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Evidence-Based Diabetes Management July 2014

Aging and Cognitive Decline in Diabetes

Surabhi Dangi-Garimella, PhD
The association between diabetes and cognition has been known for a while. However, until recently, the primary focus of diabetes-related complications has been on hypertension, renal failure, vision loss, autonomic and peripheral neuropathy, myocardial infarction and cerebrovascular disease, including stroke. Neuropathy, in particular, is responsible for additional comorbidities, resulting in a significantly increased cost of treatment.1 Of late, the effect of hyperglycemia on the cognitive ability of patients has been regaining interest, after research efforts were abandoned in the United States by 1970.2

Global Numbers of the Cognitive Syndrome

According to the World Health Organization, dementia—a cognitive degeneration syndrome—affects 35.6 million people globally, with about 7.7 million added every year. Almost 60% to 70% of dementia cases are a result of pathological degeneration caused by Alzheimer’s,3 and recent data suggest that diabetes could be one of the causative factors for the remaining 30% of cases.
In the United States, 16 million people were estimated to be living with cognitive impairment in 2010. With the baby boomers fast approaching and crossing 65 years of age, that number is expected to increase significantly.4 The cost of patient care can be an enormous strain on the healthcare system, both in direct healthcare costs and indirect costs, such as the loss of income for a caregiver within the family. Treating patients with Alzheimer’s and other related dementias were estimated to cost Medicaid nursing facilities an average of $647 million in 2010, which did not include prescription drug costs or home- and community-based care.4 The direct costs of Alzheimer’s alone are estimated at $214 billion in 2014, $150 billion of which would be Medicare and Medicaid expenses. In terms of indirect costs, 15.5 million caregivers provided unpaid care to Alzheimer’s patients in 2013, valued at a whopping $220 billion.5

Cognitive Decline and Diabetes

The managed care statistics make it imperative that we try to understand and regulate some of the risk factors of reduced cognition. Based on numerous recent studies, as well as historical evidence, the Alzheimer’s Association has recognized diabetes as a risk factor for cognitive disease.6

Persons with type 2 diabetes mellitus (T2DM) experience compromised verbal and nonverbal memory, reduced attention, and reduced processing speed, while type 1 diabetes mellitus patients additionally suffer from an impaired visuospatial performance, psychomotor efficiency, and general intelligence.7 A study conducted in over 800 elderly men and women found that chronic, uncontrolled hyperglycemia can result in slowly progressive functional and structural abnormalities in the brain, with a 65% higher risk of Alzheimer’s disease in those with T2DM.8 A mouse model that evaluated the effect of aging and diabetes on learning and hippocampal synaptic plasticity, observed significant learning impairments in aged diabetic rats compared with controls.9

“Older individuals with T2DM are at a higher risk of developing Alzheimer’s than the younger population,” said Gail Musen, PhD, assistant professor of pscychiatry,  Harvard Medical School and assistant investigator in the section on clinical, behavioral, and outcomes research at Joslin, in an interview with Evidence-Based Diabetes Management. Musen’s research is focused on identifying risk factors for Alzheimer’s disease in persons aged 45 to 65 years suffering from T2DM. “T2DM increases the risk of Alzheimer’s disease. Why? We don’t know the reason for that yet, although there are reports of insulin resistance or certain vascular problems being responsible for this.” Musen said that these patients show only a slight decline in their cognitive abilities that emerge as interesting patterns in the brain magnetic resonance imaging (MRI). “However,” she said, “among the older population, those above 65 years of age, a rapid decline in cognitive abilities is observed, highlighting a different etiology between the 2 populations.”

In Alzheimer’s disease, “The default mode network is most susceptible to the build-up of amyloid plaques and hypometabolism,” she said. There are no visible early signs of the disease in 20- to 40-year-old individuals, so awareness of family history of cognitive impairment in T2DM patients would be a good indication. “If T2DM is the primary risk factor, it’s easier to control,” with medication, diet, and exercise. “However, if there are genetic factors involved, that’d be a lot more difficult to regulate.” Musen’s research group is working toward identifying risk factors for early disease intervention. “Unfortunately, we do not as yet have any reliable serum or blood markers available,” she said, although proteins like sirtuin 1 have been projected as early markers of Alzheimer’s.10

According to Medha N. Munshi, MD, head of Joslin’s Geriatric Diabetes Clinic and assistant professor of medicine at the Beth Israel Deaconess Medical Center, “Older diabetes patients are usually more compliant with medication adherence and disease management. When they don’t, you wonder why?” Speaking with Evidence-Based Diabetes Management, Munshi explained why she was interested in the phenomenon of cognitive dysfunction in the geriatric diabetic population. Her clinical observations in the older patient population that she treated demonstrated that cognitive dysfunction, depression, and an overall declining functional status were a barrier to achieving good glycemic control.

Munshi’s research group assessed these unrecognized barriers by screening adults over 70 years of age for the presence of depression, functional disabilities, and cognitive dysfunction. The finding: 32% of men and 34% of women reported depressive symptoms, which could influence functional disability. Patients recognized to have cognitive dysfunction had poorer glycemic control, probably due to an incorrect dose or timing of insulin or of their oral medication, omission of meals that can lead to hypoglycemia, etc.11

According to Munshi, these patients had a fairly good memory–the problem was with executive dysfunction–so integrating their treatment regimen was an issue, resulting in compromised self-care abilities.

MRI of the brain of 614 diabetic patients observed that a longer duration of high fasting plasma glucose level is associated with lower normal and total gray matter volumes, essentially a reduction in the total brain volume.12,13 The study found that patients who had been diagnosed for 15 years or more had less gray matter than those who had the disease for 4 years or less. While previous studies had attributed the reduced brain size to a reduction in the blood flow, the authors of this study, conducted at the University of Pennsylvania, observed an accelerated rate of degeneration of the brain tissue in hyperglycemic patients, which they defined as a “neurodegenerative insult on the brain.” Follow-up studies, evaluating the effect of aggressive treatment in slowing down the rapid rapid cognitive decline, are ongoing.13

A Gap in the Knowledge Base

When asked about the efforts being undertaken by treatment institutes and diabetes organizations, like the American Diabetes Association (ADA), in raising awareness about cognitive impairment as a comorbidity of diabetes, Munshi acknowledged that “there is a big gap in the knowledge base–not just among patients and caregivers, but also providers themselves.” She continued, “There are not many programs that address some of the additional comorbidities in the older diabetic patients, such as depression, cognitive dysfunction, and polypharmacy. At Joslin, each patient is screened for cognitive decline, unlike most diabetes care providers.”

Can Overcoming Insulin Resistance Slow Down the Process?

A clinical trial, conducted as a part of the ACCORD Memory in Diabetes (MIND) study, evaluated the potential of intensive glycamic therapy to reduce glycated hemoglobin (A1C) to <6%, compared with standard therapy that would reduce A1C to between 7% and 7.9%. Of the 2977 patients randomized in the study, 1358 patients received intensive therapy and 1416 received standard therapy. Brain MRIs of these patients presented a significantly lower (26%) decline in the total brain volume of patients receiving intensive therapy compared with those receiving standard therapy. Surprisingly, while the cognitive outcomes were no different between the 2 groups, the intensive therapy was associated with increased mortality, an increase in hypoglycemic events, and weight gain, without any cardiovascular benefits, in the main ACCORD trial.14 The results of this particular trial do not support the use of intensive therapy to improve cognitive outcomes.

However, insulin and insulin-mediated signaling pathways are known to regulate normal emotional and cognitive brain functions, and may contribute to memory and learning. Historical data points to an association between glucose metabolism and cognitive impairment.2 Therefore, a different approach might be essential. A recent proof-of-concept clinical trial, that Munshi participated in, did just that–intranasal insulin delivery to the brain was observed to improve cognitive performance in 15 older T2DM patients, without any effect on blood glucose levels.

Binding of insulin, an important neuromodulator, to its corresponding receptors in the brain is regulated by insulin transport through the blood-brain barrier (BBB). Insufficient delivery of this peptide hormone can reduce perfusion and cortical activity, with corresponding effects on cognition (Figure 1). Intranasal delivery bypasses the BBB and also avoids systemic effects of insulin. The authors conclude that the shared insulin signaling in vascular and metabolic pathways can provide new therapeutic targets to prevent brain atrophy and consequent cognitive decline in older T2DM patients.15

Cognition and Disease Management

Managing a complex disease like diabetes is extremely difficult and requires the patient to rigorously follow specific disease-management protocols. Impaired cognition could result in cardiovascular effects or severe hypoglycemic events, making it imperative to develop strategies to reduce the risk of cognitive impairment.14

A retrospective study conducted by Munshi and her colleagues, evaluating the barriers to glycemic control in the older diabetic population, identified that communication with an educator who is familiar with a patient’s barriers can improve self-care frequency, help maintain functionality, and lower stress in the patients.16 The study concluded that telephone follow-up with the patients in-between clinic visits would greatly improve diabetes control in the elderly, cognition-impaired population.

Taken together, there still seems to be a lack of awareness on cognitive impairment as a risk factor for diabetes, and improving the understanding among patients, caregivers, and physicians is essential. Additionally, treatment plans should incorporate therapeutic strategies for brain health, especially among older T2DM patients.
References

1. Zhao Y, Ye W, Boye KS, Holcombe JH, Hall JA, Swindle R. Prevalence of other diabetes-associated complications and comorbidities and its impact on health care charges among patients with diabetic neuropathy. J Diabetes Complications. 2010;24(1):9-19.

2. Kaidanovich-Beilin O, Cha DS, McIntyre RS. Metabolism and the brain. The Scientist website. http://www.the-scientist.com/?articles.view/articleNo/33338/title/Metabolism-and-the-Brain/. Published December 1, 2012. Accessed June 18, 2014.

3. Dementia. World Health Organization website. http://www.who.int/mediacentre/factsheets/fs362/en/. Accessed June 17, 2014.

4. Cognitive impairment: a call for action now! World Health Organization website. http://www.cdc.gov/aging/pdf/cognitive_impairment/cogimp_poilicy_final.pdf. Accessed June 17, 2014.

5. Alzheimer’s facts and figures. Alzheimer’s Association website. http://www.alz.org/alzheimers_disease_facts_and_figures.asp#cost.Accessed June 17, 2014.

6. Diabetes and cognitive decline. Alzheimer’s Association website. https://www.alz.org/national/documents/topicsheet_diabetes.pdf.Published February 2014. Accessed June 17, 2014.

7. S Roriz-Filho J, Sá-Roriz TM, Rosset I, et al. (Pre)diabetes, brain aging, and cognition. Biochim Biophys Acta. 2009;1792(5):432-443.

8. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Arch Neurol. 2004;61(5):661-666.

9. Kamal A, Biessels GJ, Duis SE, Gispen WH. Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing. Diabetologia. 2000;43(4):500-506.

10. Kumar R, Chaterjee P, Sharma PK, et al. Sirtuin1: a promising serum protein marker for early detection of Alzheimer’s disease. PLoS One. 2013;8(4):e61560.

11. Bryan RN, Bilello M, Davatzikos C, et al. Effect of diabetes on brain structure: the action to control cardiovascular risk in diabetes MR imaging baseline data. Radiology. 2014. http://dx.doi.org/10.1148/radiol.14131494.

12. Park A. Diabetes ages the brain by two years, says study. Time. http://time.com/77874/diabetes-ages-brain-by-two-years/. Published April 29, 2014. Accessed June 17, 2014.

13. Launer LJ, Miller ME, Williamson JD, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol. 2011;10(11):969-977.

14. Novak V, Milberg W, Hao Y, et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care. 2014;37:751–759.

15. Novak V, Milberg W, Hao Y, et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care. 2014;37:751–759.

16. Munshi MN, Segal AR, Suhl E, et al. Assessment of barriers to improve diabetes management in older adults: a randomized controlled study. Diabetes Care. 2013;36(3):543-549.
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