By Salynn Boyles | Mar 19, 2014
Onset of type 2 diabetes in middle age appears to affect late-life cognition by reducing brain volume, MRI studies revealed in a population-based cohort without dementia.
Compared with never developing diabetes, developing diabetes in midlife was associated with an 85% increase in subcortical infarctions on MRI analysis (OR, 1.85 [95% CI 1.09-3.15; P=0.02), a 4% reduction in hippocampal volume (95% CI -7.0-minus 1.0; P=0.01), and a 2.9% reduction in whole brain volume (95% CI -4.1-minus 1.6; P<0.001), according to researcher Rosebud O. Roberts, MB, Ch.B,of the Mayo Clinic, Rochester, and colleagues.
Diabetes onset after age 64 did not appear to impact brain pathology or cognitive performance, suggesting that the deleterious impact of the disease on memory and other aspects of brain function occurs over decades, they wrote in the April 1 issue of the journalNeurology.
Midlife hypertension was associated with subcortical infarctions and whole brain volume declines, and was marginally associated with reduced performance in executive function during cognitive testing.
"Our study shows that the earlier you have these conditions, the worse your brain pathology is late in life," Roberts told MedPage Today.
Diabetes and hypertension have been associated with ischemic lesions in the brain and other organs in previous studies, as well as Alzheimer's pathology and brain atrophy, but the mechanisms by which these conditions influence cognitive impairment are not well understood, the researchers wrote.
They hypothesized that earlier onset diabetes and hypertension would be associated with more brain atrophy on imaging studies, but most earlier imaging studies have not included information about when participants developed the conditions.
The new research included participants in The Mayo Clinic Study on Aging (MCSA), a population-based prospective study initiated in 2004 to examine risk factors for mild cognitive impairment (MCI) and dementia among residents of Olmsted County, Minn.
The current substudy included 1,437 MCSA participants without dementia whose median age at enrollment in the study was 80. All were evaluated by a nurse and a physician and all underwent neuropsychological testing and MRI scanning to determine cortical or subcortical infarctions, white matter hyperintensity (WMH) volume, hippocampal volume (HV), and whole brain volume (WBV).
Medical records were also reviewed for a prior diagnosis of diabetes or hypertension, and middle-age onset was defined as ages 40 to 64.
In addition to greater incidence of infarctions, and reduced HV and WBV associated with midlife diabetes onset, the study revealed that:
- Midlife diabetes onset was associated with a two-fold increase in mild-cognitive impairment risk (MCI) compared with having no diabetes (P=0.01).
- The association between diabetes and MCI persisted with adjustment for infarctions and WMH volume but was attenuated after adjustment for WBV (OR 1.60, 95% CI 0.87-2.95, P=0.13) and HV (OR 1.82, 95% CI 1.00-3.32, P=0.05).
- Midlife hypertension was associated with infarctions and WMH volume and was marginally associated with reduced performance in executive function, but there were few effects of late-life onset diabetes and hypertension on brain pathology and cognitive function.
A multivariable model suggested that markers of brain atrophy are in the causal pathway and may mediate the association of midlife diabetes with cognition, but the association was found to be independent of infarctions and WMH volume and of other vascular risk factors and APOE status.
"These findings suggest that in persons with diabetes, brain volume loss may be a mechanism for the association of diabetes with Alzheimer disease or may share a common mechanistic pathway," the researchers wrote. "The lack of an association of late-life diabetes with cognition further suggests that the pathophysiologic process requires decades to manifest pathologically or as symptoms."
Roberts and colleagues suggested that dysfunctional insulin signaling and altered glucose metabolism in the brain of diabetics might play a role in tau protein degradation, amyloidogenesis, or some other process that is toxic to neurons, or that altered insulin signaling may increase tau phosphorylation, increase insulin binding to insulin-degrading enzyme, decrease beta-amyloid clearance, and lead to neurodegeneration.
"Our findings suggest that earlier onset of diabetes and hypertension leads to brain pathology in late-life brain, and that the effects of whole brain and hippocampal atrophy are a mechanism by which diabetes affects cognition in late life," they concluded. "The potential clinical implications of our findings are that the prevention and control of diabetes and hypertension may prevent or delay the ischemic injury and brain neurodegeneration and the onset of clinical manifestation of cognitive impairment."