Cognitive Impairment and Dementia in Type 2 Diabetes Mellitus

Alexandra Mastro, Physician Assistant Candidate; James B. Caputo, RPh, PharmD; Mary C. Vagula, PhD


US Pharmacist. 2014;39:33-37. 

In This Article

Pathogenesis of Cognitive Impairment in T2DM

Diabetes and diabetes-related CI continue to grow due to the increase in obesity and longevity of the modern-day human population, with significant effect on society. In this light, it is essential to understand the pathophysiological alterations that cause the development and progression of diabetes-related CI and also to devise treatments to reverse or prevent these complications.

Hypoglycemia vs. Hyperglycemia

Hypoglycemia is the number-one reason for temporary or short-term CI.[7] A normal and controlled glycemic level is defined as 4 to 7 mmol/L or 72 to 126 mg/dL. Levels can fluctuate in this range, and the diabetic patient can function adequately; but when levels fall below 4 mmol/L, cognitive deficits can be seen. When the brain does not have a sufficient amount of glucose to function, typically defined as <3.5 mmol/L or 63 mg/dL, certain symptoms can present and should be immediately corrected (Table 2).[6,7] It is possible for these short-term hypoglycemic states to result in permanent brain damage. Even repeated bouts of mild hypoglycemia have been shown to cause CI. Marked decreases in IQ were measured over a 6-year time period in one particular study.[8]

Many studies have been done on the effects of hypoglycemia and CI.[9] The Edinburgh Type 2 Diabetes Study showed that severe hypoglycemia was linked to cognitive impairment later in life. The Fremantle Diabetes Study was able to document dementia and cognitive decline. A recent 7-year follow-up study done in Taiwan used 1 million random subjects as the largest sample size to date. The study found that many different parameters were statistically significant predictors of dementia. Among the parameters studied, female gender, older age, insulin use, and previous episodes of hypoglycemia all put the patients in the study at high risk for dementia. Cases with previous episodes of hospitalized hypoglycemia resulted in a three-fold increase in dementia by the end of the study.[9]

Hyperglycemia, when prolonged, can also have negative effects such as neuropathy, retinopathy, nephropathy, and CI.[1] Brain imaging using MRI of patients with hyperglycemia for long periods of time can show visible lesions. These lesions represent damage to the neurons, which in turn translates to CI in that patient. A decrease in white matter volume in particular has been linked to reduced processing of information and loss of executive function.[7] A tighter glycemic control can help to prolong or even to some extent prevent the CI that can occur with T2DM.

Microvascular Changes

The common microvascular complications in diabetes include diabetic nephropathy, neuropathy, and retinopathy. Cerebral microvascular changes as seen in diabetic retinopathy can be the most common complication of T2DM. Predominantly, microvascular disease has been shown to affect the thalamus, basal ganglia, and white matter.10 An increased severity of microvascular changes shows a worse prognosis with regard to mental flexibility, verbal fluency, and processing speed. This was seen more in men than in women. The decline in processing speed was also found with hypertensive retinopathy.[11] Executive-functioning deficits are also a concern because of the involvement of frontal subcortical atrophy.[10]

Macrovascular Changes

The most noted macrovascular complications in diabetes include coronary artery disease, peripheral arterial disease, and stroke. Atherosclerosis is a leading cause of acute coronary syndrome as well as cerebrovascular accident and is accelerated by hyperglycemia secondary to T2DM. Macrovascular changes can affect heart and brain function by occlusion and ischemia. Cognitive impairment related to stroke alone could be directly linked to prolonged periods of hyperglycemia.[7] In addition, diabetes promotes hyperglycemia when not properly controlled, which combined with hypertension and hyperlipidemia, can result in cognitive decline from brain structure atrophy due to large deposits of amyloid and other fatty products.[10,11] Figure 1 shows the probable mechanisms leading to CI during diabetes.[12]

Figure 1.

Possible Mechanistic Contribution to Cognitive Impairment Seen in Diabetes Mellitus
Source: Reference 12

Inflammatory Changes

Obesity and T2DM can be associated with some systemic inflammation; this inflammation is believed to increase the risk for vascular disease. It is also thought that the inflammation is directly related to CI because inflammation of the brain itself is much like inflammatory changes seen in dementia. Although most studies have not focused on this link between inflammatory cytokines and CI, some information has been documented. Increases in interleukin (IL)-6, tumor necrosis factor (TNF), and C-reactive protein (CRP) have all been linked to lower cognitive functions.[11]