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    Abstract
    Introduction
    Methodology
    Type 2 Diabetes ...
    Glycemic Control...
    Pathophysiology ...
    Brain Imaging St...
    Conclusions and ...
    Acknowledgments
    References

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INVITED ARTICLE Table of Contents   
Year : 2009  |  Volume : 51  |  Issue : 5  |  Page : 35-38
Type 2 diabetes mellitus, cognition and brain in aging: A brief review


Academic Unit of Psychological Medicine, Australian National University Medical School, College of Medicine, Biology and Environment, Canberra Hospital, Canberra, Australia

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   Abstract 

Diabetes mellitus is a complex disease with many potential complications. Whilst there have been inconsistent results in regard to an association between cognition and type 2 diabetes, there is evidence that verbal memory and processing speed are the cognitive domains usually impaired. In elderly diabetic subjects, other cognitive domains may also be involved, due to ageing. Glycemic control is implicated in the development of cognitive dysfunction, although more research is needed in this area. Insulin dysregulation and hyperglycemia play an important role in neurodegeneration. Using structural neuroimaging, it has been shown that brain atrophy is an important feature in those with type 2 diabetes. Integrative research is needed using behavioral, cognitive, imaging, and genetic platforms.

Keywords: Brain atrophy, cognition, diabetes mellitus, magnetic resonance imaging, neurodegeneration

How to cite this article:
Kumar R, Looi JC, Raphael B. Type 2 diabetes mellitus, cognition and brain in aging: A brief review. Indian J Psychiatry 2009;51, Suppl S1:35-8

How to cite this URL:
Kumar R, Looi JC, Raphael B. Type 2 diabetes mellitus, cognition and brain in aging: A brief review. Indian J Psychiatry [serial online] 2009 [cited 2020 Oct 25];51, Suppl S1:35-8. Available from: https://www.indianjpsychiatry.org/text.asp?2009/51/5/35/44858



   Introduction Top


Diabetes mellitus is a complex endocrine disease that can lead to many complications particularly when untreated. The association between type 2 diabetes mellitus and dementia has been of great interest, and this is particularly relevant with the increase in prevalence of both diabetes and dementia with increasing life expectancy. [1],[2],[3] Although type 2 diabetes is associated with several other vascular risk factors of dementia, diabetes itself has been implicated as an independent risk factor for cognitive impairment and dementia. [4],[5],[6],[7]

Neurocognitive research in diabetes mellitus has provided us with greater understanding of the relationship between brain and cognition. This has been possible mainly by the application of neuroimaging and use of comprehensive standardized neuropsychological assessments. Animal research into basic pathophysiological mechanisms has indicated possible pathways of neurodegeneration. In this brief review, we discuss some of the important findings from studies on cognition, neuroimaging, and pathophysiology in type 2 diabetes mellitus. It is known that depression may contribute to cognitive changes in diabetes, but this review concentrates on studies excluding those with depression, focusing on cognition and diabetes.


   Methodology Top


We conducted a selective brief review of literature. A MEDLINE search was conducted using the following medical subject heading terms: cognition, dementia, cognitive impairment, brain atrophy, white matter hyperintensities, brain imaging, magnetic resonance imaging (MRI) and pathophysiology; all combined with "diabetes". Relevant articles were retrieved based on their importance from reading the abstract. Important articles were also reviewed from authors' collection.


   Type 2 Diabetes and Cognition Top


In a previous literature review, it was concluded that while cross-sectional studies yielded conflicting results, longitudinal studies have clearly demonstrated that diabetes mellitus is associated with increased rate of cognitive decline or an increased incidence of dementia. [4] There is ongoing debate about the nature and magnitude of cognitive dysfunction in subjects with type 2 diabetes. The cognitive domains that have been studied in type 2 diabetes include: memory, psychomotor speed, visuospatial functions, frontal executive functions, processing speed, verbal fluency, attention, and complex motor functions. In a comprehensive review of literature on the association between impaired glucose tolerance, type 2 diabetes, and cognitive function, it was concluded that the most consistently reported measures were impairment in verbal memory and processing speed, with preservation of functions in other areas including visuospatial function, attention, semantic memory, and language. [8] However, it has been argued that the preservation of memory and learning functions in some studies occurred mainly in subjects younger than 65 years of age in contrast to older subjects where impairments in those domains were largely because of interaction between diabetes-related changes and the normal ageing changes in the brain. [9] Younger subjects with type 2 diabetes mellitus consistently showed impairment in psychomotor efficiency, similar to subjects with type 1 diabetes. However, the impact of such cognitive deficits on day-to-day functioning is unclear, but in combination with depression, which is common in diabetes, may be significant. In a recent study, Bruce et al . [10] showed that about 17% of elderly diabetic patients had moderate to severe impairments in activities of daily living, 11% were cognitively impaired and 14% depressed.


   Glycemic Control and Cognition Top


Hyperglycemia, impaired glucose tolerance, and hypoglycemic episodes have been implicated as causes for impaired cognitive function in diabetic patients. Glycosylated haemoglobin (HbA1c) is a marker of glycemic control, and in a study by Yaffe et al . [11] an Hb1Ac of more than 7% was associated with a 4-fold increase in occurrence of mild cognitive impairment. An impairment in working memory, frontal executive functions, learning and complex psychomotor abilities have also been found associated with a higher level of HbA1c. [12],[13],[14] However, other studies failed to show such associations. [15],[16] Impaired glucose tolerance, in the absence of a diagnosis of diabetes has been associated with cognitive dysfunction. [17],[18] The results are inconsistent, with some studies showing negative results. [19],[20] Reasons for such inconsistencies could be due to lack of adequate control of confounders such as education, comorbid medical and neurological conditions and the blood sugar level at the time of testing. Negative effects of recurrent and severe hypoglycemic episodes on cognition have been studied and the results have proved inconclusive. A detailed discussion is beyond the scope of this review as most data is based upon children and adolescents with type 1 diabetes, with limited or no data on older subjects such as those with type 2 diabetes. Acute hypoglycemia has been associated with impaired cognition. [21],[22] Of the long-term effects of hypoglycemic episodes on cognition, there are some reports of an association. [23],[24]


   Pathophysiology of Cognitive Dysfunction Top


Proposed pathogenetic mechanisms of cognitive dysfunction in diabetes include chronic hypoglycemia, vascular disease, cumulative effect of hypoglycemic events, and possible direct effects of insulin on the brain. [25] It is unclear whether these factors individually, or in combination, mediate the pathogenesis of the cognitive dysfunction. In diabetes, there is a significant cumulative burden of cerebrovascular disease resulting from diabetic microangiopathy, hyperlipidaemia, and potentiation of other vascular risk factors such as hypertension. Another key mechanism of neurodegeneration in diabetics may be insulin dysregulation. [26] This may result in increased inflammation, oxidative stress, advanced glycation end products, decreased neuronal repair and neurogenesis. Insulin can promote the release of intracellular Ab in neuronal cultures [27] and intracellular accumulation of Ab has been considered as a pertinent factor in the pathogenesis of Alzheimer's disease (AD). [28] These findings indicate that diabetes, through neurodegenerative processes resulting from dysfunctional metabolism, may lead to direct neuronal injury manifest as brain atrophy, and a structural basis for dementia.


   Brain Imaging Studies Top


Since brain imaging provides an avenue for understanding the nature and magnitude of brain pathology associated with diseases that affect cognition, it has been utilized in several studies of cognition and diabetes. [29] Structural brain imaging has essentially investigated two aspects of brain pathology, cerebrovascular disease (white matter lesions, lacunar infarctions) and neuronal degeneration (subcortical and cortical cerebral atrophy). These studies involved subjects from both clinic [30],[31],[32],[33],[34] and community settings [35],[36],[37],[38] providing interesting, but inconsistent results. Most studies have involved older subjects and observer-visual rating of white matter lesions and brain atrophy. To address this issue, we investigated this in a 60-64 year old community-dwelling sample of 39 subjects with type 2 diabetes and 428 normal comparison subjects. [39] All subjects underwent physical examinations, assessment of depression, cognitive assessments, brain magnetic resonance imaging scans (MRI), and fasting blood tests. We used brain MRI automated measures of atrophy, white matter intensities, and hippocampal volumetry. We found that diabetic subjects showed increased brain atrophy and poor motor function, independent of depression in comparison to healthy community controls. Brands et al . [40] from Netherlands showed similar results that subjects with type 2 diabetes were more depressed, had worse MRI ratings than controls, and poor performance on cognitive tests, however, there was no interaction between depression and cognitive disturbances. Brain atrophy has been an important finding in many studies. [38],[41],[42],[43] Others have also reported hippocampal atrophy. [31],[35] Thus, increased brain atrophy associated with poor motor function and cognitive dysfunction, independent of depression, have been found in those with type 2 diabetes.


   Conclusions and Future Directions Top


Based on the studies discussed above, it is clear that type 2 diabetes has an effect on cognition, brain structural integrity, and function. An issue still remains is that what is the main pathophysiology that leads to cognitive impairment - is it purely degenerative, exclusively vascular or a combination of these two? More importantly, several other associated variables could also interact in patients with diabetes. These include hypertension, obesity, hypercholesterolemia, stroke, microvascular diseases, etc. Another important variable, which is understudied in the context of cognitive impairment and brain structural and functional pathology is depression. Since depression is a common problem in diabetics, this should be looked at carefully in future studies of cognitive impairment in diabetes. In an era of genetics and genomics, we should take advantage of such platforms in collaborative research involving studies of cognition and brain in diabetics, and the insights from such studies would lead to development of effective therapeutic strategies. Newer neuroimaging modalities such as diffusion tensor imaging could be useful to study very early brain changes in the white matter of diabetic patients. In our view, an integrative research approach using multiple platforms of behavioral, cognitive, imaging and genetic disciplines is the ideal way forward for future neurocognitive research in all neuropsychiatric disorders especially diabetes mellitus.


   Acknowledgments Top


The Canberra Hospital Specialists Private Practice Trust Fund for support of research into cognition and type 2 diabetes.

 
   References Top

1.Launer LJ. Diabetes and brain aging: Epidemiologic evidence. Curr Diabetes Rep 2005;5:59-63.  Back to cited text no. 1    
2.Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O'Brien PC, et al . The risk of dementia among persons with diabetes mellitus: A population-based cohort study. Ann N Y Acad Sci 1997;826:422-7.  Back to cited text no. 2    
3.Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999;53:1937-42.  Back to cited text no. 3    
4.Allen KV, Frier BM, Strachan MW. The relationship between type 2 diabetes and cognitive dysfunction: Longitudinal studies and their methodological limitations. Eur J Pharmacol 2004;490:169-75.  Back to cited text no. 4    
5.Coker LH, Shumaker SA. Type 2 diabetes mellitus and cognition: An understudied issue in women's health. J Psychos Res 2003;54:129-39.  Back to cited text no. 5    
6.Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetes-systematic overview of prospective observational studies. Diabetologia 2005;48:2460-9.  Back to cited text no. 6    
7.Ryan CM. Diabetes, aging and cognitive decline. Neurobiol Aging 2005;26:21-5.  Back to cited text no. 7    
8.Awad N, Gagnon M, Messier C. The relationship between impaired glucose tolerance, type 2 diabetes and cognitive function. J Clin Exp Neuropsychol 2004;26:1044-80.  Back to cited text no. 8    
9.Ryan MR, Geckle M. Why is learning and memory dysfunction in Type 2 diabetes limited to older adults? Diabetes Metab Res Rev 2000;16:308-15.  Back to cited text no. 9    
10.Bruce DG, Casey GP, Grange V, Clarnette RC, Almeida OP, Foster JK, et al . Cognitive impairment, physical disability and depressive symptoms in older diabetic patients: The Fremantle Cognition in Diabetes Study. Diabetes Res Clin Pract 2003;61:59-67.  Back to cited text no. 10    
11.Yaffe K, Blackwell T, Whitmer RA, Krueger K, Barrett Connor E. Glycosylated hemoglobin level and development of mild cognitive impairment or dementia in older women. J Nutr Health Aging 2006;10:293-5.  Back to cited text no. 11    
12.Reaven GM, Thompson LW, Nahum D, Haskins E. Relationship between hyperglycemia and cognitive function in older NIDDM patients. Diabetes Care 1990;13:16-21.  Back to cited text no. 12    
13.Munshi M, Grande L, Hayes M, Ayres D, Suhl E, Capelson R, et al . Cognitive dysfunction is associated with poor diabetes control in older adults. Diabetes Care 2006;29:1794-9.  Back to cited text no. 13    
14.Pearlmuter LC, Hakami MK, Hodgson-Harrington C, Ginsberg J, Katz J, Singer DE, et al . Decreased cognitive function in aging non-insulin-dependant diabetic patients. Am J Med 1984;77:1043-8.  Back to cited text no. 14    
15.Scott RD, Kritz-Silverstein D, Barrett-Connor E, Wiederholt WC. The association of non-insulin-dependant diabetes mellitus and cognitive function in an older cohort. J Am Geriatr Soc 1998;46:1217-22.  Back to cited text no. 15    
16.Lindeman RD, Romero LJ, LaRue A, Yau CL, Schade DS, Koehler KM, et al . A biethnic community survey of cognition in participants with type 2 diabetes, impaired glucose tolerance and normal glucose tolerance: The New Mexico Elder Health Survey. Diabetes Care 2001;24:1567-72.  Back to cited text no. 16    
17.Kanaya AM, Barrett-Connor E, Gildengorin G, Yaffe K. Change in cognitive function by glucose tolerance status in older adults: A 4-year prospective study of the Rancho Bernardo study cohort. Arch Intern Med 2004;164:1327-33.  Back to cited text no. 17    
18.Vanhanen M, Koivisto K, Kuusisto J, Mykkδnen L, Helkala EL, Hδnninen T, et al . Cognitive function in an elderly population with persistent impaired glucose tolerance. Diabetes Care 1998;21:398-402.  Back to cited text no. 18    
19.Fontbonne A, Berr C, Ducimetiere P, Alpιrovitch A. Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: Results of the Epidemiology of Vascular Aging Study. Diabetes Care 2001;24:366-70.  Back to cited text no. 19    
20.Kumari M, Marmot M. Diabetes and cognitive function in a middle-aged cohort: Findings from the Whitehall II study. Neurology 2005;65:1597-603.  Back to cited text no. 20    
21.Sommerfield AJ, Deary IJ, McAulay V, Frier BM. Short-term, delayed, and working memory are impaired during hypoglycemia in individuals with type 1 diabetes. Diabetes Care 2003;26:390-6.  Back to cited text no. 21    
22.Widom B, Simonson DC. Glycemic control and neuropsychologic function during hypoglycemia in patients with insulin-dependant diabetes mellitus. Ann Intern Med 1990;112:904-12.  Back to cited text no. 22    
23.Kaufman FR, Epport K, Engilman R, Halvorson M. Neurocogntive functioning in children diagnosed with diabetes before age 10 years. J Diabetes Complications 1999;13:31-8.  Back to cited text no. 23    
24.Rovet J, Alvarez M. Attentional functioning in children and adolescents with IDDM. Diabetes Care 1997;20:803-10.  Back to cited text no. 24    
25.Biessels GJ, van der Heide LP, Kamal A, Bleys RL, Gispen WH. Ageing and diabetes: Implications for brain function. Eur J Pharmacol 2002;441:1-14.  Back to cited text no. 25    
26.Craft S, Watson SG. Insulin and neurodegenerative disease: Shared and specific mechanisms. Lancet Neurol 2004;3:169-78.  Back to cited text no. 26    
27.Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, et al . Stimulation of β -amyloid precursor protein trafficking by insulin reduces intraneuronal β -amyloid and requires mitogen-activated protein kinase signaling. J Neurosci 2001;21:2561-70.  Back to cited text no. 27    
28.Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al . Triple-transgenic model of Alzheimer's disease with plaques and angles: Intracellular Aβ and synaptic dysfunction. Neuron 2003;39:409-21.  Back to cited text no. 28    
29.van Harten B, de Leeuw FE, Weinstein HC, Scheltens P, Biessels GJ. Brain imaging in patients with diabetes: A systematic review. Diabetes Care 2006;29:2539-48.  Back to cited text no. 29    
30.Akisaki T, Sakurai T, Takata T, Umegaki H, Araki A, Mizuno S, et al . Cognitive dysfunction associates with white matter hyperintensities and subcortical atrophy on magnetic resonance imaging of the elderly diabetes mellitus Japanese elderly diabetes intervention trial (J-EDIT). Diabetes Metab Res Rev 2006;22:376-84.  Back to cited text no. 30    
31.Gold SM, Dziobek I, Sweat V, Tirsi A, Rogers K, Bruehl H, et al . Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia 2007;50:711-9.  Back to cited text no. 31    
32.Korf ES, van Straaten EC, de Leeuw FE, van der Flier WM, Barkhof F, Pantoni L, et al . Diabetes mellitus, hypertension and medial temporal lobe atrophy: The LADIS study. Diabet Med 2007;24:166-71.  Back to cited text no. 32    
33.Manschot SM, Brands AM, van der Grond J, Kessels RP, Algra A, Kappelle LJ, et al . Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 2006;55:1106-13.  Back to cited text no. 33    
34.van Harten B, Oosterman J, Muslimovic D, van Loon BJ, Scheltens P, Weinstein HC. Cognitive impairment and MRI correlates in the elderly patients with type 2 diabetes mellitus. Age Ageing 2007;36:164-70.  Back to cited text no. 34    
35.den Heijer T, Vermeer SE, van Dijk EJ, Prins ND, Koudstaal PJ, Hofman A, et al . Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 2003;46:1604-10.  Back to cited text no. 35    
36.Knopman DS, Mosley TH, Catellier DJ, Sharrett AR; Atherosclerosis Risk in Communities (ARIC) Study. Cardiovascular risk factors and cerebral atrophy in a middle-aged cohort. Neurology 2005;65:876-81.  Back to cited text no. 36    
37.Longstreth WT Jr, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, et al . Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people: The Cardiovascular Health Study. Stroke 1996;27:1274-82.  Back to cited text no. 37    
38.Schmidt R, Launer LJ, Nilsson LG, Pajak A, Sans S, Berger K, et al . Magnetic resonance imaging of the brain in diabetes: The Cardiovascular Determinants of Dementia (CASCADE) Study. Diabetes 2004;53:687-92.  Back to cited text no. 38    
39.Kumar R, Anstey KJ, Cherbuin N, Wen W, Sachdev PS. Association of type 2 diabetes with depression, brain atrophy, and reduced fine motor speed in a 60-64 year old community sample. Am J Geriatr Psychiatry 2008;16:989-98.  Back to cited text no. 39    
40.Brands AM, Van den Berg E, Manschot SM, Biessels GJ, Kappelle LJ, De Haan EH, et al . A detailed profile of cognitive dysfunction and its relation to psychological distress in patients with type 2 diabetes mellitus. J Int Neurophychol Soc 2007;13:288-97.  Back to cited text no. 40    
41.Araki Y, Nomura M, Tanaka H, Yamamoto H, Yamamoto T, Tsukaguchi I, et al . MRI of the brain in diabetes mellitus. Neuroradiology 1994;36:101-3.  Back to cited text no. 41    
42.Biessels GJ, Koffeman A, Scheltens P. Diabetes and cognitive impairment. Clinical diagnosis and brain imaging in patients attending a memory clinic. J Neurol 2006;253:477-82.  Back to cited text no. 42    
43.Longstreth WT Jr, Arnold AM, Manolio TA, Burke GL, Bryan N, Jungreis CA, et al . Clinical correlates of ventricular and sulcal size on cranial magnetic resonance imaging of 3,301 elderly people: The Cardiovascular Health Study. Neuroepidemiology 2000;19:30-42.  Back to cited text no. 43    

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Correspondence Address:
Rajeev Kumar
Advanced Training in Consultation-Liaison Psychiatry, RANZCP, ACT, The Canberra Hospital & Mental Health ACT, P.O.Box-11, Woden, ACT-2606
Australia
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