Differences
This shows you the differences between two versions of the page.
| Both sides previous revision Previous revision Next revision | Previous revision | ||
|
group_4_presentation_2_-_cte [2018/11/02 00:03] shabin [Diagnosis] |
group_4_presentation_2_-_cte [2018/11/04 01:21] (current) kimr1 |
||
|---|---|---|---|
| Line 4: | Line 4: | ||
| ===== Introduction ===== | ===== Introduction ===== | ||
| - | Chronic Traumatic Encephalopathy (CTE) is a type of neurodegenerative disease found most commonly in people who have had multiple injuries to the head, mainly athletes that competed in contact sports. Symptoms include cognitive issues, changes in behavior, and lapses in memory. Most symptoms first start appearing years after the injuries, and will often get worse with time. In many cases, CTE can deteriorate into dementia. The only definitive means of diagnosis is through autopsy. It has been found to occur in approximately 30% of people with multiple head injuries. However, it is unclear how many head injuries increase the risk for developing the disease. Currently, there are no known treatments for CTE. Research is being conducted in an effort to find early diagnostic markers. Prevention of head injuries are the best methods of minimizing the risk of developing the disease. | + | Chronic Traumatic Encephalopathy (CTE) is a type of neurodegenerative disease found most commonly in people who have had multiple injuries to the head, mainly athletes that competed in contact sports (Asken et al., 2017). Symptoms include cognitive issues, changes in behavior, and lapses in memory. Most symptoms first start appearing years after the injuries, and will often get worse with time. In many cases, CTE can deteriorate into dementia (Asken et al., 2017). The only definitive means of diagnosis is through autopsy (Asken et al., 2017). It has been found to occur in approximately 30% of people with multiple head injuries (Asken et al., 2017). However, it is unclear how many head injuries increase the risk for developing the disease (Asken et al., 2017). Currently, there are no known treatments for CTE. Research is being conducted in an effort to find early diagnostic markers. Prevention of head injuries are the best methods of minimizing the risk of developing the disease. |
| - | + | ||
| ===== Epidemiology ===== | ===== Epidemiology ===== | ||
| Line 29: | Line 27: | ||
| ===== Risk Factors ===== | ===== Risk Factors ===== | ||
| - | The major risk for developing CTE is trauma to the central nervous system, therefore individuals who experience more head trauma are at a higher risk (DeKosky, Blennow, Ikonomovic & Gandy, 2013). Other factors such as the age at first head trauma and the length of the exposure to the head trauma also need to be taken into account and can increase risk to developing the disorder. Studies show that individuals who experience their first head trauma before the age of 12 are at a higher risk for developing CTE and have worse outcomes (Stamm et al., 2015). Furthermore, individuals who have a career with longer exposures to head trauma have a higher risk for CTE than those with a shorter career (Lakhan & Kirchgessner, 2012). Further research needs to be done on the genetic risk factors of CTE, as several have been proposed but remain to be established (DeKosky, Blennow, Ikonomovic & Gandy, 2013). | + | The major risk for developing CTE is trauma to the central nervous system, therefore individuals who experience more head trauma are at a higher risk (DeKosky, Blennow, Ikonomovic & Gandy, 2013). Other factors such as the age at first head trauma and the length of the exposure to the head trauma also need to be taken into account and can increase risk to developing the disorder. Studies show that individuals who experience their first head trauma before the age of 12 are at a higher risk for developing CTE and have worse outcomes (Stamm et al., 2015). Furthermore, individuals who have a career with longer exposures to head trauma have a higher risk for CTE than those with a shorter career (Lakhan & Kirchgessner, 2012). Further research needs to be done on the genetic risk factors of CTE, as some have been proposed but not yet confirmed (DeKosky, Blennow, Ikonomovic & Gandy, 2013). |
| {{ :screen_shot_2018-10-25_at_10.14.54_pm.png?300 |}} | {{ :screen_shot_2018-10-25_at_10.14.54_pm.png?300 |}} | ||
| Line 35: | Line 33: | ||
| ===== Symptoms ===== | ===== Symptoms ===== | ||
| - | |||
| Symptoms of Chronic traumatic encephalopathy (CTE) have not been well-defined yet due to lack of research and limitations in studies. However, based on present knowledge, the symptoms develop in 3 stages. First, there are deteriorations in memory, attention and concentration. Symptoms observed in the first stage include disorientation, headaches, confusion, short-term memory loss and dizziness. Next, as deteriorations progress, patients have poor critical skills, lack of insight and can develop dementia. Some of the symptoms seen in stage 2 are erratic behavior, social instability and preliminary symptoms of Parkinson disease. With progressive cognitive dysfunction, overt dementia is seen. Advanced dementia in addition to gait and speech abnormalities appear during the third stage (McKee et al., 2009). | Symptoms of Chronic traumatic encephalopathy (CTE) have not been well-defined yet due to lack of research and limitations in studies. However, based on present knowledge, the symptoms develop in 3 stages. First, there are deteriorations in memory, attention and concentration. Symptoms observed in the first stage include disorientation, headaches, confusion, short-term memory loss and dizziness. Next, as deteriorations progress, patients have poor critical skills, lack of insight and can develop dementia. Some of the symptoms seen in stage 2 are erratic behavior, social instability and preliminary symptoms of Parkinson disease. With progressive cognitive dysfunction, overt dementia is seen. Advanced dementia in addition to gait and speech abnormalities appear during the third stage (McKee et al., 2009). | ||
| - | {{ :ctesymptoms.png |}} | + | {{ :ctesymptoms.png?500 |}} |
| **Figure 3:** Overview of the various symptoms of CTE. | **Figure 3:** Overview of the various symptoms of CTE. | ||
| Other suspected symptoms include dysphagia (difficulty with swallowing), dysarthria (motor speech disorder), irritability, suicidal thoughts and vision problems (“Chronic Traumatic Encephalopathy”, 2016). Advanced cases usually include impeded speech, vertigo, deafness and slowing of muscular movements. The severity of CTE is correlated with the amount and rigorousness of traumatic brain injuries (McKee et al., 2009). | Other suspected symptoms include dysphagia (difficulty with swallowing), dysarthria (motor speech disorder), irritability, suicidal thoughts and vision problems (“Chronic Traumatic Encephalopathy”, 2016). Advanced cases usually include impeded speech, vertigo, deafness and slowing of muscular movements. The severity of CTE is correlated with the amount and rigorousness of traumatic brain injuries (McKee et al., 2009). | ||
| - | ===== Diagnosis ===== | ||
| + | ===== Diagnosis ===== | ||
| There is currently no dependable way to diagnose CTE. Since the diagnosis requires evidence of brain tissue degeneration and of deposits of tau and other proteins in the brain, it can only be detected upon examination after death (autopsy). Researchers are working persistently to find a test that can detect CTE while the patient is still alive. Some of the tests researchers are working on include finding biomarkers and brain imaging to diagnose CTE (Reams et al., 2016). | There is currently no dependable way to diagnose CTE. Since the diagnosis requires evidence of brain tissue degeneration and of deposits of tau and other proteins in the brain, it can only be detected upon examination after death (autopsy). Researchers are working persistently to find a test that can detect CTE while the patient is still alive. Some of the tests researchers are working on include finding biomarkers and brain imaging to diagnose CTE (Reams et al., 2016). | ||
| Line 57: | Line 54: | ||
| * __Susceptibility-weighted imaging (SWI)__ is a type of MRI that shows tiny bleeds (hemorrhages) that result from injury to the central nervous system (Baugh et al., 2012). | * __Susceptibility-weighted imaging (SWI)__ is a type of MRI that shows tiny bleeds (hemorrhages) that result from injury to the central nervous system (Baugh et al., 2012). | ||
| - | **Positron emission tomography (PET):** A PET scan uses a low-level radioactive tracer that is injected in a vein. Then, a scanner tracks the tracer's flow through the brain. Researchers are actively working to develop PET markers to detect tau abnormalities associated with neurodegenerative diseases. The goal is to develop a marker to identify the tau pathology of CTE in people who are alive. Researchers are using various substances that bind to tau and other proteins on PET scans. (Reams et al., 2016). | + | {{:dti.png?250|}} {{:mrs.png?330|}} {{:swi.png?225|}} |
| + | |||
| + | **Figure 4: ** (Left to right) Image of a DTI scan of the brain; image of a MRS scan of the brain; and image of a SWI scan of the brain | ||
| **Event-related potentials (ERPs) and quantitative EEG:** These noninvasive tests use electroencephalography (EEG), in which a mesh cap covered with electrodes is placed on a person's head. It allows doctors to detect, record and analyze brain waves, which may find brain changes that result from multiple traumatic brain injuries (Baugh et al., 2012). | **Event-related potentials (ERPs) and quantitative EEG:** These noninvasive tests use electroencephalography (EEG), in which a mesh cap covered with electrodes is placed on a person's head. It allows doctors to detect, record and analyze brain waves, which may find brain changes that result from multiple traumatic brain injuries (Baugh et al., 2012). | ||
| + | |||
| + | **Positron emission tomography (PET):** A PET scan uses a low-level radioactive tracer that is injected in a vein. Then, a scanner tracks the tracer's flow through the brain. Researchers are actively working to develop PET markers to detect tau abnormalities associated with neurodegenerative diseases. The goal is to develop a marker to identify the tau pathology of CTE in people who are alive. Researchers are using various substances that bind to tau and other proteins on PET scans. (Reams et al., 2016). | ||
| + | |||
| + | {{ :pet.png?400 |}} | ||
| + | **Figure 5: ** (Left to right) PET scans of a healthy brain, CTE patient and a person with Alzheimer's disease. | ||
| + | |||
| ===== Pathophysiology and Mechanisms ===== | ===== Pathophysiology and Mechanisms ===== | ||
| Currently, the neurological effects of chronic traumatic encephalopathy (CTE) can only be studied post-mortem. The pathophysiology of the disease is unclear as there is a lack of clinical evidence and the symptoms can also be attributed to other factors such as aging, medications, and other diseases (Petraglia et al., 2014). | Currently, the neurological effects of chronic traumatic encephalopathy (CTE) can only be studied post-mortem. The pathophysiology of the disease is unclear as there is a lack of clinical evidence and the symptoms can also be attributed to other factors such as aging, medications, and other diseases (Petraglia et al., 2014). | ||
| - | To be diagnosed with CTE as opposed to other neurological diseases such as Alzheimer’s disease, the following four criteria need to be present in the brain tissue: the presence of perivascular foci of phospho-tau (p-tau) immunoreactive astrocytic tangles and neurofibrillary tangles, presence of irregular cortical distribution of p-tau immunoreactive neurofibrillary tangles and astrocytic tangles (with a predilection for the depth of cerebral sulci), groups of subpial and periventricular astrocytic tangles in the cerebral cortex, diencephalon, basal ganglia and brainstem, and finally the presence of neurofibrillary tangles in the cerebral cortex located preferentially in the superficial layers (McKee et al., 2013). Other pathological findings from individuals diagnosed with CTE are general atrophy (with greatest concentration in the frontal and temporal lobes, somewhat in parietal lobe, and nearly none in occipital lobe), scarring of cerebellar tonsils, a fenestrated cavum septum pellucidum, and enlargement of the ventral and third ventricles (Yi, Padalino, Chin, Montenegro, and Cantu, 2013). | + | To be diagnosed with CTE as opposed to other neurological diseases such as Alzheimer’s disease, the following four criteria need to be present in the brain tissue: the presence of phospho-tau (p-tau) around the brain's blood vessels, irregular cortical distribution of p-tau immunoreactive neurofibrillary tangles and astrocytic tangles (with a preference for the cerebral sulci), groups of subpial and periventricular astrocytic tangles in the cerebral cortex, diencephalon, basal ganglia and brain stem, and finally the presence of neurofibrillary tangles located preferentially in the superficial layers of the cerebral cortex (McKee et al., 2013). Other pathological findings from individuals diagnosed with CTE are general atrophy (with greatest concentration in the frontal and temporal lobes, somewhat in parietal lobe, and nearly none in occipital lobe), scarring of cerebellar tonsils, a fenestrated cavum septum pellucidum, and enlargement of the ventral and third ventricles (Yi, Padalino, Chin, Montenegro, and Cantu, 2013). |
| + | |||
| + | {{:cte_1.jpg?300|}} {{:cte_2.jpg?300|}} | ||
| + | |||
| + | |||
| + | **Figure 5: ** (Left to right) Degeneration of brain tissue associated with each stage of CTE (McKee et al., 2013) | ||
| In one study, researchers evaluated the development of CTE by exposing unanesthetized mice to closed head impacts. There were three groups in this study: control, single-hit, and repetitive. The study found increased p-tau immunoreactivity in the single-hit mice group and the repetitive-hit group after one month. Both groups also had elevated inflammatory cytokine levels, mediated by microglial and astroglial cells. However, after six months, the single-hit group recovered substantially while the repetitive-hit group’s p-tau immunoreactivity increased significantly. The repetitive-hit group also had substantial and widespread microglial and astroglial activation, indicating a major neuroinflammatory response (Petraglia et al., 2014). | In one study, researchers evaluated the development of CTE by exposing unanesthetized mice to closed head impacts. There were three groups in this study: control, single-hit, and repetitive. The study found increased p-tau immunoreactivity in the single-hit mice group and the repetitive-hit group after one month. Both groups also had elevated inflammatory cytokine levels, mediated by microglial and astroglial cells. However, after six months, the single-hit group recovered substantially while the repetitive-hit group’s p-tau immunoreactivity increased significantly. The repetitive-hit group also had substantial and widespread microglial and astroglial activation, indicating a major neuroinflammatory response (Petraglia et al., 2014). | ||
| + | |||
| + | |||
| + | {{ :cte_3.jpg?300 |}} | ||
| + | **Figure 6: ** Comparison of brains taken from a control mouse and a repetitive-hit mouse (Petraglia et al., 2014) | ||
| + | |||
| In another study, immunoexcitotoxicity was explored as a potential mechanism for CTE. Excitotoxicity refers to the apoptotic reaction that occurs when neurons are exposed to excessive amounts of glutamate. When any brain injury occurs, glutamate is released by the microglia and astrocytes, to facilitate the entry of proinflammatory cytokines for our immune response. These cytokines increase neuronal sensitivity to glutamate, which can result in damages due to the increased sensitivity. These damages include mitochondrial suppression, synaptic injury, damage to microtubules, dendritic retraction, and the accumulation of hyperphosphorylated tau (Blaylock and Maroon, 2011). | In another study, immunoexcitotoxicity was explored as a potential mechanism for CTE. Excitotoxicity refers to the apoptotic reaction that occurs when neurons are exposed to excessive amounts of glutamate. When any brain injury occurs, glutamate is released by the microglia and astrocytes, to facilitate the entry of proinflammatory cytokines for our immune response. These cytokines increase neuronal sensitivity to glutamate, which can result in damages due to the increased sensitivity. These damages include mitochondrial suppression, synaptic injury, damage to microtubules, dendritic retraction, and the accumulation of hyperphosphorylated tau (Blaylock and Maroon, 2011). | ||
| + | |||
| + | |||
| + | {{ :cte_4.jpg?300 |}} | ||
| + | **Figure 7: ** Illustration of the neurotoxic effects of proinflammatory cytokines and chemokines acting together with amino acids (mainly glutamate) (Blaylock and Maroon, 2011) | ||
| + | |||
| ===== Treatment ===== | ===== Treatment ===== | ||
| Line 77: | Line 97: | ||
| Another crucial aspect of prevention is the improvement of protective gear worn by athletes (Saulle & Greenwald, 2012). It has been shown that properly fitting and padded helmets as well as mouthguards function well in protecting players from severe head injury (Saulle & Greenwald, 2012). A study conducted by Viano and Halstead has shown that newer American football helmets are heavier, more padded, and larger than older helmets, and were better at absorbing impacts (Saulle & Greenwald, 2012). | Another crucial aspect of prevention is the improvement of protective gear worn by athletes (Saulle & Greenwald, 2012). It has been shown that properly fitting and padded helmets as well as mouthguards function well in protecting players from severe head injury (Saulle & Greenwald, 2012). A study conducted by Viano and Halstead has shown that newer American football helmets are heavier, more padded, and larger than older helmets, and were better at absorbing impacts (Saulle & Greenwald, 2012). | ||
| - | Despite being untreatable, the symptoms of CTE can be treated and managed. According to the Alzheimer's Association, treatment of CTE symptoms is similar to treatment of the symptoms of Alzheimers. An example is the treatment of aggression using behavioral methods, or the treatment of depression using medication and therapy. Furthermore, as with Alzheimer’s and dementia patients, a calming environment helps the patient to maintain focus and function and modified tasks help section tasks into easier steps. | + | Despite being untreatable, the symptoms of CTE can be treated and managed. According to the Alzheimer's Association (n.d.), treatment of CTE symptoms is similar to treatment of the symptoms of Alzheimers. An example is the treatment of aggression using behavioral methods, or the treatment of depression using medication and therapy (Alzheimer's Association n.d.). Furthermore, as with Alzheimer’s and dementia patients, a calming environment helps the patient to maintain focus and function and modified tasks help section tasks into easier steps (Alzheimer's Association n.d.). |
| ===== Research ===== | ===== Research ===== | ||
| - | The first known case of CTE was published in 2005 by forensic pathologist Bennet Omalu along with his team, based on the autopsy conducted on former NFL player Mike Webster. Another paper was published the following year citing the same condition found in the brain of Terry Long, another former NFL player. Currently, there has not been enough research conducted on CTE to determine in development and progress. As of 2018, the majority of research has been focused on building a database from brain donations of professional athletes. However, research will continue to be slow in progression since brains can only be analyzed after death. In 2013, former president Barack Obama announced the creation of federally funded research projects aimed at investigating long term effects of brain injury, including CTE. The projects are being lead by Virginia Commonwealth University along with research groups across the United States. As of recently, the focus has been on conducting longitudinal studies aimed at following participants over time and studying the disease’s progression. | + | The first known case of CTE in football was published in 2005 by forensic pathologist Bennet Omalu along with his team, based on the autopsy conducted on former NFL player Mike Webster (Ommalu et al. 2005). Another paper was published the following year citing the same condition found in the brain of Terry Long, another former NFL player. Currently, there has not been enough research conducted on CTE to determine in development and progress. As of 2018, the majority of research has been focused on building a database from brain donations of professional athletes. However, research will continue to be slow in progression since brains can only be analyzed after death. |
| + | |||
| + | In 2013, former president Barack Obama announced the creation of federally funded research projects aimed at investigating long term effects of brain injury, including CTE (Bryant, 2013). The projects are being lead by Virginia Commonwealth University along with research groups across the United States (Fact Sheet: Largest federal grant in VCU's history, 2013). As of recently, the focus has been on conducting longitudinal studies aimed at following participants over time and studying the disease’s progression. | ||
| ===== Final Remarks ===== | ===== Final Remarks ===== | ||
| Line 86: | Line 110: | ||
| ===== References ===== | ===== References ===== | ||
| - | Baugh, C. M., Stamm, J. M., Riley, D. O., Gavett, B. E., Shenton, M. E., Lin, A., . . . Stern, R. A. (2012). Chronic traumatic encephalopathy: Neurodegeneration following repetitive concussive and subconcussive brain trauma. Brain Imaging and Behavior, 6(2), 244-254. doi:10.1007/s11682-012-9164-5 | + | Alzheimer's Association (n.d.). Chronic Traumatic Encephalopathy (CTE). Retrieved from https://www.alz.org/alzheimers-dementia/what-is-dementia/related_conditions/chronic-traumatic-encephalopathy-(cte) |
| + | |||
| + | Asken B., Sullan M., DeKosky S., Jaffee M., Bauer R. (2017). Research Gaps and Controversies in Chronic Traumatic Encephalopathy: A Review. JAMA Neurology. 74 (10): 1255–1262. doi:10.1001/jamaneurol.2017.2396. PMID 28975240 | ||
| + | |||
| + | Baugh, C. M., Stamm, J. M., Riley, D. O., Gavett, B. E., Shenton, M. E., Lin, A., Stern, R. A. (2012). Chronic traumatic encephalopathy: Neurodegeneration following repetitive concussive and subconcussive brain trauma. Brain Imaging and Behavior, 6(2), 244-254. doi:10.1007/s11682-012-9164-5 | ||
| Blaylock, R. L., & Maroon, J. (2011). Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy—a unifying hypothesis. Surgical neurology international, 2. | Blaylock, R. L., & Maroon, J. (2011). Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy—a unifying hypothesis. Surgical neurology international, 2. | ||
| - | Chronic Traumatic Encephalopathy. (2016, April 20). Retrieved October 26, 2018, from https://www.mayoclinic.org/diseases-conditions/chronic-traumatic-encephalopathy/symptoms-causes/syc-20370921 | + | Bryant, J. (2013). Obama Introduces New PTSD and Education Programs. military.com. |
| + | |||
| + | Chronic Traumatic Encephalopathy. (2016). Retrieved October 26, 2018, from https://www.mayoclinic.org/diseases-conditions/chronic-traumatic-encephalopathy/symptoms-causes/syc-20370921 | ||
| - | Chronic Traumatic Encephalopathy (CTE). (n.d.). Retrieved from https://www.alz.org/alzheimers-dementia/what-is-dementia/related_conditions/chronic-traumatic-encephalopathy-(cte) | + | DeKosky, S., Blennow, K., Ikonomovic, M., & Gandy, S. (2013). Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers. Nature Reviews Neurology, 9(4), 192-200. doi: 10.1038/nrneurol.2013. |
| - | DeKosky, S., Blennow, K., Ikonomovic, M., & Gandy, S. (2013). Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers. Nature Reviews Neurology, 9(4), 192-200. doi: 10.1038/nrneurol.2013.36 | + | Fact Sheet: Largest federal grant in VCU's history. (2013). spectrum.vcu.edu. |
| Gardner, R. C., & Yaffe, K. (2015). Epidemiology of mild traumatic brain injury and neurodegenerative disease. Molecular and Cellular Neuroscience, 66, 75-80. | Gardner, R. C., & Yaffe, K. (2015). Epidemiology of mild traumatic brain injury and neurodegenerative disease. Molecular and Cellular Neuroscience, 66, 75-80. | ||
| Line 105: | Line 135: | ||
| McKee, A. C., Stein, T. D., Nowinski, C. J., Stern, R. A., Daneshvar, D. H., Alvarez, V. E., ... & Riley, D. O. (2013). The spectrum of disease in chronic traumatic encephalopathy. Brain, 136(1), 43-64. | McKee, A. C., Stein, T. D., Nowinski, C. J., Stern, R. A., Daneshvar, D. H., Alvarez, V. E., ... & Riley, D. O. (2013). The spectrum of disease in chronic traumatic encephalopathy. Brain, 136(1), 43-64. | ||
| + | |||
| + | Omalu B., DeKosky S., Minster R., Kamboh I., Hamilton R., Wecht C. (2005). Chronic Traumatic Encephalopathy in a National Football League Player, Neurosurgery, Volume 57, Issue 1, Pages 128–134, https://doi.org/10.1227/01.NEU.0000163407.92769.ED | ||
| Petraglia, A. L., Plog, B. A., Dayawansa, S., Dashnaw, M. L., Czerniecka, K., Walker, C. T., ... & Huang, J. H. (2014). The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy. Surgical neurology international, 5. | Petraglia, A. L., Plog, B. A., Dayawansa, S., Dashnaw, M. L., Czerniecka, K., Walker, C. T., ... & Huang, J. H. (2014). The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy. Surgical neurology international, 5. | ||
| - | |||
| Reams, N., Eckner, J. T., Almeida, A. A., Aagesen, A. L., Giordani, B., Paulson, H., Lorincz, M. T., … Kutcher, J. S. (2016). A Clinical Approach to the Diagnosis of Traumatic Encephalopathy Syndrome: A Review. JAMA neurology,73(6), 743-9. | Reams, N., Eckner, J. T., Almeida, A. A., Aagesen, A. L., Giordani, B., Paulson, H., Lorincz, M. T., … Kutcher, J. S. (2016). A Clinical Approach to the Diagnosis of Traumatic Encephalopathy Syndrome: A Review. JAMA neurology,73(6), 743-9. | ||
| - | |||
| Saulle, M., & Greenwald, B. D. (2012). Chronic traumatic encephalopathy: a review. Rehabilitation research and practice, 2012. | Saulle, M., & Greenwald, B. D. (2012). Chronic traumatic encephalopathy: a review. Rehabilitation research and practice, 2012. | ||
