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: 10578665
• 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/10578665
• 关键词: Address; Adult; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Autopsy; Blood Pressure; Blood flow; Brain; Caring; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Cognition; Cognitive; Control Groups; Dementia; Development; Diabetes Mellitus; Diagnosis; Disease Marker; Early identification; Endothelium; Femur; Glycosylated hemoglobin A; Goals; Health; Hemorrhage; Hippocampus; Impaired cognition; Individual; Infarction; Inflammation; Intervention; Laboratories; 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; aged; arterial spin labeling; arterial stiffness; biomarker identification; 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; improved; improved outcome; interest; magnetic resonance imaging biomarker; medication compliance; method development; middle age; neuroimaging; neuropathology; non-diabetic; novel; response; structural imaging; 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，增加了认知功能障碍的风险。 损伤和痴呆，包括阿尔茨海默病（AD）。我们已经证明，T2 DM-即使在 中年-与认知能力的急剧下降有关， AD病理学的好发部位和尸检时更大的神经病理学变化（Bangen等人，二〇一三年; Bangen等人，2016; Bangen等人，准备中）。确定最有可能下降的人 重要的大脑变化的发生是必不可少的，这样，在广泛的 脑血管病变和认知改变。因此，研究早期认知 在已经发生神经病理学变化的中年，神经影像学变化对于 优化大脑健康，改善T2 DM和其他高危人群的预后。 大多数先前关于T2 DM认知障碍相关脑变化的神经影像学研究， 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，如白色高信号（WMH）和 梗塞然而，MRI的最新进展已经允许开发敏感的、复杂的 脑血流量（CBF）和脑动脉顺应性（AC）的非侵入性测量方法， 或血管响应血压变化而扩张或增加体积的能力。等 这些方法可能有助于阐明不可逆性糖尿病发展之前的机制。 实质/结构损伤，也可能产生风险中认知能力下降的重要风险标志物。 人口。尽管使用颈动脉-股动脉脉搏发现T2 DM与外周动脉硬化相关， 波速度，没有研究检查颅内动脉硬化（即，AC降低）， 2型糖尿病。 因此，我们建议通过评估神经心理功能，大血管AC 和微血管CBF，并在120例样本中建立了AD和脑血管疾病的MR标记物 有和没有诊断为T2 DM的中年退伍军人（45-60岁）。参与者将经历 全面的神经心理学评估;实验室测试，以评估血液相关的标记物 炎症和内皮功能;淀粉样蛋白和tau蛋白的CSF测量;神经影像学 包括高分辨率结构成像和高度新颖的动脉自旋标记（ASL）MRI方法的检查 来评估脑动脉顺应性和血流量。该项目的目标是调查是否 脑血管功能的早期变化（即，AC和CBF降低）与CVD的MRI标志物相关 病变、AD标志物和认知。我们还将调查潜在的可修改因素 例如炎症和内皮功能障碍改变AC、CBF、CVD标志物、AD 标记和认知。调查结果将有助于解决一个重要和紧迫的公共卫生需求， 2型糖尿病认知功能下降的生物标志物，并阐明这些生物标志物的潜在可改变机制 变化研究结果还有望有助于促进有针对性的干预措施，以减少痴呆症 同时改善T2 DM退伍军人的健康和功能。

项目成果

Longitudinal Intraindividual Cognitive Variability Is Associated With Reduction in Regional Cerebral Blood Flow Among Alzheimer's Disease Biomarker-Positive Older Adults.

• DOI: 10.3389/fnagi.2022.859873
• 发表时间: 2022
• 期刊: Frontiers in aging neuroscience
• 影响因子: 4.8

White Matter Microstructure is Associated with Serum Clusterin and Everyday Functioning in a Sample of Nondemented Older Adults.

在非痴呆老年人样本中，白质微观结构与血清簇蛋白和日常功能相关。

• DOI: 10.2174/1567205019666211227102350
• 发表时间: 2021
• 期刊: Current Alzheimer research
• 影响因子: 2.1
• 作者: Clark,AlexandraL;Solders,SeraphinaK;Thomas,KelseyR;Bangen,KatherineJ
• 通讯作者: Bangen,KatherineJ

Relationship between Retinal Vascular Occlusions and Cognitive Dementia in a Large Cross-Sectional Cohort.

大型横截面队列中视网膜血管闭塞与认知痴呆之间的关系。

• DOI: 10.1016/j.ajo.2021.01.026
• 发表时间: 2021-06
• 期刊: AMERICAN JOURNAL OF OPHTHALMOLOGY
• 影响因子: 4.2
• 作者: Chan, Alison X.;Bakhoum, Christine Y.;Bangen, Katherine J.;Bakhoum, Mathieu F.
• 通讯作者: Bakhoum, Mathieu F.