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，它增加了认知障碍和 痴呆症，包括阿尔茨海默病(AD)。在我们之前的工作中，我们已经证明T2 DM与 AD易发部位认知功能下降和脑血流量(CBF)减少 病理学。在大脑发生变化之前确定可能会下降的个体是至关重要的 以便在广泛的脑血管病变和认知改变发生之前进行干预。 大多数先前关于T2 DM认知功能障碍背后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，如脑白质病变(WML)。然而，最近 磁共振成像的进步使非侵入性测量的灵敏方法得以发展。 脑血流量和脑动脉顺应性(AC)，或血管扩张或增加容量的能力 对血压变化的反应。这些方法可能有助于阐明先于 发生不可逆的实质/结构损害，并可能产生重要的危险标志 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有关 在脉搏波速度方面，还没有研究发现T2 DM患者的颅内动脉硬化(即AC降低)。 我们建议在100名老年人样本中评估认知、AC和CBF，并建立MRI标志物CVD 成年2型糖尿病患者和50名非糖尿病对照受试者。参与者将接受实验室测试，以 评估与血糖、心脏代谢健康和神经成像相关的血液标记物，包括新的 动脉自旋标记(ASL)磁共振成像方案，评估基线时的脑动脉顺应性和血流量， 随访12个月，随访24个月。我们的目标是调查早期的变化是否 脑血管功能(即AC和CBF降低)与脑血管病变的MRI标志物和认知有关。 目前提议设立一项研究补充资料，以促进与健康有关的研究的多样性 为Einat Brenner博士提供资金，让她在我的实验室增加一年的博士后奖学金。通过这件事 多样性补充，她建议延长亲本R01，以获得脑源性血清的测量 神经营养因子(BDNF)。她的目标是检查(1)血清BDNF水平降低是否与较低的 脑血流/动脉顺应性和脑源性神经营养因子水平之间的适度相关性 脑血管疾病的血流/动脉顺应性和MRI标志物以及(2)血清BDNF水平降低 与较差的记忆力和执行功能有关，而脑源性神经营养因子水平适中之间的联系 脑血流/动脉顺应性和认知。她的主要目标是制定并提交一份K奖 并学习纵向数据分析。她还将继续学习新的成像技术(例如，动脉旋转 标记以测量脑血流量和动脉顺应性)，并与新的人群(例如，老年人)合作 成年2型糖尿病患者)，为独立研究人员的职业生涯做好准备。

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.