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Glycemic Control Linked to Brain Function and Structure

An accelerated decline in brain function is an important risk that needs to be examined further in relation to glycemic control in older people with long-standing diabetes.

Lenore Launer, PhD, director of neuroepidemiology at the National Institute on Aging, part of the National Institutes of Health (NIH) in Bethesda, Maryland, reported that, at a mean age of 62 years, participants in MIND study were “already experiencing an annual decline of total brain volume in a range reported for people 15 years older, when the incidence of dementia increases logarithmically.”

“MIND participants are at an age when disease processes in the brain begin to accelerate, eventually leading to double the risk of dementia in people with type 2 diabetes compared to people without this disorder.” The aim of MIND was to test the efficacy of intervening on cardiovascular risk factors to reduce the rate of cognitive decline and structural brain changes measured on magnetic resonance imaging (MRI) in middle-age to older patients with long-standing type 2 diabetes.

Starting in October 2003, researchers recruited 2977 participants from the ACCORD trial, 1469 of whom were in the intensive glycemic control group (targeting hemoglobin A1c [HbA1c] to below 6%), and 1508 of whom were receiving standard therapy (targeting HbA1c to between 7% and 7.9%).

Total brain volume, the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a subset of participants (n = 503). The primary cognitive outcome, the Digit Symbol Substitution Test (DSST), was assessed at baseline and then again in participants who underwent another MRI examination at 20 and/or 40 months.

At baseline participants were a mean age of 62.5 years, and 47% were female; the mean duration of diabetes was 10.4 years, the mean HbA1c was 8.3%, and the mean body mass index was 33 kg/m2.

There was a correlation between higher HbA1c at baseline and lower DSST score. A relationship was also seen between increasing duration of diabetes and decreasing total brain volume. However, at 40 months, the researchers found no differences in DSST score between patients in the intensive therapy or standard therapy groups. “Both groups declined from baseline but there were no differences between the groups,” she said.

In terms of brain volume, MRI did demonstrate “very significant” differences between the groups, with individuals in the intensive treatment group showing less decline in total brain volume than the standard therapy group (-13.0 vs. -17.7 cm3), for a total difference of 4.6 cm3 (P = .0007).

Despite this difference, Dr. Launer said the findings do not demonstrate that an intensive glycemic strategy provided benefit to cognitive function. “There was a small difference in total brain volume favoring intensive therapy, but the difference does not support the use of intensive treatment to reduce brain atrophy, given the effects of the intensive intervention in ACCORD,” she said.

She was referring to ACCORD results showing increased mortality associated with intensive therapy, plus an increase in hypoglycemic events and weight gain with no overall benefit in cardiovascular disease.

Dr. Launer suggested that although cognitive decline is similar in both treatment groups, it may not remain that way.

“We postulate in this age group structural changes in the brain happen before cognitive changes and that, over time, the cognitive differences between the groups will emerge,” she said.

It has been suggested that up to age 70 little measurable cognitive decline occurs in people with type 2 diabetes, and those who develop mild cognitive impairment or Alzheimer’s disease start to diverge after that age, she explained.

Research suggests that total brain volume in cognitively stable nondiabetic people in their mid-70s declines by about 0.4% per year, compared with 0.8% in those who eventually convert to mild cognitive impairment or dementia.

“In our study of 62-year-olds, there was decline of 0.4% in the intensive treatment arm — similar to the cognitively stable nondiabetic people in their 70s — but there was a 0.57% decline in the standard treatment group,” Dr. Launer noted.

Anne Peters, MD, professor of clinical medicine at the Keck School of Medicine at the University of Southern California (USC) and director of the USC Clinical Diabetes Program in Los Angeles, who was not part of the study, commented that, “The lack of impact of glycemic control is not surprising.” “It is likely that the cause for the impairment in cognitive function in diabetes is multi-factorial and includes dyslipidemia, hypertension, and inflammation.” “In ACCORD, patients either had CVD or were at higher risk for CVD, were older, and had a longer duration of diabetes with a high baseline A1c. A period of intensive glucose lowering for a relatively brief 3 years seems unlikely to reverse or even prevent cognitive decline and/or structural brain changes.”

Dr. Peters said recent studies have suggested that to optimize benefit, patients need to have near-normal glucose levels starting early after their diabetes diagnosis and maintain it near-normal levels for many years.

“Perhaps it was too late for the ACCORD patients to show an effect on cognitive function, or those in the intensive arm experienced a negative cognitive impact from increased episodes of hypoglycemia. Therefore, although these data underscore the need to study the effects of various therapies, including glycemic control, on cognitive function and structural brain changes, future studies need to be of longer duration and begun in patients at an earlier point in their diabetes.”

On a clinical level, she said the results should not affect treatment, “except to underscore the need for multifactorial intervention in patients with diabetes with screening and treatment for cognitive dysfunction if it occurs.”

International Diabetes Federation (IDF) World Diabetes Congress 2011, Abstract # O-297, presented December 8, 2011