A multi-step inflammatory cascade appears to connect hyperglycemia and brain dysfunction.
Patients with type 2 diabetes have impaired cerebral blood flow that's tied to cognitive changes, even over the short time period of 2 years, researchers found.
In a prospective 2-year study, diabetic patients had diminished cerebral vasoreactivity compared with controls, which was associated with greater declines in cognitive function, Vera Novak, MD, PhD, of Beth Israel Deaconess Medical Center in Boston, and colleagues reported online in Neurology.
"People with type 2 diabetes have impaired blood flow regulation," Novak said in a statement. "Our results suggest that diabetes and high blood sugar impose a chronic negative effect on cognitive and decision-making skills."
Type 2 diabetes is a known risk factor for cognitive impairment and dementia. Both hyperglycemia and accompanying inflammation have been tied to endothelial dysfunction and impaired cerebrovascular regulation. Diminished vasoreactivity can lead to impaired cerebral blood flow to neurons, the researchers explained, potentially leading to impairments in cognitive function.
Novak and colleagues studied 40 patients -- 21 of whom had diabetes -- using MRI to measure cerebral perfusion and vasoreactivity. They also conducted neuropsychological tests and assessed serum inflammatory markers.
They found that patients with type 2 diabetes had diminished global and regional cerebral vasoreactivity from baseline, compared with controls, noting that diabetic patients had a decline of more than 50% in vasoreactivity over the 2-year period.
Those with diabetes also had significant declines in multiple measures of cognitive performance, including executive function and activities of daily living, during that time. Healthy controls did not experience such changes, they said.
"These correlations provided the link between altered cerebral vasoregulation and cognitive deterioration in participants with type 2 diabetes that can be tracked prospectively even over a relatively short time period of 2 years," the researchers wrote.
Novak and colleagues also found that greater levels of serum inflammatory markers, including vascular adhesion molecules, cortisol, and C-reactive protein were associated with greater decreases in cerebral vasoreactivity among patients with type 2 diabetes -- a finding that "underscores the effects of hyperglycemia and glycemic variability on brain tissue and function," they wrote.
"These correlations suggest that inflammation has a critical role in the degradation of cerebral vasoregulation in the milieu of chronic hyperglycemia regardless of glycemic control," they added.
The researchers explained how the relationship between hyperglycemia, cerebral vasoreactivity, and cognitive impairment might work: Hyperglycemia and insulin resistance lead to oxidative stress in the mitochondria and endoplasmic reticulum, which triggers the release of pro-inflammatory cytokines and activates pro-apoptotic pathways.
"This cascade ultimately leads to endothelial dysfunction," they wrote. "Adhesion molecules are expressed concomitantly with altered endothelial cell motility through nitric oxide-dependent pathways, angiogenic activity, and neovascularization, indicating an ongoing inflammation-remodeling process of endothelium."
"A combination of hyperglycemia and inflammation appears to accelerate neuronal loss and atrophy in the affected regions," they continued. "Vasoreactivity in the cerebral cortex is negatively affected by increased capillary thickness, microangiopathy, and altered endothelial permeability. A shift in the balance between vasodilation and vasoconstriction may be an important factor in the pathophysiology of hyperglycemia-mediated microangiopathy. As a result, metabolic vascular reactivity diminishes."
They said their findings also suggest that endothelial problems may develop early in the course of hyperglycemic damage, before any structural changes occur -- implying that early detection and monitoring of cerebral blood flow regulation may predict the acceleration of cognitive decline in patients with type 2 diabetes.
"Early detection and monitoring of blood flow regulation may be an important predictor of accelerated changes in cognitive and decision-making skills," Novak said in the statement.
Hyperglycemia's negative impact on cognitive function has been shown in other studies that have concluded higher HbA1c levels are associated with faster cognitive decline. Still, the researchers called for additional analyses involving a larger number of patients over a longer period of time, in order to better understand the relationships among hyperglycemia, cerebral blood flow, and cognitive trajectories.
The authors disclosed no financial relationships with industry.
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