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 病理学（Bangen等人，2018; Bangen等人，准备中）。确定最有可能下降的个人 重要的是，在发生重大的大脑变化之前， 出现广泛的脑血管病变和认知改变。研究调查早期认知和 痴呆症发展之前的大脑变化对于优化大脑健康和改善结果至关重要。 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）。 因此，我们建议通过纵向评估神经心理功能，AC 和CBF，并在150名老年人（年龄65-85岁）的样本中建立了MRI标记物CVD，其中包括100名 T2 DM和50名非糖尿病对照受试者。参与者将接受全面的神经心理学检查 评估;实验室检测，以评估与心脏和心脏代谢健康相关的血液标志物; 和神经影像学检查，包括高分辨率结构成像和新型动脉自旋标记（ASL） 评估基线、12个月随访时脑动脉顺应性和血流量的MRI方案，以及 24-月跟进。我们的目标是研究脑血管功能的早期变化（即， AC和CBF减少）与T2 DM中CVD病变和认知的MRI标记物有关。我们亦会研究 糖尿病相关因素（例如，持续时间、血糖控制）和共病心脏代谢疾病 (e.g.,高血压）AC、CBF、CVD标志物和认知之间的中度相关性。发现将有助于 通过识别T2 DM认知功能下降的标志物并阐明 这些变化背后潜在的可修改机制。结果还可能有助于促进有针对性的 考虑到认知功能障碍的存在，干预可能会影响剂量和更广泛的管理， T2 DM患者。

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 (Bangen et al., 2018; 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. Studies investigating incipient cognitive and brain changes prior to the development of dementia are critical to optimize brain health and improve outcomes. 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 therefore propose to advance the field by longitudinally assessing neuropsychological functioning, AC and CBF, and established MRI markers CVD in a sample of 150 older adults (aged 65-85) including 100 with T2DM and 50 non-diabetic control participants. Participants will undergo comprehensive neuropsychological assessment; laboratory testing to assess blood-based markers related to glycemia and cardiometabolic health; and neuroimaging exams including high resolution structural imaging and 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 in T2DM. We will also investigate whether diabetes related factors (e.g., duration, glycemic control) and comorbid cardiometabolic conditions (e.g., hypertension) moderate associations between AC, CBF, CVD markers, and cognition. Findings will help address an important public health need by identifying markers of cognitive decline in T2DM and elucidating potentially modifiable mechanisms underlying these changes. Results may also assist in facilitating targeted interventions given that presence of cognitive dysfunction may affect both dosing and broader management of individuals with T2DM.