Division of Neuropathology

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Traumatic Brain Injury


Brain Injury and Repair Program

There are about 1.7 million new cases of Traumatic brain injury (TBI) in the US every year, most of them from motor vehicle accidents (MVA) or falls. Although many cases of TBI cause brief changes in mental status (i.e. concussions) that usually improve over a few weeks or months, a substantial number lead to chronic disability because of permanent damage or, in some cases, progressive disease. Severe forms of TBI include focal contusions often associated with falls, and diffuse axonal lesions usually associated with rotational acceleration as occurs in MVA. The association of TBI with boxing (dementia pugilistica) is also well recognized, and concern is growing that repeat concussions in football and other contact sports may lead, in some athletes, to chronic traumatic encephalopathies (CTE) very similar to dementia pugilistica. The Iraq and Afghanistan wars have exposed upwards of 150,000 soldiers to TBI. Much of this exposure relates to explosion (blast) from mines or intermittent explosive devices, and blast injury to brain has become one of the signature problems of these recent wars. Finally, it has been suggested that TBI confers risk to several late life diseases, including Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS). In our Division, we plan to use our extensive experience in neurodegenerative diseases and animal models to understand mechanisms and design novel therapeutics for TBI.

To achieve that, we have assembled a multidisciplinary team focused on discovering the anatomical and molecular basis of the various types of TBI in order to develop improved diagnostic tests and novel therapies. Our approach is to develop and analyze animal models of brain injury in parallel with studies of patients with TBI and to establish key translational themes that will allow the understanding of the fundamental mechanisms of TBI and later life illnesses with which it is associated. Investigators in the Division of Neuropathology have a 25 year-history of studying neural injury and repair, including characterization of the responses of central and peripheral neurons to axonal injury; characterization of mechanisms of apoptosis and neuronal cell death; demonstration of the roles of neurotrophic peptides as therapeutics in models of neural injury; and pioneering the use of stem cells to support or replace dying neurons and to restore simple neural circuits. Furthermore, our investigators have pioneered genetic rodent models of neurodegenerative diseases including AD and ALS and have clarified key molecular steps leading to pathogenic protein aggregation in these disorders; these technologies and discoveries will play key roles in investigations of neurodegenerative mechanisms initiated by some forms of TBI.

Dr. Vassilis Koliatsos has a longstanding interest in the clinical, translational, and basic science of brain injury and has the principal responsibility for TBI research effort in the Division. Additional faculty playing active roles in this research are: Drs. Juan Troncoso and Barbara Crain, who have over 20 years of experience evaluating human TBI pathology at Johns Hopkins Hospital and the State of Maryland Office of the Chief Medical Examiner; Drs. Phil Wong and Tong Li, who are creating transgenic mouse models that may shed light on the genetic susceptibility to TBI; Dr. Charles Eberhart, who is assisting in assessing the effects of TBI on the optic nerve and retina; and Dr. Alena Savonenko, who has expertise in evaluating the behavioral and cognitive effects of TBI in rodent models. As described below, our research projects also include key collaborators in other Departments at Johns Hopkins University, as well as outside institutions such as the Applied Physics Laboratory (APL), the Armed Forces Institute of Pathology (AFIP), Virginia Commonwealth University (VCU), and the University of Glasgow.

The overall goals of our studies are: a) to model the problems underlying brain trauma due to blast, concussions and axonal injuries; b) to correlate experimental findings in rodent models with observations from traumatic injury in human brains in order to better understand pathogenic mechanisms; and c) to formulate and test experimental treatment approaches involving small organic compounds, trophic factors, and stem cells. Described below are three separate but linked projects that focus on these issues.

SPECIFIC PROJECTS INCLUDE:

  1. Animal models of diffuse axonal injury/multiple-system disconnection. This project involves the use of the impact acceleration model of Marmarou and sets the main temporal and cellular/molecular parameters of axonal pathology as well as functional and behavioral consequences. It also involves direct comparisons between neurobiological and MRI/DTI measures of axonal injury. The model also allows cell-death prevention and circuit repair efforts using trophic and cellular approaches.
  2. Blast injury in human brain and animal models. This project utilizes brain tissues from veterans exposed to combat blast scenarios provided through a collaborative agreement with AFIP. In parallel, the project uses a shock tube model of blast injury that was developed in collaboration with Dr Ibolja Cernak of the APL. The neuropathological consequences of blast injury in humans and experimental animals are characterized and compared. Lessons from animal models are used to clarify mechanisms of blast injury in the human brain.
  3. Animal models of chronic traumatic encephalopathies. This project focuses on the cellular and molecular mechanisms of injury-induced tauopathies using a repeat-concussion model. This model is based on the impact acceleration (Marmarou) apparatus that was adjusted for use in mice. Mice of various genetic backgrounds are used, such as to explore the burden of genetic and concussive contributions to traumatic encephalopathies (diathesis-stress design). Experimental therapies are explored with anti-tau compounds.