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功能损害的程度、性质和发病机制 （T1DM）知之甚少。T1DM患者的寿命更长，因此通常进入一个年龄段， (50+）当这种损害变得更加明显，但尚未得到充分研究时。过去，小型研究 提示可能受T1DM影响的认知、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。糖尿病控制及并发症 糖尿病干预措施和并发症的试验/流行病学（DCCT/EDIC）研究提供了一个无与伦比的 有机会使用从疾病早期收集的30多年的纵向数据，其中， 特征性队列，以检查有关的频率和发病机制的重要和未解决的问题， 随着患者进入高危年龄，神经认知障碍。DCCT/EDIC参与者已经 持续高参与率（目前存活队列的94%），现在正在返回 对正在进行的和新的生物医学评估进行额外5年随访（2017 - 2022），包括 认知功能和抑郁症的评估。本申请是根据RFA-DK-16 - 007提交的， 将利用从过去的评估和新的计划5年中收集的该队列的可用数据， 随访我们计划评估风险因素的影响，包括： DCCT/EDIC期间的HbA1c测量值、复发性重度低血糖事件、使用中的变化 动态葡萄糖监测（CGM）、高血压、高脂血症病史和存在微- 血管和大血管并发症对脑完整性的磁共振评价 影像学（MRI），以及大脑变化与神经视网膜变性的关联，通过一种新的评估方法， 方法-眼相干断层扫描（OCT）。我们假设存在T1DM，既往常规 DCCT治疗分配、HbA1c水平升高和重度低血糖病史将导致 总脑容量，我们的主要结果，也导致可检测的血管，神经退行性，神经- 通过MRI评估的化学和功能变化。此外，我们假设，这些主要的风险因素， 与其他次要风险因素（例如：血糖变化，高血压和微血管和宏观， 血管疾病），将不同地影响额部和颞部区域。大脑的变化会与 认知功能下降，特别是在心理效率的测量上。达到这些目标 从DCCT/EDIC队列中随机选择400例T1DM受试者，以代表广泛的生物医学 结果将与年龄和社会/教育相似的非糖尿病对照人群（n = 100）进行比较 背景技术使用相同的认知和神经成像技术。这些目标的实现将决定 T1DM患者神经认知障碍的关键预测因素，并指导个性化策略， 在为T1DM患者提供临床护理时降低该风险。

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.