Long term instability of glycemic control and hippocampal function

描述（由申请人提供）：这是一项R21研究，研究血糖控制不稳定对海马的长期影响。受试者将从我们的R01 （AG034087，此后为父母研究）“炎症，历史糖尿病-特征和认知能力下降”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）的几种特征如何影响认知能力下降的发展。父母研究是纽约州西奈山医学院（MSSM）、以色列示巴医疗中心和以色列第二大卫生组织马卡比卫生服务（MHS）的一项合作，以18个月为间隔招募和随访1200名T2D患者，招募时认知完整，65岁及以上，居住在以色列特拉维夫。该样本的特点是：a)超过15年的数据来自丰富的MHS糖尿病登记处（包括HbA1c，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

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.