GLYCEMIC CONTROL, BRAIN STRUCTURE AND COGNITION IN YOUTH WITH T1DM

描述(由申请人提供)：本提案是R01 DK64832的竞争性续订，以前的标题为“T1 DM患者低血糖的神经认知效应”。这项资助假设先前的严重低血糖会降低患有1型糖尿病(T1 DM)的青年患者的记忆力和海马体体积。在解决这个相对狭隘的问题的过程中，我们收集了一个独特的大型发育神经成像和认知数据集，该数据集针对患有T1 DM的青年，现在使我们能够检查更广泛和更复杂的问题。根据新的数据和假设，我们将这项研究重新命名为“T1 DM患者的血糖控制、脑结构和认知发展”。我们现在能够解决严重低血糖(Hypo)和慢性高血糖(Hyper)对大脑区域发育轨迹的不同影响，以及这些结构性影响是否反映在认知功能的变化上。在我们到目前为止的分析中，我们发现，在患有T1 DM的青年患者中，回顾严重低血症的病史与后颞叶-顶叶皮质体积减少和记忆技能下降有关。相比之下，在这些年轻人中，回顾Hyper的病史与枕顶内侧皮质体积减少和言语智商降低有关。这些结果与越来越多的证据一致，即暴露在极端血糖环境中会对这些皮质区域的结构和功能完整性产生永久性后果。然而，这些数据来自回溯性研究，因此因果关系的方向只能是假设的。为了解决这种模棱两可的问题，非常需要前瞻性的数据。我们之前的资助招募了一大批患有T1 DM的年轻人，并对他们进行了两年的跟踪调查。我们现在有了新的初步前瞻性数据，表明在两年的随访期内，与过度暴露相关的大脑灰质和白质的发育轨迹发生了变化。然而，在这段时间里，重度Hypo的低频率并不允许我们测试Hypo对大脑发育的影响的假设。为了获得更广泛的暴露，并增强我们检验假设的能力，我们建议再跟踪这一独特特征的队列3年，以评估T1 DM整整5年中大脑结构和认知功能的变化。此外，根据新的初步数据显示，暴露于Hyper除了影响局部脑体积外，还会影响脑白质微结构的完整性(用扩散张量成像或DTI测量)，我们建议增加最先进的DTI措施，以补充我们现有的措施。最后，为了更有说服力地确定T1 DM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。这项计划与我们的神经成像专业知识和充分描述的现有队列相结合，使我们处于一个独特的位置，可以测试关于青少年T1 DM患者的极端血糖、大脑结构完整性和认知功能是如何相关的强有力的假设。公共卫生相关性：该项目的目标是帮助确定在T1 DM的发展过程中，中枢神经系统的结构和功能是否应该与周围神经系统、视网膜和肾脏一起作为危险系统。这一知识将对青少年T1 DM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.