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High But Normal Blood Sugar Levels May Have a Negative Effect on Memory

Fitzgerald, Susan

doi: 10.1097/01.NT.0000438834.92512.e3
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Investigators reported that higher glucose levels may impair the functioning of the hippocampus. The findings were based on glucose testing, standardized memory tests, and brain imaging scans administered to the participants.

Chronically elevated blood glucose levels may have a negative effect on memory even if the sugar level does not meet the definition for type 2 diabetes or pre-diabetes, according to a study from Germany.

The study, which involved 141 healthy older persons, found that higher glucose levels may impair the functioning of the hippocampus, a region of the brain that is important for memory. The findings were based on glucose testing, standardized memory tests, and brain imaging scans administered to the participants.

“Strategies aimed at lowering glucose levels even in the normal range may beneficially influence cognition in the older population,” concluded the study, published in the Oct. 23 online edition of Neurology.

It is generally accepted that impaired glucose tolerance (IGT), which is also referred to as pre-diabetes, and type 2 diabetes mellitus (T2DM) are associated with impaired cognitive function in older persons and a higher incidence of dementia, including Alzheimer's. But the question of whether high normal sugar levels can be deleterious is far from being conclusively answered.







The new study was designed to assess the association between short-term and long-term glucose levels and memory performance. It also examined the association between sugar levels and hippocampal volume and microstructure.

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The study participants, who were between the ages of 50 and 80, were recruited via advertisements in Berlin. They were free of diabetes and other major medical conditions, scored normally on the Mini-Mental State Examination, and had a body mass index (BMI) of between 25 and 29 kg, which, while not obese, is in the overweight category.

The participants were given a blood test to measure for fasting glucose, glycosylated hemoglobin (HbA1c), and insulin. To evaluate individual learning and memory performance, the participants were tested using the Rey Auditory Learning Test. MRI scans were done to measure hippocampal volume and hippocampal microstructure was analyzed by using diffusion tensor imaging (DTI) to calculate the mean diffusivity within the hippocampus.

The study found overall that participants with lower blood sugar performed better than those with higher levels on tests that measure delayed recall, learning ability, and memory consolidation.

“On a test where participants needed to recall a list of 15 words 30 minutes after hearing them, fewer words was associated with higher sugar levels,” said study coauthor Agnes Flöel, MD, professor at the NeuroCure Clinical Research Center at Charité-University Hospital in Berlin. Dr. Flöel told Neurology Today that, for example, “an increase of about 7 mmol/mol of HbA1c went along with recalling two fewer words.”

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The brain scans also suggested that higher blood sugar levels can be problematic. “Higher levels of HbA1c and glucose correlated with decreased volume and microstructure of the hippocampus,” the researchers wrote. They said their study was the first to identify that higher long- and short-term glucose levels negatively affect hippocampal microstructure.

“Looking at hippocampal microstructure gives more detailed insight into the condition of the hippocampus,” Dr. Flöel said. She said participants with higher blood sugar levels tended to have higher mean diffusivity values, which can “be interpreted as a sign for disrupted neuronal membranes and increased extracellular water content, which can lead to decreased information transfer between cells and further to memory impairment.”

The researchers cautioned that the finding of an association between normal sugar levels and memory impairment does not prove cause and effect. They also noted that their sample size was small and may not be representative of the general population.

Even so, they concluded that “our study may provide the rationale for targeting glucose control in individuals who do not have T2DM and IGT with lifestyle intervention, a hypothesis to be evaluated in future trials.”

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Jason Hassenstab, PhD, assistant professor of neurology and psychology at Washington University in St. Louis, said “a unique feature of the study was the linkage between glucose levels, memory deficits, and the size and structural integrity of the hippocampus.”

“We see studies that can make inferences about a biomarker and a behavioral finding, or a biomarker and a neuroimaging finding, but rarely can a study demonstrate a relationship between multiple biomarkers, cognitive functioning, and the volume and microstructure of the hippocampus,” he said. “That said, the effects reported in the study were very small, but the fact that they held up even after adjusting for several possible confounding factors, makes the results fairly convincing.”

Dr. Hassenstab said that “monitoring glucose and insulin levels in older adults, even among those who do not appear to be at imminent risk for developing impaired glucose tolerance or type 2 diabetes, may be an important part of preventive care.”

The new findings are consistent with the results of a large community-based study published in the Aug. 8 edition of the New England Journal of Medicine (NEJM). The NEJM study, which tracked 2,067 persons 65 or older in Washington state for an average of 6.8 years, found that higher average daily glucose levels were associated with an increased risk of dementia, even when the levels were in the normal range. That research, which is ongoing, based its finding on multiple glucose readings and cognitive assessments of participants. [For a report on the NEJM study, see Neurology Today's “High Glucose Levels Associated with Increased Risk for Dementia”:]

Lenore Launer, PhD, chief of the Neuroepidemiology Section at the National Institute on Aging, told Neurology Today that the German study was interesting from a research perspective because it adds information on hippocampal microstructural tissue integrity, building on other studies that have looked at hippocampal volume and glucose levels.

“There is emerging evidence in the literature that diabetes has more effect on gray matter than white matter,” Dr. Launer said, and these latest findings would lend support to that theory.

Her own research, which is population-based, has found no evidence that high normal-range glucose levels increase the risk for cognitive impairment, she said, though the research is clear that “diabetes can have an effect on the brain.”

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Richard Caselli, MD, professor of neurology at Mayo Clinic School of Medicine in Scottsdale, AZ, agreed that the new study from Germany provided some added insight into the relationship between blood glucose levels and cognitive function, “particularly the finding that hippocampal microstructure seems to be affected.”

But he said the study findings should be interpreted with caution when it comes to everyday management of patients. “I worry about saying that people who are not sick, who are in the normal range, are doing less well,” Dr. Caselli said. He noted that the participants in the study tended to be overweight, which can drive up blood sugar levels and increase the risk for diabetes.

“People should watch their weight to control normal blood sugar levels even more,” Dr. Caselli said. But too low blood sugar levels can be problematic, too, particularly in elderly people.

The German researchers suggested that “lifestyle strategies aimed at long-term improvement of glucose control may be a promising strategy to prevent cognitive decline in aging.”

Dr. Flöel said such strategies include avoiding weight gain, particularly in midlife; exercising regularly; and eating a diet rich in fruits, vegetables, fish and whole-grain products. Her research team is now studying whether intervention strategies, such as exercise and nutritional supplements, can improve cognitive function in older adults.

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•. Kerti L, Witte V, Winkler A, et al. Higher glucose levels associated with lower memory and reduced hippocampal microstructure. Neurology 2013; E-pub 2013 23 Oct.
    •. Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med 2013; 369:540–548.
      •. Neurology archive on blood glucose and cognition:
        © 2013 American Academy of Neurology