Accelerated Progression from Mild Cognitive Impairment to Dementia in People with Diabetes

Discussion

The incidence of dementia is increased in patients with diabetes by 50–100% compared with people without diabetes, as shown by several reports, including those from our group.^[2] We are now able to extend these findings by showing that diabetes and pre-diabetes increase the risk of conversion from MCI to dementia. In this large longitudinal study of elderly adults, we found that 1) diabetes and pre-diabetes substantially accelerate the progression from MCI to dementia; 2) the risk effect of pre-diabetes on the progression from MCI to dementia appears stronger than diabetes; 3) diabetes and pre-diabetes anticipate dementia occurrence by more than 3 years; and 4) we confirm an increased risk of dementia, but not of MCI, in subjects with diabetes or pre-diabetes.

To date, Italian^[10] and French^[17] population-based longitudinal studies have examined the role of vascular risk factors, including diabetes, in the progression of MCI to dementia, and failed to find an association. There are several reasons for the discrepant findings. First, as pre-diabetes was not assessed in these two studies, subjects with this condition were included in the nondiabetes group, which might have diluted the effect of diabetes on dementia risk due to the strong influence of pre-diabetes on the progression from MCI to dementia, as shown in our report. Second, in the two studies, diabetes was identified based on fasting blood glucose ≥7.2 and ≥7.8 mmol/l, respectively, which are higher than the WHO criteria of 7.0 mmol/l.^[29] Finally, in both studies, the follow-up time was only 3.5 to 4 years, and the populations were younger than our cohort. As a result, the statistical power of the two studies may be limited because of the small number of incident dementia cases.

Findings from brain imaging and neuropathologic studies support the notion that the increased risk of cognitive decline and dementia in elderly people with diabetes reflects a dual pathologic process involving both cerebrovascular damage and neurodegenerative changes.^[36–38] In addition to vascular pathways, several possible pathophysiologic mechanisms, including hyperglyceamia, insulin resistance, oxidative stress, advanced glycation end products, and inflammatory cytokines, may explain the effect of glucose deregulation on dementia risk. Recent genetic studies have found that chromosome 10 contains the genes for both late-onset AD and type 2 diabetes.^[39] Interestingly, a clinicopathologic study suggested that there may be a shared predisposition for developing amyloid in both the pancreas and the brain.^[40] All these mechanisms may explain the accelerated progression from MCI to dementia observed in this study. In addition, in subjects with MCI, cognitive deficits may affect the ability to manage complex behaviors such as those required for diabetes self-care,^[41] which may lead to a vicious circle. Therefore, an additional increased risk of developing dementia resulting from diabetes can be expected in people with MCI.

The stronger effect of pre-diabetes than diabetes on the conversion from MCI to dementia may be caused by the high glycemic level in pre-diabetes that is a commonly ignored condition. In our study, about 30% of patients with diabetes had normal random blood glucose level by hypoglycemic treatment and dietary control; effective glycemic control may reduce the risk of dementia in people with diabetes.^[20] Further, insulin resistance (hyperinsulinemia without hyperglycemia) is stronger in people with pre-diabetes than those with frank diabetes.^[42]

A number of studies that evaluated the cognitive function in patients with diabetes or pre-diabetes have shown that poor glucose regulation is associated with global cognitive decline, with impaired verbal memory in particular, but the evidence for deficits in other cognitive domains is weak.^[43] However, a recent prospective study suggested that diabetes-related cognitive deficits and MCI may represent different entities that do not necessarily affect the same domains.^[44] Another longitudinal study reported that diabetes may be related to psychomotor slowing, but not to deficits in other cognitive domains typically involved in MCI.^[45] Results from our study showed that diabetes and pre-diabetes were associated with MCI and its subgroups, neither cross sectionally nor longitudinally. This is in agreement with an Italian longitudinal study^[10] and a case-control study from the Mayo Clinic.^[8] However, the latter study found an association of MCI with a longer duration and greater severity of diabetes, and Luchsinger et al.^[9] reported a higher risk of both aMCI and oCIND in diabetic patients in a population with very high prevalence of diabetes. These findings suggest that only severe and longstanding diabetes may be related to MCI. Unfortunately, our study sample was too small to verify this hypothesis. An alternative explanation suggested by van den Berg^[46] is the old age of the study population involved, where the lower cognitive level at baseline may have masked any additional impact of diabetes. In other words, the standard MCI criteria may not be sensitive enough to identify those people with global cognitive deficits due to diabetes.^[16] Finally, another possibility is that in very old people, diabetes and pre-diabetes may accelerate the process of dementia so rapidly that a possible association between diabetes and MCI cannot be detected when follow-up examinations are carried out with intervals longer than 1 year.

The main strengths of our study are the population-based cohort study, the long-term prospective study design, and the assessment of diabetes at baseline and each follow-up examination. However, some limitations should be noted. First, we used random blood glucose to define diabetes and pre-diabetes, which might result in an attenuation of the associations. However, the prevalence of diabetes in our study population (8.9%) is comparable with those reported from an elderly Swedish population.^[47] Second, as there are no specific recommended tools to diagnose MCI, the operationalization of the criteria may differ slightly from those in other studies. In addition, prevalent MCI cases were included in the MCI cohort, which might contain persons with long-term cognitive impairment that remains stable over time. However, similar results were obtained when the incident MCI cohort identified at first follow-up examination was used. Third, as the Kungsholmen Project is based on an elderly population (the mean age was 82 years at baseline), the dropouts from the screening phase to the third follow-up were mainly because of death.^[48] Diabetes, MCI, and dementia are all associated with elevated mortality,^[20,49] which may lead to an underestimation of the strength of the diabetes-dementia or diabetes-MCI association due to selective survival. Thus, caution is needed when generalizing our findings to younger populations. Finally, the diagnoses of dementia were made on a clinical basis. However, the clinical assessment for dementia was comprehensive and validated in a previous study.^[22] Although neuroimaging data may help detect vascular lesions in the brain, it is difficult to determine the significance of these lesions, as coexistence of AD-related pathologic changes and vascular lesions in the brain is very common in late life.^[50]

In summary, our results provide further support for the important role of diabetes and pre-diabetes in dementia, and highlight the need to control diabetes and detect pre-diabetes to prevent or postpone dementia in people with MCI. Our findings underline the importance of regularly monitoring cognitive function in people with diabetes and pre-diabetes. The lack of association between diabetes and the risk of MCI in our study suggests that diabetes may lead to dementia bypassing MCI or shortening the MCI phase in elderly people.

Diabetes. 2010;59(11):2928-2935. © 2010 American Diabetes Association, Inc.

Cite this: Accelerated Progression from Mild Cognitive Impairment to Dementia in People with Diabetes - Medscape - Nov 01, 2010.