Chapter 11 summary definitief ineke brands.indd :57:59

Transcription

1 chapter 11 Summary

2 chapter 11 Both type 1 and type 2 diabetes mellitus are associated with altered brain function, a complication referred to as diabetic encephalopathy. Previous studies have shown that patients with either type of diabetes show mild to moderate impairments on a variety of neuropsychological tests. Furthermore, changes on brain MRI have been reported, including both cortical and subcortical atrophy and white-matter abnormalities. Diabetes is also associated with a higher prevalence of mood disorders. The pathogenesis of diabetic encephalopathy is likely to be a multifactorial process that involves vascular disturbances. The issues surrounding the cognitive and emotional status following the diagnosis of diabetes remain complex and controversial. The literature shows contrasting findings and especially the role of recurrent hypoglycemic episodes remains controversial. This thesis was designed to further unravel the clinical characteristics of altered central nervous system functioning in type 1 as well as type 2 diabetes and to identify risk factors. The first part of this thesis focuses on the characteristics of diabetic encephalopathy in type 1 diabetic patients. In chapter 3 previous studies were reviewed. It is concluded that diabetic encephalopathy is characterised by electrophysiological and neuroradiological changes, such as delayed latencies of evoked potentials, and modest cerebral atrophy. Furthermore, individuals with type 1 diabetes may show performance deficits in a wide range of cognitive domains. Chronic metabolic and vascular changes appear to play an important role in the pathogenesis. In chapter 4 the exact nature, magnitude and risk factors of cognitive impairments in patients with type 1 diabetes were investigated through a systematic review of the literature. MedLine and PsycLit search engines were used to identify studies on cognitive performance in patients with type 1 diabetes. Effect sizes (Cohen s d) were calculated, that is, the standardised difference between the experimental 184

3 summary and the compared group. In the meta-analysis, a combined d-value was calculated, representing the overall magnitude of the effect present in the studies. Thirty-three studies were identified that met the inclusion criteria. Compared to non-diabetic controls, the type 1 diabetic group demonstrated a significant lowered performance on the cognitive domains intelligence (d= -0.7), speed of information processing (d= -0.3), psychomotor efficiency (d= -0.6), visual (d= -0.4) and sustained attention (d= -0.3), cognitive flexibility (d= -0.5) and visual perception (d= -0.4). Lowered cognitive performance in diabetic patients appeared to be associated with the presence of microvascular complications, but not with the occurrence of severe hypoglycemic episodes or with poor metabolic control. It was concluded that in patients with type 1 diabetes cognitive dysfunction is characterised by a slowing of mental speed and a diminished mental flexibility, whereas learning and memory are spared. In chapter 5 cognitive performance and MRI of the brain were assessed in older type 1 diabetic patients. Forty type 1 diabetic patients (age > 50) and forty age-matched controls were included. Neuropsychological assessment included five major cognitive domains ( information processing speed, memory, attention and executive functioning, abstract reasoning and visuoconstruction ). Pychological well-being was assessed with two questionnaires. Atrophy, white-matter abnormalities and infarcts were rated on MRI scans. Type 1 diabetic patients performed slightly (effect sizes <0.4) worse on cognitive tasks, but only speed of information processing reached statistical significance. No significant between-group differences were found on any of the MRI parameters. Type 1 diabetic patients tended to report more cognitive and depressive problems than controls, but this did not correlate with the performance on cognitive tests. It was concluded that cognition in older type 1 diabetic patients is only mildly disturbed. Apparently, chronic exposure to hyperglycemia is in itself, even at older age not sufficient to have considerable 185

4 chapter 11 impact on the brain. Although cognition in older patients with type 1 diabetic appears only mildly disturbed compared to non-diabetic controls, it may be that specific subgroups of type 1 diabetic patients, such as those with worse metabolic control, have a higher risk for cognitive decline. Patients with continuous subcutaneous insulin infusion (CSII) differ from patients on multiple daily injection (MDI) regime on important metabolic parameters. Therefore, in chapter 6, an observational study was presented that aimed to compare cognition, psychological well-being and brain MRI between older type 1 diabetic patients with and without CSII. For this project forty patients with type 1 diabetes (52-77 yrs, mean duration diabetes 34 yrs) were included, of whom nineteen received CSII (mean duration: 6.5 ± 3.5 yrs) and twenty-one used MDI. Neuropsychological assessment covered five main cognitive domains. Psychological well-being was assessed by Symptom Checklist (SCL)-90-R and the Beck Depression Inventory-II (BDI-II). Atrophy, white-matter abnormalities (WML) and infarcts were rated on MRI scans. Patients with and without CSII did not differ on neuropsychological measures, but patients with CSII subjectively experienced more cognitive problems than patients without insulin pump therapy. Patients with CSII had better MRI ratings on cortical atrophy measures, but not on the other MRI measures. It was concluded that it could be worthwhile to compare CSII with other treatment regimes in a longitudinal randomised controlled trial. The second part of this thesis focuses on type 2 diabetic patients. In chapter 7 cognition and brain MRI in type 2 diabetic patients were compared to non-diabetic controls. In addition, the relation between cognition and MRI findings, blood pressure and metabolic control was assessed. Brain MRI scans were obtained from

5 summary patients and 51 matched controls and rated for white-matter lesions, cortical and subcortical atrophy and infarcts. Neuropsychological test scores were divided into 5 cognitive domains and expressed as standardised z-values. Type 2 diabetes was associated with deep white-matter lesions (p=0.02), cortical (p<0.001) and subcortical atrophy (p<0.05) and silent infarcts (p=0.06) and impairments in cognitive functioning on the domains attention and executive functioning, memory and speed of information processing (all p<0.05). Adjustment for hypertension did not affect the results. Within the type 2 diabetic group cognitive functioning was inversely related to white-matter lesions, atrophy and the presence of infarcts (adjusted for age, estimated IQ and gender) and there was a modest association with HbA1c and diabetes duration. This association was strongest for age, even more so than in controls. It was concluded that cognitive impairments in patients with type 2 diabetes are associated with subcortical ischemic changes in the brain, but also with increased brain atrophy. In chapter 8 the cognitive profile and levels of psychological well-being of 119 patients with type 2 diabetes (mean age: 66 ± 6; mean duration: 9 ± 6 years) were compared to 55 age and education matched control participants. Groups were compared on cognitive performance in five major cognitive domains, psychological well-being (assessed by Symptom Checklist (SCL)-90-R and the Beck Depression Inventory (BDI-II)) and abnormalities on brain MRI. An interrelationship between cognition, MRI abnormalities and psychological well-being was hypothesised. Type 2 diabetic patients performed significantly worse than controls on cognitive tasks, especially on tasks that required more mental efficiency, although the differences were modest (effect sizes Cohen s d<0.6). It was speculated that type 2 diabetic patients have a diminished ability to efficiently process unstructured information. Patients with type 2 diabetes had significantly higher scores on the SCL-90-R (p<0.001) and on 187

6 chapter 11 the BDI-II (p<0.001) and worse MRI ratings than controls, but psychological distress did not correlate with cognition, MRI ratings or biomedical characteristics. Contrary to our hypothesis, cognitive disturbances and psychological distress thus seem independent symptoms of the same disease. It has been suggested that cognitive impairments are more pronounced in type 2 diabetes than in type 1 diabetes, but studies that directly compare the effects of these 2 types of diabetes on cognition are lacking. Therefore, in chapter 9 a study is reported where forty patients with type 1 diabetes for at least 30 years were compared with forty age- and education-matched patients who were known with type 2 diabetes for a mean duration of seven years. Patients were assessed with respect to cognitive performance in five major cognitive domains, psychological well-being and brain MRI. Patients with type 1 diabetes had experienced significantly more hypoglycaemic episodes, and had a higher HbA1c level. Vascular risk factors, such as higher BMI, fasting triglycerides, the prevalence of hypertension or macrovascular events, or hypercholesterolemia were more common in the type 2 diabetic group. No systematic between-group differences were observed on neuropsychological measures nor on levels of psychological well-being. Type 2 diabetic patients showed significantly more deep white-matter lesions and cortical atrophy on MRI (p<0.01). It was concluded that type 1 diabetic patients, with more than thirty years of diabetes, have a similar cognitive profile and better MRI ratings than age and education matched type 2 diabetic patients with only seven years of diabetes. In conclusion, the studies presented in this thesis provide new insights in the clinical features and risk factors implicated in diabetic encephalopathy. Diabetic patients manifest a form of diabetic encephalopathy, but the cognitive deficits and brain 188

7 summary abnormalities seem to be far more subtle than assumed in the classical definition of this concept. In most patients with diabetes cognitive impairment consists of mental slowing. This is similar to the reduction of mental efforts that occurs during normal ageing, except that in patients with diabetes the onset of cognitive downfall is seen at a younger age. The magnitude of these cognitive deficits is mild to moderate, but it is important to stress the clinical relevance of even mild forms of cognitive dysfunction that might hamper everyday activities, since they can be expected to present problems in more demanding situations. Risk factors for the development of this diabetic encephalopathy are chronic hyperglycemia and atherosclerotic vascular disease. The occurrence of repeated episodes of hypoglycemia probably does not induce neurocognitive dysfunction. Longitudinal studies could play an important role in further disentangling the many factors that underlie cognitive impairments in diabetes. More specifically, future studies should focus on neural activation patterns and on white-matter integrity to correlate the extent of white-matter abnormalities to tasks that require more, and less, cognitive efforts. 189

8