Effects of Biomedical Risk Factors on Neuro-cognition Using MRI: Long term follow-up of the Diabetes Control & Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Cohort

摘要 1型糖尿病患者神经认知损害的程度、性质和发病机制 (T1 DM)则知之甚少。T1糖尿病患者的寿命更长，因此通常进入一个年龄 (50+)当这种损害变得更加明显，但尚未得到充分研究时。过去，小规模的研究 提示可能受T1 DM影响的认知、大脑结构、功能和化学方面 随着年龄的增长，严重程度和临床重要性增加。糖尿病控制与并发症 糖尿病干预和并发症试验/流行病学(DCCT/EDIC)研究提供了无与伦比的 有机会使用从病程早期收集的30多年的纵向数据，在这口井中 特点的队列，以检查重要的和悬而未决的问题的频率和发病机制 当患者进入最高风险年龄时，神经认知障碍。DCCT/EDIC参与者拥有 持续高的参与率(目前占幸存队列的94%)，现在正在返回 为正在进行的生物医学评估和新的生物医学评估提供额外五年的后续行动(2017-2022年)，包括 认知功能和抑郁的评估。本申请书是根据RFA-DK-16-007号文件提交的， 将利用从过去的评估和新的计划5年中收集的可用数据 后续行动。我们计划评估风险因素的影响，包括：暴露于高血糖，如 DCCT/EDIC期间的HbA1c测量，反复发生的严重低血糖事件，使用 连续血糖监测(CGM)、高血压、高脂血症病史和微量 磁共振评估脑血管和大血管并发症对大脑完整性的影响 一项新的研究评估了脑部变化与神经视网膜变性之间的关系 方法：眼相干断层扫描(OCT)。我们假设T1 DM的存在，之前的常规 DCCT治疗分配、HbA1c水平升高和严重低血糖病史将导致 总脑体积，我们的主要结果，也导致可检测到的血管，神经退行性变，神经- 通过磁共振成像评估化学和功能的变化。此外，我们假设这些主要风险因素在 与其他次要危险因素(如：血糖变化、高血压、微血管和大脑血管)的一致性 血管疾病)，将不同程度地影响额区和颞区。大脑的变化将与 认知功能下降，特别是在精神运动效率方面。为了实现这些目标 从DCCT/EDIC队列中随机选择400名T1 DM患者，代表广泛的生物医学 结果将与年龄和社会/教育程度相似的非糖尿病对照组人群(n=100)进行比较 背景使用相同的认知和神经成像技术。这些目标的完成将决定 T1 DM患者神经认知损害的关键预测因素并指导个性化策略 在为T1 DM患者提供临床护理时降低这一风险。

Abstract The extent, nature and pathogenesis of neuro-cognitive impairments among individuals with type 1 diabetes (T1DM) are poorly understood. Patients with T1DM are living longer and thus are commonly entering an age (50+) when such impairments become more evident, but are, as yet, understudied. Past, small studies suggest aspects of cognition, brain structure, function and chemistry that may be affected by T1DM and may increase in severity and clinical importance with aging. The Diabetes Control & Complications Trial/Epidemiology of Diabetes Interventions & Complications (DCCT/EDIC) study affords an unparalleled opportunity to use longitudinal data gathered over 30 years from early in the course of illness, among this well- characterized cohort, to examine important and unresolved questions about the frequency and pathogenesis of neuro-cognitive impairments as patients enter the age of highest risk. DCCT/EDIC participants have had continuously high rates of participation (currently 94% of the surviving cohort), and are now returning for an additional five years of follow-up (2017-2022) for ongoing and new biomedical assessments including evaluation of cognitive functioning and depression. This application, submitted in response to RFA-DK-16-007, will leverage available data collected in this cohort from past evaluations and from the new planned 5-year follow-up. We plan to assess effects of risk factors including: exposure to hyperglycemia as documented by HbA1c measurements during DCCT/EDIC, recurrent severe hypoglycemic events, variation in glycemia using continuous glucose monitoring (CGM ), history of hypertension, hyperlipidemia, and presence of micro- vascular and macro-vascular complications on the integrity of the brain evaluated by magnetic resonance imaging (MRI), and the association of brain changes with neuro-retinal degeneration assessed by a novel method-Ocular Coherence Tomography (OCT). We hypothesize that the presence of T1DM, prior conventional DCCT treatment assignment, elevated HbA1c levels and history of severe hypoglycemia will lead to reduced total brain volume, our primary outcome, and also result in detectable vascular, neuro-degenerative, neuro- chemical and functional changes assessed by MRI. In addition, we postulate that these primary risk factors in concert with other secondary risk factors (e.g.: glycemic variation, hypertension & micro-vascular and macro- vascular disease), will differentially affect frontal & temporal regions. Changes in the brain will be associated with decreased cognitive functioning, especially on measures of psychomotor efficiency. To reach these goals 400 T1DM subjects from the DCCT/EDIC cohort randomly selected to represent a broad range of biomedical outcomes will be compared with a non-diabetic control population (n=100) of similar age and social/educational background using identical cognitive and neuro-imaging techniques. Completion of these aims will determine key predictors of neuro-cognitive impairments in patients with T1DM and guide personalized strategies to mitigate this risk in providing clinical care for patients with T1DM.