Type 2 diabetes mellitus (T2DM) is associated with slowly progressive changes in the brain, a complication referred to as diabetic encephalopathy. Previous studies have shown that patients with T2DM show mild to moderate decrements in cognitive functioning and an increased risk of dementia. The central topic of the studies in this thesis was to examine at which stage of the diabetes these cognitive decrements start to develop and how they progress over time. In addition, the role of exposure to vascular risk factors in the relation between T2DM and cognition was examined in detail. A systematic review of the literature on the impact of T2DM, hypertension, obesity and dyslipidemia on cognitive functioning and the risk of dementia showed that these risk factors are associated with mild cognitive decrements, mainly in memory, cognitive speed and mental flexibility (effect size -0.3). Also, a 1.5 to 2-fold increased risk of dementia is consistently reported in relation to these vascular risk factors. The progression from normal glucose tolerance to definite T2DM is gradual process. Cognitive decrements may already start to develop in the early stages of the disease, even before the actual onset of hyperglycemia. Cognitive functioning was therefore compared between 64 patients with recent onset T2DM, 83 persons with the metabolic syndrome (= a ‘pre-diabetes’ group that included persons who had vascular risk factor profile similar to the T2DM group, but no diabetes) and 100 control participants. Both patient groups showed worse cognitive performance compared to the controls, but there was no difference in performance between persons with T2DM or metabolic syndrome. The next part of the thesis addressed the progression of cognitive decrements in persons with known T2DM. A detailed neuropsychological examination in 122 elderly patients with T2DM revealed mild cognitive impairments in memory, information-processing speed and mental flexibility compared to 56 control participants. These patients also had more vascular and degenerative abnormalities on brain MRI. Re-examination of the sample after 4 years, however, revealed no accelerated decline in cognition for persons with T2DM. In the final part of the thesis the relation between T2DM, metabolic syndrome and cognition was examined in a population of 599 85- to 90-year-old persons. T2DM was associated with cognitive decrements, but persons with the metabolic syndrome showed a decelerated cognitive decline during follow-up. In conclusion, the studies presented in this thesis indicate that diabetes-associated cognitive decrements are the result of an insidious process, starting years before the onset of T2DM. It involves prolonged exposure to vascular risk factors, such as hypertension and obesity, and may change over time as a consequence of both exposure time and the changes in the level of these risk factors that occur with increasing age. The neuropsychological profile appears to reflect an overall diminished performance level rather than deficits in specific cognitive functions. The challenge for future studies is to find out how these cognitive decrements are best dealt with in daily clinical care and to try and identify those patients who are particularly at risk of serious cognitive decline and dementia
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