GLYCEMIC CONTROL, BRAIN STRUCTURE AND COGNITION IN YOUTH WITH T1DM

描述（由申请人提供）：该提案是R01 DK64832的竞争性更新，先前标题为“T1DM中低血糖的神经认知效应”。该研究假设先前的严重低血糖会降低青年1型糖尿病（T1DM）患者的记忆和海马体积。在解决这个相对狭窄的问题的过程中，我们收集了一个独特的大型T1DM青年发育神经成像和认知数据集，现在允许我们研究更广泛和更复杂的问题。鉴于新的数据和假设，我们将该项目重新命名为“糖尿病患者的血糖控制、大脑结构和认知发展”。我们现在能够确定严重低血糖症（Hypo）和慢性高血糖症（Hyper）对大脑区域发育轨迹的不同影响，以及这些结构影响是否反映在认知功能的变化中。在我们迄今为止的分析中，我们发现患有T1DM的青年严重Hypo的回顾性病史与后颞顶叶皮质体积减少和记忆能力下降有关。相反，在这些青年中回顾Hyper病史与内侧枕顶叶皮质体积减小和语言智力降低有关。这些结果与越来越多的证据一致，即暴露于极端血糖对这些皮质区域的结构和功能完整性有永久性的影响。然而，这些数据来自回顾性研究，因此因果关系的方向只能是假设的。为了解决这种模糊性，非常需要前瞻性数据。我们之前的资助招募并描述了大量T1DM青年样本，并对他们进行了两年的随访。我们现在有了新的初步前瞻性数据，证明在两年的随访期间，大脑灰质和白质的发育轨迹与高暴露有关。然而，在此期间，严重Hypo的低频率使我们无法测试关于Hypo对大脑发育影响的假设。为了获得更广泛的接触范围并增强我们测试假设的能力，我们建议对这一独特特征的队列进行3年以上的随访，以评估T1DM患者在整整5年的时间里大脑结构和认知功能的变化。此外，根据新的初步数据表明，除了局部脑容量外，暴露于Hyper还会影响白质微结构完整性（通过扩散张量成像或DTI测量），我们建议添加最先进的DTI测量来补充我们现有的测量方法。最后，为了更确切地确定T1DM在基线时是否有任何差异，我们将在我们的纵向研究中增加一个新诊断的队列。该计划结合我们的神经成像专业知识和现有的良好特征队列，使我们处于一个独特的位置，可以测试关于极端血糖、大脑结构完整性和认知功能在青年T1DM患者中如何相关的强有力假设。公共卫生相关性：该项目的目的是帮助确定在T1DM的发展过程中，中枢神经系统的结构和功能是否应该加入周围神经系统、视网膜和肾脏的危险系统。这一知识将对青年T1DM患者的最佳护理具有重要的临床意义。

DESCRIPTION (provided by applicant): This proposal is a competitive renewal of R01 DK64832 previously titled "Neurocognitive effects of hypoglycemia in T1DM". That grant hypothesized that prior severe hypoglycemia would reduce memory and hippocampal volume in youth with type 1 diabetes mellitus (T1DM). In the process of addressing this relatively narrow question, we have collected a uniquely large developmental neuroimaging and cognitive dataset in youth with T1DM that now allows us to examine broader and more complex issues. In light of new data and hypotheses, we have renamed the grant "Glycemic control, brain structure and cognitive development in T1DM". We now are able to address whether there is a differential effect of severe hypoglycemia (Hypo) and chronic hyperglycemia (Hyper) on the developmental trajectories of brain regions and whether these structural effects are reflected in changes in cognitive function. In our analyses to date, we found that a retrospective history of severe Hypo in youth with T1DM was associated with reduced volume in the posterior temporal- parietal cortex and reduced memory skills. In contrast, a retrospective history of Hyper in these same youth was associated with reduced volume in medial occipital-parietal cortex and lower verbal intelligence. These results are consistent with growing evidence that exposure to glycemic extremes has permanent consequences for the structural and functional integrity of these cortical regions. However, these data have come from retrospective studies and so the direction of causality can only be hypothesized. To address this ambiguity, prospective data are greatly needed. Our prior grant enrolled and characterized a large sample of youth with T1DM and followed them for two years. We now have new preliminary prospective data that demonstrate altered developmental trajectories of gray and white matter in the brain related to Hyper exposure during a 2 year follow-up period. However, the low frequency of severe Hypo during this time did not allow us to test hypotheses about Hypo's effects on brain development. To capture a wider range of exposure and enhance our power to test hypotheses we propose to follow this uniquely characterized cohort for 3 more years to assess change in brain structure and cognitive function over a full 5 years of T1DM. In addition, on the basis of new preliminary data suggesting that exposure to Hyper affects white matter microstructural integrity (measured with diffusion tensor imaging or DTI) in addition to regional brain volume, we propose to add state- of-the-art DTI measures to complement our existing measures. Finally, in order to more conclusively determine whether there are any differences at baseline in T1DM, we will add a newly diagnosed cohort to our longitudinal study. This plan, combined with our neuroimaging expertise and well-characterized existing cohort, places us in a unique position to test strong hypotheses about how glycemic extremes, brain structural integrity and cognitive function are related in youth with T1DM. PUBLIC HEALTH RELEVANCE: The goal of this project is to help determine whether central nervous system structure and function should join the peripheral nervous system, retina and kidneys as systems at risk during development in T1DM. This knowledge would have significant clinical implications for the optimal care of youth with T1DM.