Studies In Man Neuropathology And Brain Imaging

Up till two decades ago, studies on the structural basis of impaired cognition in man largely depended on neuropathology. Much has changed since the introduction of powerful neuroimaging techniques, such as computed tomography, and even more so Magnetic resonance imaging (MRI). Neuroimaging now plays a key role both in daily clinical practice and in cognition and dementia research. In patients suspected of dementia, MR in particular not only serves to exclude (rare) treatable causes of dementia, but increasingly adds to a more accurate diagnosis of dementia syndromes, also in the early stages (62). For research purposes structural and functional brain changes are evaluated

Fig. 2. Examples of white matter lesions and lacunar infarcts on magnetic resonance imaging scans obtained from type 2 patients with diabetes. The images have been acquired with fluid attenuated inversion recovery sequences. Two types of white matter lesions can be distinguished, based on their location. Periventricular lesions are located directly adjacent to the cerebral ventricles (middle, closed triangle), whereas deep subcortical lesions are patchy lesions located in the deep white matter (left, open triangle). White matter lesions can be distinguished from lacunar infarcts (right, arrow) because the latter are hypointense on fluid attenuated inversion recovery and Tl-weighted images.

Fig. 2. Examples of white matter lesions and lacunar infarcts on magnetic resonance imaging scans obtained from type 2 patients with diabetes. The images have been acquired with fluid attenuated inversion recovery sequences. Two types of white matter lesions can be distinguished, based on their location. Periventricular lesions are located directly adjacent to the cerebral ventricles (middle, closed triangle), whereas deep subcortical lesions are patchy lesions located in the deep white matter (left, open triangle). White matter lesions can be distinguished from lacunar infarcts (right, arrow) because the latter are hypointense on fluid attenuated inversion recovery and Tl-weighted images.

using a variety of methods, ranging from very simple semiquantitative visual scales to highly sophisticated computerized tools (63). These methods allow the assessment of cortical and subcortical atrophy, of "silent" or symptomatic brain infarcts, and of so-called white matter lesions (Fig. 2). These white matter lesions are a common finding in aged subjects with vascular risk factors or ischaemic vascular disease. Their direct role in causing cognitive deterioration has not been established, although their frequency is higher in demented subjects than in normal controls, and they are associated with specific cognitive deficits, particularly those related to impairment of frontal lobe functions (64).

Neuropathological Studies

Neuropathological studies of diabetic patients are relatively limited in number. In the mid-sixties a case series was published, involving 16 type 1 patients with diabetes widespread macro and microvascular disease, half of whom also showed "mental distur-bances"(65). Macroscopic examination revealed moderate to severe atrophy in five cases. Microscopic examination revealed gliosis in the cerebral cortex, and subependymal gliosis of the periventricular regions. Atherosclerosis was observed in large arteries, and basement membrane thickening in capillaries. These microvascular changes were also reported in another autopsy study (66).

In a large retrospective study of 7579 necropsies, including 935 subjects with diabetes, macroscopic brain infarcts were more prevalent in subjects with diabetes than in controls, for all ages studied (67). In subjects older than 70 the percent of diabetic subjects with ischemic lesions was 40-50%, vs 30% in controls.

More recent studies have assessed the relation between diabetes and the occurrence of neuropathological lesions that are common in AD, such as neurofibrillary tangles and amyloid plaques (68-70), but the results are inconclusive. Possibly, diabetes in interaction with the APOE e4 genotype leads to accelerated Alzheimer-type pathology (68).

Neuroimaging Studies

A number of studies have assessed atrophy or white matter lesions in type 1 patients with diabetes. Some of these studies included a direct comparison with nondiabetic controls (71-73), but sample sizes were small (generally <20 per group). Other studies compared type 1 patients diabetes with microvascular complications (e.g., retinopathy) (45) or a history of repeated severe hypoglycemia (74) to patients without these complications. Taken together, these studies suggest that there may be some degree of cerebral atrophy in type 1 patients diabetes (73,74), which may be linked to the occurrence of hypoglycemia (74) (but see ref. 45), but not to the presence of microvascular complications such as retinopathy (45). In addition, white matter lesions may be more common in type 1 diabetic patients than in controls (71). Additional studies on the brain MRI features of type 1 diabetes are necessary before solid conclusions can be drawn. Given the relatively modest changes in cognition in type 1 diabetes, these studies should apply MR rating methods that are sensitive enough to pick up subtle differences, and should have adequate statistical power.

Data on the brain imaging features of type 2 diabetes can be extracted from a number of large population based surveys on risk factors for cerebrovascular disease and on age-related MR changes. These studies indicate that type 2 diabetes is a risk factor for (lacunar) infarcts (75,76), cortical, and subcortical atrophy (77) and possibly white matter lesions (77,78). Studies with a case-control design provide more detailed information (79-82). These latter studies show that type 2 diabetes is associated with both cortical and subcortical atrophy, relative to age-matched nondiabetic controls (79,82,54). Atrophy has also been reported in the medial temporal lobe (80), and may already be present in prediabetic stages (83). These latter observations are of particular interest, as atrophy in this region of the brain is also one of the early manifestations of AD. Schmidt et al. (79) reported a nonsignificant increase in the severity of white matter lesions in type 2 diabetic patients relative to controls (79), using a relatively insensitive interval scale. In our own cross-sectional survey on MRI and cognition in a population of 125 type 2 patients with diabetes and 65 matched controls (54), an evident increase is observed in white matter lesion load in patients compared with controls (Fig. 3).

The amount of data on the relation of these MR changes in type 2 diabetes to different disease variables is still limited. It has been suggested that hypertension is an important determinant of cerebral atrophy in type 2 diabetes (79), but in our own study hypertension had only modest effects on atrophy and white matter lesions (54; Fig. 3).

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