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Traumatic Brain Injury Research Program

Roskamp Institute Traumatic Brain Injury ResearchEach year 1.4 million people in the United States sustain a traumatic brain injury (TBI), contributing to 30% of injury-related fatalities in the US. TBI consists of both an initial primary injury to the brain caused by the mechanical and sheering forces of impact and a delayed secondary injury driven by downstream events in the hours and days thereafter. The delayed nature of secondary brain injury means that there may be a window of opportunity for therapeutic intervention to prevent neurodegeneration, but at the moment there are no approved drugs available for reducing secondary injury after TBI.

The majority of traumatic brain injuries that occur are mild in nature, but recent studies by our research team and others have shown an association of increased and progressive long-term damage associated with repetitive mild injuries. At the Roskamp Institute we are developing, characterizing and applying models of repetitive mild TBI in order to target molecular pathways involved in the secondary injury processes and find potential treatments to ameliorate the detrimental long term consequences of injury. Recently we have begun applying our model of repetitive mild traumatic brain injury to examine progressive intraneuronal Tau alterations which correlate with behavioral dysfunctions after TBI. Understanding the molecular consequences of injury may lead to novel therapeutic approaches. We have also evaluated potential therapeutic compounds targeting neuroinflammation after TBI, including the dietary supplement anatabine. Anatabine shows great promise at rescuing memory in animals, even when taken at long term time points after the initial insult.



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TBI Research Team

Fiona Crawford, Ph.D. -
Director, TBI Research Program

Corbin Bachmeier, Ph.D.

Scott Ferguson, Ph.D.

Benoit Mouzon, Ph.D.

Joseph Ojo, Ph.D.

Rad Tzekov, M.D., Ph.D.

Moustafa Algamal, M.S., Ph.D.

Robby Pelot, Ph.D. student

Cillian Lynch, M.S., Ph.D. student

TBI Research Projects

The Institute is researching the neurobiological and translational science behind the chronic effects of mild traumatic brain injury (mTBI) and its impact on neurodegenerative disease and other comorbidities. Along with our collaboration with the James Haley Veterans Hospital, we have been involved in the development of a single and repetitive novel animal model of closed head injury, which recapitulates the pathological hallmarks of mTBI in humans. We have been studying the long-term consequences of such repeated hits of the brain by recording and analyzing changes in behavior, cognition, and motor response that occur post injury. Our model includes analyses at 6 month, 12 month, and 24 month time points post injury, making our model one of the few to study the effect of mTBI at such extensive time points post-injury.

Based on some of the human post-mortem samples available of individuals that have suffered repetitive concussions, there has been discussion of the role of Tau protein in TBI. We have been studying tau in our rodent model as well in order to see what role it has if any on the pathogenesis of CTE (chronic traumatic encephalopathy).
Epidemiological studies indicate that repetitive traumatic brain injury (TBI) is associated with increased risk of neurodegenerative diseases. Given the proposed pathophysiological role for chronic neuroinflammation in neurodegenerative disease, our data showing progressive neuroinflammation in our repetitive mild TBI model support this as a valid therapeutic target in TBI.  However, as there appear to be beneficial and detrimental roles for neuroinflammation in the aftermath of TBI, defining the role of different microglial/macrophage activation phenotypes in in the acute and chronic periods of recovery post TBI will help to refine treatment strategies.

The Roskamp Institute is investigating the role of Tau pathobiology in repetitive mTBI using hTau mice.  Also, we are investigating the pathogenic inter-relationship between mTBI and Alzheimer's disease (AD). This project briefly involves characterization and comparison of the temporal brain and plasma molecular profiles of mouse models of AD (PSAPP and hTau mice), and mTBI (C57/BL6, hTau), using lipidomics and proteomics techniques.

Our goal is to characterize the physiological, morphological and biochemical consequences of mild repeated TBI for the visual system under controlled conditions in models of the disease and to develop treatments focused on shortening the recovery period from TBI or, in more severe cases - slowing down or even prevention of the associated visual deficits. Traumatic brain injury (TBI) occurs when a sudden external mechanical force traumatically injures the brain. TBI can be classified by severity as mild, moderate and severe, and the severity is correlated with the duration of the symptoms and the prognosis for recovery. It has been shown that even a mild TBI can be risk factor for neurodegeneration (Gavett et al. 2010) and that neurodegenrative processes can be triggered many years after even a single TBI (Johnson et al. 2012).

Vision impairment as a result from TBl has been recognized since ancient times. The Hippocratic Corpus, collection of medical works from ancient Greece, mentions concussion, later translated to commotio cerebri, and discusses loss of speech, hearing and sight that can result from "commotion of the brain" (Masferrer et al. 2000). In modern times, visual complaints are considered an important part of TBI symptomatology; self-reported visual complaint can be found in up to 75% of the patients (Cockerham et al. 2009). Light sensitivity, blurred vision, difficulty fixating and difficulty reading are only few of the symptoms reported, which can last from few weeks to many years, and, in some cases, can lead to permanent visual impairment.

 

VisionReserachProgram TBI1


Repeated occurrence of TBI, even if only as mild, can result in cumulative sensory and cognitive deficits. Visual symptoms can be the same as after single TBI, but they could last longer and could interfere more with daily activities.
In some cases, patients may not be even aware that they have visual function deficits (especially peripheral visual field defects) and, thus, the true extent of visual impairment after repeated mild TBI may be underestimated.

 

VisionReserachProgram TBI2


Research has shown that the optic nerve can be affected after TBI even without a direct injury to the eye or the orbit. Clinically, this is referred to as indirect traumatic optic neuropathy (ITON) and it can occur in up to 5% of the patients after TBI, although good epidemiological studies are lacking and it is likely that some effect on the optic nerve structure and function, especially when subclinical, are more prevalent.

Our goal is to characterize the physiological, morphological and biochemical consequences of mild repeated TBI for the visual system under controlled conditions in models of the disease and to develop treatments focused on shortening the recovery period from TBI or, in more severe cases - slowing down or even prevention of the associated visual deficits.


Dr. Rad Tzekov joined the Roskamp Institute in 2011 with extensive pre-clinical and clinical experience in academic and pharmaceutical industry settings. His main area of expertise is developing, characterizing and using models of retinal and optic nerve diseases to improve the available diagnostic and therapeutic options. He also conducts advanced clinical visual function testing at the USF Eye Institute in Tampa, FL.  More information about our Vision Research Program and refrences can be found here.


Insufficient cerebral blood flow after traumatic brain injury is a critical factor in recovery.  We are investigating the cerebral vascular condition and normal functioning post mTBI as we strive to develop therapies for treatment.  Research initiatives at The Roskamp Institute have shown evidence in our preclinical model that a single mTBI is able to initiate a clinical syndrome and pathology that then remains latent in the period following injury, while repetitive injuries can produce behavioral and pathological changes that continue to evolve many months after the period of initial injuries. These findings recapitulate important aspects of human long term TBI sequelae, in particular persistent neuroinflammation, white matter injury, and axonal pathology in the corpus callosum. 
Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) have been described as the major signature injuries of the recent conflicts in Iraq and Afghanistan. The clinical heterogeneity and large degree of overlap between mTBI and PTSD, including the diagnosis of both conditions either individually or co-morbidly, remains extremely challenging. Hitherto, most pre-clinical studies investigating response to psychological trauma and biomechanical head injury have remained largely separate focusing on both arms of the disorders in isolation, with only a few studies attempting to address the unique and overlapping features in a comorbid animal model. RI is focusing on the development and implementation of a relevant translational pre-clinical model that extrapolates the uni-dimensional or multi-dimensional hallmarks of both disorders. We have combined our previously developed model of concussive head injury, which has been extensively characterized from 24 hours to 24 months post-injury, with a newly developed model of combat-related PTSD in mice. PTSD paradigm involves unpredictable predator odor exposure (to trimethylthiazoline - TMT, a component of fox urine) under restraint, and a conditioned stimulus. We are currently characterizing the behavioral, histopathological and biochemical profiles of this model at acute and chronic timepoints. Our goal involves; (i) assessing some of the vital interactions between both psychological and biomechanical trauma, (ii) identification of novel biomarkers using proteomic and lipidomic techniques, and (iii) exploiting different therapeutic strategies to ameliorate the neurological consequences of both disorders.
Roskamp Institute has a well-established biomarker research program, which is particularly focused on translating animal modeling work to clinical application.  We have identified in our research several inflammatory markers at the protein level that, after an animal model TBI, express significantly diminished response post injury.   Studying human plasma using Omics technology profiling lipids, proteins and genetic risk factors, our scientists have shown promise for identification of diagnostic biomarkers for mTBI and other conditions.  Given the heterogeneity of TBI and the complexity of TBI pathogenesis it is anticipated that a valid biomarker panel of broad application will require assessment of many markers, best identified through the omic approaches we are pursuing leading to development of therapeutic targets for TBI treatment.

Publications:

Lipidomic analyses identify injury-specific phospholipid changes 3 mo after traumatic brain injury. Abdullah L, Evans JE, Ferguson S, Mouzon B, Montague H, Reed J, Crynen G, Emmerich T, Crocker M, Pelot R, Mullan M, Crawford F. FASEB J. 2014 Sep 10. pii: fj.14-258228.

Neurobehavioral, neuropathological and biochemical profiles in a novel mouse model of co-morbid post-traumatic stress disorder and mild traumatic brain injury.  Ojo JO, Greenberg MB, Leary P, Mouzon B, Bachmeier C, Mullan M, Diamond DM, Crawford F.  Front Behav Neurosci. 2014 Jun 23;8:213. doi:10.3389/fnbeh.2014.00213. eCollection 2014.

Chronic neuropathological and neurobehavioral changes in a repetitive mild traumatic brain injury model.  Mouzon BC, Bachmeier C, Ferro A, Ojo JO, Crynen G, Acker CM, Davies P, Mullan M, Stewart W, Crawford F.  Ann Neurol. 2014 Feb;75(2):241-54. doi: 10.1002/ana.24064. Epub 2014 Feb 20.

Repetitive mild traumatic brain injury augments tau pathology and glial activation in aged hTau mice.  Ojo JO, Mouzon B, Greenberg MB, Bachmeier C, Mullan M, Crawford F. J Neuropathol Exp Neurol. 2013 Feb;72(2):137-51. doi: 10.1097/NEN.0b013e3182814cdf.

Repetitive Mild Traumatic Brain Injury in a Mouse Model Produces Learning and Memory Deficits Accompanied by Histological Changes.  Mouzon B, Chaytow H, Crynen G, Bachmeier C, Stewart J, Mullan M, Stewart W, Crawford F.  J Annual Meeting National Neurotrauma Society. 2012 Dec 10;29(18):2761-73. doi: 10.1089/neu.2012.2498. Epub 2012 Nov 23. 

Identification of plasma biomarkers of TBI outcome using proteomic approaches in an APOE mouse model.  Crawford F, Crynen G, Reed J, Mouzon B, Bishop A, Katz B, Ferguson S, Phillips J, Ganapathi V, Mathura V, Roses A, Mullan M (2012)  J Annual Meeting National Neurotrauma Society. 29:246-260.

Apolipoprotein E genotype and oxidative stress response to traumatic brain injury.  Ferguson S, Mouzon B, Kayihan G, Wood M, Poon F, Doore S, Mathura V, Humphrey J, O'Steen B, Hayes R, Roses A, Mullan M, Crawford F (2010)  Annual Meeting Society for Neuroscience. 168:811-819.

Apolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury.   Crawford F, Wood M, Ferguson S, Mathura V, Gupta P, Humphrey J, Mouzon B, Laporte V, Margenthaler E, O'Steen B, Hayes R, Roses A, Mullan M (2009) Annual Meeting Society for Neuroscience. 159:1349-1362.

Genomic analysis of response to traumatic brain injury in a mouse model of Alzheimer's disease (APPsw).  Crawford FC, Wood M, Ferguson S, Mathura VS, Faza B, Wilson S, Fan T, O'Steen B, Ait-Ghezala G, Hayes R, Mullan MJ (2007)  Brain Res. 1185:45-58.

RI Media and Presentations:

Open House for Veterans and Military in honor of Veterans Day  Open House for Veterans and Military in honor of Veterans Day
 Friday, November 7, 2014 10AM
 


 

Spatial Memory Normalization after Treatment with Anatabine Beginning Nine Months after Repetitive Mild TBI. Ferguson S, Mouzon B, Abdullah L, Crynen G, Paris D, Mullan M, Crawford F. Annual Meeting National Neurotrauma Society Symposium 2014.

 

Exploring the pathogenic inter-relationship between TBI and AD in mouse models using proteomic and lipidomic technology. Ojo JO, Reed JM , Evans J, Crynen G, Abdullah L, Mullan M, Crawford F.  Annual Meeting Society for Neuroscience 2014.
 

 

Treatment with anatabine significantly improves chronic outcome in a mouse model of repetitive mild TBI. Ferguson S, Mouzon B, Ojo J, Crynen G, Mathura V, Mullan M, Crawford F. Annual Meeting Society for Neuroscience 2013.

Longitudinal characterization of neurobehavioral and neuropathological outcomes in young hTau transgenic mice after single or repetitive mild TBI.

Longitudinal evaluation of histological and neurobehavioral changes in a mouse model of r-mTBI: a follow up at 2 years post injury.  Mouzon B, Bachmeier C, Olubunmi J, Acker C, Ferguson S, Crynen G, Stewart W, Davies P, Mullan M, Crawford F. 2014. Annual Meeting National Neurotrauma Society 2014.

 

Neurobehavioral, neuropathological and biochemical profiles of a novel mouse model of combined trauma and mild traumatic brain injury. Ojo J, Greenberg M, Leary P,  Mouzon B, Mullan M,  Diamond D, Crawford F. Annual Meeting Society for Neuroscience 2013.

Longitudinal characterization of neurobehavioral and neuropathological outcomes in young hTau transgenic mice after single or repetitive mild TBI

Longitudinal characterization of neurobehavioral and neuropathological outcomes in young hTau transgenic mice after single or repetitive mild TBI. Mouzon B, Bachmeier C, Olubunmi J, Acker C, Ferguson S, Crynen G, Pelot R, Stewart W, Davies P, Mullan M, Crawford F. Annual Meeting Society for Neuroscience 2013.
 

Characterization of neurobehavioral, neuropathological and proteomic profiles in a novel animal model of co-morbid posttraumatic stress disorder and mild traumatic brain injury.

Characterization of neurobehavioral, neuropathological and proteomic profiles in a novel animal model of co-morbid posttraumatic stress disorder and mild traumatic brain injury. Ojo J, Greenberg M, Reed J, Crynen G, Ferguson S, Mouzon B, BachmeierC, Diamond D, Mullan M, Crawford F. Annual Meeting Society for Neuroscience 2013.

Repetitive mild traumatic brain injury produces persistent memory deficits accompanied by chronic histological changes.

Repetitive mild traumatic brain injury produces persistent memory deficits accompanied by chronic histological changes. Mouzon B, Ferro A, Crynen G, Bachmeier C, Mullan M, Stewart W, Crawford F. Annual Meeting National Neurotrauma Society 2013 and Tampa VA Research Day 2013.

Behavioral and neuropathological characterization of concussive injury in hTau mice.

Behavioral and neuropathological characterization of concussive injury in hTau mice. Mouzin B, Ojo JO, Austin F, Ferguson S, Bachmeier C, Mullan M, Crawford F. Annual Meeting Society for Neuroscience 2012.

Acute neurobehavioral and neuropathological changes after repetitive versus single mild traumatic brain injury in young hTau transgenic mice.

Acute neurobehavioral and neuropathological changes after repetitive versus single mild traumatic brain injury in young hTau transgenic mice.  Mouzon B, Olubunmi J, Ferro A, Crynen G, Bachmeier C, Stewart W, Mullan M, Crawford F. Annual Meeting Society for Neuroscience 2012.

 

TBI-Induced Spatial Memory Loss is Averted by Treatment with the Dietary Supplement Anatabine. Ferguson S, Mouzon B, Ojo J, Bishop A , Crynen G, Phillips J,  Mathura V, Mullan M, Crawford F. Annual Meeting Society for Neuroscience 2012.

Behavioral and pathological outcome in a mouse model of single and repetitive concussions.

Behavioral and pathological outcome in a mouse model of single and repetitive concussions. Mouzon B, Chaytow H, Crynen G, Bachmeier C, Stewart J, Stewart W, Mullan M, Crawford F. The Ninth World Congress on Brain Injury International Brain Injury Association and Annual Meeting Society for Neuroscience 2012.

Increased tau pathology and glial activation after repeat concussive injury in aged hTau mice.  

Increased tau pathology and glial activation after repeat concussive injury in aged hTau mice. Ojo JO, Mouzin B, Greenberg MB, Bachmeier C, Mullan M, Crawford F. Annual Meeting Society for Neuroscience 2012.

Chronic Neurobehavioral and Neuropathological Changes After Repetitive Versus Single Mild Traumatice Brain Injury

Chronic Neurobehavioral and Neuropathological Changes After Repetitive Versus Single Mild Traumatic Brain Injury.  Mouzon B, Ferro A, Crynen G, Bachmeier C, Stewart W, Mullan M, Crawford F.  Annual Meeting National Neurotrauma Society 2012.

 

Inflammatory response in a mouse model of TBI following administration of therapeutic compounds.  Ferguson S, Mouzon B, Ojo JO, Crynen G, Mathura V, Mullan M, Crawford F.  Annual Meeting National Neurotrauma Society Symposium 2012.

Repetitive mild traumatic brain injury (mTBI) augments tau pathology and glial activation in aged h-Tau mice.

Repetitive mild traumatic brain injury (mTBI) augments tau pathology and glial activation in aged h-Tau mice. Ojo JO, Mouzin B, Bachmeier C, Ferguson S, Mullan M, Crawford F. Annual Meeting National Neurotrauma Society 2012.

 

Improved outcome in a mouse model of TBI following administration of a novel therapeutic compound.  Ferguson S, Mouzon B, Ojo JO, Ganapathi V, Bishop A, Crynen G, Phillips J,  Mathura V, Mullan M, Crawford F. 9th World Congress on Brain Injury (2012).

Time Course of Inflammatory Marker Response after TBI.

Time Course of Inflammatory Marker Response after TBI. Ferguson S, Bishop A, Mouzon B, Phillips J, Crynen G, Reed J, Chaytow H, Myles Mullan, Mathura V, Mullan M, Crawford F. Annual Meeting Society for Neuroscience 2011.

CD40 Ligand Deficiency Improves Rate of Functional Recovery Following Traumatic Brain Injury. Ferguson S, Mouzon B, Phillips J, Crynen G, Chaytow H, Bishop A, Abdullah L, Mullan M, Mathura V, Mullan M, Crawford F.  Annual Meeting National Neurotrauma Society Symposium 2011.

Behavioral and pathological outcome in a mouse model of single and repetitive concussions.

Behavioral and pathological outcome in a mouse model of single and repetitive concussions. Mouzon B, Chaytow H, Crynen G, Bachmeier C, Stewart J, Stewart W, Mullan M, Crawford F. Annual Meeting National Neurotrauma Society 2011.

Behavioral outcome in a mouse model of single and multiple concussions.

Behavioral outcome in a mouse model of single and multiple concussions. Mouzon B, Chaytow H, Bachmeier C, Mullan M, Crawford F. Tampa VA Research Day 2011.

Proteomic identification of plasma biomarkers and pathogenic mechanisms in APOE3 and APOE4 mouse models of TBI

Proteomic identification of plasma biomarkers and pathogenic mechanisms in APOE3 and APOE4 mouse models of TBI. Mouzon B, Bishop A, Crynen G, Katz B, Reed J, Ferguson S, Mathura V, Roses A, Mullan M, Crawford F.  Annual Meeting Society for Neuroscience 2010 and Tampa VA Research Day 2010.

Genomic variations in the inflammatory response of APOE transgenic mice following traumatic brain injury.

Genomic variations in the inflammatory response of APOE transgenic mice following traumatic brain injury. Wood ML, Mathura V, Laporte V, Humphrey J, Poon F, Mouzon B, Ferguson S, Brewster K, Margenthaler E, Doore S, Gupta P, Osteen B, Hayes R, Mullan M, Crawford F. Annual Meeting Society for Neuroscience 2008.

TBI Research Project Funding:

Listed below are TBI grants and contracts awarded to the Roskamp Institute (Years/Research Title/Grantor):

2013-2018
Chronic Effects of Neurotrauma Consortium. (Crawford)
    Joint Veterans Affairs / Department of Defense
 
2010 – 2014
Identification and Validation of Novel Therapeutic Targets for Traumatic Brain Injury. (Crawford)
    Department of Defense
 
2013 – 2015
Brain and Plasma Molecular Characterization of the Pathogenic TBI-AD Interrelationship in Mouse Models. (Crawford)
    Department of Defense
 
2012 – 2015
Proteomic Identification of Plasma TBI Biomarkers. (Crawford)
    Veterans Affairs

The TBI Research Program is also supported by the Roskamp Foundation.

Get in touch

If you have questions or wish to contact ss regarding our ongoing research of Gulf War Illness:

2040 Whitfield Ave.
Sarasota, FL 34243
Phone: 941-752-2949
Fax: 941-752-2948
Email: info@roskampinstitute.net


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