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，定量 仍然缺乏适合用作这些疾病临床试验终点的生物标志物。目标 本项目的目标是 1) 在 UH2 阶段，评估和识别基于 MRI 的微血管生物标志物 具有诊断性和预测性，特别关注一种称为脑血管的新型标记物 反应性； 2）在UH3阶段，与协调中心及联盟内其他项目合作， 进一步评估多站点环境中最有前途的生物标志物候选物。 传统的解剖成像（例如 T2-FLAIR）可以识别代表白质高信号 小型船只损坏的后果。在这个项目中，我们将强调几种新技术 探讨小血管认知障碍和痴呆（VCID）的潜在生理驱动力。 具体来说，我们将重点关注索引神经血管单元动态耦合能力的标记， 这里称为脑血管反应性（CVR）。我们之前对 CVR 的研究表明：1） CVR 对年龄的敏感度是静息灌注的三倍。 2) AD 痴呆患者的 CVR 降低。 3) 处理速度的下降（​​四年多）与 CVR 下降（四年多）显着相关。 4) 如 T2-FLAIR 所示，大脑的 CVR 与结构性病变密切相关。因此，目前 项目将重点开发 CVR MRI 作为小血管成像生物标志物，并附加 考虑其他几个微血管参数，包括微出血计数和脑血流量 （CBF）。这些小血管测量值（血管成像标记物）将被组合成一个综合指数 基于它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、预测和目标参与。 我们在 UH2 阶段的具体目标是： 1）检查认知功能与 一组患有混合血管病和阿尔茨海默病的老年人的候选血管成像标记物 病理; 2）对血管成像方法进行技术评估，以证明它们是多部位的 具备适用性和再现性； 3) 与协调中心和其他开发部门合作 建立联盟的项目，为 UH3 阶段做准备。可量化的里程碑是 为这些目标以及项目进入 UH3 阶段的准备而定义，其中具体目标是 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 开发最有前途的候选生物标志物。 影响：该项目完成后，我们将开发出一种小血管成像生物标记物， 已准备好进行大规模多站点临床验证研究。