Intracranial arterial compliance, cerebral blood flow, and dementia risk in older adults with type 2 diabetes

2型糖尿病（T2 DM）的患病率正在上升，增加了认知障碍的风险， 痴呆，包括阿尔茨海默病（AD）。在我们之前的工作中，我们已经表明T2 DM与以下因素相关： 在AD的好发部位，认知能力下降更快，脑血流量（CBF）减少 病理在大脑发生变化之前，识别出哪些人可能会下降是至关重要的 这样就可以在广泛的脑血管病变和认知变化发生之前进行干预。 大多数先前关于T2 DM认知功能障碍的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，如白色病变（WML）。但最近的 MRI的进步已经允许开发用于非侵入性测量的灵敏方法， CBF和脑动脉顺应性（AC），或血管扩张或体积增加的能力， 对血压变化的反应。这些方法可能有助于阐明发生在细胞凋亡之前的机制。 不可逆的实质/结构损伤的发展，并可能产生重要的风险标志物， 认知能力下降尽管T2 DM与使用颈动脉-股动脉的外周动脉硬化相关， 脉搏波速度，没有研究检查颅内动脉硬化（即，AC降低）。 我们建议在100名老年人中评估认知、AC和CBF，并建立MRI标记物CVD。 成人T2 DM和50名非糖尿病对照参与者。参与者将接受实验室测试， 评估与心血管和心脏代谢健康和神经影像学相关的血液标志物，包括新的 动脉自旋标记（ASL）MRI方案，用于估计基线时的脑动脉顺应性和血流量， 12-1个月随访和24个月随访。我们的目标是调查是否早期的变化， 脑血管功能（即，AC和CBF降低）与CVD损伤和认知的MRI标记物有关。 目前关于编写研究补编以促进与卫生有关的研究的多样性的建议将 为Einat Brenner博士提供资金，以增加她在我实验室的一年博士后研究金。通过这个 为了补充多样性，她建议延长母体R 01，以获得脑源性血清指标。 神经营养因子（BDNF）。她的目的是研究（1）血清BDNF水平的降低是否与降低 脑血流量/动脉顺应性和BDNF水平之间存在中度相关性 血流/动脉顺应性和脑血管疾病的MRI标记物，以及（2）降低血清BDNF水平 与记忆力和执行功能较差有关，BDNF水平调节了记忆力和执行功能之间的关联。 脑血流/动脉顺应性和认知。她的主要目标是开发和提交K奖 学习纵向数据分析。她还将继续学习新的成像技术（例如，动脉自旋 标记以测量脑血流量和动脉顺应性）并与新群体一起工作（例如，老年 成年T2 DM患者），为她作为独立研究人员的职业生涯做准备。

Type 2 diabetes mellitus (T2DM), which is rising in prevalence, increases risk of cognitive impairment and dementia, including Alzheimer’s disease (AD). In our prior work we have shown that T2DM is associated with steeper cognitive decline and reduced cerebral blood flow (CBF) in regions that are predilection sites for AD pathology. Identifying individuals who are likely to decline prior to the occurrence of brain changes is essential so that interventions can be applied before extensive cerebrovascular lesions and cognitive changes develop. Most previous neuroimaging studies of brain changes underlying cognitive dysfunction 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 lesions (WML). However, recent advances in MRI have allowed for the development of sensitive methods for the non-invasive measurement of 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 mechanisms that precede the development of irreversible parenchymal/structural damage and may yield important markers of risk for cognitive decline. 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 T2DM. We propose to assess cognition, AC and CBF, and established MRI markers CVD in a sample of 100 older adults with T2DM and 50 non-diabetic control participants. Participants will undergo laboratory testing to assess blood-based markers related to glycemia and cardiometabolic health and neuroimaging including novel arterial spin labeling (ASL) MRI protocols that estimate cerebral arterial compliance and blood flow at baseline, 12-month follow up, and 24-month follow up. Our goals are to investigate whether early changes in cerebrovascular functioning (i.e., reduced AC and CBF) relate to MRI markers of CVD lesions and cognition. The current proposal for a research supplement to promote diversity in health-related research would provide funding for Dr. Einat Brenner to add one year to her postdoctoral fellowship in my lab. Through this diversity supplement, she is proposing to extend the parent R01 to obtain serum measures of brain-derived neurotrophic factor (BDNF). Her aims examine whether (1) reduced serum BDNF levels relate to lower cerebral blood flow/arterial compliance and BDNF levels moderate associations between cerebral blood flow/arterial compliance and MRI markers of cerebrovascular disease and (2) reduced serum BDNF levels relate to poorer memory and executive functioning and BDNF levels moderate the associations between cerebral blood flow/arterial compliance and cognition. Her primary goals are to develop and submit a K-award and learn longitudinal data analysis. She will also continue to learn new imaging techniques (e.g., arterial spin labeling to measure cerebral blood flow and arterial compliance) and work with new populations (e.g., older adults with T2DM) to prepare her for a career as an independent researcher.