Long term instability of glycemic control and hippocampal function

描述（由申请人提供）：这是一项研究血糖控制不稳定对海马的长期影响的R21。 受试者将从我们的R 01（AG 034087，此后称为母研究）“炎症、既往糖尿病特征和认知能力下降”中招募，这是一项前瞻性5年研究，包括检查2型糖尿病（T2 D）的几种特征如何影响认知能力下降的发展。父母研究是西奈山医学院（MSSM），纽约，以色列的Sheba医学中心和Maccabi健康服务（MHS，以色列第二大HMO）的合作，以18个月的间隔招募和随访1200名T2 D个体，招募时认知完整，65岁及以上，居住在以色列特拉维夫。 该样本的特征在于具有a）来自丰富的MHS糖尿病登记处的超过15年的数据（包括HbA 1c，血糖控制的金标准测量）-B）完全计算机化的集中处理的MHS医疗记录-c）通过以下分析： MHS集中实验室对患者免费，确保完全使用-d）MHS药房的补贴药物，记录每次购买-e）由于生病的受试者由MHS照顾，因此联系损失最小-f）通过终止客户资金及时通知死亡。Sheba的痴呆症诊断程序与MSSM阿尔茨海默病研究中心的诊断程序完全集成，并具有诊断共识电话会议。拟定研究将通过比较3组60例受试者（血糖控制不稳定、血糖控制稳定和非T2 D组），检查多年血糖控制不稳定对海马功能（目标1）、体积（目标2）和血脑屏障功能障碍（目标3）的潜在有害影响。受试者将在年龄、性别和受教育年限方面进行个体匹配。 血糖控制的长期不稳定性与高平均水平HbA 1c影响之外的并发症增加相关，但对其对大脑和痴呆的有害影响知之甚少。 这项研究有望促进对长期血糖控制对T2 D相关认知功能损害和痴呆的神经病理学和血管病理生理学变化的贡献的理解。由于受试者在入组时无痴呆，将不稳定的血糖控制与所提出的三种海马性能下降的模式相关联，可能会将其确定为早期变化的生物标志物-最有效干预的窗口-在痴呆发展中至关重要的大脑区域。 纳入非T2 D对照组可使结果推广至非T2 D老年人。虽然T2 D是一种慢性疾病，但血糖控制是可以改变的，因此了解其对大脑的持久影响可能会导致制定预防糖尿病受试者认知能力下降的策略。由于T2 D和痴呆症的发病率随着人口结构向老年人的强烈转变而不成比例地增加，因此这项研究可能具有重大的公共卫生意义。

DESCRIPTION (provided by applicant): This is an R21 investigating the long-term effects of instability in glycemic control on the hippocampus. Subjects will be recruited from our R01 (AG034087, henceforth, the Parent Study) "Inflammation, historical diabetes-characteristics, and cognitive decline", a prospective 5-year study that includes examination of how several characteristics of type 2 diabetes (T2D) affect the development of cognitive decline. The Parent Study is a collaboration of the Mount Sinai School of Medicine (MSSM), NY, the Sheba Medical Center, Israel, and the Maccabi Health Services (MHS, the second largest HMO in Israel), to recruit and follow-at 18-month intervals-1200 T2D individuals, cognitively intact at recruitment, 65 years and older, living in Tel-Aviv, Israel. Ths sample is extraordinarily well characterized by having a) over 15 years of data from he rich MHS Diabetes Registry (including HbA1c, the gold standard measure of glycemic control)~ b) fully computerized centrally processed MHS medical records~ c) analyses by the MHS centralized laboratory at no charge to patients, ensuring complete use~ d) subsidized medication from MHS pharmacies, which record every purchase~ e) minimal loss to contact since ill subjects are cared for by MHS~ and f) prompt death notification by ending of client funding. The dementia diagnostic procedures at Sheba are fully integrated with those of the MSSM Alzheimer's Disease Research Center, with diagnostic consensus teleconferences. The proposed study will examine the potential deleterious effect of instability of glycemic control over many years on hippocampal function (Aim 1), volume (Aim 2) and blood brain barrier dysfunction (Aim 3) by comparing 3 groups of 60 subjects: unstable glycemic control, stable glycemic control, and a non-T2D group. Subjects will be individually matched on age, sex, and years of education. Long-term instability of glycemic control s associated with increased complications above and beyond the effect of high mean levels of HbA1c, yet little is known about its deleterious effects on the brain and on dementia. Thi study is expected to advance understanding of the contribution of long-term glycemic control to neuropathologic and vascular pathophysiologic changes in T2D- related cognitive compromise and dementia. As subjects will be non-demented at entry, associating unstable glycemic control with the proposed three modalities of decreased hippocampal performance may identify it as a biological marker of early changes-the window for most effective intervention-in a brain region that is critical in the development of dementia. Inclusin of a non-T2D control group may permit generalization of results to non-T2D elderly. Although T2D is a chronic disease, glycemic control is modifiable, so understanding its lasting effects on the brain may lead to development of strategies to prevent cognitive decline in diabetic subjects. Since rates of T2D and dementia are disproportionately increasing as the population structure shifts strongly toward the aged, this study may have major public health implications.