Neurocognitive Outcomes of Type One Diabetes in Children - Annotated Bibliography Example

Neurocognitive Outcomes of Type Diabetes in Children Table of Contents Introduction to type diabetes mellitus A. What is diabetes Mellitus? B. Prevalence and demographics C. Neural basis of T1DM D. Treatment Cognitive outcomes on memory 1. Neural basis of memory 2. Cognitive outcome of T1DM on memory Structural changes in the brain as a result of T1DM: MRI studies A. Hippocampus 1. Purpose and function 2. Previous studies on T1DM and hippocampal Volume 3. Cognitive Effects of T1DM on Hippocampal Volume B. Effect of T1DM on other brain areas Conclusion: A. Summary of literature findings B. Direction of future research 1. What remains unknown on T1DM clinical applications and memory 2. What is not known about clinical applications of T1DM and changes in Brain Structure I. Introduction to type 1 diabetes mellitus A. What is type 1 diabetes Mellitus? Jones, T. W., & Davis, E. A. (2003). Hypoglycemia in children with type 1 diabetes: current issues and controversies. Pediatric Diabetes, 4(3), 143-150. Type 1 Diabetes Mellitus (T1DM) is a disease caused by the inability of the body to produce insulin. As a result of the human defenses against autoimmune disorders, insulin producing cells in the body are identified as foreign and therefore targeted by immune cells for destruction. Insulin is a hormone produced by the pancreas, which is responsible for regulating blood glucose levels through the regulation of glucose uptake from blood into storage cells. High levels of blood glucose can result in damage of organs such as the kidney, liver, pancreas and brain. The main symptoms of diabetes include weight loss, polynuria and presence of sugar in urine. It is characteristic of T1DM for symptoms to develop quickly especially in young people. B. Prevalence and demographics Ennis, K., Tran, P. V., Seaquist, E. R., &Rao, R. (2008). Postnatal age influences hypoglycemia-induced neuronal injury in the rat brain. Brain research, 1224, 119-126. Prevalence of Type 1 Diabetes Mellitus has been on the rise, with the center for disease control estimating that there was a 23% increase in cases of type 1diabetes in the United Statesbetween 2001 and 2009.In Canada, there is a wide variation in the prevalence of the disease across provinces with Labrador having the highest rates estimated at 0.035% in children below 18 years. A study was done in children and youth below 20 yearsof age by Gaudieri et al (2008), in which it was found that the condition affects people of all ages but its onset is earlier than type two diabetes mellitus; before a patient is 40 years old. Most cases of diabetes in children are type 1diabetes (Haces et al 2010). C. Treatment Ferguson, S. C., Blane, A., Wardlaw, J., Frier, B. M., Perros, P., McCrimmon, R. J., &Deary, I. J. (2005). Influence of an early-onset age of type 1 diabetes on cerebral structure and cognitive function. Diabetes care, 28(6), 1431-1437. Type 1 diabetes mellitus is a chronic illness and requires the injection of insulin for the rest of the patient’s lifetime. Good nutrition practices should also be adopted which comprises of a balanced diet with less sugary foods. There are other treatments that are believed to delay the onset or stop the disease from developing completely in predisposed persons.Early diagnosis is important for effective management of the condition. The injection of insulin is the most common method of managing Diabetes mellitus both type 1 and 2 according to the Canadian diabetes association (2008). The association recommends that insulin is administeredintravenously or intramuscularly since oral administration may lead to breakdown of the insulin by proteolitic enzymes found in the stomach.Due to the high frequency of injections, diabetes specialists have developed the best equipment to use for injection such as the insulin pen and a schedule to follow so that the injections are not concentrated at the same location. The use of injectable insulin causes changes in concentration of the hormone in the body and my cause episodes of hypoglycemia in the patient. A few minutes after injection, the concentration is very high and most of the glucose in the blood is taken up for storage. The levels drop gradually to normal levels and later reduce to below normal at which time another injection is required. Islet cell transplant is a promising therapy to cure diabetes mellitus type 1.Insulin is produced in beta cells found in the islet region of the pancreas. In diabetic patients, these cells are either missing or non-functional. The therapy involves transplanting islet cell from a normal pancreas into a T1DM patient so that they can synthesis insulin. To other patients, pancreas transplant is recommended. It involves the transfer of a full functional pancreas from a donor into a patient. This is a high risk operation that can only be performed in a few hospitals that have the required equipment and personnel. The challenge to this method being adopted is the availability of donors to provide the cadaver. II. Cognitive outcomes on memory 1. Neural basis of memory Ghetti, S., Lee, J. K., Sims, C. E., DeMaster, D. M., & Glaser, N. S. (2010). Diabetic ketoacidosis and memory dysfunction in children with type 1 diabetes. The Journal of pediatrics, 156(1), 109-114. Memory has been established to be a result of separate parts of the brain functioning independently. Through brain lesion studies, it has been established that while the functions carried out by the destroyed region are impaired following damage, functions by other sections of the brain remain normal. There are three distinct components of memory; the first component is the registration of information also referred to as the encoding component. This component is responsible for storing the information acquired either through vision or hearing. The second component is responsible for retention and it is responsible for packaging the information received either verbal on non verbal and keeping it for future use. The third and last component is the retrieval where information stored by the brain is recalled either verbally, through repeating an action or responding to a situation based on a previous experience. The brain is very sensitive to stress and a slight change in the levels of glucose or oxygen may cause extensive damage to the structures associated with memory. Dorsey, J. A., Meyer, E., Rutlin, J., Perantie, D. C., White, N. H., Arbelaez, A. M., & Hershey, T. (2013). White matter microstructural integrity in youth with type 1 diabetes. Diabetes, 62(2), 581-589. Memory can be declarative, where a person stores information deliberately through processes like learning, an example is the storage of facts in memory. It can also be Nondeclarative in cases where the information acquired and retained in memory is from experiences that one is exposed to in life. Information can be stored for a short term or for a long term. Working memory is the memory for storing information for a short term and the information can easily be retrieved. When damage occurs in a section of the brain, the functions of that section of the brain will be impaired either partly or permanently. The cells may regenerate and the function return to normal or if it does not, then the functions are permanently impaired. 2. Cognitive outcome of T1DM on memory Cato, M. A., Mauras, N., Ambrosino, J., Bondurant, A., Conrad, A. L., Kollman, C., & Hershey, T. (2014). Cognitive functioning in young children with type 1 diabetes. Journal of the International Neuropsychological Society, 20(02), 238-247. The effect of type 1 diabetes mellitus on the brain and the central nervous system, though not clearly established, has been suggested by various studies. Hypoglycemia and hyperglycemia as a result of Type 1 diabetes mellitus may result in defective development of some regions of the brain or alteration of brain pathway functions (Dorsey et al 2013). The brain is still in its developmental stage in children and therefore highly vulnerable to the chronic hyperglycemia caused by diabetes mellitus. There are a number of cognitive functions that are affected by hypoglycemia as a result of type 1 diabetes mellitus. The most affected functions are those of memory and attention. (Musen et al 2006).Musen et al (2006) suggests that working memory in T1dm patients is impaired. This memory is vital for the allocating of attention to the most important tasks and in short term information manipulation. Therefore Since the two functions are very important for normal functioning of the body, they pose a risk to the patient and therefore they should avoid high risk activities such as operating machines and driving. Deficits in memory does not result from T1DM directly but rather from secondary complication associated with T1DM such as hypoglycemia, Hyperglycemia and Diabetic ketoacidosis among others (Hershey et al 2003). The memory deficits have been associated with mild cerebral hypoxia which may be caused by T1DM related conditions or by other factors. The hypoxia damages the hippocampus, which is the structure, associated with working memory and other memory functions. Hershey et al argues that, T1DM is responsible for ischemia and ischemia, resulting either from T1DG or from any other cause, is responsible for the memory deficits. III. Structural changes in the brain as a result of T1DM: MRI studies A. Hippocampus Dorsey, J. A., Meyer, E., Rutlin, J., Perantie, D. C., White, N. H., Arbelaez, A. M., & Hershey, T. (2013). White matter microstructural integrity in youth with type 1 diabetes. Diabetes, 62(2), 581-589. 1. Purpose and function The hippocampus is a brain section that is responsible for consolidation of information in the brain. It is found in the right and left sides of the brain in the temporal lobe (Gispen and Biessels 2000). It is responsible for the conversion of information into permanent memory from short-term memory. There are a number of theories that explain the function of the hippocampus in the human brain; the behavioral inhibition theory suggests that the hippocampus controls activity, and if removed, animals exhibit hyperactivity and are not able to show conditional reflexes taught to them, such as those that are involved with staying quiet to avoid predators or catch prey. The role of hippocampus in memory has also been suggested with evidence provided showing that patients with hippocampal damage lost memory of events that took place in the recent past but could recall events that happened early in their life. The hippocampus is also believed to play a part in recognizing familiar locations within the environment. (Draeloset al 1995). 2. Previous studies on T1DM and hippocampal Volume Hershey, T., Perantie, D. C., Wu, J., Weaver, P. M., Black, K. J., & White, N. H. (2010). Hippocampal volumes in youth with type 1 diabetes. Diabetes, 59(1), 236-241. Type 1 diabetes mellitus has been shown to increase the hippocampus size (Ferguson et al 2005). The constant episodes of hypoglycemia and hyperglycemia have a negative effect on the neurons of the hippocampus in the brain of the patient. Hershey et al (2010) established that by exposing the hippocampus to severe hypoglycemia, it enlarged in size. They suggested that the increase in the size of the hippocampus is as a result of disruption of the brain development process occasioned by conditions such as gliosis- a process that leads to formation of fibrous matter within the brain. It is advisable that patients check their glucose level constantly in order to guard against long episodes of either hypoglycemia or hyperglycemia so as to ensure normal brain development. Hershey, T., Perantie, D. C., Wu, J., Weaver, P. M., Black, K. J., & White, N. H. (2010). Hippocampal volumes in youth with type 1 diabetes. Diabetes, 59(1), 236-241. Hershey et al (2010) in their study of the effect of T1DM on hippocampus size observed that children with the highest number of hypoglycemic episodes also had the highest increase in the hippocampal size. This varies from data obtained in adults in which case there was no change in hippocampal volume observed. Therefore it can be suggested that the response by an adult’s hippocampus differs from that of a child when both are exposed to low blood sugar levels. 3. Cognitive Effects of T1DM on Hippocampal Volume T1DM patients experience slowed mental function and low flexibility in mental performance as well as difficulties in learning and remembering things. The damage is progressive and may lead to total loss of memory in severe cases (Kaufman, et al 1999). Neuropsychological tests are the best way to check the effects of T1DM on brain functions and from various studies carried out, it has demonstrated a relationship between T1DM and brain functioning (Ferguson et al 2005). They established that T1DM patients use more brain resources in carrying out functions such as memory than non diabetic individuals. Therefore the patients require more glucose to support enhanced substrate level phosphorilation. The patients show general inability to interpret acquired information and apply it in various situations. B. Effect of T1DM on other brain areas Biessels, G. J., &Reijmer, Y. D. (2014). Brain MRI in children with type 1 diabetes: snapshot or road map of developmental changes?. Diabetes, 63(1), 62-64. Biessels and Reijmer (2014) in their study of structural changes in children with T1DM, sampled children between 6 and 18 years who were symptomatic. They carried out magnetic resonance Imaging (MRI), and evaluation of brain function after 48 hours, after one week, after one month and after six months. In the study, they did not include children with any form of brain damage or those with any brain related functional impairment. They established that children develop cerebral edema when affected by T1DM and that the areas in the brain that are most affected are the white matter. They also established that the cause of this damage is ketoacidosis resulting from the disease. Diabetic ketoacidosis (DKA) is the accumulation of ketone bodies in T1DM patient’s blood as a result of breakdown of fatty acids. The condition affects 25 to 40 percent of patients with onset T1DM and is believed to cause brain injury. There are two possible causes of the altered diffusion in the T1DM patient’s white matter, the first reason is the fact that there is rapid glucose restoration following hypoglycemia and a slower loss of solutes causing swelling of nerve cells(Ennis et al 2008). The second probable cause is the breakdown of the blood brain barrier which results in fluids moving from the blood into the white matter of the brain causing a brain water imbalance.(Dorsey et al 2013). Apart from edema, there are other structural changes that were viewed on the MRI scans including inflammation on the white matter, and micro-hemorrhage of sub cortical white matter in the frontal and parietal cortices. Type 1 diabetes mellitus patient’s show decreased response to sensory stimulation when compared to non diabetic individuals. (Stem ,2012). The brain requires higher stimulation levels to reach a cognitive performance level similar to that in normal people can be attributed to a reduction in cerebral efficiency. Hypoglycemia resulting from T1DM can cause a patient to have seizures or go into a coma. In his study of cognitive brain function in T1DM patients, Stem (2012) established that during hypoglycemia episodes, there was increased activation in brain regions such as hippocampus and the parietal cortices. T1DM patients are the most affected by DKA (Jones et al 2003). It results from the use of triglycerides in ATP production through the fatty acid oxidation pathway in the process producing ketone bodies. Patients having KDA are likely to have undiagnosed T1DM or may not be managing the condition as well as it is required. 4. Conclusion: A. Summary of literature findings There has been extensive research to elucidate the effects of T1DM on brain development, structure and functions but none has been conclusive (Musen et al 2006; Cato et al 2014) .Ketoacidosis has been proven to impact negatively on cognitive performance in diabetic children below 18 years. Some studies found an association between Diabetic ketoacidocis(DKA) and conditions such as sclerosis of the temporal lobe of the brain while others found no association.(Kaufman et al 2009). There was clearer evidence of cerebral edema observed by imaging systems as a result of DKA. Cerebral metabolites were also shown to be altered in a similar way as during ischemic injury in children. If DKA is left untreated it causes cytotoxic edema in the cerebral cortex, but if it is treated, then accumulation of fluid in the cerebral cortex was observed. From the findings it was shown that damage to the brain may result from both untreated DKA as well as during treatment. Draelos et al (1995) studied the effect of T1DM on the brain and established that besides DKA other factors that reduce memory in patients with T1DM are the sex of the patient, with male patients being affected more than female patients; age and the time of onset also determines the extent of damage. B. Direction of future research Hershey, T., Lillie, R., Sadler, M., &White, N. H. (2003). Severe hypoglycemia and long-term spatial memory in children with type 1 diabetes mellitus: a retrospective 1. What remains unknown on T1DM clinical applications and memory Overall, children with T1DM have normal brain function, except when it comes to memory. The originof deficits is not well understood because of the many independent factors that can lead to brain damage. There is a high prevalence of DKA in children with onset diabetes as compared to adult patients due to their inability to manage the condition fully. It is advisable that children are taught how to manage diabetes early so that they are able to take care of their health through diet and insulin injection. Future research shall be focused to establishing the relationship between diabetes ketoacidosis and reduction in the memory function of the brain (Kaufman et al 2009). The studies should involve monitoring of the patients exclusively as previous studies depended on recollection of events by parents or guardians which might not be very accurate. There is also little understood about how T1DM causes conditions such as uterine and colorectal cancer and future research should focus on establishing the mechanism. It is not clear whether T1DM is caused by genetic pre-disposition, exposure to a specific antigen or mutations that result in the triggering of the condition. It has been established that the brain has a mechanism to maintain functionality by increased activity in affected regions. What is not known is the impact of the changes on other brain functions and on the function of memory in old age. What is not known about clinical applications of T1DM and changes in Brain structure Future studies should also establish the relationship between IQ and learning ability to the changes in brain structure in T1DM. How important early diagnosis and management of T1DM are, in ensuring DKA does not develop and cause structural brain damage. The relationship between age of a patient and the effect of diabetes also should be studied further since there has been an indication that there is more damage witnessed in young patients than in adults. Ernis et al (2008) researched on rats and in their findings reported that postnatal age rats had the highest brain damage as a result of T1DM related hypoglycemia. Further research in humans is important in order to establish if this effect can be reproduced. By correlating cognitive function in children and adults with the hippocampal volume, researchers will be able to design more accurate diagnostic tools for the condition. Previous studies have correlated hyperglycemia episodes with volume of hippocampus but limited information is available on the relationship between hippocampus volume and cognitive functions. Whether the changes in the structure of the hippocampus can be reversed is also a research area that should be given attention References Biessels, G. J., &Reijmer, Y. D. (2014). Brain MRI in children with type 1 diabetes: snapshot or road map of developmental changes? Diabetes, 63(1), 62-64. Biessels, G. J., Deary, I. J., & Ryan, C. M. (2008). Cognition and diabetes: a lifespan perspective. The Lancet Neurology, 7(2), 184-190. Canadian Diabetes Association. (2008). Clinical practice guidelines for the prevention and management of diabetes in Canada, 2008.Can J Diabetes; 32(Suppl. 1): S1–201. Cato, M. A., Mauras, N., Ambrosino, J., Bondurant, A., Conrad, A. L., Kollman, C., & Hershey, T. (2014). Cognitive functioning in young children with type 1 diabetes. Journal of the International Neuropsychological Society, 20(02), 238-247. Dorsey, J. A., Meyer, E., Rutlin, J., Perantie, D. C., White, N. H., Arbelaez, A. M., & Hershey, T. (2013). White matter microstructural integrity in youth with type 1diabetes. Diabetes, 62(2), 581-589. Draelos, M. T., Jacobson, A. M., Weinger, K., Widom, B., Ryan, C. M., Finkelstein, D. M., & Simonson, D. C. (1995).Cognitive function in patients with insulin-dependent diabetes mellitus during hyperglycemia and hypoglycemia. The American journal of medicine, 98(2), 135-144. Ennis, K., Tran, P. V., Seaquist, E. R., &Rao, R. (2008). Postnatal age influences hypoglycemia-induced neuronal injury in the rat brain. Brain research, 1224, 119-126. Ferguson, S. C., Blane, A., Wardlaw, J., Frier, B. M., Perros, P., McCrimmon, R. J., &Deary, I. J. (2005). Influence of an early-onset age of type 1 diabetes on cerebral structure and cognitive function. Diabetes care, 28(6), 1431-1437. Gaudieri, P. A., Chen, R., Greer, T. F., & Holmes, C. S. (2008). Cognitive function in children with type 1 diabetes a meta-analysis. Diabetes Care, 31(9), 1892-1897. Ghetti, S., Lee, J. K., Sims, C. E., DeMaster, D. M., & Glaser, N. S. (2010). Diabetic ketoacidosis and memory dysfunction in children with type 1 diabetes. The Journal of pediatrics, 156(1), 109-114. Gispen, W. H., &Biessels, G. J. (2000).Cognition and synaptic plasticity in diabetes mellitus. Trends in neurosciences, 23(11), 542-549. Haces, M. L., Montiel, T., &Massieu, L. (2010).Selective vulnerability of brain regions to oxidative stress in a non-coma model of insulin-induced hypoglycemia. Neuroscience, 165(1), 28-38. Hershey, T., Lillie, R., Sadler, M., &White, N. H. (2003). Severe hypoglycemia and long-term spatial memory in children with type 1 diabetes mellitus: a retrospective study. Journal of the International Neuropsychological Society, 9(05), 740-750. Hershey, T., Perantie, D. C., Wu, J., Weaver, P. M., Black, K. J., & White, N. H. (2010). Hippocampal volumes in youth with type 1 diabetes. Diabetes, 59(1), 236-241. Jones, T. W., & Davis, E. A. (2003). Hypoglycemia in children with type 1 diabetes: current issues and controversies. Pediatric Diabetes, 4(3), 143-150. Kaufman, F. R., Epport, K., Engilman, R., & Halvorson, M. (1999). Neurocognitive functioning in children diagnosed with diabetes before age 10 years. Journal of Diabetes and its Complications, 13(1), 31-38. Musen, G., Lyoo, I. K., Sparks, C. R., Weinger, K., Hwang, J., Ryan, C. M.,& Jacobson, A. M. (2006). Effects of type 1 diabetes on gray matter density as measured by voxel-based morphometry. Diabetes, 55(2), 326-333. Stern Y. (2012) What is cognitive reserve? Theory and research application of the reserve concept. J IntNeuropsychol; 8: 448–460 Read More