Hippocampal Neurogenesis and Regional Cerebral Glucose Metabolism, Functional Connectivity Evaluation Using F-18 FDG PET in Type II Diabetic Rat Model

Abstract

Diabetes is a representative risk factor of various neurodegenerative and neurovascular diseases. Many epidemiological and clinical studies have shown that diabetic patients more develop cognitive decline. We investigated the effect of diabetes on adult neurogenesis (AN) and functional connectivity using a rat model and fluorine-18-fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET). For type II diabetes (T2DM) model, Zucker diabetic fatty (ZDF) male rats (6 weeks old 5, 12 weeks old 5) were used, and same number and same aged of Zucker lean control (ZLC) male rats were used as control. F-18 FDG brain PET images of each rat were acquired to evaluate regional cerebral glucose metabolism which reflects regional neuronal activity. Image normalization to the MRI template and analysis were performed using SPM8. We extracted 58 count of brain regional volume of interest (VOI). Functional connectivity was evaluated. Doublecortin (DCX) immunohistochemistry (IHC) was done to evaluate the neurogenesis in the dentate gyrus (DG). GLUT3 IHC was performed to evaluate the correlation between the AN and glucose metabolism. 12 weeks old ZDF rats showed the decreased regional glucose metabolism in the bilateral hippocampus compared to age-matched ZLC group (p<0.05). In the 6 weeks old group, there was no significant difference of regional glucose metabolism. In functional connectivity analysis, there was no significant difference between 6 weeks old group. However, in 12 weeks old ZDF showed increased or decreased hippocampus connectivity compared with control (p<0.005). The number of neuroprogenitor cells was decrease in the hippocampus of 12 weeks old ZDF compared with same aged ZLC, although there was no significant difference of neuroprogenitor cells in 6 weeks. 12 weeks old ZDF rats showed decreased of the GLUT3-positive cells in the hippocampus compared with same age ZLC rats. That means the decreased glucose metabolism in the hippocampus of the T2DM rats is due to decreased GLUT3 expression and the result of decreased DCX expression in the same area may suggest decreased adult neurogenesis, which may affect variable functioning connectivity with other brain loci. This result may help to understand the pathophysiologic mechanism of cognitive dysfunction occurring in diabetic patients, and to our knowledge, this is the first functional study with connectivity which is correlated with pathologic alteration using T2DM rat models and F-18 FDG PET. The hippocampal early changes may play an important role in treating and preventing neurodegenerative disease such as Alzheimers disease (AD) in diabetic patients.