Long-term exposure to increased glucose levels is known to cause damage to the kidneys, retinas and other organs. Now, it appears that long-term exposure to hyperglycemia may also have significant and measurable effects on the brain, and greater efforts are needed to evaluate and monitor patients with diabetes for dementia and Alzheimer’s disease, according to experts.
“I think we all need to have our antenna up. It is a risk, and we need to get our patients into evaluation and treatment centers when we begin to see the problem,” said endocrinologist Janet McGill, MD, who is a professor of medicine in the division of endocrinology, metabolism and lipid research at Washington University School of Medicine in St. Louis. “Do we need wholesale random screening? That may not be cost-effective, but we need to be aware of the early signs.”
Diabetes Effects on the Brain
A recent review published in the American Journal of Psychiatry has found that individuals with mild cognitive impairment (MCI) are at higher risk for developing dementia if they have diabetes or psychiatric symptoms such as depression.1
Researchers at University College London analyzed data from 62 separate studies, following a total of 15,950 people diagnosed with MCI. They found that among patients with MCI, those with diabetes were 65% more likely to progress to dementia. The review further suggests incorporating appropriate preventative strategies to lessening the increasing societal burden of dementia in older adults with diabetes.
Another study conducted by researchers at the Mayo Clinic has also found that individuals who develop diabetes and high blood pressure (BP) in middle age are more likely to have brain cell loss and other damage to the brain. In addition, patients with diabetes were found to be more likely to have problems with memory and thinking skills compared with individuals without diabetes or hypertension, according to the study published in Neurology.2
Study author Rosebud Roberts, MB, ChB, who is an epidemiologist at the Mayo Clinic in Rochester, Minnesota, said by controlling diabetes and hypertension in middle age, it may be possible to prevent or delay the brain damage that occurs decades later leading to memory problems and dementia.
Dr. Roberts and her colleagues evaluated the thinking and memory skills of 1,437 people with a median age of 80 years. The participants had either no thinking or memory problems or MCI. In this study, middle age was defined as age 40 to 64 years and old age was defined as age 65 years and older.
Brain scans revealed that individuals who developed diabetes in middle age had smaller total brain volume by an average of 2.9% compared with those without diabetes. In the hippocampus, the volume was 4% smaller.
According to the data, patients with diabetes were also twice as likely to have thinking and memory problems. Dr. Roberts said patients who developed diabetes even in old age were more likely to have areas of brain damage. Conversely, not many effects related to high BP were noted that developed in old age.
These findings suggest that diabetes has adverse effects regardless of the age at which the disease develops, she said.
“We concluded that midlife type 2 diabetes was not simply a vascular risk factor but rather had a more general negative effect on brain integrity. It could directly affect nerve cell and synapse physiology, perhaps by enhancing Alzheimer-type neurodegeneration, or the loss of brain volume could be separate though additive with Alzheimer pathology,” said study co-author David Knopman, MD, in an interview with Endocrinology Advisor. “We do not know whether the issue is simply elevated blood glucose, elevated HbA1c, the degree of insulin resistance or something else that is the fundamental culprit.”
Hyperglycemia and Dementia Risk
In Seattle, researchers have found that higher blood sugar levels are associated with higher dementia risk, even among people who do not have diabetes.3 In a study that included more than 2,000 patients aged 65 years and older, researchers found that blood sugar levels averaged over a 5-year period were associated with an increasing risk for dementia.
Results indicated that the risk for dementia was 18% higher for people with an average glucose level of 115 mg/dL compared with those with an average glucose level of 100 mg/dL. Additionally, the dementia risk was 40% higher for patients with diabetes with an average glucose level of 190 mg/dL compared with those with an average glucose level of 160 mg/dL.
Lead study author Paul Crane, MD, MPH, who is an associate professor of medicine at the University of Washington in Seattle, said the most interesting finding was that every incrementally higher glucose level was associated with an increased risk for dementia in people who did not have diabetes. However, there was no threshold value for lower glucose values where risk leveled off.
“The cells in the hippocampus appear to be extremely sensitive to glucose levels,” said Dr. Crane. “There have been an increasing number of studies that have confirmed that glucose levels appear to be associated with various brain outcomes, and this reinforces blood sugar as a clinically significant risk factor. We have to find out if this is a factor that is amenable to interventions and whether exercise can moderate it. The field has moved in that direction, and that is gratifying.”
He said endocrinologists in particular may want to have a discussion about this with their patients with diabetes. Dementia is something that many adults fear, Dr. Crane noted, which may motivate these patients to take a more active role in the management of their disease.
“Dementia is an outcome that many older patients are motivated by more so than heart disease. There is a lot of fear about dementia, so that is something that an endocrinologist would want to go over with their patients,” Dr. Crane said in an interview with Endocrinology Advisor.
“I think endocrinologists should be thinking about brain health when conceptualizing the patient. They have to deal with a variety of things such as cardiovascular health and kidney health, and those are things that endocrinologists think about, but brain health is becoming an issue of increasing importance.”
Age, Gender Differences
A large population-based study of randomly selected participants in Germany also confirms that brain health is a paramount issue that must be addressed in patients with diabetes, with researchers finding that MCI occurred twice as often in individuals diagnosed with type 2 diabetes.4
Interestingly, however, this strong association was only observed in middle-aged participants (50 to 65 years), whereas in older participants (66 to 80 years), the association vanished. The researchers also found significant gender differences.
The Heinz Nixdorf Recall (Risk Factors, Evaluation of Coronary Calcium and Lifestyle) study is an observational, population-based, prospective study that examined 4,814 participants (50% men) between 2000 and 2003 in the metropolitan Ruhr area in Germany. After 5 years, a second examination was conducted with 90% of the participants taking part.
Data demonstrated a strong association between type 2 diabetes and MCI and MCI subtypes, but only in middle-aged participants. Further, examination of differences by gender revealed a stronger association of diabetes with amnestic MCI in middle-aged women and, by contrast, a stronger association with non-amnestic MCI in middle-aged men.
Participants were considered amnestic MCI if they had impairment in the memory domain and they were categorized as non-amnestic MCI if they had deficits in non-memory domains.
These results suggest that middle-aged patients with diabetes are particularly vulnerable to MCI, with gender-specific effects on subtypes of MCI. The researchers concluded that this highlights the importance of high-quality treatment of diabetes especially in middle age, not only because of CV damage, but also because it might help to prevent or delay cognitive decline.
Brain Scan Studies
Brain scan studies are now revealing how the brains of patients with diabetes are being altered. Chinese researchers conducted MRI studies and found deficiencies in working memory in patients with diabetes and the relation between cognitive function and degree of neuronal activity and their relevance to Alzheimer’s risk.5
In this particular study, the researchers found that patients with diabetes exhibited worse executive and memory abilities than control patients. In addition, the patterns of brain activation changed under different working memory loads in those with diabetes.
The study also showed that patients with diabetes exhibited reduced activation in the left inferior frontal gyrus under low loads and reduced activation in the left middle frontal gyrus and superior frontal gyrus under high loads.
In light of these findings, the researchers reported that longitudinal studies are now warranted to replicate these results and to evaluate the clinical value of brain imaging methods in the prediction of disease progression in those with diabetes.
“The MCI patients with diabetes showed more diffused functional changes in a variety of brain regions including the frontal lobe, the temporal lobe, the hippocampus, the amygdala and the precuneus during a resting state than the MCI patients without diabetes. All these studies draw us a definite and defined conclusion that type 2 diabetes destroys (the) central nervous system, especially in the brain,” study author Zhanjun Zhang, MD, who is with Beijing Normal University, Beijing, China, told Endocrinology Advisor.
He said endocrinologists now have enough evidence to strongly counsel their patients with type 1 diabetes about the fact that they are at significantly higher risk for memory impairment if they are not vigilant in managing their disease.
“We already know that reasonable diet and adequate exercise are very beneficial and effective approaches to control glucose levels. Our previous study also found that healthy diet and greater involvement in physical, intellectual, and social activities are associated with a lower risk of MCI,” said Dr. Zhang.
- Cooper C et al. Am J Psychiatry. 2014;doi:10.1176/appi.ajp.2014.14070878.
- Roberts RO et al. Neurology. 2014;doi:10.1212/WNL.0000000000000269.
- Crane PK et al. N Engl J Med. 2013;369:540-548.
- Winkler A et al. J Alzheimers Dis. 2014;doi:10.3233/JAD-140696.
- Chen Y et al. Diabetes Care. 2014;doi:10.2337/dc14-1683.