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(班根等人，2018年；班根等人，在准备中)。确定最有可能拒绝的人 在大脑发生重大变化之前是必不可少的，这样才能在 出现广泛的脑血管病变和认知改变。调查早期认知和认知的研究 痴呆症发生前的大脑变化对于优化大脑健康和改善预后至关重要。 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)。 因此，我们建议通过纵向评估神经心理功能来推动这一领域的发展 和CBF，并在150名老年人(65-85岁)中建立了MRI标志物CVD，其中包括100名患有 T2 DM组和50例非糖尿病对照组。参与者将接受全面的神经心理学 评估；实验室测试，以评估与血糖和心脏代谢健康有关的血液标志物； 和神经成像检查，包括高分辨率结构成像和新的动脉自旋标记(ASL) MRI方案评估基线、12个月随访的脑动脉顺应性和血流量 24个月随访。我们的目标是调查脑血管功能的早期变化(即， AC和CBF降低)与T2 DM患者脑血管病变的MRI标志物和认知功能有关。我们还将调查 糖尿病相关因素(如病程、血糖控制)和共病的心脏代谢状况 (例如，高血压)AC、CBF、CVD标记物和认知之间的中度关联。调查结果将有所帮助 通过确定T2 DM认知功能下降的标志物并阐明 这些变化背后的潜在可修改机制。结果也可能有助于促进定向 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 2型糖尿病患者。

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.