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.

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