Diabetic encephalopathy: a cerebrovascular disorder?

Animal study: The aim was to investigate the role of vascular disturbances in the development of experimental diabetic encephalopathy. We describe the effects of treatment with the Angiotensin Converting Enzyme(ACE)-inhibitor enalapril (treatment aimed at the vasculature) on measures of cerebral function in streptozotocin (STZ) diabetic rats. We found that experimental diabetes is associated with reduced cerebral perfusion, and treatment with enalapril can partially improve cerebral blood flow, deficits in Morris maze learning and hippocampal synaptic plasticity. Furthermore, we found that STZ-diabetes is associated with deficits in peripheral nerve conduction velocity and increased evoked potential latencies and that treatment with enalapril can partially prevent or reverse these impairments. Finally, we found that long term treatment with enalapril prevented deficits in nerve conduction velocity, and partially prevented deficits in BAEP and VEP latencies, comparable to the previous study. However, we observed an increased mortality in the long-term enalapril treated animals, probably due to hypotension in combination with the effects of the STZ-model We thus showed that impaired cerebral perfusion probably plays an important role in the development of diabetic encephalopathy in experimental diabetes, and showed for the first time that treatment aimed at improvement of perfusion of the brain can partially prevent deficits in cerebral function. Clinical study: The aim was to examine associations between vascular risk factors, cognitive functioning and structural changes in the brain in patients with DM2. To do so, we initiated the Utrecht Diabetes Encephalopathy Study (UDES), a large cross-sectional study involving 125 patients with DM2 and 64 matched non-diabetic controls. We found that patients with DM2 had more cortical and subcortical atrophy and more deep white matter lesions (DWML) and infarcts on brain MRI than controls. The overall performance of patients with DM2 on the neuropsychological examination was worse, particularly affecting the domains attention and executive functioning, information processing speed and memory. Within the DM2 group cognitive function was inversely related with white matter lesions (WML), atrophy and the presence of infarcts. Furthermore, we found that patients with DM2 had more microvascular complications, more macrovascular (atherosclerotic) disease and more hypertension than controls. Within the DM2 group impaired cognitive functioning was associated with higher HbA1c levels, brain infarcts on MRI and a history of vascular events. DM2 patients with retinopathy or with infarcts on MRI had more severe cortical atrophy, whereas insulin levels, mean arterial pressure, and macrovascular disease were associated with WML. We did not find a relation between peripheral neuropathy and cerebral deficits in patients with DM2, in contrast to previous findings in DM1 patients. Finally, we showed that cerebrovascular reserve capacity (CVR) in patients with DM2 is similar to that in controls. CVR was not affected by diabetes duration, metabolic control, the presence of hypertension, intima/media thickness, or albuminuria. In conclusion, diabetic encephalopathy is a multifactorial condition, for which a history of macrovascular atherosclerotic disease seems to be the most important risk factor. Hyperglycaemia, vascular risk factors like hypertension and microvascular complications seem to be of lesser importance

Angiotensin converting enzyme inhibition patially prevents defecits in water maze performance, hippocampal synaptic plasticity and cerebral blood flow in streptozotocin-induced-diabetic rats

Vascular dysfunction is important in the pathogenesis of peripheral complications of diabetes. However, the effects of diabetes on cerebral blood flow and the role of vascular deficits in the pathogenesis of diabetic encephalopathy are still unknown. The present study examined whether experimental diabetes is associated with reduced cerebral blood flow and whether treatment with enalapril can improve cerebral perfusion and function (blood flow and functional cerebral deficits). Streptozotocin-diabetic rats were treated with the ACE inhibitor enalapril (24 mg/kg) from onset of diabetes. After 14 weeks of diabetes, 12 enalapril treated and 12 untreated diabetic rats, and 12 nondiabetic age-matched control rats were tested in a spatial version of the Morris water maze. After 16 weeks of diabetes, in the same groups, blood flow in the hippocampus and thalamus was measured by hydrogen clearance microelectrode polarography. In a separate study, hippocampal long-term potentiation was measured after 26 weeks of diabetes. Water maze performance and hippocampal long-term potentiation were impaired in diabetic rats. Furthermore, blood flow in diabetic rats was reduced by 30% (P<0.001) in the hippocampus and by 37% (P<0.005) in the thalamus compared to nondiabetic controls. Enalapril treatment significantly improved water maze performance (P<0.05), hippocampal long term potentiation (P<0.05) and hippocampal blood flow (P<0.05). Cerebral perfusion is reduced in diabetic rats compared to controls. Treatment aimed at the vasculature can improve cerebral blood flow, deficits in Morris maze performance and long term potentiation. These findings suggest that vasculopathy plays a role in the development of cerebral dysfunction in diabetic rats