RESUMO
Chronic neurodegeneration following a history of neurotrauma is frequently associated with neuropsychiatric and cognitive symptoms. In order to enhance understanding about the underlying pathophysiology linking neurotrauma to neurodegeneration, a multi-model preclinical approach must be established to account for the different injury paradigms and pathophysiologic mechanisms. We investigated the development of tau pathology and behavioral changes using a multi-model and multi-institutional approach, comparing the preclinical results to tauopathy patterns seen in post-mortem human samples from athletes diagnosed with chronic traumatic encephalopathy (CTE). We utilized a scaled and validated blast-induced traumatic brain injury model in rats and a modified pneumatic closed-head impact model in mice. Tau hyperphosphorylation was evaluated by western blot and immunohistochemistry. Elevated-plus maze and Morris water maze were employed to measure impulsive-like behavior and cognitive deficits respectively. Animals exposed to single blast (~50 PSI reflected peak overpressure) exhibited elevated AT8 immunoreactivity in the contralateral hippocampus at 1 month compared to controls (q = 3.96, p < 0.05). Animals exposed to repeat blast (six blasts over 2 weeks) had increased AT8 (q = 8.12, p < 0.001) and AT270 (q = 4.03, p < 0.05) in the contralateral hippocampus at 1 month post-injury compared to controls. In the modified controlled closed-head impact mouse model, no significant difference in AT8 was seen at 7 days, however a significant elevation was detected at 1 month following injury in the ipsilateral hippocampus compared to control (q = 4.34, p < 0.05). Elevated-plus maze data revealed that rats exposed to single blast (q = 3.53, p < 0.05) and repeat blast (q = 4.21, p < 0.05) spent more time in seconds exploring the open arms compared to controls. Morris water maze testing revealed a significant difference between groups in acquisition times on days 22-27. During the probe trial, single blast (t = 6.44, p < 0.05) and repeat blast (t = 8.00, p < 0.05) rats spent less time in seconds exploring where the platform had been located compared to controls. This study provides a multi-model example of replicating tau and behavioral changes in animals and provides a foundation for future investigation of CTE disease pathophysiology and therapeutic development.
RESUMO
Despite the extensive media coverage associated with the diagnosis of chronic traumatic encephalopathy (CTE), our fundamental understanding of the disease pathophysiology remains in its infancy. Only recently have scientific laboratories and personnel begun to explore CTE pathophysiology through the use of preclinical models of neurotrauma. Some studies have shown the ability to recapitulate some aspects of CTE in rodent models, through the use of various neuropathological, biochemical, and/or behavioral assays. Many questions related to CTE development, however, remain unanswered. These include the role of impact severity, the time interval between impacts, the age at which impacts occur, and the total number of impacts sustained. Other important variables such as the location of impacts, character of impacts, and effect of environment/lifestyle and genetics also warrant further study. In this work, we attempt to address some of these questions by exploring work previously completed using single- and repetitive-injury paradigms. Despite some models producing some deficits similar to CTE symptoms, it is clear that further studies are required to understand the development of neuropathological and neurobehavioral features consistent with CTE-like features in rodents. Specifically, acute and chronic studies are needed that characterize the development of tau-based pathology.
RESUMO
The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulation of glymphatic activity, including sleep deprivation and cisternotomy, suppressed or eliminated TBI-induced increases in serum S100ß, GFAP, and neuron specific enolase. We conclude that routine TBI patient management may limit the clinical utility of blood-based biomarkers because their brain-to-blood transport depends on glymphatic activity.
Assuntos
Lesões Encefálicas/metabolismo , Líquido Extracelular/metabolismo , Taxa de Depuração Metabólica , Animais , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Barreira Hematoencefálica/metabolismo , Lesões Encefálicas/sangue , Lesões Encefálicas/líquido cefalorraquidiano , Feminino , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/metabolismo , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/líquido cefalorraquidiano , Privação do Sono/sangue , Privação do Sono/líquido cefalorraquidiano , Privação do Sono/metabolismoRESUMO
Mild traumatic brain injury (TBI) has become a rising epidemic, affecting millions of people each year. Even though it is the most common type of brain injury, our understanding of the science underlying mild TBI is just in its infancy. There has been an explosion of basic science research interest in mild TBI, as emerging clinical evidence is suggestive that concussion and subconcussion may result in detrimental long-term neurological sequelae, particularly when occurring repetitively. Many animal models have been developed to study the different pathological mechanisms implicated in TBI, and more recently there has been a heightened focus on modeling mild TBI in the laboratory as well. The most widely used models of TBI have been adapted for experimental mild TBI research, although more work still remains. The ability to create improved diagnostic measures and treatment approaches for concussion depend on the development and characterization of clinically relevant models of mild TBI. This review aims to provide a broad general overview of the current efforts to model mild TBI in animals and the challenges and limitations that exist in translating this behavioral, physiological, and anatomic knowledge from the bench to the clinical arena.
Assuntos
Lesões Encefálicas , Modelos Animais de Doenças , Animais , HumanosRESUMO
The majority of traumatic brain injuries (TBI) in the USA are mild in severity. Sports, particularly American football, and military experience are especially associated with repetitive, mild TBI (mTBI). The consequences of repetitive brain injury have garnered increasing scientific and public attention following reports of altered mood and behavior, as well as progressive neurological dysfunction many years after injury. This report provides an up-to-date review of the clinical, pathological, and pathophysiological changes associated with repetitive mTBI, and their potential for cumulative effects in certain individuals.
Assuntos
Traumatismos em Atletas , Concussão Encefálica/patologia , Lesões Encefálicas/patologia , Encéfalo/patologia , Animais , Concussão Encefálica/diagnóstico , Concussão Encefálica/fisiopatologia , Lesões Encefálicas/diagnóstico , Lesões Encefálicas/etiologia , Humanos , Sono/fisiologia , EsportesRESUMO
There has been an increased focus on the neurological sequelae of repetitive mild traumatic brain injury (TBI), particularly neurodegenerative syndromes, such as chronic traumatic encephalopathy (CTE); however, no animal model exists that captures the behavioral spectrum of this phenomenon. We sought to develop an animal model of CTE. Our novel model is a modification and fusion of two of the most popular models of TBI and allows for controlled closed-head impacts to unanesthetized mice. Two-hundred and eighty 12-week-old mice were divided into control, single mild TBI (mTBI), and repetitive mTBI groups. Repetitive mTBI mice received six concussive impacts daily for 7 days. Behavior was assessed at various time points. Neurological Severity Score (NSS) was computed and vestibulomotor function tested with the wire grip test (WGT). Cognitive function was assessed with the Morris water maze (MWM), anxiety/risk-taking behavior with the elevated plus maze, and depression-like behavior with the forced swim/tail suspension tests. Sleep electroencephalogram/electromyography studies were performed at 1 month. NSS was elevated, compared to controls, in both TBI groups and improved over time. Repetitive mTBI mice demonstrated transient vestibulomotor deficits on WGT. Repetitive mTBI mice also demonstrated deficits in MWM testing. Both mTBI groups demonstrated increased anxiety at 2 weeks, but repetitive mTBI mice developed increased risk-taking behaviors at 1 month that persist at 6 months. Repetitive mTBI mice exhibit depression-like behavior at 1 month. Both groups demonstrate sleep disturbances. We describe the neurological sequelae of repetitive mTBI in a novel mouse model, which resemble several of the neuropsychiatric behaviors observed clinically in patients sustaining repetitive mild head injury.
Assuntos
Ansiedade/psicologia , Lesão Encefálica Crônica/psicologia , Depressão/psicologia , Modelos Animais de Doenças , Transtornos da Memória/psicologia , Transtornos do Sono-Vigília/psicologia , Animais , Ansiedade/etiologia , Ansiedade/patologia , Lesões Encefálicas/complicações , Lesões Encefálicas/patologia , Lesões Encefálicas/psicologia , Lesão Encefálica Crônica/complicações , Lesão Encefálica Crônica/patologia , Depressão/etiologia , Depressão/patologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/patologiaRESUMO
BACKGROUND: Subarachnoid hemorrhage (SAH) is a neurologic catastrophe and poor outcome is typically attributed to vasospasm; however, there is also evidence that SAH causes a pro-inflammatory state and these two phenomena may be interrelated. SAH causes activation of microglia, but the time course and degree of microglial activation after SAH and its link to poor patient outcome and vasospasm remains unknown. NEW METHOD: Transgenic mice expressing eGFP under the control of the CX3CR1 locus, in which microglia are endogenously fluorescent, were randomly assigned to control or SAH groups. Immunohistochemistry for CD-68 and CD-31 was performed at different time points after SAH. Using confocal microscopy and MatLab software, we have developed a novel technique to detect and quantify the stages of microglial activation and return to quiescence using an automated computerized morphometric analysis. RESULTS: We detected a statistically significant decrease in microglial process complexity 2 and 7 days following SAH. In addition, we detected a statistically significant increase in microglial domain volume 1 day following SAH; however, microglial domain volume returned to baseline by 2 days. COMPARISON WITH EXISTING METHOD: Most techniques for microglia assessment are qualitative, not quantitative, and are therefore inadequate to address the effects of anti-inflammatory drug treatment or other therapies after SAH. CONCLUSIONS: Using novel image analysis techniques we were able to reproducibly quantify activation of microglia following SAH, which will improve our ability to study the biology of microglial activation, and may ultimately improve management of disease progression and response to therapies directed at microglial activation.
Assuntos
Processamento de Imagem Assistida por Computador/métodos , Imuno-Histoquímica/métodos , Microglia/patologia , Microglia/fisiologia , Hemorragia Subaracnóidea/imunologia , Hemorragia Subaracnóidea/patologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/imunologia , Encéfalo/patologia , Receptor 1 de Quimiocina CX3C , Capilares/imunologia , Capilares/patologia , Contagem de Células , Tamanho Celular , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal/métodos , Regiões Promotoras Genéticas , Distribuição Aleatória , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
BACKGROUND: An animal model of chronic traumatic encephalopathy (CTE) is essential for further understanding the pathophysiological link between repetitive head injury and the development of chronic neurodegenerative disease. We previously described a model of repetitive mild traumatic brain injury (mTBI) in mice that encapsulates the neurobehavioral spectrum characteristic of patients with CTE. We aimed to study the pathophysiological mechanisms underlying this animal model. METHODS: Our previously described model allows for controlled, closed head impacts to unanesthetized mice. Briefly, 12-week-old mice were divided into three groups: Control, single, and repetitive mTBI. Repetitive mTBI mice received six concussive impacts daily, for 7 days. Mice were then subsequently sacrificed for macro- and micro-histopathologic analysis at 7 days, 1 month, and 6 months after the last TBI received. Brain sections were immunostained for glial fibrillary acidic protein (GFAP) for astrocytes, CD68 for activated microglia, and AT8 for phosphorylated tau protein. RESULTS: Brains from single and repetitive mTBI mice lacked macroscopic tissue damage at all time-points. Single mTBI resulted in an acute rea ctive astrocytosis at 7 days and increased phospho-tau immunoreactivity that was present acutely and at 1 month, but was not persistent at 6 months. Repetitive mTBI resulted in a more marked neuroinflammatory response, with persistent and widespread astrogliosis and microglial activation, as well as significantly elevated phospho-tau immunoreactivity to 6-months. CONCLUSIONS: The neuropathological findings in this new model of repetitive mTBI resemble some of the histopathological hallmarks of CTE, including increased astrogliosis, microglial activation, and hyperphosphorylated tau protein accumulation.
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We describe a 44-year-old man with infertility, acromegaly, and hypergonadotropic hypogonadism. Clinical examination of the patient revealed hyperpigmented macules on the lips, buccal mucosa, and face which were histologically confirmed as cutaneous myxomas and blue nevi. Ultrasound revealed testicular calcifications and multiple hypoechoic thyroid nodules. MR imaging showed a pituitary microadenoma and resection revealed it to be a growth hormone and prolactin-secreting adenoma with the unusual finding of admixed individual mucin-producing cells. We discuss mucin cells in pituitary adenoma, an unreported pathologic finding in a patient with Carney complex.
Assuntos
Adenoma/diagnóstico , Complexo de Carney/diagnóstico , Mucinas/metabolismo , Neoplasias Hipofisárias/diagnóstico , Anormalidades Múltiplas , Adenoma/metabolismo , Adulto , Biomarcadores Tumorais/metabolismo , Complexo de Carney/metabolismo , Diagnóstico Diferencial , Hormônio do Crescimento/metabolismo , Humanos , Masculino , Neoplasias Hipofisárias/metabolismo , Prolactina/metabolismoRESUMO
There has been a growing interest in the diagnosis and management of mild traumatic brain injury (TBI), or concussion. Repetitive concussion and subconcussion have been linked to a spectrum of neurological sequelae, including postconcussion syndrome, chronic traumatic encephalopathy, mild cognitive impairment, and dementia pugilistica. A more common risk than chronic traumatic encephalopathy is the season-ending or career-ending effects of concussion or its mismanagement. To effectively prevent and treat the sequelae of concussion, it will be important to understand the basic processes involved. Reviewed in this paper are the forces behind the primary phase of injury in mild TBI, as well as the immediate and delayed cellular events responsible for the secondary phase of injury leading to neuronal dysfunction and possible cell death. Advanced neuroimaging sequences have recently been developed that have the potential to increase the sensitivity of standard MRI to detect both structural and functional abnormalities associated with concussion, and have provided further insight into the potential underlying pathophysiology. Also discussed are the potential long-term effects of repetitive mild TBI, particularly chronic traumatic encephalopathy. Much of the data regarding this syndrome is limited to postmortem analyses, and at present there is no animal model of chronic traumatic encephalopathy described in the literature. As this arena of TBI research continues to evolve, it will be imperative to appropriately model concussive and even subconcussive injuries in an attempt to understand, prevent, and treat the associated chronic neurodegenerative sequelae.