As discussed in the previous sections, neurocognitive research suggests that type 1 diabetes is primarily associated with psychomotor slowing and reductions in mental efficiency. This pattern is more consistent with damage to the brain's white matter than with grey-matter abnormalities. Unfortunately, the relation between cognitive impairments and structural changes in the brain is a topic that has not yet been investigated in sufficient detail in patients with type 1 diabetes. The combined results of the papers discussed below indicate that MRI changes in the brain of patients with type 1 diabetes are relatively subtle. In terms of effect sizes, these are at best large enough to distinguish the patient group from the control group, but not large enough to classify an individual subject as being patient or control. Figure 2a and b
gives an illustration of age-related white-matter lesions and atrophy that can be found in type 1 diabetes, but it is important to note that brain alterations in type 1 diabetes are not profoundly different from the age-related changes on brain MRI seen in control subjects of the same age.
The first neuropathological report on structural changes in the brain was performed in the 1960s (15). That study showed that patients with severe diabetic complications showed signs of cerebral atrophy. The few studies on structural changes in the brain in patients with type 1 diabetes that have been published in the 1990s (16, 17) reported findings that were comparable to MRI findings in non-diabetic groups, in that similar rates of (silent) infarcts and white-matter lesion (WML) severity have been reported in random samples from the general population of the same age group (18-20). It should be noted, however, that these early studies used small sample sizes, included relatively young patient groups, and used rather insensitive rating scales.
More recent studies used voxel-based morphometry (VBM) analysis of the MRI data. VBM is a sensitive method to detect subtle brain alterations in grey or white matter and thus is appropriate for use in evaluating brain-structural changes in diabetic patients. Still, these detailed studies on structural brain changes come up with contradictory reports. For example, one small study in 13 type 1 diabetic patients reported a 3% decrease in total cerebral volume, whereas hippocampal volume did not differ between type 1
diabetic patients and control subjects (21). Recently, an interesting paper on the effects of type 1 diabetes on grey-matter densities (GMD) as measured by VBM was published (22). This study investigated whether lower GMD in patients with type 1 diabetes were present, and if so, whether they were associated with glycaemic control and/or a history of severe hypoglycaemic events. It was found that, compared with healthy controls, patients with type 1 diabetes showed lower GMD in several brain areas. Especially the posterior, temporal, and cerebellar regions of the brain were affected. They concluded that the data suggest that areas of the brain such as the hippocampus and parahippocampal gyrus that contribute to memory and the superior temporal gyrus and angular gyrus that are important in language processing show GMD loss. This density loss was associated with both hyperglycaemia and hypoglycaemia.
Another study using VBM (23) investigated GMD loss in two groups of type 1 diabetic patients (with and without proliferative diabetic retinopathy) in comparison with an age- and education-matched control group of healthy participants. It showed that the patients with retinopathy, compared to the patients without retinopathy, showed reduced GMD in four brain areas: the right inferior frontal gyrus, right occipital lobe, left cerebellum, and left middle frontal gyrus. Two of these regions, the right inferior frontal gyrus and the right occipital lobe, also showed reduced GMD in comparison with the healthy participants. The patient group without retinopathy did not show reduced GMD compared with healthy participants.
Another recent study by Weinger and colleagues (24) examined white-matter (WM) integrity in a larger sample of young adults with type 1 diabetes of long duration and in a group of demographically similar non-diabetic adults. This study reported a similar prevalence of grade 1 and grade 2 WM hyperintensities in young adults with or without diabetes mellitus. These WM hyperintensities were not associated with depressive history or with clinical characteristics of diabetes including retinopathy, history of severe hypoglycaemia or lifetime glycaemic control. Moreover, these were not robustly associated with the cognitive test scores of either people with diabetes or in age-matched controls. These findings are consistent with those of another study (10) that obtained MRI and cognitive measures from 40 older diabetic participants and 40 age-matched non-diabetic comparison participants, although it has to be mentioned that this study used rather insensitive rating scales.
On the other hand, a study by Wessels and colleagues (25) showed that patients with a microvascular complication had a significantly smaller white-matter volume than non-diabetic controls (p = 0.04), and smaller white-matter volume was associated with worse performance on the domains of speed of information processing and attention and executive function. Also a co-occurrence of retinopathy (as a marker of microvascular damage) and brain abnormalities evidence was reported in another study (26). That study showed that background retinopathy was associated with small punctate WM lesions corresponding to enlarged perivascular spaces.
The neuroradiological reports discussed here all used a cross-sectional design. Cross-sectional designs do not permit a distinction between acquired volume loss as a possible consequence of diabetes duration and a diminished development of brain tissue as a consequence of early diabetes onset. In theory, longitudinal studies could provide more details on the course of structural brain abnormalities and thus provide more insight into the underlying processes.
Furthermore, future studies using more sensitive neuroimaging paradigms, such as fMRI, might be more informative with respect to the apparent subtle changes in brain functioning. One example of such a study (27) reported a different pattern of brain activation in a group of patients with type 1 diabetes during a cognitively demanding working-memory task. Patients with diabetic retinopathy showed significantly less de-activation in the anterior cingulate and the right orbital frontal gyrus than those without retinopathy. Since the actual performance on this task was similar in the two groups, this different pattern of brain activation may reflect a compensatory mechanism (27).
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