Identifying lifelong factors that impact brain health and outcomes in type 1 diabetes: The Cognition and Longitudinal Assessments of Risk Factors over 30 Years (CLARiFY) Diabetes Complications Study

摘要 1型糖尿病（T1 D）与大脑和认知变化以及有充分记录的长期 微血管和大血管并发症。大脑变化和认知缺陷对功能失调的影响- 然而，目前的数据不太清楚，大多数数据与T1 D青年有关。所以，T1 D是一个有意义的概念。 物质健康和功能性发病率，以及除了个人成本，社区和公共卫生负担， 随着全球T1 D患病率的上升，这一数字可能会显著增加。目前关于 T1 D结局来自随访期较短的横断面或纵向研究。这些都 提供了关于T1 D对个人的短期影响的丰富数据，但无法辨别因果阿索， 影响和长期影响。纵向研究检查大脑和认知的个体内变化， 为了更好地确定影响长期外部环境的具体风险和复原力因素， 来了皇家儿童医院（RCH）糖尿病队列研究是唯一的前瞻性研究的个人 从儿童诊断到成年的T1 D，有四波数据收集。在基线时， 患有T1 D的参与者在智商、特定认知技能或情绪健康方面与健康对照组没有差异。 随后的数据收集记录了大脑结构和功能的变化，认知能力的下降， 与健康对照组相比，T1 D患者在成年早期的功能结局较差。我们现在亲- 提出了进一步的后续行动，这一队列，研究（认知和纵向评估的 糖尿病并发症30年以上危险因素研究），以记录大脑、认知和功能。 T1 D发病后约30年的中年期临床结局。我们将使用当前研究的纵向数据 并从先前的数据收集波中识别哪些血糖损伤对 大脑/认知以及神经发育的年龄/阶段。将检验以下特定假设： 1)在横断面分析中，T1 D受试者的脑容量较低，认知评分较低， 在成年中期的功能结果比非T1 D受试者，在纵向分析中，T1 D受试者 将表现出更大的认知能力下降，这与中期MRI差异更大有关。 成年期，以及诊断后12年至30年MRI脑体积的更大变化;以及2）超 儿童期（<18岁）的血糖水平将是影响中年期大脑健康的最强的血糖障碍决定因素 生活此外，青春期前高血糖症和大脑结果之间的关联将是最明显的 在（a）T1 D发病年龄<6岁;（B）早期暴露后重度低血糖和/或DKA发作的患者中， 一定要高血糖症，和（c）在中期脑外微血管和/或大血管疾病的证据， 成人生活基于经验的血糖神经毒性“风险”分层，因为它在整个生命周期中会发生变化， 允许临床医生提供最佳的临床管理，旨在实现良好的代谢结果， 同时保护发育中的大脑和认知功能。

ABSTRACT Type 1 diabetes (T1D) is associated with brain and cognition changes as well as well-documented longer-term micro- and macrovascular complications. The impact of brain changes and cognitive deficits on functional out- comes, however, is less clear, and most current data relates to T1D youth. Thus, T1D is associated with signif- icant health and functional morbidity, and in addition to personal costs, community and public health burden is significant and likely increasing in line with the rising global T1D prevalence. Much current information about T1D outcomes is derived from cross-sectional or longitudinal studies with short follow-up periods. These have provided rich data about the short-term T1D impact on individuals, but have an inability to discern causal asso- ciations and longer-term effects. Longitudinal studies examining within-individual changes in brain and cogni- tion over time are required to better define specific risk and resilience factors that influence long-term out- comes. The Royal Children’s Hospital (RCH) diabetes cohort study is the only prospective study of individuals with T1D from childhood diagnosis through adulthood, with four previous waves of data collection. At baseline, participants with T1D did not differ from healthy controls on IQ, specific cognitive skills, or emotional well-being. Subsequent waves of data collection documented structural and functional brain changes, cognitive decre- ments, and poorer functional outcome in T1D compared to healthy controls into early adulthood. We now pro- pose a further follow-up of this cohort, the CLARiFY study (The Cognition and Longitudinal Assessments of Risk Factors over 30 Years (CLARiFY) Diabetes Complications Study), to document brain, cognition, and func- tional outcomes in mid-adult life ~30 years after T1D onset. We will use longitudinal data from the current study and from previous waves of data collection to identify which glycemic insults are most detrimental to the brain/cognition and at which age/stage of neurodevelopment. The following specific hypotheses will be tested: 1) in cross-sectional analyses, T1D subjects will have lower brain volumes, lower cognitive scores, and poorer functional outcomes at middle adulthood than non-T1D subjects, and in longitudinal analyses, T1D subjects will exhibit a greater decline in cognitive performance that associates with greater MRI differences at middle adulthood, and greater change in MRI brain volumes from 12 years to 30 years post-diagnosis; and 2) hyper- glycemia in childhood (<18 years) will be the strongest dysglycemic determinant of brain health in mid-adult life. Further, the association between pre-pubertal hyperglycemia and brain outcomes will be most pronounced in those with (a) T1D onset at <6 years of age; (b) severe hypoglycemia and/or DKA episodes after early expo- sure to hyperglycemia, and (c) evidence of extra-cerebral microvascular and/or macrovascular disease in mid- adult life. An empirically based stratification of glycemic neurotoxic ‘risk’ as it varies across the life cycle would allow clinicians to offer optimal clinical management designed to both achieve good metabolic outcomes while at the same time protecting the developing brain and preserving cognitive function.