Development of MRI microvascular biomarkers in cognitive impairment and dementia

认知障碍和痴呆 MRI 微血管生物标志物的开发

• 批准号: 10001049
• 负责人: MARILYN S. ALBERT
• 金额: $ 115.44万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001049
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Biochemical; Biological Markers; Blood Vessels; Brain; Cardiovascular Diseases; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Clinical; Clinical Trials; Cognition; Cognitive; Complement; Coupling; Cross-Sectional Studies; Dementia; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Elderly; Funding; Goals; Health; Homeostasis; Hypertension; Image; Impaired cognition; Individual; Infrastructure; Institution; Lacunar Infarctions; Lesion; Liquid substance; Longitudinal cohort; Magnetic Resonance Imaging; Measures; Microvascular Dysfunction; Participant; Pathologic; Patients; Perfusion; Phase; Physiological; Preparation; Process; Readiness; Records; Regression Analysis; Reproducibility; Research Personnel; Rest; Risk Factors; Scanning; Site; Spinal Puncture; Structure; Techniques; Time; Universities; White Matter Hyperintensity; Work; anatomic imaging; base; candidate marker; cardiovascular risk factor; cerebrovascular; clinical research site; cognitive function; cognitive testing; cohort; driving force; hypercholesterolemia; imaging biomarker; imaging modality; indexing; neurovascular unit; novel marker; novel therapeutics; processing speed; prognostic; recruit; targeted biomarker; tau Proteins; validation studies; vascular contributions; vascular risk factor

Project Summary/Abstract: Small vessel cerebrovascular disease is a major risk factor in Alzheimer’s disease. However, quantitative biomarkers that are suitable for use as endpoints in clinical trials for these conditions are still lacking. The goals of the present project are to 1) in the UH2 phase, evaluate and identify MRI-based microvascular biomarkers that are diagnostic and predictive, with a particular focus on a novel marker referred to as cerebrovascular reactivity; 2) in the UH3 phase, work with the Coordinating Center and other projects in the consortium to further evaluate the most promising biomarker candidates in a multi-site setting. Conventional anatomic imaging (e.g. T2-FLAIR) can identify white matter hyperintensities that represent the consequence of small vessel damage. In this project, we will emphasize several newer techniques that probe the potential physiological driving force of small vessel cognitive impairment and dementia (VCID). Specifically, we will focus on a marker indexing the dynamic coupling capacity of the neurovascular unit, referred to here as cerebrovascular reactivity (CVR). Our previously studies on CVR have revealed that: 1) CVR is three times as sensitive to age as resting perfusion. 2) CVR is diminished in patients with AD dementia. 3) Decline in processing speed (over four years) is significantly associated with CVR decline (over four years). 4) CVR of the brain is strongly correlated with structural lesions as seen on T2-FLAIR. Therefore, the present project will emphasize the development of CVR MRI as a small vessel imaging biomarker, with additional consideration of several other microvascular parameters including microbleeds count and cerebral blood flow (CBF). These small vessel measures (vascular imaging markers) will be combined into a composite index based on their contributions to cognitive impairment, which will form a composite imaging biomarker for diagnosis, prediction, and target engagement of VCID. Our Specific Aims in the UH2 phase are: 1) Examine the association between cognitive function and candidate vascular imaging markers in a group of elderly individuals with mixed vascular and Alzheimer’s pathology; 2) Conduct technical assessment of the vascular imaging methods to show that they are multi-site ready in terms of applicability and reproducibility; 3) Work with Coordinating Center and other Development Projects to establish the consortium in preparation for the UH3 phase. Quantifiable milestones have been defined for these aims and for the readiness of the project to enter the UH3 phase, in which the specific aim is to perform collaborative studies as part of the small vessel biomarker consortium to further evaluate and develop the most promising biomarker candidates. Impact: Upon the completion of this project, we will have developed a small vessel imaging biomarker that is ready for large scale multi-site clinical validation studies.

项目概要/摘要： 小血管脑血管病是阿尔茨海默病的主要危险因素。但是，定量 仍然缺乏适合用作这些病症的临床试验终点的生物标志物。的目标 本项目的主要目的是：1）在UH 2阶段，评价和识别基于MRI的微血管生物标志物 具有诊断性和预测性，特别关注称为脑血管的新标记物， 反应性; 2）在UH 3阶段，与协调中心和联合体的其他项目合作， 在多位点环境中进一步评估最有希望的生物标志物候选物。 常规的解剖成像（例如T2-FLAIR）可以识别白色物质高信号， 小血管损伤的后果。在这个项目中，我们将强调几个较新的技术， 探讨小血管认知功能障碍和痴呆（VCID）的潜在生理驱动力。 具体来说，我们将集中在一个标记索引的动态耦合能力的神经血管单位， 在此称为脑血管反应性（CVR）。我们以前对CVR的研究表明：1） CVR对年龄的敏感性是静息灌注的三倍。2)AD痴呆患者的CVR降低。 3)处理速度下降（超过4年）与CVR下降（超过4年）显著相关。 4)脑的CVR与T2-FLAIR上所见的结构性病变密切相关。因此本 该项目将强调开发CVR MRI作为小血管成像生物标志物， 考虑其他几个微血管参数，包括微出血计数和脑血流量 （CBF）.这些小血管指标（血管成像标记物）将组合成一个复合指数 基于他们对认知障碍的贡献，这将形成一个复合成像生物标志物， VCID的诊断、预测和目标接合。 我们在UH 2阶段的具体目标是：1）检查认知功能与 一组混合血管性和阿尔茨海默病的老年人中的候选血管成像标记物 病理学; 2）对血管成像方法进行技术评估，以显示它们是多部位的 在适用性和可重复性方面做好准备; 3）与协调中心和其他开发部门合作 为筹备UH 3阶段而建立联合体的项目。可量化的里程碑已经 为这些目标和项目进入UH 3阶段的准备工作而定义，具体目标是 作为小血管生物标志物联盟的一部分进行合作研究，以进一步评估和 开发最有前途的生物标志物候选物。 影响：该项目完成后，我们将开发出一种小血管成像生物标志物， 已准备好进行大规模的多中心临床验证研究。