Long term instability of glycemic control and hippocampal function

描述(申请人提供)：这是一种R21，研究血糖控制不稳定对海马体的长期影响。受试者将从我们的R01(AG034087，以下称为父母研究)“炎症、既往糖尿病特征和认知下降”中招募，这是一项为期5年的前瞻性研究，包括检查2型糖尿病(T2D)的几个特征如何影响认知下降的发展。家长研究是由纽约州西奈山医学院(MSSM)、以色列Sheba医疗中心和Maccabi Health Services(MHS，以色列第二大医疗保健机构)合作进行的，目的是招募并跟踪-每隔18个月跟踪-1200名T2D个体，招募时认知完好，65岁及以上，居住在以色列特拉维夫。这个样本的特点是：a)来自丰富的MHS糖尿病登记中心(包括血糖控制的黄金标准HbA1c)15年来的数据~b)完全计算机化的中央处理的MHS医疗记录~c)通过 MHS中央实验室对患者免费，确保完全使用~d)MHS药店提供的补贴药物，这些药店记录每一次购买~e)由于疾病受试者由MHS照顾而造成的最小接触损失~f)通过结束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程序完全整合，并举行了诊断共识电话会议。这项拟议的研究将通过比较三组60名受试者：不稳定的血糖控制、稳定的血糖控制和非T2D组，来研究多年来血糖控制不稳定对海马区功能(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、性别和受教育年限上进行单独匹配。血糖控制长期不稳定的S除了HbA1c平均水平高的影响外，还伴随着并发症的增加，但对其对大脑和痴呆症的有害影响却知之甚少。这项研究有望促进对长期血糖控制在T2D相关认知损害和痴呆的神经病理和血管病理生理变化中的作用的理解。由于受试者在入院时没有痴呆，将不稳定的血糖控制与提出的三种海马体功能下降模式联系起来，可能会确定它是早期变化的生物标志--最有效的干预窗口--在痴呆症的发展中至关重要的大脑区域。纳入非T2D控制组可允许将结果推广到非T2D老年人。尽管T2D是一种慢性疾病，但血糖控制是可以改变的，因此了解它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T2D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，这项研究可能会对公共卫生产生重大影响。

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.