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(T1D)与大脑和认知的改变以及有充分证据的长期病程有关 微血管和大血管并发症。脑变化和认知缺陷对功能性OUT的影响 然而，来了就不太清楚了，而且大多数当前的数据都与T1D青年有关。因此，T1D与信号IF相关联- 除个人费用外，社区和公共卫生负担是 随着全球T1D患病率的上升，T1D的发病率可能会大幅上升。关于以下方面的许多最新信息 T1D结果来自于具有较短随访期的横断面或纵向研究。这些都有 提供了关于T1D对个人的短期影响的丰富数据，但无法识别因果关系- 影响和长期影响。纵向研究考察了个体内部大脑和认知的变化 随着时间的推移，需要更好地定义影响长期外流的特定风险和弹性因素- 来了。皇家儿童医院(RCH)糖尿病队列研究是唯一一项针对个体的前瞻性研究 从童年诊断到成年后的T1D，以及之前的四波数据收集。在基线上， 患有T1D的参与者在智商、特定认知技能或情绪幸福感方面与健康对照组没有区别。 随后的数据收集记录了大脑结构和功能的变化，认知能力下降 在成年早期，与健康对照组相比，T1D患者的功能结局更差。我们现在支持- 提出这一队列的进一步后续行动，澄清研究(对 风险因素30年(澄清)糖尿病并发症研究)，记录大脑、认知和功能- T1D发病后约30年的中年生活结局。我们将使用来自当前研究的纵向数据 并从之前的数据收集中确定哪些血糖侮辱对 大脑/认知以及神经发育的年龄/阶段。我们将检验以下具体假设： 1)在横断面分析中，T1D受试者的脑体积较低，认知分数较低，且较差 与非T1D受试者相比，以及纵向分析中，T1D受试者在成年中期的功能结果 会表现出更大的认知能力下降，这与中期MRI的差异更大相关 成年期，以及诊断后12年至30年内MRI脑体积的更大变化；以及2)高 儿童时期(18岁)的血糖是影响中年人大脑健康的最重要的血糖紊乱决定因素。 生活。此外，青春期前高血糖和大脑结果之间的联系将最为明显。 对于那些有(A)T1D在6岁起病；(B)在早期博览会后出现严重低血糖和/或DKA发作的人- 肯定是高血糖，以及(C)有脑外微血管和/或大血管疾病的证据 成年人的生活。根据经验对血糖神经毒性“风险”进行分层，因为它在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 同时保护发育中的大脑，保护认知功能。

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.