As with type 2 diabetes, the prevalence of cognitive impairment leading to dementia increases with advancing age (Park etal., 2003). Identification of any aetiological factors predisposing to cognitive decline is important in order to reduce the burden on patients, their carers and health and social services. Epidemiological evidence from both cross-sectional and longitudinal studies suggests that individuals with diabetes have a twofold increased risk of cognitive impairment and dementia compared with the general population (Areosa Sastre and Grimley Evans, 2003). This association between impaired cognition and diabetes appears to be strengthened by duration of the disease and the use of insulin therapy, likely reflecting illness severity in the case of type 2 diabetes.
Longitudinal population-based studies confirm that diabetes is a risk factor for both vascular dementia and Alzheimer's disease (Peila etal., 2002; Areosa Sastre and Grimley Evans, 2003) Vascular dementia is a general diagnostic label for loss of cognitive function caused by ischaemic or haemorrhagic cerebral lesions due to cerebrovascular disease or other cardiovascular pathology (Roman, 2003). There are a number of different diagnostic criteria and scoring systems for vascular dementia but this label should only be applied when there is evidence of cerebrovascular disease, dementia and a temporal relationship between these two disorders. Vascular dementia is the second most common cause of dementia in the elderly, accounting for 10-30% of all cases. The ischaemic types of vascular dementia are divided into two broad groups: large vessel and small vessel. In the large-vessel subtype, post-stroke dementia is the commonest form of acute-onset vascular dementia and has an estimated prevalence of 10-16% (Barba etal., 2000). Dementia after stroke may be caused by a single strategically located cortical or subcortical stroke, or by multiple strokes, so-called multi-infarct dementia. Small-vessel vascular dementia may be of abrupt onset (e.g. due to lacunar infarction) but more commonly develops more slowly due to diffuse subcortical disease. These patients may have characteristic computed tomography (CT) features of symmetrically decreased density of periventricular and subcortical white matter, and correlation has been shown between the extent of these lesions and the degree of cognitive impairment.
The risk of dementia is substantially increased in people with both diabetes and stroke. A longitudinal study in Hispanic Americans aged over 60 years confirmed that 43% of all incident dementia cases were attributable to type 2 diabetes, stroke or a combination of these two risk factors (Haan etal., 2003). Longitudinal population studies suggest that diabetes is also associated with an increased risk of developing Alzheimer-type dementia (Peila etal., 2002; Honig etal., 2003). The association between diabetes and Alzheimer's disease is more difficult to explain. For some diabetic patients, cerebral infarction may play an additive role in the development of Alzheimer's disease, for example by a critical silent-stroke uncovering early and previously asymptomatic dementia. A study of 1766 Medicare recipients without dementia at baseline confirmed that the annual incidence of Alzheimer's disease was 5.2% in people with a history of stroke compared with 4% in those without clinically apparent cerebrovascular disease (Honig etal., 2003). In these patients, the presence of both stroke and diabetes led to a significant increase in the risk of Alzheimer's disease (relative risk 4.6). More importantly, amongst vascular risk factors, only diabetes was related to the risk of Alzheimer's disease in the absence of stroke. This and evidence from other studies suggest that cerebrovascular disease alone cannot solely account for the increased likelihood of Alzheimer's disease in diabetic individuals (den Heiger etal., 2003; Honig etal., 2003).
There are a number of other potential mechanisms to explain the observed association between diabetes and Alzheimer's disease. These include impairment of insulin transport into the brain or dysfunction of insulin signal transduction. Any disturbance of cerebral insulin pathways could result in impaired amyloid metabolism and less prevention of tau phosphorylation, leading to accumulation of plaques and neurofibrillary tangles, the pathological hallmarks of Alzheimer's dementia. Of note, non-enzymatic advanced glycosylation end-products (so-called AGEs) can cause cross-linking of amyloid proteins, and AGEs have been detected within the plaques and tangles in the brains of those with Alzheimer's disease (Thomas etal., 1996; Munch etal., 1998). In addition, there may be a genetic explanation for the relationship between diabetes and Alzheimer's disease. The major gene associated with increased risk of Alzheimer's is apolipoprotein E (ApoE), with the ApoE4 variant in particular conferring a substantial risk. The association between diabetes and Alzheimer's dementia is particularly strong for type 2 diabetics with this allele, with a relative risk of 5.5 compared with individuals without these two risk factors (Peila etal., 2002). These data are supported by autopsy evidence, which demonstrated increased numbers of plaques and neurofibrillary tangles in diabetic carriers of the ApoE4 genotype. Further support for an aetiological role for diabetes in Alzheimer's disease comes from the Rotterdam study, a large population-based cohort study of chronic disease in older people (den Heiger etal., 2003). In vivo assessment of the volume of the hippocampus and amygdala by volumetric magnetic resonance imaging (MRI) provides a good estimate of the degree of Alzheimer's pathology, even in older people with no clinical features of dementia. Type 2 diabetes was associated with atrophy of the hippocampus and amygdala on MRI, and this was not related to any coexistent vascular disease.
Vascular dementia and Alzheimer's disease share certain vascular risk factors such as diabetes, hypertension and smoking. Nevertheless, current research suggests that cognitive decline and dementias are linked to diabetes by mechanisms over and above cerebrovascular disease. There is evolving evidence for an overlap between pathophysiological changes such as AGEs, which lead to complications of diabetes and also degenerative brain disease due to Alzheimer's pathology. However, there is as yet no convincing evidence relating the type or intensity of diabetic therapy to the prevention or treatment of cognitive impairment in type 2 diabetes (Areosa Sastre and Grimley Evans, 2003).
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