Brain development in youth

Children and adolescents with type 1 diabetes have an increased risk of cognitive dysfunction which is likely a consequence of changes within the central nervous system. These structural and functional changes to the brain are most apparent in those children who developed diabetes early in life – before the age of 6 or 7, and in those who have a history of poorer metabolic control. Episodes of ketoacidosis as well as recurrent episodes of hypoglycemia have also been implicated as risk factors. Studies of adults have identified the development of diabetes-associated microvascular complications as risk factors, but this is most likely to be manifest after 5 to 10 years of diabetes. Very recent studies have also demonstrated that obese adolescents who meet criteria for metabolic syndrome or type 2 diabetes also manifest neurocognitive anomalies which, somewhat surprisingly, tend to be larger in scope than what has been reported in their peers with type 1 diabetes.

Cognitive Manifestations of Type 1 Diabetes

Two recent meta-analyses have demonstrated that when the overall cognitive functioning of children and adolescent with type 1 diabetes is consistently poorer, relative to their peers without diabetes. Effect sizes – expressed in standard deviation units, tended to be small (between 0.15 and 0.25), but it is clear that those children with diabetes consistently earn somewhat lower IQ scores, perform more poorly on measures of academic achievement – especially language skills, are slower on tasks that require mental and motor speed, and have difficulty paying attention [1][2]. Although these differences do not meet criteria for clinically significant impairment, they are nevertheless sufficient to reduce children’s overall efficiency at school and in the workplace, although the magnitude of those effects has never been quantified. On the other hand, when those with an early onset of diabetes are compared to those with a later onset of diabetes [2], somewhat larger effect sizes are seen (between ~0.20 and 0.40), and additional cognitive domains – particularly learning and memory, are adversely affected. Results from a large study of adolescent with early or later-onset diabetes indicates that approximately 24% of the early onset subjects meet criteria for clinically significant impairment, as compared to 6% of the later onset subjects, and 6% of healthy controls [3].

Cognitive dysfunction does not require many years to develop in children, but may be seen within 2 years of diagnosis [4]. Of particular concern are the recent demonstrations that toddlers (~4.5 years of age) with diabetes showed large differences (~5 points) on measures of general intelligence as compared to those without diabetes, and also performed more poorly on measures of expressive language and eye-hand coordination. One would surmise from this that if cognitive dysfunction is evident within 2 years of diagnosis, then after 30 or 40 years one might expect to see profound cognitive dysfunction. Fortunately, there is no evidence to support that view. The effect sizes reported in studies of children and adolescents with type 1 diabetes are comparable to those reported in studies of middle-aged and older adults who have had diabetes for a very extended period of time.

Brain Structure Manifestations of Type 1 Diabetes

The study of brain structure in children and adolescents is complicated by the fact that at different developmental stages there may be increases or decreases in brain volume that may occur at somewhat different rates in children of the same age. Furthermore, the volumetric analysis methods that are typically used are relatively crude and because they are sensitive to misalignment errors, may be relatively insensitive to the subtle changes in brain structure that seem to be characteristic in people with diabetes. Nevertheless, the few large studies that have begun to compare brain structures in children with and without diabetes have indicated that both chronic hyperglycemia and recurrent hypoglycemia may differentially affect these normal developmental processes. One large study of children, 7 to 17 years of age, compared those with and without Type 1 diabetes and found no between-group differences in regional brain volume. However, they noted that in those with diabetes, severe hypoglycemia was associated with smaller gray matter volume in the left superior temporal region, whereas more exposure to consistently higher blood glucose levels was associated with less gray matter volume in the right cuneus and precuneus, more gray matter in the right prefrontal region, and smaller white matter volume in the right posterior region [5]. When these subjects were re-evaluated 2 years later, it was found that higher HbA1c values were associated with a greater decrease in whole brain gray matter volume, whereas the occurrence of severe hypoglycemia during follow-up was associated with a marked decrease in white matter volume, particularly in the occipitoparietal region [6].

The recent use of more sensitive measures of white matter integrity (diffusion tensor imaging) has demonstrated that the microstructural integrity of white matter tracts is disrupted in the parietal, temporal, and callosal fibers of adolescents with diabetes, as compared to those without diabetes [7]. Evidence that these effects reflect neuronal dysfunction and death comes from magnetic resonance spectroscopy (MRS) studies of adolescents and young adults that have identified changes in neuro-metabolites, including N-acetyl-aspartate and myo-inositol [8][9]. Whether the axonal damage and loss of fiber coherence within the white matter tracts of those adult subjects developed over an extended period of time, or whether they reflect the development of brain damage soon after diagnosis, as seems to be the case in pediatric studies [7], remains to be determined. These very intriguing studies emphasize the need for larger prospective studies that use sophisticated neuroimaging techniques – particularly assessments of white matter integrity and neural connectivity analyses, and also include the use of sensitive, age-appropriate cognitive testing so that one can determine the extent to which these brain changes disrupt cognition.

Diabetes-Associated Risk Factors

Early research studies implicated recurrent episodes of moderately severe hypoglycemia as the primary cause of neurocognitive problems in children and adults with diabetes [10]. Most recently, however, two meta-analyses [1][2] have found little evidence to support that view, and now implicate poorer metabolic control (i.e., higher HbA1c values) as a potent risk factor. It is, however, not possible to entirely rule out a role for recurrent, moderately severe hypoglycemia insofar as some brain imaging research has identified relationships between hypoglycemia and reduced brain volume [5]. Unfortunately, not only is it challenging to reliably quantify episodes of moderate hypoglycemia, but it is often the case that those episodes are a consequence of insulin overtreatment following a more prolonged period of elevated blood glucose levels. Especially in children, both hyper- and hypoglycemia may be inextricably intertwined.

Developing diabetes early in life is another important risk factor for CNS anomalies in children (and adults) with type 1 diabetes. The first 5 to 7 years of life are critical periods for normal brain development, and it is certainly possible that the occurrence of metabolic events that can affect the integrity of the blood brain barrier, as is the case with the induction of diabetes or the occurrence of ketoacidosis may lead, in turn, to disruptions of the normal process of brain development and increase the individual’s vulnerability to subsequent metabolic fluctuations [11]. This could explain the nearly ubiquitous finding that cognitive dysfunction tends to be more severe, and more pervasive, in those children who develop diabetes within the first 7 years of life.

Type 2 Diabetes, Metabolic Syndrome, and Neurocognitive Sequelae in Obese Youth

Multiple recent studies of obese adults have a greatly increased risk of cognitive dysfunction [12] and structural changes in the brain [13]. Remarkably, similar results have been reported in children and adolescents who are obese, have the metabolic syndrome, or have type 2 diabetes [14]. Cognitive dysfunction is most apparent on measures requiring attention, executive functioning, and ‘fluid intelligence’. Compared to adolescents with type 1 diabetes, those who have had type 2 diabetes for only several years manifest both cognitive deficits and volumetric changes in brain structures that are more than twice as large – with effect sizes ranging from 0.7 to 1.3 [14]. While larger, longitudinal studies are currently lacking, these early results indicate that the prevention of obesity is critically important in ensuring optimal neurocognitive functioning in children and adolescents.

Future Perspectives

Excellent observational studies provide compelling data that both type 1 diabetes and obesity can have a detrimental impact on brain function and structure, but we currently lack a good understanding of the underlying pathophysiological mechanisms. Growing evidence supports the view that chronically elevated blood glucose levels are associated with brain changes to a greater extent than are moderately severe hypoglycemic events. There is also some support for the view that events occurring around the time of diagnosis – including the occurrence of ketoacidosis, may play an important role is disrupting brain integrity in children and adolescents with type 1 diabetes. For obese youngsters, increasing insulin resistance appears to be a predictor of brain dysfunction, but again, the pathophysiological basis is not well understood, nor is clear whether this dysfunction is reversible. What is clear is that not only is more research needed, but clinicians treating children and adolescents with diabetes must be extremely attentive in ensuring that blood glucose values be maintained as close to the normal range as possible. Similarly, health care providers treating obese youth must be vigilant in managing weight, and should consider the use of treatment regimens that can reduce the occurrence of insulin resistance and other components of the metabolic syndrome.

References

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  2. ^ Gaudieri PA, Chen R, Greer TF, Holmes CS: Cognitive function in children with type 1 diabetes: A meta-analysis. Diabetes Care 31:1892-1897, 2008

  3. ^ Ryan C, Vega A, Drash A: Cognitive deficits in adolescents who developed diabetes early in life. Pediatrics 75:921-927, 1985

  4. ^ 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

  5. ^ Perantie DC, Wu J, Koller JM, Lim A, Warren SL, Black KJ, Sadler M, White NH, Hershey T: Regional brain volume differences associated with hyperglycemia and severe hypoglycemia in youth with type 1 diabetes. Diabetes Care 30:2331-2337, 2007

  6. ^ Perantie DC, Koller JM, Weaver PM, Lugar HM, Black KJ, White NH, Hershey T: Prospectively Determined Impact of Type 1 Diabetes on Brain Volume During Development. Diabetes 60:3006-3014, 2011

  7. ^ Aye T, Barnea-Goraly N, Ambler C, Hoang S, Schleifer K, Park Y, Drobny J, Wilson DM, Reiss AL, Buckingham BA: White matter structural differences in young children with type 1 diabetes: A diffusion tensor imaging study. Diabetes Care 35:2167-2173, 2012

  8. ^ Northam EA, Rankins D, Lin A, Wellard RM, Pell GS, Finch SJ, Werther GA, Cameron FJ: Central nervous system function in youth with type 1 diabetes 12 years after disease onset. Diabetes Care 32:445-450, 2009

  9. ^ Sarac K, Akinci A, Alkan A, Baysal T, Özcan C: Brain metabolite changes on proton magnetic resonance spectroscopy in children with poorly controlled type 1 diabetes. Neuroradiology 47:562-565, 2005

  10. ^ Ryan C, Gurtunca N, Becker D: Hypoglycemia: A complication of diabetes therapy in children. Pediatric Clinics of North America 52:1705-1733, 2005

  11. ^ Ryan CM: Searching for the origin of brain dysfunction in diabetic children: Going back to the beginning. Pediatric Diabetes 9:527-530, 2008

  12. ^ Smith E, Hay P, Campbell L, Trollor JN: A review of the association between obesity and cognitive function across the lifespan: Implications for novel approaches to prevention and treatment. Obesity Reviews 12:740-755, 2011

  13. ^ Stanek KM, Grieve SM, Brickman AM, Korgaonkar MS, Paul RH, Cohen RA, Gunstad JJ: Obesity is associated with reduced white matter integrity in otherwise healthy adults. Obesity 19:500-504, 2011

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