisciplinary multimodality non-demented novel novel marker preservation prevent structural imaging symposium targeted treatment tau Proteins tau aggregation tissue injury vascular cognitive impairment and dementia white matter

项目摘要

Project Summary The small vessel diseases of the brain are responsible not only for ischemic and hemorrhagic strokes but also vascular cognitive impairment and dementia, major sources of disability and death in older adults. Despite the fact that hypertensive cerebral small vessel disease (HTN-cSVD) is the most common type of brain microangiopathy, the mechanisms linking this condition to brain tissue injury and cognitive impairment are unknown, therefore no specific preventive or therapeutic method targeting physiopathological processes exist. We propose a systematic, multidisciplinary analysis of the mechanisms underlying HTN-cSVD related cerebrovascular dysfunction, impaired perivascular clearance and their connections to brain damage including pathological amyloid/tau protein accumulations. The unique patient cohort is composed of nondemented survivors of a hypertensive intracerebral hemorrhage (HTN-ICH), a well-characterized indicator of severe HTN- cSVD. Specific experiments are designed to compare advanced physiological MRI measures of vascular reactivity and vascular compliance between patients with HTN-ICH and healthy older adults in addition to delineating the relationship of vascular dysfunction with established markers of HTN-cSVD [Specific Aim (SA) 1a and 1b]. These experiments are geared towards testing the hypothesis that HTN-cSVD causes vascular dysfunction which in turn might mediate larger-scale brain tissue injury. The second set of experiments will test the potential effects of HTN-cSVD on accumulation of amyloid and tau proteins in the brain, answering the key question of whether decreased clearance related to small vessel dysfunction might contribute to the accumulation of these pathological hallmarks of Alzheimer’s Disease (SA 2a and 2b). The third set of studies will analyze the effects of vascular, structural and molecular changes on cognition using both cross-sectional and longitudinal assessments (SA 3a and 3b). The proposal builds on a wide range of cutting-edge methodologic advances such as multimodal physiological imaging with 7T ultrahigh field functional MRI, molecular Aß and tau PET imaging, and the use of state-of-the-art structural imaging markers of HTN-cSVD. Successful completion of the proposed highly translational experiments will determine the physiological and molecular mechanisms of brain tissue damage related to HTN-cSVD and the impact of these processes on cognition. These results will represent a major step towards understanding the contributions of the most common vascular brain disease (HTN-cSVD) to dementia, thereby allowing design of clinical trials aimed at preserving or enhancing vascular function using validated imaging markers of the vascular physiology.

项目摘要脑小血管疾病不仅是缺血性和出血性中风的原因，血管性认知障碍和痴呆是老年人残疾和死亡的主要原因。尽管高血压性脑小血管病（HTN-cSVD）是最常见的脑血管病类型，微血管病，这种情况与脑组织损伤和认知障碍的联系机制是未知，因此不存在靶向生理病理过程的特定预防或治疗方法。我们提出了一个系统的，多学科的分析HTN-cSVD相关的机制，脑血管功能障碍、血管周围清除障碍及其与脑损伤的联系，包括病理性淀粉样蛋白/tau蛋白积聚。独特的患者队列由非痴呆患者组成，高血压性脑出血（HTN-ICH）的幸存者，这是严重HTN的一个良好表征指标， cSVD。设计了具体的实验来比较血管的高级生理MRI测量。 HTN-ICH患者和健康老年人之间的反应性和血管顺应性，描述血管功能障碍与已确立的HTN-cSVD标志物的关系[特异性目的（SA） 1a和1b）。这些实验旨在检验HTN-cSVD导致血管性心脏病的假设。这反过来可能介导更大规模的脑组织损伤。第二组实验将测试 HTN-cSVD对大脑中淀粉样蛋白和tau蛋白积累的潜在影响，与小血管功能障碍相关的清除率降低是否可能导致阿尔茨海默病的这些病理学标志的累积（SA 2a和2b）。第三组研究将分析血管，结构和分子变化对认知的影响，和纵向评估（SA 3a和3b）。该提案建立在广泛的尖端技术基础上，方法学的进步，如多模态生理成像与7 T双磁场功能MRI，分子ApoE和tau PET成像，以及使用HTN-cSVD的最先进的结构成像标志物。成功完成所提议的高度转化实验将确定生理和与HTN-cSVD相关的脑组织损伤的分子机制以及这些过程对认知.这些结果将是朝着了解最不发达国家的贡献迈出的重要一步。常见的血管性脑疾病（HTN-cSVD）的痴呆症，从而允许设计的临床试验，旨在使用血管生理学的经验证的成像标记来保持或增强血管功能。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Altered sleep architecture in children and adolescents with Down syndrome.

患有唐氏综合症的儿童和青少年的睡眠结构发生了改变。

DOI：
10.1002/ajmg.c.32073
发表时间：
2023
期刊：
American journal of medical genetics. Part C, Seminars in medical genetics
影响因子：
0
作者：
Gardner,KellyJ;Wang,Wei;Klerman,ElizabethB
通讯作者：
Klerman,ElizabethB

Stroke Prevention in Atrial Fibrillation: Our Current Failures and Required Research.

房颤中的中风预防：我们当前的失败和所需的研究。

DOI：
10.1161/strokeaha.123.040447
发表时间：
2024
期刊：
Stroke
影响因子：
8.3
作者：
Gurol,MEdip;Wright,ClintonB;Janis,Scott;Smith,EricE;Gokcal,Elif;Reddy,VivekY;Merino,JoséG;Hsu,JonathanC
通讯作者：
Hsu,JonathanC

Advances in Neurocardiology: Focus on Anticoagulation for Valvular Heart Disease With and Without Atrial Fibrillation.

DOI：
10.1161/strokeaha.122.039310
发表时间：
2022-12
期刊：
STROKE
影响因子：
8.3
作者：
Gurol, M. Edip;Sposato, Luciano A.
通讯作者：
Sposato, Luciano A.

Advances in Neurocardiology: Focus on Atrial Fibrillation.

神经心脏病学的进展：关注心房颤动。

DOI：
10.1161/strokeaha.121.033970
发表时间：
2021
期刊：
Stroke
影响因子：
8.3
作者：
Sposato,LucianoA;Gurol,MahmutEdip
通讯作者：
Gurol,MahmutEdip

Clinical and neuroimaging risk factors associated with the development of intracerebral hemorrhage while taking direct oral anticoagulants.

直接服用口服抗凝剂时与脑出血发生相关的临床和神经影像学危险因素。

DOI：
10.1007/s00415-022-11333-2
发表时间：
2022
期刊：
Journal of neurology
影响因子：
6
作者：
Das,AlvinS;Gökçal,Elif;Regenhardt,RobertW;Warren,AndrewD;Biffi,Alessandro;Goldstein,JoshuaN;Kimberly,WTaylor;Viswanathan,Anand;Schwamm,LeeH;Rosand,Jonathan;Greenberg,StevenM;Gurol,MEdip
通讯作者：
Gurol,MEdip