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Return to Age-Related Rise in Blood Sugar Linked to Memory Decline Overview

More on Age-Related Rise in Blood Sugar Linked to Memory Decline

Age-Related Rise in Blood Sugar Linked to Memory Decline

New York (Jul 16, 2009)

Illustration of human brain

Normal changes in glucose handling that occur with age might be an underlying cause of age-related memory decline, a recent study by NewYork-Presbyterian Hospital neurologist Scott Small, MD and colleagues suggests. "Blood glucose levels are less and less well regulated starting in the fourth decade, and through a mechanism yet to be defined, glucose targets the dentate gyrus, one of the hippocampal regions involved in fixing new memories," Dr. Small said. He and his colleagues reported these findings in the December 2008 issue of the Annals of Neurology.

How Memory Works

The hippocampus's several regions (the entorhinal cortex, dentate gyrus, CA1 subfield and subiculum) work together as a circuit in learning new memories, according to Dr. Small – "the name of someone you met recently, where you put your keys, a new software program." Each subregion contains a molecularly distinct population of neurons, which may explain why different physiologic processes such as aging, disease, and stroke appear to affect different regions of the hippocampus. Alzheimer's disease, for example, affects the entorhinal cortex, and vascular disease affects the CA1 subfield and the subiculum, while normal cognitive aging targets the dentate gyrus. "The early stages of Alzheimer's and normal aging look very similar using standard memory tasks, though, because they access the whole circuit. It's as though different parts of your computer are down, but the end result is the same, it's not working."

About Dr. Small's Study

In this study Dr. Small and his colleagues used high-resolution functional magnetic resonance imaging (fMRI), a variant of MRI, to map cerebral blood volume (CBV) in the subregions of the hippocampus. CBV has a high correlation with other basal measures of brain function such as cerebral blood flow (as measured with MRI) or glucose uptake (as measured with positron emission tomography).

High-resolution fMRI had several advantages for this study, Dr. Small said. "High-resolution fMRI has some relatively unique features – one is that it has very high spatial resolution so it enables us to look at the different parts of the hippocampus, which are very tiny. The second is that we can use this same imaging technique across species," a big advantage in this study since subjects included rhesus monkeys and mice as well as humans.

High Glucose and Poor Cognition

In the first phase of the study the researchers generated high-resolution fMRI snapshots of the hippocampal formation in 240 nondemented elders (mean age 79.7 years). Among the analyses they performed was an examination of the relationship between blood glucose, insulin, and hippocampal CBV to determine whether glucose and insulin underlie dentate gyrus dysfunction. They found that blood glucose levels were inversely correlated with dentate gyrus CBV, and were also inversely correlated with total recall on the Selective Reminding Test, a cognitive measure of hippocampal function.

In the study's second phase Dr. Small tested the hypothesis that an increase in blood glucose is differentially linked to the dentate gyrus by mapping hippocampal CBV in aging rhesus monkeys. "We found that the monkeys with elevated blood glucose were more likely to have dysfunction in the dentate gyrus than in the other subregions," he said, adding that, "The first two studies confirmed each other, but they're correlational." In the final phase the researchers induced elevations in blood glucose in mice to observe the effects of systematic increases. The mice were treated with streptozosin at three and six months of age, killing the insulin producing cells of the pancreas, which resulted in an abnormal increase in blood glucose. Using fMRI the researchers found significant dysfunction in the dentate gyrus, confirming their earlier findings.

Glucose Regulation Diminishes Over Time

An increase in blood glucose is a natural and inevitable aspect of aging, according to Dr. Small. "As we age we gradually have a harder time absorbing sugars that we eat," he said. Starting in our 30s we all begin to experience spikes in blood glucose levels, particularly after meals, and as a result our brains are exposed to higher and higher levels of blood glucose over time. The major reason for this is that we all become gradually and subtly insulin insensitive. The mechanisms by which insulin enables the body to 'sponge up' blood glucose work less and less well with age, so we don't take up the glucose as well.

Although Dr. Small and colleagues have identified glucose as a likely factor in memory decline, they do not understand its role. "This study really framed that question," he said. "Now, we really need to figure out what it does."

Exercise is Beneficial

Dr. Small said that this research suggests that any manipulation – behavioral or pharmacological – that reduces glucose could potentially ameliorate age-related memory decline. He noted that these results clarified the findings of a previous study he and his colleagues published in Proceedings of the National Academy of Sciences (PNAS 2007 104:5638-5643). In that study physical exercise (in humans and mice) preferentially benefited the dentate gyrus. "We didn't clearly understand why at the time, but this latest finding does give a very plausible mechanism," he said. "As you exercise, your muscles start expressing a glucose transporter allowing muscles to be spongier to glucose. This suggests that physical exercise benefits the dentate gyrus because it allowed subjects to have better glucose handling." It may also account for other findings in which physical exercise is actually beneficial to cognition, he added. "That's one of the things we're very keen on trying to pin down."

Large-scale epidemiological studies often produce conflicting results, Dr. Small said. "One day milk is good, then milk is bad, or eggs are good, eggs are bad. In all of the studies of aging and disease what always comes out as 'good' is exercise," he pointed out. "At this point, there is nothing else to recommend." Dr. Small added that he is working with colleagues to develop a number of compounds derived from food that might imitate the benefits of exercise, "but that's into the future."

Scott Small, MD is an Associate Attending Neurologist at NewYork-Presbyterian Hospital/Columbia University Medical Center, and an Associate Professor in Neurology at Columbia University College of Physicians and Surgeons.

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