Diabetes Age at Onset Affects Later Cognitive Risk

Pauline Anderson

March 19, 2014

A new study shows that older patients who developed diabetes in midlife are more likely to have brain changes, including brain atrophy, than those who developed the disease at a later age or not at all, and that loss of brain volume is a key link between diabetes and mild cognitive impairment (MCI).

Dementia develops over a long period, during which time diabetes can have a progressively more devastating effect on the brain, said lead author Rosebud O. Roberts, MB, ChB, professor of epidemiology, Mayo Clinic, Rochester, Minnesota.

"In the absence of a cure for dementia, our findings emphasize the importance of prevention and control of type 2 diabetes as a means to reducing the burden of dementia due to Alzheimer's or vascular dementia," Dr. Roberts told Medscape Medical News.

The study was published online March 19 in Neurology.

Diabetes, Hypertension

The study included 1437 persons without dementia, median age 80 years, from the Mayo Clinic Study of Aging, a population-based prospective study initiated in 2004 to investigate risk factors for MCI and dementia among Olmsted County, Minnesota, residents. From medical records, researchers characterized participants as having onset of diabetes or hypertension in midlife (age 40 to 64 years) or in late life (age 65 years or older). They used participants who never developed these diseases as reference groups.

The mean age at onset of diabetes was 56.2 years for midlife and 71.9 for late life. For hypertension, mean onset was 52.7 years for midlife and 71.6 years for late life.

Participants underwent regular tests of cognitive function and extensive neurologic testing. They also underwent MRI that provided various brain parameters.

Compared with participants who did not have diabetes, onset of the disease in midlife was associated with subcortical infarctions (odds ratio [OR], 1.85; P = .02), reduced hippocampal volume (–4%; P = 0.01), reduced whole brain volume (–2.9; P < .001), and MCI (OR, 2.08; P = .01).

Participants who developed diabetes in late life also had some brain effects, although less pronounced. Dr. Roberts noted that the risk for cortical infarctions was similar in those who had onset in midlife and late-life (OR, 1.84 for late life vs 1.73 for midlife). However, the association with midlife onset was not statistically significant; this could be due to relatively fewer numbers of patients with midlife onset because of earlier death from infarctions (stroke) or from a refusal to participate in the study due to more severe diabetes.

For cognitive measures, midlife diabetes was associated with reduced performance in executive function, a reduced global cognitive score, and an elevated risk for MCI that was independent of other vascular risk factors and apolipoprotein E ε4 allele status. Late-life onset of diabetes was marginally associated with reduced performance in memory and executive function.

Diabetes damages both small and large vessels of the brain, which leads to neuronal injury, neuronal death, loss of brain tissue (reduction in whole brain and hippocampal volumes), and, ultimately, MCI and dementia, reported Dr. Roberts. "Once we adjusted for reduced brain volumes in our analyses, the association of diabetes with MCI decreased and was no longer significant."

This, she said, suggests that reduced brain volumes mediate the association or are a link between diabetes and cognitive impairment.

Other potential mechanisms connecting diabetes to cognitive impairment and dementia, include dysfunctional insulin signaling and altered glucose metabolism in the brain, which may contribute to neurofibrillary tangle formation, amyloid-β deposition, and oxidative damage, said the authors.

The study showed that participants who developed hypertension in midlife were more likely to have vascular damage, such as a much higher volume of white matter hyperintensity, cortical and subcortical infarctions, and minimally reduced whole brain volume, compared with those without hypertension. Midlife hypertension was also marginally associated with reduced performance in executive function, and late-life onset was marginally associated with MCI.

Although diabetes was associated with both vascular damage and reduced brain volumes (whole brain and hippocampal volumes) regardless of the age at onset, only hypertension in midlife was linked to vascular damage. Because diabetes is often associated with hypertension, reducing diabetes prevalence will also reduce the number of people with hypertension, said Dr. Roberts.

Logical Inference

Commenting on the study, Donn Dexter, MD, a neurologist at the Mayo Clinic, Mayo Clinic Health System, Eau Claire, Wisconsin, and a member of the American Academy of Neurology who did not participate in the research, said it was "interesting" and was carried out by a "very well-respected team of experts" in behavioral neurology.

"It confirms what may be a logical inference, that diseases that affect brain structure, for example, diabetic vascular disease, will show evidence of decreased brain function — in this case cognition," said Dr. Dexter.

"The study provides another piece of supporting information to share with our patients that will help to encourage them to aggressively manage their diabetes — or even better yet, prevent it."

The study was supported by grants from the National Institute on Aging and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program, and was made possible by the Rochester Epidemiology Project. Additional funding sources include National Institutes of Health and the Robert Wood Johnson Foundation and the European Union Regional Development Fund. Dr. Roberts receives research support from AbbVie Health Economics and Outcome Research and from Walter S and Lucienne Driskill Foundation. Dr. Dexter has disclosed no relevant financial relationships.

Neurology. 2014;82:1132-1141. Published online March 19, 2014. Abstract

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