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1.
Brain ; 143(6): 1826-1842, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32464655

RESUMO

Repetitive mild traumatic brain injury in American football players has garnered increasing public attention following reports of chronic traumatic encephalopathy, a progressive tauopathy. While the mechanisms underlying repetitive mild traumatic brain injury-induced neurodegeneration are unknown and antemortem diagnostic tests are not available, neuropathology studies suggest a pathogenic role for microvascular injury, specifically blood-brain barrier dysfunction. Thus, our main objective was to demonstrate the effectiveness of a modified dynamic contrast-enhanced MRI approach we have developed to detect impairments in brain microvascular function. To this end, we scanned 42 adult male amateur American football players and a control group comprising 27 athletes practicing a non-contact sport and 26 non-athletes. MRI scans were also performed in 51 patients with brain pathologies involving the blood-brain barrier, namely malignant brain tumours, ischaemic stroke and haemorrhagic traumatic contusion. Based on data from prolonged scans, we generated maps that visualized the permeability value for each brain voxel. Our permeability maps revealed an increase in slow blood-to-brain transport in a subset of amateur American football players, but not in sex- and age-matched controls. The increase in permeability was region specific (white matter, midbrain peduncles, red nucleus, temporal cortex) and correlated with changes in white matter, which were confirmed by diffusion tensor imaging. Additionally, increased permeability persisted for months, as seen in players who were scanned both on- and off-season. Examination of patients with brain pathologies revealed that slow tracer accumulation characterizes areas surrounding the core of injury, which frequently shows fast blood-to-brain transport. Next, we verified our method in two rodent models: rats and mice subjected to repeated mild closed-head impact injury, and rats with vascular injury inflicted by photothrombosis. In both models, slow blood-to-brain transport was observed, which correlated with neuropathological changes. Lastly, computational simulations and direct imaging of the transport of Evans blue-albumin complex in brains of rats subjected to recurrent seizures or focal cerebrovascular injury suggest that increased cellular transport underlies the observed slow blood-to-brain transport. Taken together, our findings suggest dynamic contrast-enhanced-MRI can be used to diagnose specific microvascular pathology after traumatic brain injury and other brain pathologies.


Assuntos
Concussão Encefálica/diagnóstico por imagem , Concussão Encefálica/patologia , Imageamento por Ressonância Magnética/métodos , Adolescente , Adulto , Animais , Atletas , Barreira Hematoencefálica/metabolismo , Encéfalo/patologia , Isquemia Encefálica/patologia , Encefalopatia Traumática Crônica/patologia , Imagem de Tensor de Difusão , Futebol Americano/lesões , Humanos , Masculino , Microvasos/diagnóstico por imagem , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/patologia , Tauopatias/patologia , Estados Unidos , Substância Branca/patologia , Proteínas tau/metabolismo
2.
Brain ; 141(2): 422-458, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29360998

RESUMO

The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001.


Assuntos
Traumatismos em Atletas/complicações , Concussão Encefálica/etiologia , Traumatismos Craniocerebrais/complicações , Traumatismos Craniocerebrais/etiologia , Tauopatias/etiologia , Lesões do Sistema Vascular/etiologia , Potenciais de Ação/fisiologia , Adolescente , Animais , Atletas , Encéfalo/patologia , Proteínas de Ligação ao Cálcio , Estudos de Coortes , Simulação por Computador , Traumatismos Craniocerebrais/diagnóstico por imagem , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/fisiologia , Hipocampo/fisiopatologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos , Modelos Neurológicos , Córtex Pré-Frontal/fisiopatologia , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores de Interleucina-8A/genética , Receptores de Interleucina-8A/metabolismo , Adulto Jovem
4.
Sci Rep ; 11(1): 4292, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33619310

RESUMO

Galactic cosmic radiation (GCR) composed of high-energy, heavy particles (HZE) poses potentially serious hazards to long-duration crewed missions in deep space beyond earth's magnetosphere, including planned missions to Mars. Chronic effects of GCR exposure on brain structure and cognitive function are poorly understood, thereby limiting risk reduction and mitigation strategies to protect against sequelae from exposure during and after deep-space travel. Given the selective vulnerability of the hippocampus to neurotoxic insult and the importance of this brain region to learning and memory, we hypothesized that GCR-relevant HZE exposure may induce long-term alterations in adult hippocampal neurogenesis, synaptic plasticity, and hippocampal-dependent learning and memory. To test this hypothesis, we irradiated 3-month-old male and female mice with a single, whole-body dose of 10, 50, or 100 cGy 56Fe ions (600 MeV, 181 keV/µm) at Brookhaven National Laboratory. Our data reveal complex, dynamic, time-dependent effects of HZE exposure on the hippocampus. Two months post exposure, neurogenesis, synaptic plasticity and learning were impaired compared to sham-irradiated, age-matched controls. By six months post-exposure, deficits in spatial learning were absent in irradiated mice, and synaptic potentiation was enhanced. Enhanced performance in spatial learning and facilitation of synaptic plasticity in irradiated mice persisted 12 months post-exposure, concomitant with a dramatic rebound in adult-born neurons. Synaptic plasticity and spatial learning remained enhanced 20 months post-exposure, indicating a life-long influence on plasticity and cognition from a single exposure to HZE in young adulthood. These findings suggest that GCR-exposure can persistently alter brain health and cognitive function during and after long-duration travel in deep space.


Assuntos
Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Radiação Cósmica/efeitos adversos , Astronautas , Biomarcadores , Encéfalo/fisiopatologia , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Giro Denteado/efeitos da radiação , Exposição Ambiental/efeitos adversos , Feminino , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Hipocampo/efeitos da radiação , Humanos , Masculino , Neurogênese/efeitos da radiação , Exposição à Radiação/efeitos adversos , Voo Espacial , Aprendizagem Espacial/efeitos da radiação , Fatores de Tempo
5.
Front Neurol ; 8: 240, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28620350

RESUMO

Animal models of concussion, traumatic brain injury (TBI), and chronic traumatic encephalopathy (CTE) are widely available and routinely deployed in laboratories around the world. Effective animal modeling requires careful consideration of four basic principles. First, animal model use must be guided by clarity of definitions regarding the human disease or condition being modeled. Concussion, TBI, and CTE represent distinct clinical entities that require clear differentiation: concussion is a neurological syndrome, TBI is a neurological event, and CTE is a neurological disease. While these conditions are all associated with head injury, the pathophysiology, clinical course, and medical management of each are distinct. Investigators who use animal models of these conditions must take into account these clinical distinctions to avoid misinterpretation of results and category mistakes. Second, model selection must be grounded by clarity of purpose with respect to experimental questions and frame of reference of the investigation. Distinguishing injury context ("inputs") from injury consequences ("outputs") may be helpful during animal model selection, experimental design and execution, and interpretation of results. Vigilance is required to rout out, or rigorously control for, model artifacts with potential to interfere with primary endpoints. The widespread use of anesthetics in many animal models illustrates the many ways that model artifacts can confound preclinical results. Third, concordance between key features of the animal model and the human disease or condition being modeled is required to confirm model biofidelity. Fourth, experimental results observed in animals must be confirmed in human subjects for model validation. Adherence to these principles serves as a bulwark against flawed interpretation of results, study replication failure, and confusion in the field. Implementing these principles will advance basic science discovery and accelerate clinical translation to benefit people affected by concussion, TBI, and CTE.

6.
J Robot Surg ; 6(2): 131-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27628276

RESUMO

To determine if the difficulty of a robotic hysterectomy for endometrial cancer can be predicted by MRI, CT or other methods. All robotic cases from 1 August 2006 through 30 July 2009 were identified. Data collected prospectively included co-morbidities, body mass index, surgical times, estimated blood loss (EBL), uterine weight, and pre- and postoperative complications. Those patients who received an MRI or CT scan prior to robotic hysterectomy had additional data gathered from imaging, including uterine volume, pelvic measurements and abdominal wall thickness. Cases were labeled difficult for the following reasons: outliers greater than 2 SD from the mean EBL, hysterectomy time and total console time. Additional factors identifying difficult cases included the need to undock to remove the specimen or conversion to laparotomy. Data were analyzed for their possible role in causing difficulty in a robotic hysterectomy. Comparative statistics utilized included chi-square and t-test, ANOVA and logistic regression analysis.From 2 August 2006 through 30 July 2009, 119 patients underwent robotic surgery for endometrial cancer and are included in this study. Of these patients, 25/119 (20.0%) were identified as difficult cases. Difficulty was found in those patients with greater than 2 SD from the mean for hysterectomy time, >90.9 min (n = 3, 2.5%), total console time of >178.1 min (n = 6, 5.0%), EBL >232 cc (n = 7, 5.9%) and undocking to remove the uterine specimen in 8 (6.7%) cases; 1/119 (0.8%) was converted to laparotomy. Lymphadenectomy (P = 0.005) was associated with case difficulty. In a logistic regression analysis CT/MRI measurements of uterine volume greater than 793 cm³ and CT/MRI pelvimetry, as well as abdominal wall thickness were independent predictors of a difficult case (P = 0.0116). MRI and CT scans can detect the probability that a robotic surgery will be difficult by determining uterine volume and pelvimetry; however, these were not the strongest predictors in our study. A narrow pelvic outlet as measured on CT/MRI and uterine volume of greater than 793 cc should raise a flag of caution when planning robotic hysterectomy for endometrial cancer.

7.
Sci Transl Med ; 4(134): 134ra60, 2012 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-22593173

RESUMO

Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein-linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.


Assuntos
Traumatismos por Explosões/complicações , Traumatismos por Explosões/patologia , Lesão Encefálica Crônica/complicações , Lesão Encefálica Crônica/patologia , Militares/psicologia , Veteranos/psicologia , Aceleração , Adolescente , Adulto , Animais , Atletas , Axônios/patologia , Comportamento Animal , Traumatismos por Explosões/fisiopatologia , Concussão Encefálica/complicações , Concussão Encefálica/patologia , Concussão Encefálica/fisiopatologia , Lesão Encefálica Crônica/fisiopatologia , Modelos Animais de Doenças , Cabeça/patologia , Cabeça/fisiopatologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Hipocampo/ultraestrutura , Humanos , Pressão Intracraniana , Potenciação de Longa Duração , Masculino , Camundongos , Pessoa de Meia-Idade , Fosforilação , Mudanças Depois da Morte , Transmissão Sináptica , Adulto Jovem , Proteínas tau/metabolismo
8.
Genes Chromosomes Cancer ; 43(4): 383-9, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15884100

RESUMO

From 5% to 10% of 9;22 translocations in chronic myeloid leukemia (CML) are reported to occur in variant form, that is, with the involvement of other regions of the genome in 3-way or more rearrangements. The literature indicates that the alternative breakpoints are not distributed randomly in the genome but show hotspots. We present data on 289 unpublished cases of CML with variant 9;22 translocations having a total of 342 variant breakpoints, the largest independent series to date. We found that the distribution of breaks was in loose agreement with the literature but that some new hotspots were identified; furthermore, some published hotspots were not fully supported by our data. Moreover, when our 342 variant breakpoints were plotted against profiles of CG heterogeneity in the genome, a significant positive correlation between breakpoint locations and CG composition was observed. In an ancillary study, we compared the frequency of variant t(9;22) with that of variants of t(15;17) associated with acute promyelocytic leukemia (AML M3). We found that the frequency of the former, 9.3%, was significantly higher than that of the latter, 2.6%.


Assuntos
Composição de Bases , Cromossomos Humanos Par 22 , Cromossomos Humanos Par 9 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Translocação Genética , Quebra Cromossômica , Bases de Dados Factuais , Genoma Humano , Humanos , Leucemia Mieloide Aguda/genética
9.
Hum Genet ; 111(3): 290-6, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12215843

RESUMO

Paternal duplications of distal 11p result in Beckwith Wiedemann syndrome (BWS), whereas maternal duplications have not, to our knowledge, been reported previously in the literature. We present three unrelated patients with maternal duplications of distal 11p. Patient 1 is a 31-year-old female with a de novo inverted duplication of distal 11p, i.e. inv dup del(11)(qter-->p15.5::p15.5-->15.3); this rearrangement was shown to be maternal in origin by microsatellite analysis and methylation-specific polymerase chain reaction. Patient 2 is a 4-year-old female with a derived chromosome 20, which arose from adjacent 1 malsegregation of a maternal t(11;20)(p15.3;q13.33). Patient 3 presented as an intrauterine death with trisomy for the majority of chromosome 11p as a result of 3:1 segregation of a maternal t(11;15)(p11.2;q11.2). In view of the imprinted status of this region, it is pertinent that none of our patients showed features of BWS; indeed, all had growth retardation, in contrast to the overgrowth characteristic of BWS. It is of note that, of the living patients, Patient 1 went into early puberty at 9.5 years and Patient 2 showed breast development in infancy. Both patients shared some dysmorphological features, namely short palpebral fissures, a prominent nasal tip, a short philtrum and 5th finger clinodactyly.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Transtornos do Crescimento/genética , Anormalidades Múltiplas/genética , Adulto , Síndrome de Beckwith-Wiedemann/genética , Pré-Escolar , Metilação de DNA , Feminino , Morte Fetal/genética , Impressão Genômica , Humanos , Cariotipagem , Masculino , Fenótipo , Gravidez , Puberdade Precoce/genética
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