Introduction
Diabetes mellitus is associated with slowly progressive changes in the brain [
1]. Neuropsychological studies show that patients with type 2 diabetes mellitus have mild to moderate impairments in attention and executive functioning, information processing speed and memory (for reviews see [
2,
3]). Patients with type 2 diabetes also show changes on brain magnetic resonance imaging (MRI), such as cortical and hippocampal atrophy [
4,
5]. We have recently shown that cognitive dysfunction in patients with type 2 diabetes was associated with white matter lesions (WML), (silent) brain infarcts and to a lesser extent with atrophy [
6].
The determinants of changes in cognition and abnormalities on brain MRI of patients with type 2 diabetes are uncertain [
2]. Some studies report associations with hypertension [
3,
4,
7,
8], but this was not supported by others [
5,
9,
10]. Associations between impaired cognition and chronic hyperglycaemia have also been noted [
9]. Studies on other diabetic complications may provide leads for potentially relevant determinants. Complications like nephropathy, retinopathy and neuropathy are thought to be due to hyperglycaemia-induced microangiopathy [
11,
12], with additional involvement of hypertension and macrovascular disease [
13‐
15]. Since atherosclerosis and hypertension are established risk factors for age-related cognitive decline and brain MRI changes in the general population [
16‐
19], we hypothesised that the combined effects of atherosclerotic macrovascular disease, chronic hyperglycaemia and hypertension are involved in the development of cognitive impairments in patients with type 2 diabetes.
The aim of the present study was to identify possible metabolic and vascular determinants of cognitive dysfunction and changes on brain MRI in patients with type 2 diabetes. Given the uncertainty about these determinants, an exploratory design was chosen. A detailed neuropsychological examination and brain MRI were obtained from a large cross-sectional sample of type 2 diabetes patients and related to different measures of glucose metabolism, vascular risk factors, microvascular complications and macrovascular disease.
Discussion
Patients with type 2 diabetes had more cortical and subcortical atrophy and more DWML than control participants and their overall performance in the five cognitive domains was worse. As expected, patients with type 2 diabetes had more microvascular complications, more macrovascular (atherosclerotic) disease and more hypertension than the control group. In multivariate regression analyses within the type 2 diabetes group, hypertension and a history of vascular events were associated with worse cognitive performance, while statin use was associated with better performance. Retinopathy and brain infarcts on MRI were associated with more severe cortical atrophy and statin use with less atrophy. Insulin level and brain infarcts were associated with more severe WML and statin use with less severe WML.
Cognitive function in patients with type 2 diabetes has been studied extensively (for reviews see [
2,
3]). Performance in the domains verbal memory and information processing speed, and probably also executive functioning and non-verbal memory, is moderately impaired. Our results are in keeping with these findings. Thus far, relatively few studies have specifically addressed brain MRI abnormalities in patients with type 2 diabetes. In agreement with our observations, modest cortical and subcortical atrophy and symptomatic or asymptomatic infarcts have been found more often in type 2 diabetes patients than in control individuals [
4,
5,
29]. Results of previous studies on the association between type 2 diabetes and WMLs are less consistent [
30]. This might be due to the study populations involved and the use of relatively insensitive WML rating scales [
30].
Chronic hyperglycaemia might be a determinant of cerebral changes in patients with type 2 diabetes. In the present study, HbA
1c levels were related to the composite cognitive
z score, but only in de univariate analysis. Moreover, retinopathy, which is generally considered to be a consequence of chronic exposure to hyperglycaemia [
11], was related to cortical atrophy. Previous studies on cognition in patients with type 2 diabetes have also reported an association with HbA
1c levels [
2,
9,
31]. The relation with fasting blood glucose or duration of diabetes is, however, inconsistent [
31,
32]. No previous studies have provided detailed data on the association between glycaemic control and MRI changes in type 2 diabetes. Studies in type 1 diabetes mellitus, however, have shown an association between diabetic retinopathy (as a proxy of chronic hyperglycaemia) and both brain atrophy [
33,
34] and cognitive functioning [
35]. There are no previous studies on the relation between insulin levels and cerebral complications in type 2 diabetes. The association with WML severity, observed by us in the present study, is of particular interest in the light of recent studies in the general population, which link insulin to vascular abnormalities and degenerative changes in the brain [
36,
37].
Previous studies in the general population indicate that risk factors for vascular disease, such as hypertension, dyslipidaemia, increased BMI and smoking, are associated with an increased risk of cognitive decline and dementia and with brain MRI changes, including WML (e.g. [
38‐
41]). Previous studies on the modulating effect of hypertension on cognitive function in type 2 diabetes show conflicting results [
7,
9,
42,
43]. In the present study, hypertension was related with impaired cognitive performance and mean arterial pressure with PWML severity. To our knowledge, the relation between other vascular risk factors and both cognition and brain MRI in patients with type 2 diabetes has not been examined previously. The reverse association between the use of statins and both cognition and MRI findings is intriguing. Nevertheless, this observation cannot be regarded as proof of a possible treatment effect. It should be noted that the association between statin use and both cognition and age-related brain MRI changes in the general population is still being debated [
44]. The present findings will need to be confirmed by further studies.
Macrovascular atherosclerotic disease appeared to be the most consistent determinant of impaired cognition and brain MRI abnormalities in the type 2 diabetes patients in the present study. We have not found any previous studies that presented detailed data on the relation between macrovascular disease and cerebral changes in people with type 2 diabetes. In the general population, however, several studies have shown that macrovascular atherosclerotic disease is associated with age-related cognitive impairment and changes in brain MRI. In a large cross-sectional study, for example, previous vascular events, presence of plaques in the carotid arteries and presence of peripheral arterial atherosclerotic disease were negatively associated with cognitive performance [
17]. In another study, the association between the number of cardiovascular disease conditions and cognitive impairment appeared to show a ‘dose–response’ relationship [
18]. With regard to brain MRI changes, a history of stroke or myocardial infarction has been associated with the presence of WML [
19] and plaques in the carotid artery with PWML [
16,
45].
The strength of our study is that we combined detailed data on cognitive function and brain MRI with detailed data on metabolic and vascular risk factor clusters, thus allowing an accurate assessment of the relation between these factors. Possible limitations include patient selection, the cross-sectional design and the large number of explanatory variables addressed. With regard to patient selection, we aimed to obtain a representative sample of functionally independent patients with type 2 diabetes from the general population. Although the rather demanding testing protocol may have deterred patients with relatively severe mental or physical limitations, the prevalence of microvascular and macrovascular disease, hypertension and smoking habits, as well as the level of metabolic control in our study sample is comparable with those found in other population-based studies in the Netherlands [
46‐
48]. To minimise the effects of lifestyle and socioeconomic factors, control participants were recruited from the direct environment of the type 2 diabetic patients. Consently, the prevalence of risk factors such as hypertension and high BMI was higher than would be expected in the general population in the Netherlands. If anything, this would have decreased the differences in cognition and MRI ratings between the groups. The cross-sectional design of our study precludes inferences about causal relationships. Moreover, the cognitive and imaging outcome measures were probably influenced by a large number of factors, some of which are specific to type 2 diabetes mellitus (e.g. chronic hyperglycaemia, diabetes treatment) and some not (e.g. age, hypertension, atherosclerosis). Our exploratory analysis included a large number of explanatory variables, which has certain drawbacks. First, different explanatory variables might be interrelated. The relatively small regression coefficients and effect sizes affect the evaluation of these interrelations and limit statistical power. This may also explain why some of the variables that reached statistical significance in the univariate analyses dropped out of the multivariate model. Nevertheless, the multivariate analysis as presented in Table
5 does indicate which variables were the strongest independent determinants of cognition and MRI abnormalities in the model used. The second drawback is that the large number of regression analyses can lead to type I errors. Nevertheless, we feel that this first detailed study of cognition and brain MRI in type 2 diabetes patients in relation to metabolic and vascular risk factors does provide important leads that could be further evaluated in future studies. Such studies should: (1) preferably have a longitudinal design; (2) include assessment of cognition and brain MRI in relation to chronic hyperglycaemia and atherosclerotic vascular disease; and (3) allow the assessment of potential confounders (e.g. hypertension).
Type 2 diabetes is associated with modest impairments in cognition, as well as with atrophy and vascular lesions on MRI. This ‘diabetic encephalopathy’ is a multifactorial condition, for which atherosclerotic (macroangiopathic) vascular disease is an important determinant. Chronic hyperglycaemia, hypertension and hyperinsulinaemia may play additional roles.
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