Diabetes is one of the world’s most widespread diseases, affecting some 250 million people worldwide and about 60 million new cases diagnosed each year. The know effects and complications of diabetes include changes in large and small blood vessels, which in turn can lead to peripheral neuropathy, loss of vision, renal failure, heart attacks as well as cerebrovascular disease including stroke. Neurological co-morbidities of diabetes have recently begun to attract more interest. They are among the most common but also under-recognized complications of diabetes.

Individuals who are obese and/or with alterations of insulin homeostasis, including diabetes, are at an increased risk of developing dementia and Alzheimer’s disease. The risk of vascular dementia is increased 2 to 2.5 fold in people with type 2 diabetes, that of developing Alzheimer’s disease is 1.5 to 2 fold. The association between type 2 diabetes and Alzheimer’s disease is particularly pronounced in carriers of the apolipoprotein E epsilon 4 allele. Carriers of this allele who also have type 2 diabetes have a two-fold increased risk of developing Alzheimer’s disease compared to those who have the allele but not diabetes.

The neurocognitive effects of diabetes are most clearly visible in children and the elderly. In people with type 1 diabetes, changes are seen in the first five to seven years of life when the brain is developing. The elderly, over 65 years of age in whom the brain undergoes neurodegenerative changes are also particularly vulnerable to the neurocognitive effects of diabetes. These neurodegenerative changes include generalized brain atrophy, with larger lesions than those found in controls without diabetes, often in subcortical areas of the brain. Leukocaryosis, also known as white matter hyperintensive lesions are usually seen in people of the age of 80, but appear earlier and are more extensive in the brains of people with diabetes. MRIs often shows atrophy of the amygdala in people with diabetes. Finally patients with diabetes often have extensive amyloid plaques that are otherwise characteristic of Alzheimer’s disease.

The occurrence of amyloid plaques in the brains of people with diabetes points to a link between the pathophysiology of Alzheimer’s disease and diabetes. In patients with insulin resistance, too much insulin enters the brain. Both insulin and amyloid are metabolized by the insulin degrading enzyme (IDE). Since IDE has a much higher specificity for insulin than amyloid, the overabundance of insulin in the brain effectively blocks the clearance of amyloid and so promotes plaque formation. In summary, diabetes appears to accelerate the aging process of the brain by increasing atrophy and reducing the cognitive reserve.

So, do these pathophysiological changes in the brain lead to cognitive impairment? In people with type 1 diabetes, the reduced cognitive performance becomes apparent in childhood in the form of reduced psychomotor ability or speed, attention, memory and verbal IQ scores. The factors that most affect the intelligence of people with type 1 diabetes are age at diagnosis and glycemic control. Diagnosis before the age of 4 is associated with impaired executive skills, attention, and processing speed, most likely because the development of the brain is disrupted by the metabolic disturbance caused by diabetes. Notably, academic performance improves with better glycemic control.

In people with type 2 diabetes, the neurocognitive deficits are decreased psychomotor speed complex motor function, executive functions, memory skills, immediate and delayed recall, verbal fluency, attention, visuospatial ability. These deficits were recently assessed by Whitehead and colleagues, who tested whether neurocognitive speed or inconsistency was the better clinical marker of type 2 diabetes. Patients with type 2 diabetes performed slower and more inconsistently than the non-diabetic control subjects. In a longitudinal study, Espeland and colleagues observed the decline of cognitive function and fine motor speed. The study assessed women between the ages of 65 and 80 years, 179 with type 2 diabetes and 1984 non-diabetics. The study found a significantly accelerated of decline for verbal knowledge and verbal memory, but the use of oral diabetes medications was associated with relatively better cognitive function.

References

S Roriz-Filho J, Sá-Roriz TM, Rosset I, Camozzato AL, Santos AC, Chaves ML, Moriguti JC, & Roriz-Cruz M (2009). (Pre)diabetes, brain aging, and cognition. Biochimica et biophysica acta, 1792 (5), 432-43 PMID: 19135149

Whitehead BP, Dixon RA, Hultsch DF, & MacDonald SW (2011). Are neurocognitive speed and inconsistency similarly affected in type 2 diabetes? Journal of clinical and experimental neuropsychology, 33 (6), 647-57 PMID: 21416426

Espeland MA, Miller ME, Goveas JS, Hogan PE, Coker LH, Williamson J, Naughton M, Resnick SM, & Whisca Study Group (2011). Cognitive function and fine motor speed in older women with diabetes mellitus: results from the women’s health initiative study of cognitive aging. Journal of women’s health (2002), 20 (10), 1435-43 PMID: 21819251

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