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.

项目摘要/摘要： 小血管脑血管疾病是阿尔茨海默病的主要危险因素。然而，量化的 在这些疾病的临床试验中，适合用作终点的生物标记物仍然缺乏。目标 本项目的目的是：1)在UH2阶段，评估和识别基于MRI的微血管生物标记物 具有诊断性和预测性，特别关注一种被称为脑血管的新标记物 反应性；2)在UH3阶段，与协调中心和财团中的其他项目合作 进一步评估在多地点设置中最有希望的生物标志物候选。 常规解剖成像(例如T2-FLAIR)可以识别代表脑白质的高信号 小血管受损的后果。在本项目中，我们将重点介绍几种较新的技术 探讨小血管认知损害和痴呆(VCID)的潜在生理驱动力。 具体地说，我们将重点介绍一个标示神经血管单位动态耦合能力的标记， 这里称为脑血管反应性(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CVR降低。 3)处理速度下降(四年以上)与CVR下降(四年以上)显著相关。 4)脑的CVR与T2-FLAIR上的结构性病变密切相关。因此，现在 该项目将重点开发CVR MRI作为一种小血管成像生物标志物，并增加 考虑其他几个微血管参数，包括微出血计数和脑血流量 (CBF)。这些小血管测量(血管成像标记物)将被组合成综合指数 基于他们对认知障碍的贡献，这将形成一个综合的成像生物标记物 VCID的诊断、预测和目标交战。 我们在UH2阶段的具体目标是：1)检查认知功能和 一组老年混合性血管和阿尔茨海默病患者的候选血管成像标志物 病理；2)对血管成像方法进行技术评估，以显示它们是多部位的 在适用性和重复性方面做好准备；3)与协调中心和其他开发人员合作 建立该财团的项目，为UH3阶段做准备。可量化的里程碑一直是 为这些目标和项目进入UH3阶段的准备情况而定义，在UH3阶段，具体目标是 作为小血管生物标记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记物候选者。 影响：在这个项目完成后，我们将开发出一种小血管成像生物标记物 已经为大规模多点临床验证研究做好了准备。