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) 与大脑和认知变化以及有据可查的长期变化有关 微血管和大血管并发症。大脑变化和认知缺陷对功能输出的影响 然而，具体情况还不太清楚，目前大多数数据都与 T1D 青少年有关。因此，T1D 与显着相关 巨大的健康和功能发病率，除了个人成本之外，社区和公共卫生负担也很严重 随着全球 T1D 患病率的上升，这一数字显着增加，并且可能会增加。目前有很多关于 T1D 结果源自短期随访的横断面或纵向研究。这些有 提供了有关 T1D 对个人的短期影响的丰富数据，但无法辨别因果关系 论文和长期影响。纵向研究检查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结果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针对个体的前瞻性研究 T1D 从儿童诊断到成年，之前有四波数据收集。在基线处， 患有 T1D 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者没有差异。 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 与成年早期的健康对照相比，T1D 患者的功能结果较差。我们现在亲 CLARiFY 研究（The Cognition and Longitudinal Assessments of 30 年来的危险因素 (CLARiFY) 糖尿病并发症研究），记录大脑、认知和功能 T1D 发病后约 30 年的中年生活的结局。我们将使用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损伤对身体最有害 大脑/认知以及神经发育的年龄/阶段。将测试以下具体假设： 1) 在横断面分析中，T1D 受试者的脑容量较低，认知得分较低，且较差 成年中期的功能结果高于非 T1D 受试者，并且在纵向分析中，T1D 受试者 认知能力会表现出更大的下降，这与中层的 MRI 差异更大有关 成年期，诊断后 12 至 30 年间 MRI 脑体积变化较大； 2）超 儿童期（<18 岁）的血糖将是中年人大脑健康的最强血糖异常决定因素 生活。此外，青春期前高血糖与大脑结果之间的关联最为明显 (a) 1 型糖尿病 (T1D) 在 6 岁以下发病； (b) 早期暴露后严重低血糖和/或 DKA 发作 肯定有高血糖，以及（c）中年有脑外微血管和/或大血管疾病的证据 成人生活。根据经验对血糖神经毒性“风险”进行分层，因为它在整个生命周期中会有所不同 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并保持认知功能。

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.