23 Aug 2013

While people with type 2 diabetes are at greater risk for Alzheimer’s disease, predicting who among them will go on to develop dementia remains difficult. Two new studies offer some clues. In the inaugural Lancet Diabetes & Endocrinology, scientists led by Rachel Whitmer, Kaiser Permanente Division of Research, Oakland, California, reported a system to rate the likelihood of future cognitive decline in diabetes patients. They base their risk score on eight risk factors most associated with dementia, including depression. That factor took the spotlight in an August 14 JAMA Psychiatry paper, as well. First author Mark Sullivan, University of Washington, Seattle, and colleagues reported that higher depression scores corresponded with greater cognitive decline over an observation period of 40 months in a cohort of diabetics. "These papers provide another indication that diabetes is not good for your brain," said Lenore Launer, National Institute on Aging, Bethesda, Maryland, senior author on the Sullivan paper.

A number of scoring methods exist to predict dementia in the general population (see ARF related news story and Jessen et al., 2011). Diabetes patients are different, however, because they have unique comorbidities such as severe hypoglycemic episodes. Whitmer's group, including first author Lieza Exalto, set out to design a risk score specific to type 2 diabetes (T2D). The researchers scoured the literature for factors that associate T2D with dementia and came up with 45 candidates. They then looked at records of 29,961 T2D patients in the Kaiser Permanente Northern California (KPNC) Diabetes Registry, to see how well those factors predicted dementia. All participants were older than 60 years and free of dementia at baseline.

The strongest predictive factors were age, education, microvascular disease, cerebrovascular disease, cardiovascular disease, acute metabolic events such as hyper- or hypoglycemia, depression, and "diabetic foot," a neuropathic complication of diabetes that encompasses lower limb gangrene, ulcers, and amputations. Exalto and colleagues assigned each factor a point value depending on how strongly it predicted dementia. Age was the strongest risk factor, as it is for sporadic AD. After applying the point system to the KPNC cohort, the researchers found that the highest-scoring patients were 37 times more likely to develop dementia over a decade than people with the lowest scores. Patients with higher scores also developed dementia more quickly than low-scoring individuals. The researchers validated this scoring system in a separate cohort of 2,413 patients.

Though the study offers a new scoring tool, Launer noted that such indices have not yet added much predictive value beyond age. Whitmer countered that the score can detect differences within a given age group, which would escape detection if the entire risk burden came from age.

Whitmer said the next step would be to perform cognitive tests and brain imaging in people with the highest scores. That may help shed light on whether vascular dementia or Alzheimer's disease is responsible for the cognitive decline in diabetes patients, she said. Previous studies have not reached a consensus on that point (see Arvanitakis et al., 2006 and Ahtiluoto et al., 2010).

Whitmer's group previously reported that depression doubled the risk of dementia in diabetes patients (see Katon et al., 2010 and Katon et al., 2012). However, these studies relied on non-standardized diagnoses from medical records that may overlook some cases, wrote Sullivan and colleagues in their paper. To scrutinize the association, the Seattle group prospectively observed 2,977 cognitively normal people enrolled in the Action to Control Cardiovascular Risk in Diabetes–Memory in Diabetes (ACCORD-MIND) study (see Buse et al., 2007). The researchers used the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and the modified Stroop test to assess cognition, and the Patient Health Questionnaire to evaluate depression. They also took into account previous cardiovascular disease, age, and diabetes-related treatments.

People who scored highest for depression declined fastest on each of the cognitive tests, regardless of other health factors. For instance, non-depressed patients declined an average of 1.7 points on the digit symbol test, while depressed patients declined 2.7 points. That researchers demonstrated a relationship between cognitive decline and depression before the onset of dementia supports the idea that depression may contribute to decline, rather than just appear as a prodrome, Launer told Alzforum. Depressed patients are less likely to manage their diabetes through diet, exercise, and medication, and both depression and diabetes cause inflammation, insulin resistance, and autonomic dysfunction, the authors pointed out. Any of these factors could contribute to dementia, Launer said.

These results could have implications for prevention of cognitive decline, Whitmer claims. "Depression is a modifiable risk factor. If we treat it, can we lower dementia risk? That's a follow up question," she told Alzforum. Since this was an observational study, the researchers emphasized that they did not control for depression treatment. Further research will have to assess whether treatment can stave off dementia in diabetics.—Gwyneth Dickey Zakaib.
 

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References

News Citations

1. Risky Business—New Index Predicts Dementia in Older Adults 14 May 2009

Paper Citations

1. Jessen F, Wiese B, Bickel H, Eiffländer-Gorfer S, Fuchs A, Kaduszkiewicz H, Köhler M, Luck T, Mösch E, Pentzek M, Riedel-Heller SG, Wagner M, Weyerer S, Maier W, van den Bussche H, . Prediction of dementia in primary care patients. PLoS One. 2011;6(2):e16852. PubMed.
2. Arvanitakis Z, Schneider JA, Wilson RS, Li Y, Arnold SE, Wang Z, Bennett DA. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology. 2006 Dec 12;67(11):1960-5. PubMed.
3. Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, Sulkava R, Kivipelto M. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology. 2010 Sep 28;75(13):1195-202. PubMed.
4. Katon WJ, Lin EH, Williams LH, Ciechanowski P, Heckbert SR, Ludman E, Rutter C, Crane PK, Oliver M, Von Korff M. Comorbid depression is associated with an increased risk of dementia diagnosis in patients with diabetes: a prospective cohort study. J Gen Intern Med. 2010 May;25(5):423-9. PubMed.
5. Katon W, Lyles CR, Parker MM, Karter AJ, Huang ES, Whitmer RA. Association of depression with increased risk of dementia in patients with type 2 diabetes: the Diabetes and Aging Study. Arch Gen Psychiatry. 2012 Apr;69(4):410-7. PubMed.
6. , Buse JB, Bigger JT, Byington RP, Cooper LS, Cushman WC, Friedewald WT, Genuth S, Gerstein HC, Ginsberg HN, Goff DC, Grimm RH, Margolis KL, Probstfield JL, Simons-Morton DG, Sullivan MD. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol. 2007 Jun 18;99(12A):21i-33i. PubMed.

Further Reading

Papers

1. Mandal AK, Skoch J, Bacskai BJ, Hyman BT, Christmas P, Miller D, Yamin TT, Xu S, Wisniewski D, Evans JF, Soberman RJ. The membrane organization of leukotriene synthesis. Proc Natl Acad Sci U S A. 2004 Apr 14; PubMed.
2. , Buse JB, Bigger JT, Byington RP, Cooper LS, Cushman WC, Friedewald WT, Genuth S, Gerstein HC, Ginsberg HN, Goff DC, Grimm RH, Margolis KL, Probstfield JL, Simons-Morton DG, Sullivan MD. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol. 2007 Jun 18;99(12A):21i-33i. PubMed.
3. Katon WJ, Lin EH, Williams LH, Ciechanowski P, Heckbert SR, Ludman E, Rutter C, Crane PK, Oliver M, Von Korff M. Comorbid depression is associated with an increased risk of dementia diagnosis in patients with diabetes: a prospective cohort study. J Gen Intern Med. 2010 May;25(5):423-9. PubMed.
4. Ahtiluoto S, Polvikoski T, Peltonen M, Solomon A, Tuomilehto J, Winblad B, Sulkava R, Kivipelto M. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study. Neurology. 2010 Sep 28;75(13):1195-202. PubMed.
5. Jessen F, Wiese B, Bickel H, Eiffländer-Gorfer S, Fuchs A, Kaduszkiewicz H, Köhler M, Luck T, Mösch E, Pentzek M, Riedel-Heller SG, Wagner M, Weyerer S, Maier W, van den Bussche H, . Prediction of dementia in primary care patients. PLoS One. 2011;6(2):e16852. PubMed.
6. Roy T, Lloyd CE. Epidemiology of depression and diabetes: a systematic review. J Affect Disord. 2012 Oct;142 Suppl:S8-21. PubMed.

News

1. No Hill of Beans: AlzRisk Adds Obesity, Expands Diabetes 4 Feb 2013
2. Risky Business—New Index Predicts Dementia in Older Adults 14 May 2009
3. Clinical Trials Roundup: Four Hits, No Home Runs 1 Aug 2013
4. Single-Blind Trial: Diabetes Drug Helps Parkinson’s, Maybe 3 Jun 2013
5. Dementia Incidence Said to Drop as Public Health Improves 17 May 2013
6. Vascular Dementia or Alzheimer’s: Is the Delineation Emerging? 22 Feb 2013