Cerebral arterial compliance, blood flow, and cognition in Veterans with diabetes

患有糖尿病的退伍军人的脑动脉顺应性、血流和认知

• 批准号: 10295158
• 负责人: Katherine Bangen
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295158
• 关键词: Address; Adult; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Autopsy; Biological Markers; Blood Pressure; Blood flow; Brain; Caring; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Cognition; Cognitive; Control Groups; Dementia; Development; Diabetes Mellitus; Diagnosis; Disease Marker; Endothelium; Glycosylated hemoglobin A; Goals; Health; Hippocampus (Brain); Image; Impaired cognition; Individual; Infarction; Inflammation; Intervention; Laboratories; Lead; Lesion; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Memory; Methods; Microvascular Dysfunction; Nerve Degeneration; Neuropsychology; Non-Insulin-Dependent Diabetes Mellitus; Nursing Homes; Participant; Peripheral; Physiologic pulse; Populations at Risk; Public Health; Quality of life; Research; Resolution; Risk; Risk Factors; Risk Marker; Sampling; Site; Testing; Veterans; White Matter Hyperintensity; arterial spin labeling; arterial stiffness; blood-based biomarker; brain health; cerebral microbleeds; cerebrovascular; cerebrovascular lesion; cognitive change; cognitive function; cognitive performance; dementia risk; disability; early detection biomarkers; endothelial dysfunction; executive function; experience; high risk population; imaging biomarker; imaging modality; improved; improved outcome; interest; magnetic resonance imaging biomarker; medication compliance; method development; middle age; neuroimaging; non-diabetic; novel; response; tau Proteins; tau-1; white matter

Type 2 diabetes mellitus (T2DM), which is highly prevalent among Veterans, increases the risk of cognitive impairment and dementia, including Alzheimer’s disease (AD). We have shown that T2DM—even during midlife—is associated with steeper cognitive decline, reduced cerebral blood flow (CBF) in regions that are predilection sites for AD pathology, and greater neuropathologic changes at autopsy (Bangen et al., 2013; Bangen et al., 2016; Bangen et al., in prep). Identifying individuals who are most likely to decline prior to the occurrence of significant brain changes is essential, so that interventions can be applied before extensive cerebrovascular lesions and cognitive changes develop. Accordingly, studies investigating incipient cognitive and neuroimaging changes in middle age when neuropathologic changes are already occurring are critical to optimize brain health and improve outcomes in T2DM and other high-risk populations. Most previous neuroimaging studies of brain changes underlying cognitive impairment in T2DM have applied conventional structural magnetic resonance imaging (MRI) to detect end-stage macrostructural changes associated with cerebrovascular disease (CVD) such as white matter hyperintensities (WMH) and infarcts. However, recent advances in MRI have allowed for the development of sensitive, sophisticated methods for the non-invasive measurement of cerebral blood flow (CBF) and cerebral arterial compliance (AC), or the ability of vessels to distend or increase in volume in response to changes in blood pressure. Such methods may help elucidate the mechanisms that precede the development of irreversible parenchymal/structural damage and may also yield important markers of risk for cognitive decline in at-risk populations. Although T2DM has been associated with peripheral arterial stiffening using carotid-femoral pulse wave velocity, no studies have examined intracranial arterial stiffening (i.e., decreased AC) in the context of T2DM. We therefore propose to advance the field by assessing neuropsychological functioning, macrovascular AC and microvascular CBF, and established MR markers of AD and cerebrovascular disease in a sample of 120 middle-aged Veterans with and without a diagnosis of T2DM (aged 45-60). Participants will undergo comprehensive neuropsychological assessment; laboratory testing to assess blood-based markers related to glycemia, inflammation, and endothelial function; CSF measurement of amyloid and tau; and neuroimaging exams including high resolution structural imaging and highly novel arterial spin labeling (ASL) MRI methods that estimate cerebral arterial compliance and blood flow. The goals of this project are to investigate whether early changes in cerebrovascular functioning (i.e., reduced AC and CBF) relate to MRI markers of CVD lesions, AD markers, and cognition in T2DM. We will also investigate whether potentially modifiable factors such as inflammation and endothelial dysfunction alter associations between AC, CBF, CVD markers, AD markers, and cognition. Findings will help address an important and pressing public health need by identifying biomarkers of cognitive decline in T2DM and elucidating potentially modifiable mechanisms underlying these changes. Results are also expected to assist in facilitating targeted interventions in order to reduce dementia risk while improving the health and functioning of Veterans with T2DM.

2型糖尿病(T2 DM)在退伍军人中非常普遍，它增加了认知风险 损害和痴呆，包括阿尔茨海默病(AD)。我们已经证明，T2 DM-即使在 中年-与以下区域的认知能力急剧下降、脑血流量(CBF)减少有关 AD病理的好发部位和尸检时更大的神经病理改变(Bangen等人，2013； 班根等人，2016；班根等人，正在准备中)。确定在此之前最有可能拒绝的个人 发生重大的脑部变化是必不可少的，这样才能在广泛的干预之前应用 脑血管损伤和认知改变会发生。因此，调查早期认知的研究 在已经发生神经病理变化的中年，神经成像的变化是关键的 优化大脑健康，改善T2 DM和其他高危人群的预后。 大多数先前对T2 DM认知障碍潜在的脑变化的神经成像研究 应用常规结构磁共振成像(MRI)检测终末期宏观结构 与脑血管疾病(CVD)相关的变化，如白质高信号(WMH)和 脑梗塞。然而，核磁共振的最新进展使敏感、复杂的 脑血流量(CBF)和脑动脉顺应性(AC)的无创测量方法 或血管因血压变化而扩张或增加体积的能力。是这样的 方法可能有助于阐明不可逆发展之前的机制。 实质/结构损害，也可能是高危患者认知功能下降的重要危险标志 人口。尽管T2 DM与使用颈动脉-股动脉搏动的外周动脉硬化有关 波速度方面，还没有研究在脑血管疾病的背景下检查颅内动脉硬化(即，AC降低) T2 DM。 因此，我们建议通过评估神经心理功能、大血管AC来推进这一领域 和微血管CBF，并在120例样本中建立AD和脑血管疾病的MR标志物 中年退伍军人合并和不合并2型糖尿病(45~60岁)。参赛者将接受 全面的神经心理评估；实验室测试，以评估与 血糖、炎症和内皮功能；脑脊液淀粉样蛋白和tau的测量；以及神经成像 检查包括高分辨率结构成像和高度新颖的动脉自旋标记(ASL)MRI方法 来评估大脑动脉的顺应性和血流量。这个项目的目标是调查 脑血管功能的早期改变(即AC和CBF减少)与脑血管疾病的MRI标志物有关 2型糖尿病患者的病变、AD标志物与认知功能我们还将调查潜在的可修改因素 如炎症和内皮功能障碍改变了AC、CBF、CVD标记物、AD之间关系 记号笔和认知。这些发现将有助于解决一个重要而紧迫的公共卫生需求，通过确定 2型糖尿病认知功能减退的生物标志物及其潜在的可改变机制 改变。预计结果还将有助于促进有针对性的干预，以减少痴呆 改善2型糖尿病退伍军人健康和功能的风险。