Cognitive function in diabetes

Cognitive deficits, that is clinically relevant problems in cognitive performance, are commonly observed in people with both type 1 (T1DM) as well as type 2 diabetes (T2DM). Both diseases are related specifically to slowing of mental processing speed, psycho-motor speed, executive functions and attention. In T2DM learning and memory problems are often noted but less so in T1DM. Evidence for changes in brain structure and functioning accompanying cognitive dysfunction is accumulating. Chronic hyperglycaemia and associated microvascular disease appear to be the most important determinants of cognitive decrements in diabetes.

Hypoglycaemia and hyperglycaemia

Hypoglycaemia can lead to unconsciousness, seizure, coma or even death. Mild to moderate levels of hypoglycaemia commonly affect higher-order cognitive functions. Patients may experience mood changes and difficulty with memory, planning, attention and concentration [1]. Mental speed rapidly decreases, while accuracy remains relatively unaffected. With severe hypoglycaemia, all cognitive functions may be affected, seriously decreasing a patient’s mental capabilities. Whereas blood glucose can be quickly restored, cognitive dysfunction may take up to 4 hours or more to recover fully. Acute effects of hypoglycaemia on brain structure in diabetes are rarely reported and pre-clinical data suggest that brain damage after hypoglycaemia may be the result of reactive hyperglycaemia through overcompensation of counter-regulatory actions. In neonates without diabetes, hypoglycaemia is a common cause of brain damage, delayed development and death.

The acute effect of hyperglycaemia on cognition seems relatively mild, contrary to the long-term effects, and may be associated with diabetic ketoacidosis (DKA), usually observed in children. DKA may be accompanied by disruptive blood-brain barrier functioning, observable cerebral edema, subclinical white matter damage and subcortical hemorrhage, although most knowledge is based on case reports. It is unclear whether these structural brain changes are reversible after treatment of DKA or whether minor changes are permanent.

Type 1 diabetes

Cognition

As early as 2 years after disease onset, which is usually during childhood or adolescence, cognitive decrements are found in people with T1DM [2]. These decrements persist into adulthood. A meta-analysis summarizing 33 studies in adults showed that a specific set of cognitive functions is affected by T1DM [3], including mental processing speed and flexibility and attention [3]. Other important functions, such as memory and learning, planning, and inhibition seem to be unaffected in these patients. There is some evidence that cognitive dysfunction increases over time in young to middle-aged patients [4]. Cognitive dysfunction in older patients (mean age 60 years) seems no more pronounced than younger patients. Moreover, the rate of decline in elderly is similar to the rate of decline seen in healthy elderly people [5]. The effect size of cognitive decrements is mostly moderate, between 0.3 – 0.8 [3]. Such effect sizes are comparable to the acute phase after mild traumatic brain injury . While modest on an individual level, such effect sizes can hamper daily life and some patients may be at risk of more pronounced cognitive dysfunction.

Brain changes

Relatively limited literature is available on brain changes accompanying cognitive decrements in people with T1DM. Cortical gray matter structure has been consistently found to be altered with a diffuse distribution throughout the brain in patients versus controls [6]. These cortical gray matter measures are weakly correlated with cognitive functioning, and subcortical structures should be more extensively studied. Other studies have used measures of functional (i.e. how neurons communicate with each other) and structural (i.e. the quality of white matter connections) connectivity, which are thought to be highly important for cognitive functioning. Decreased quality of white matter tracts (structural connectivity) was observed in many brain regions in T1DM [7]. Only a few studies have been published on functional connectivity and suggest that the communication between neurons may be increased in the early stages of the disease, i.e. before microvascular complications become clinically manifest, but later decreases when microangiopathy is detectible [8]. These measures of connectivity showed good correlations with cognitive functioning in people with T1DM [7][8].

Type 2 diabetes

Cognition

The profile of cognitive decrements in T2DM is generally similar to that found in T1DM [9]. The most striking difference is that T2DM is associated with decreased memory and learning performance. However, one study directly comparing age-matched 40 people with T1DM with 40 people with T2DM did not find any differences in cognitive performance between the groups, while vascular brain lesions were more prominent in the T2DM group. Over time, these functions do not seem subject to accelerated decline. Cognitive decrements have also been found in patients with the metabolic syndrome, suggesting that factors such as insulin resistance, hypertension and dyslipidemia are involved in cognitive decrements. Hence, it is difficult to disentangle all factors that may contribute to cognitive dysfunction in T2DM. Overall, people with T2DM perform slightly, about 0.3-0.6 sd, poorer on tests measuring multiple aspects of cognition, compared to controls [9]. Strikingly, T2DM has been associated with a 2-fold increased risk of dementia, both Alzheimer’s disease and vascular dementia. This is a surprising finding given the lack of dementia-like cognitive decline over time. This suggests that T2DM alone is not sufficient to develop dementia and additional risk factors, such as APOE-genotype, need to be present in order to develop dementia.

Brain changes

Brain atrophy, white matter lesions and lacunar infarcts are commonly observed in people with T2DM [9]. Atrophy of the hippocampus, a structure important for learning and memory, and surrounding medial temporal lobe structures is commonly found in T2DM and may be related to the memory and learning problems noted in these patients [9]. More advanced connectivity analyses have shown decrements in white matter integrity and poorer network functioning of the white matter, all relating to important cognitive functions [10]. Longitudinal imaging studies are scarce, but a recent 4 year follow-up study does not suggest progression of cerebral problems [11].

Risk factors

Chronic hyperglycaemia seems to be the most important pathophysiological mechanism associated with underlying cognitive decrements and cerebral problems in diabetes [9]. Alongside hyperglycaemia, microvascular complication, most commonly (proliferative) retinopathy and microalbuminuria, and increased subclinical atherosclerosis, are risk factors for brain changes. Macrovascular complications of diabetes, such as cardio- and cerebrovascular disease, are commonly among the exclusion criteria of studies, but they evidently can lead to compromised cognitive functioning and potentially severe brain damage. This will typically be the case for people with T2DM. Hypertension, dyslipidemia, obesity and insulin resistance, all part of the metabolic syndrome, are associated with cerebral compromise in pre-diabetes [12]. Interestingly, in the elderly over 85 years, being categorised as having the metabolic syndrome was related to decelerated cognitive decline. This observation suggests that the metabolic syndrome may be particularly detrimental in younger people. For T1DM it was long advocated that severe hypoglycaemia was the major culprit of cognitive dysfunction, suggesting the short-term cognitive effects of hypoglycaemia would convert into long-term cognitive dysfunction. However, the large 18.5 year DCCT/EDIC study, as well as a systematic meta-analysis, has failed to find a relationship between long-term cognitive dysfunction and hypoglycaemia [3]. They demonstrated very clearly that long-term permanent cerebral compromise in T1DM is not likely to be caused by hypoglycaemia but rather by chronic hyperglycemic exposure.

References

  1. ^ Frier B: Hypoglycemia. In Diabetes and the Brain, First ed. Biessels GJ, Luchsinger JA, Eds. New York, Humana Press, 2009

  2. ^ Northam EA, Anderson PJ, Werther GA, Warne GL, Adler RG, Andrewes D: Neuropsychological complications of IDDM in children 2 years after disease onset. Diabetes Care 21:379-384, 1998

  3. ^ Brands AM, Biessels GJ, de Haan EH, Kappelle LJ, Kessels RP: The Effects of Type 1 Diabetes on Cognitive Performance: A meta-analysis. Diabetes Care 28:726-735, 2005

  4. ^ The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group: Long-Term Effect of Diabetes and Its Treatment on Cognitive Function. N Engl J Med 356:1842-1852, 2007

  5. ^ van Duinkerken E, Brands AMA, van den Berg E, Henselmans JML, Hoogma RPLM, Biessels GJ, On behalf of the Utrecht Diabetic Encephalopathy Study Group: Cognition in older patients with type 1 diabetes mellitus: a longitudinal study. J Am Geriatr Soc 59:563-565, 2011

  6. ^ Musen G, Jacobson AM, Ryan CM, Cleary PA, Waberski BH, Weinger K, Dahms W, Bayless M, Silvers N, Harth J, White N, Group TDER: The Impact of Diabetes and its Treatment on Cognitive Function among Adolescents Who Participated in the DCCT. Diabetes Care 31:1933-1938, 2008

  7. ^ van Duinkerken E, Schoonheim MM, IJzerman RG, Klein M, Ryan CM, Moll AC, Snoek FJ, Barkhof F, Diamant M, Pouwels PJ: Diffusion tensor imaging in type 1 diabetes: decreased white matter integrity relates to cognitive functions. Diabetologia 55:1218-1220, 2012

  8. ^ van Duinkerken E, Schoonheim MM, Sanz-Arigita EJ, IJzerman RG, Moll AC, Snoek FJ, Ryan CM, Klein M, Diamant M, Barkhof F: Resting-state brain networks in type 1 diabetes patients with and without microangiopathy and their relation with cognitive functions and disease variables. Diabetes 61:1814-1821, 2012

  9. ^ McCrimmon RJ, Ryan CM, Frier BM: Diabetes and cognitive dysfunction. Lancet June 9, epub ahead of print:DOI:10.1016/S0140-6736(1012)60360-60362, 2012

  10. ^ Reijmer YD, Brundel M, de Bresser J, Kappelle LJ, Leemans A, Biessels GJ, on behalf of the Utrecht Vascular Cognitive Impairment Study G: Microstructural White Matter Abnormalities and Cognitive Functioning in Type 2 Diabetes: A diffusion tensor imaging study. Diabetes Care In Press:doi:10.2337/dc2312-0493, 2012

  11. ^ de Bresser J, Tiehuis AM, van den Berg E, Reijmer YD, Jongen C, Kappelle LJ, Mali WP, Viergever MA, Biessels GJ: Progression of cerebral atrophy and white matter hyperintensities in patients with type 2 diabetes. Diabetes Care:-, 2010

  12. ^ Yates KF, Sweat V, Yau PL, Turchiano MM, Convit A: Impact of Metabolic Syndrome on Cognition and Brain: A Selected Review of the Literature. Arterioscler Thromb Vasc Biol 32:2060-2067, 2012

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