06 Oct 2011

One thing that type 2 diabetes and Alzheimer’s disease (AD) have in common is that the incidence of each is increasing dramatically. Add to that the fact that diabetes is a risk factor for neurodegenerative disease (see ARF Webinar), and you have the potential for a perfect storm. Could treating diabetes calm the waters? To help address this question, investigators for the Memory in Diabetes (MIND) study, embedded in the larger Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial, compared the effects on brain structure and function of two versions of a blood sugar-lowering treatment in people with diabetes: a standard and a more intensive treatment that takes blood sugar down to similar levels seen in people who never had diabetes. The results, published in the September 28 Lancet Neurology online by lead author Lenore Launer of the National Institute on Aging in Bethesda, Maryland, and the ACCORD MIND investigators, reveal that after 40 months the treatment groups did not differ in cognitive function. However, people in the intensive treatment group had less brain shrinkage, as determined by magnetic resonance imaging (MRI), than those in the standard therapy groups. It is unclear what this result means, as it was not accompanied by cognitive changes. Moreover, more patients on the aggressive treatment died during the study.

Previous studies have hinted that treating diabetes could help reduce the incidence of dementia later in life (see ARF related news story on Sonnen et al., 2009 and Li et al., 2009; ARF related news story on Matsuzaki et al., 2010). However, researchers are unsure how best to go about it. “This is the first study of this size and length to look at the importance of the intensity of treatment on cognitive function in diabetic patients,” said Suzanne Craft of the University of Washington School of Medicine in Seattle, who was not involved in the MIND study. “It provides compelling evidence that increasing the intensity of treatment does not improve cognition in this group of patients.” Launer added that follow-up analysis of study participants could change that conclusion. Although the intervention has ended, consenting participants are still being regularly monitored to determine whether any differences seen during the trial persist or change over time, and whether other differences emerge. “It could be that the change in MRI we observed [during the trial] will be functionally significant down the line, but we don’t know right now,” she said.

The results do nothing to clarify the mechanism by which diabetes might contribute to cognitive problems (see ARF related news story and ARF news story). Geert Jan Biessels of University Medical Center in Utrecht, The Netherlands, wrote in an editorial accompanying the article, “Type 2 diabetes is a complex disorder, in which glucose dysmetabolism co-occurs with many factors that might adversely affect the brain. At present it is still unclear whether dysglycaemia is a key factor in accelerated cognitive decline and dementia in type 2 diabetes.”

The ACCORD trial recruited more than 10,000 people who had type 2 diabetes and a high risk for cardiovascular disease. (Cognition was not a selection criteria for this study.) Participants were randomized to one of two treatment groups. One underwent intensive treatment to drop blood sugar sufficiently to reduce levels of glycated hemoglobin A (HbA1C) to below 6 percent of total hemoglobin, while the other received standard treatment with a target HbA1C concentration of 7-7.9 percent. Doctors used a battery of approved diabetes drugs that hit many different targets. “Any one individual could have gotten different combinations of drugs,” said Launer.

For its part, MIND enrolled 2,977 participants from ACCORD, about half from each treatment group. They received several cognitive tests at baseline, 20 months, and 40 months. The primary outcome measure was the Digit Symbol Substitution Test (DSST), which evaluates how quickly a person processes information. Compared to neuropsychological tests typically given to people with AD or mild cognitive impairment (MCI), DSST is more suited to cognitively normal people (see ARF Neuropsychological Testing page). Cognitive tests further included the Rey Auditory Verbal Learning Test (RAVLT), the Stroop test of executive function, and the widely used Mini-Mental State Examination (MMSE). In addition, a subgroup of 632 participants underwent MRI at baseline and at 40 months to measure total brain volume, which can be used to estimate age-related brain atrophy (see, e.g., Kruggel, 2006).

Although all participants were to be followed for 40 months, an increase in mortality in the intensive treatment group led investigators to transition those people to the standard therapy. By this time, participants in the more aggressive treatment group had been in the trial for an average of 39 months, and those in the MRI substudy for an average of 35 months. Scientists don’t know what caused the spike in deaths.

Taking into account this change in study design, Launer and collaborators calculated that the 40-month DSST scores in both treatment groups were lower than at baseline, indicating a drop in cognitive function during the course of the trial. Both groups changed by about the same amount in all cognitive outcome measures. In all patients, brain shrinkage was significant during the course of the study. “In general, our study shows that rate of brain loss in people with diabetes is similar to that of people without diabetes who are 15 years older,” said Launer. This decrease was less pronounced in the intensive treatment group than the standard group, and it was the only outcome that showed a difference between the treatment groups.

“Many researchers consider a reduction in brain volume a proxy for neurodegenerative disease,” said Jose Luchsinger, Columbia University, New York. It seems puzzling, then, that less brain shrinkage did not correlate with less cognitive decline. Researchers are looking to couple biomarker change to clinical benefit, and this study appears to fall short of that. “It is possible that longer follow-up may reveal a change in cognition between the two groups,” Luchsinger added. He recently reported that reducing HbA1C levels to less than 7 percent of normal—a less aggressive treatment than the one pursued in MIND and that did not cause more deaths—was associated with less cognitive decline in diabetes patients, compared to a control group with a smaller decrease in HbA1C (Luchsinger et al., 2011). But others are more cautious in their interpretation. “We don’t know what the reduction in total brain volume means, especially because it is not accompanied by an effect on cognition,” said Craft.—Laura Bonetta

Comments

1. • Sanjay Pimplikar
     Case Western Reserve University
   • Posted: 12 Oct 2011

   Alzforum should be commended for highlighting the ACCORD MIND study. At first glance, the findings from this study (an aggressive treatment to control diabetes did not improve cognition and in fact may be detrimental) seem to lack direct relevance to AD, but I see two important lessons for the field. First, this study shows a clear divergence between brain volume and cognition. Since the loss of cognition remains the most devastating aspect of AD, we should be cognizant of the danger of overly relying on a particular biomarker as a surrogate for cognition or brain function. Second, this study shows that aggressive treatment does not always bring about desirable outcomes.

   This is especially important, since current thinking in the AD field is that we should treat patients before symptoms appear. AD research stands at a crossroads, and future directions are somewhat cloudy. I believe lessons from related fields can help navigate future steps and help us to formulate more realistic expectations for ongoing efforts in the AD field.

   View all comments by Sanjay Pimplikar

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References

Webinar Citations

1. The Role of Insulin Resistance in Brain Aging and Dementia 6 Nov 2009

News Citations

1. Type 2 Diabetes and Neurodegeneration—The Plot Caramelizes 29 Jan 2009
2. Insulin Resistance Correlates With Plaque, But Not Tangle, Pathology 28 Aug 2010
3. Madrid: Highs and Lows of The Insulin Connection 14 Sep 2006
4. Insulin, Insulin-like Signaling and Neurodegeneration—Is Resistance Futile? 25 Jan 2008

Paper Citations

1. Sonnen JA, Larson EB, Brickell K, Crane PK, Woltjer R, Montine TJ, Craft S. Different patterns of cerebral injury in dementia with or without diabetes. Arch Neurol. 2009 Mar;66(3):315-22. PubMed.
2. Li Y, Perry T, Kindy MS, Harvey BK, Tweedie D, Holloway HW, Powers K, Shen H, Egan JM, Sambamurti K, Brossi A, Lahiri DK, Mattson MP, Hoffer BJ, Wang Y, Greig NH. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1285-90. PubMed.
3. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology. 2010 Aug 31;75(9):764-70. PubMed.
4. Kruggel F. MRI-based volumetry of head compartments: normative values of healthy adults. Neuroimage. 2006 Mar;30(1):1-11. PubMed.
5. Luchsinger JA, Palmas W, Teresi JA, Silver S, Kong J, Eimicke JP, Weinstock RS, Shea S. Improved diabetes control in the elderly delays global cognitive decline. J Nutr Health Aging. 2011;15(6):445-9. PubMed.

Other Citations

1. ARF Neuropsychological Testing page

External Citations

1. Action to Control Cardiovascular Risk in Diabetes

Further Reading

Papers

1. Xu WL, von Strauss E, Qiu CX, Winblad B, Fratiglioni L. Uncontrolled diabetes increases the risk of Alzheimer's disease: a population-based cohort study. Diabetologia. 2009 Jun;52(6):1031-9. PubMed.
2. Beeri MS, Schmeidler J, Silverman JM, Gandy S, Wysocki M, Hannigan CM, Purohit DP, Lesser G, Grossman HT, Haroutunian V. Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology. Neurology. 2008 Sep 2;71(10):750-7. PubMed.
3. Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, Kurinami H, Shinohara M, Rakugi H, Morishita R. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Abeta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):7036-41. PubMed.

News

1. Research Brief: Eat Less to Remember More 30 Jan 2009
2. Paris: Diabetes, Insulin, and Alzheimer Disease 17 Jun 2009
3. Insulin Resistance Correlates With Plaque, But Not Tangle, Pathology 28 Aug 2010
4. Madrid: Highs and Lows of The Insulin Connection 14 Sep 2006
5. Insulin, Insulin-like Signaling and Neurodegeneration—Is Resistance Futile? 25 Jan 2008
6. Better Models Weigh In on AD-Diabetes Link 19 Mar 2010
7. Special Issue Explores Link Between Metabolic Disease and Dementia 13 Mar 2009
8. Diabetes-Insulin Roundup: Dementia Connection Grows Stronger, Part 2 16 Jan 2008
9. APP Sorting Protein May Link Alzheimer’s and Diabetes 1 Oct 2010
10. Diabetes-Insulin Roundup: Dementia Connection Grows Stronger, Part 1 16 Jan 2008
11. Type 2 Diabetes and Neurodegeneration—The Plot Caramelizes 29 Jan 2009