Imaging Microvascular Hemodynamics In Older Adults With Varying Genetic Risk For Alzheimer's Disease

对具有不同阿尔茨海默病遗传风险的老年人进行微血管血流动力学成像

• 批准号: 10194991
• 负责人: Meher R Juttukonda
• 金额: $ 45.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194991
• 关键词: Adult; Adverse effects; Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Amyloid; Amyloid deposition; Apolipoprotein E; Blood Vessels; Blood capillaries; Blood flow; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Characteristics; Conflict (Psychology); Coupled; Data; Development; Disease Marker; Elderly; Etiology; Exhibits; Genes; Genetic Risk; Genotype; Goals; Heterogeneity; High Prevalence; Hypoxia; Image; Impaired cognition; Impairment; Individual; Late Onset Alzheimer Disease; Lesion; Longitudinal Studies; Magnetic Resonance Imaging; Microvascular Dysfunction; Neurofibrillary Tangles; Oxygen; Participant; Pathologic; Pathology; Pathway interactions; Pattern; Perfusion; Physiological; Physiology; Radiology Specialty; Regulation; Reporting; Risk; Risk Factors; Role; Senile Plaques; Series; Signal Transduction; Spin Labels; Structure; Testing; Therapeutic; Tissues; Titrations; Venous; Work; aged; amyloid pathology; base; brain tissue; cerebrovascular health; genetic risk factor; hemodynamics; imaging biomarker; imaging modality; improved; novel; personalized medicine; prevent; tau Proteins; white matter; young adult

PROJECT SUMMARY Alzheimer’s disease (AD) currently affects 5.6 million Americans aged 65 years and older, with a projected increase to 13.8 million by 2050. Beta-amyloid plaques and neurofibrillary tangles are characteristic of AD pathology, but white matter lesions (WMLs) indicative of cerebral small vessel disease have also been shown to be an independent contributor to cognitive decline in AD patients. Possession of an ε4 allele of the apolipoprotein E gene (APOE) is considered the strongest risk factor for developing late-onset AD. In addition, APOE-ε4 also represents a major risk factor for cerebrovascular disease, and APOE-ε4 carriers are known to exhibit a greater burden and faster progression of WMLs compared with non-carriers. However, the physiological mechanisms through which APOE-ε4 leads to tissue hypoxia and the formation of these lesions remain incompletely understood. The overall goal of this study is to elucidate differences in microvascular physiology between APOE- ε4 carriers and non-carriers that may indicate potential mechanisms for the pathological effects of APOE-ε4 on vascular function. Such hemodynamic impairment could be caused by mechanisms associated with abnormal tissue perfusion. However, prior studies that have examined effects of APOE-ε4 on cerebral perfusion have reported conflicting results on whether perfusion is reduced or elevated APOE-ε4 carriers versus non-carriers, indicating that differences in blood flow alone may not fully explain the extent of hemodynamic compromise. Hemodynamic impairment may also result from inefficiencies in oxygen exchange from vasculature into tissue due to flow disturbances at the capillary level, which have previously been shown to be related to heterogeneities in capillary flow patterns. Recently, we have characterized venous hyperintense signal (VHS) on cerebral blood flow (CBF)-weighted images acquired using arterial spin labeling magnetic resonance imaging (MRI) as a marker of capillary-level flow disturbances and oxygen exchange inefficiency. In this work, we propose to apply noninvasive MRI methods and this novel construct to elucidate associations between tissue-level hemodynamic physiology and WML burden in older APOE-ε4 carriers and non-carriers. Specifically, we will (i) study the effect of microvascular flow disturbances on oxygen exchange efficiency, (ii) investigate the association between microvascular dysfunction and CBF according to APOE genotype, and (iii) identify differences in associations between microvascular physiology and WML burden between APOE-ε4 carriers and non-carriers. Successful completion of this work will determine the degree to which the observed higher burden of WMLs in older adults with APOE-ε4 is associated with mechanisms involving oxygen exchange inefficiency, which are indicated by VHS, versus impaired CBF. These findings could have implications for the titration of different therapeutic approaches for preventing vascular-related cognitive decline in older adults with versus without APOE-ε4.

项目总结