Type 2 diabetes and cognitive function: many questions, few answers

Type 2 diabetes and cognitive function: many questions, few answers

Comment be accompanied by a strong message that all patients who are disabled by drug-resistant seizures deserve a consultation at a specialised epil...

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be accompanied by a strong message that all patients who are disabled by drug-resistant seizures deserve a consultation at a specialised epilepsy centre.

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Jerome Engel Jr Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA [email protected]

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I have received grants for research from NIH (NS02808, NS15654, NS33310, and NS80181).




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Spencer S, Huh L. Outcomes of epilepsy surgery in adults and children. Lancet Neurol 2008; 7: 525–37. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal lobe epilepsy. N Engl J Med 2001; 345: 311–18. Engel J Jr, McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA 2012; 307: 922–930.


Engel J Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Neurology 2003; 60: 538–47. de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet 2011; 378: 1388–95. Hader WJ, Tellez-Zenteno J, Metcalfe A, et al. Complications of epilepsy surgery – a systematic review of focal surgical resections and invasive EEG monitoring. Epilepsia 2013; 54: 840–47. Engel J Jr. Why is there still doubt to cut it out? Epilepsy Curr 2013; 13: 198–204. Englot DJ, Ouyang D, Garcia PA, Barbaro NM, Chang EF. Epilepsy surgery trends in the United States, 1990-2008. Neurology 2012; 78: 1200–06. Berg AT, Langfitt J, Shinnar S, et al. How long does it take for partial epilepsy to become intractable? Neurology 2003; 60: 186–90. Haneef Z, Stern J, Dewar S, Engel J Jr. Referral pattern for epilepsy surgery after evidence-based recommendations: a retrospective study. Neurology 2010; 75: 699–704. Jehi L, Yardi R, Chagin K, et al. Development and validation of nomograms to provide individualised predictions of seizure outcomes after epilepsy surgery: a retrospective analysis. Lancet Neurol 2015; published online Jan 29. http://dx.doi.org/10.1016/S1474-4422(14)70325-4.

Type 2 diabetes and cognitive function: many questions, few answers A causal association between type 2 diabetes and dementia is difficult to establish, owing to the number and complexity of possible risk factors and pathways. Candidate risk factors for dementia in patients with type 2 diabetes include those that lead to diabetes (poor lifestyle choices resulting in insulin resistance), diabetes-specific variables (hyperglycaemia, hypoglycaemia, endothelial dysfunction, inflammation, microvascular complications, and macrovascular disease), and cardiovascular risk factors that are associated with type 2 diabetes. However, the payoff from the study of this common disease association could be substantial. First, estimates of the excess risk of dementia due to type 2 diabetes are likely to underestimate the strength of the association. Many putative dementia risk factors, including the APOE ε4 allele, likewise increase the risk of premature mortality in diabetes,1 and studies designed to assess competing risks have not been done. Additionally, most epidemiological research has been done in older (>70 years) patient groups, who are likely either to be long-term survivors of diabetes or to have developed diabetes at an older age, and hence to have had a fairly short duration of diabetes. Second, some of the major hypotheses that have been considered might be as relevant to the general population as to patients with diabetes. For example, the benefit of an approved antidiabetic drug that corrects insulin signalling abnormalities in a mouse model of Alzheimer’s disease www.thelancet.com/neurology Vol 14 March 2015

suggests a promising new treatment approach that could be applied generally.2 Other pathways that might be relevant in diabetes include chronic inflammation that can prime the brain’s innate immune system to increase neuroinflammation and cerebral microvascular disease, which might precipitate, add to, or act synergistically with Alzheimer’s disease processes. For these reasons, type 2 diabetes could provide a model for research into pathways that lead to dementia. In The Lancet Neurology, Koekkoek and colleagues3 discuss how this research might be clinically translated. Unfortunately, a major conclusion that can be drawn from their Personal View is how little specific information is available to advise patients and clinicians. Studies of pathogenesis greatly outnumber those that address clinical problems. The available trials of glycaemic control have not shown a benefit for cognitive health, but might have been too short to detect benefit. Even less information is available about how to manage patients who have diabetes with cognitive impairment and dementia. Studies of how or when to modify complex diabetes management regimens appropriately in cognitively impaired patients would be useful given the risk of severe hypoglycaemia.4 Safe withdrawal of selected antidiabetic medications seems to be feasible, at least in some older patient groups.5 The symptoms of dementia associated with diabetes might differ from dementia not

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associated with diabetes,6 and studies of the effects on caregivers coping with the combined burden of caring for a patient with cognitive impairment or dementia and taking control of diabetes management would be helpful. Koekkoek and colleagues3 interpret the cognitive function data in non-impaired adults to indicate that cognitive decrements occur secondary to diabetes, but other explanations are possible. Childhood factors strongly affect adult cognitive ability, and adverse socioeconomic circumstances early in life increase risk of both type 2 diabetes and late-life cognitive disorders. In studies with the Lothian Birth Cohort, intelligence at age 11 years predicted cognitive ability in middle and older ages,7 and in a recent study, young adult military recruits with the lowest scores on a general intelligence test had 2·1 times the risk of incident diabetes than those with the highest scores.8 Cognitive decrements in diabetes might be a result of the premorbid cognitive status of diabetesprone individuals—ie, reverse causation might be possible. The authors introduce a new term, “diabetes-associated cognitive decrements”, to differentiate cognitive change in adulthood from clinically relevant cognitive decline. This new term has merit, but is problematic in several respects, in part because of an already crowded nomenclature in which many terms have been introduced, and continue to be introduced, to classify cognitive ageing and cognitive disorders. Evidence exists that cognitive symptoms are not increased in middle-aged people with diabetes,9 and the decrements in cognitive ability, which are within the normal range, might not be specific to diabetes.10 An important clinical issue is how clinicians should frame discussion of cognitive decrements with patients. Routine clinical practice includes provision of information about diabetes and its complications to patients when they are learning how to manage their diabetes and associated risk factors. The concept that cognitive decrements are an inevitable result of diabetes is likely to be worrying for the patient, and could have important negative psychological

and social effects. Research efforts should continue to clarify the clinical significance of these cognitive findings in diabetes. By contrast, improved identification of modifiable risk factors that might delay or prevent clinically relevant cognitive decline could be presented as an opportunity to improve or motivate optimum diabetes management. Evidence that cognitive health could be improved by dietary and exercise interventions that are remarkably similar to those recommended for diabetes11 is both fortuitous and an opportunity to improve cognitive outcomes in this patient group. David G Bruce School of Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, Fremantle, WA 6959, Australia [email protected] I declare no competing interests. 1


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Davis WA, Chin E, Jee A, et al. Apolipoprotein E genotype and mortality in Southern European and Anglo-Celt patients with type 2 diabetes: the Fremantle Diabetes Study. Europ J Endocrinol 2010; 163: 559–64. Bomfim TR, Forny-Germano L, Sathler LB, et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease-associated Abeta oligomers. J Clin Invest 2012; 122: 1339–53. Koekkoek PS, Kappelle LJ, van den Berg E, et al. Cognitive function in patients with diabetes mellitus: guidance for daily care. Lancet Neurol 2015; 14: 329–40. Bruce DG, Davis WA, Casey GP, et al. Severe hypoglycaemia and cognitive impairment in older patients with diabetes: the Fremantle Diabetes Study. Diabetologia 2009; 52: 1808–15. Sjoblom P, Tengblad A, Lofgren UB, et al. Can diabetes medication be reduced in elderly patients? An observational study of diabetes drug withdrawal in nursing home patients with tight glycaemic control. Diabetes Res Clin Pract 2008; 82: 197–202. Bruce DG, Nelson ME, Mace JL, Davis WA, DavisTMF, Starkstein SE. Apathy in older patients with type 2 diabetes. Am J Geriatr Psychiatr 2014; published online Oct 2. DOI:10.1016/j.jagp.2014.09.010. Gow AJ, Johnson W, Pattie A, et al. Stability and change in intelligence from age 11 to ages 70, 79, and 87: the Lothian Birth Cohorts of 1921 and 1936. Psychol Aging 2011; 26: 232–40. Twig G, Gluzman I, Tirosh A, et al. Cognitive function and the risk for diabetes among young men. Diabetes Care 2014; 37: 2982–88. Paradise MB, Glozier NS, Naismith SL, Davenport TA, Hickie IB. Subjective memory complaints, vascular risk factors and psychological distress in the middle-aged: a cross-sectional study. BMC Psychiatry 2011; published online July 8. DOI:10.1186/1471-244X-11-108. Akbaraly TN, Kivimaki M, Shipley MJ, et al. Metabolic syndrome over 10 years and cognitive functioning in late midlife: the Whitehall II study. Diabetes Care 2010; 33: 84–89. Lindenberger U. Human cognitive aging: corriger la fortune? Science 2014; 346: 572–78.

Building bridges between neuroscientific evidence and policy Calls have been made for closer integration of research evidence in the decision-making process of the European Union (EU). However, scientists and policymakers are often left disappointed by each other; the scientists because they feel that they are not listened to by 242

policymakers, and policymakers because the advice from scientists is not what they expected or because they find it unintelligible.1 Findings from a survey2 of European policymakers showed that even though policymakers expressed a clear desire for increased links between www.thelancet.com/neurology Vol 14 March 2015