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.
The proposed study will investigate the effects of long-term instability of glycemic control on three hippocampal modalities-function, volume, an blood brain barrier-in three groups of 60 exquisitely well characterized subjects-stable glycemic control, unstable glycemic control, and 40 non-diabetic subjects- who participate in a longitudinal large-scale study of diabetes characteristics in cognitive decline. Identifying the impact of instability of glycemic control over many years on the hippocampus will provide a window into the neuropathology and vascular pathophysiology associated with cognitive compromise in diabetics, and possibly in the elderly population as a whole. Understanding long-lasting effects of diabetes on the brain is fundamental for the development of strategies to prevent cognitive decline in diabetic individuals.
