Insulin resistance in cognitively normal subjects is associated with a pattern of reduced regional cerebral glucose metabolism that is characteristic of mild cognitive impairment and early Alzheimer’s disease, according to a study published online Sept. 13 in the Archives of Neurology.
On PET scanning, subjects with insulin resistance also showed an unusual activation pattern in the brain during a memory encoding task. This coincided with their poorer performance in recalling words, compared with healthy adults who were not insulin resistant.
“Taken together, these results suggest that increased insulin resistance may be a marker of AD [Alzheimer’s disease] risk that is associated with reduced regional cerebral glucose metabolism and subtle cognitive impairments at the earliest stage of disease, even before the onset of MCI [mild cognitive impairment],” wrote Laura D. Baker, Ph.D., of the Veterans Affairs Puget Sound Health Care System and the University of Washington, Seattle, and her associates.
Since insulin resistance is known to cause type 2 diabetes and to raise the risk of Alzheimer’s disease, Dr. Baker and her colleagues tested the hypothesis that cognitively normal adults with newly diagnosed prediabetes or type 2 diabetes and insulin resistance would already show abnormal cerebral glucose metabolism in regions known to predict susceptibility to AD.
The study subjects were adults with newly diagnosed, as-yet untreated prediabetes (11 patients) or type 2 diabetes (12 patients) – all of whom had insulin resistance – as well as a control group of 6 adults matched for age and education level who had normal glucose values and no insulin resistance. The subjects underwent PET imaging in a resting state and during a 35-minute memory-encoding task, and were tested for delayed free recall after the scanning was completed.
Insulin resistance was associated with reduced glucose metabolism in the posterior cingulate cortex, precuneus region, parietal cortices, temporal/angular gyri, and anterior and inferior prefrontal cortices. In contrast, no such impairment was seen in the control subjects.
“This pattern of hypometabolism has also been observed in patients with MCI and AD, in middle-aged carriers of the APOE e4 genetic risk factor who do not have dementia, and in presymptomatic adults with the AD-causative presenilin-1 gene,” Dr. Baker and her colleagues wrote (Arch. Neurol. 2010 Sept. 13 [doi:10.1001/archneurol.2010.225]).
The link between insulin resistance and reduced glucose metabolism in this study was not affected by subjects’ age, fasting glucose values obtained just before PET scanning, degree of hyperglycemia after oral glucose tolerance testing, or APOE e4 allele status.
In addition, patients with insulin resistance showed a diffuse rather than a more focused pattern of brain activation during the memory encoding task, including activation of areas adjacent to the regions that were activated in the control group. They also showed activation or hyperactivation of areas “not typically engaged in a cognitive task,” a finding that has been reported in patients with prodromal or early AD and non-symptomatic carriers of the APOE e4 allele. This pattern may represent “a compensatory mechanism invoked following dysfunction of the neuroarchitectural network that typically would support a cognitive task,” the researchers noted.
Although the insulin-resistant subjects were not cognitively impaired according to current criteria, their recall ability was poorer than was that of the control group in the post-scanning test.
This study was limited by its small sample size, according to Dr. Baker and her associates. “Clearly, our results need to be replicated with a larger sample.”
This study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases and by the U.S. Department of Veterans Affairs. The investigators reported no financial conflicts of interest.