Substantial interest in long-term pathologic changes following brain trauma has emerged due to recent evidence that neurodegeneration may be initiated by a single incident of brain injury. These neurodegenerative changes are particularly evident in patients suffering diffuse brain injury. Therefore, we propose to explore long-term neurodegeneration using a new model of non-impact head rotational acceleration in the pig that induces diffuse axonal pathology with and without coma. We have recently found that this model of brain trauma also produces neurodegenerative changes within one week following injury. These neurodegenerative changes include Abeta and tau accumulation in axons, Abeta plaque formation, tau accumulation in neurons, neurofilament inclusions in neurons, and possible phagocytosis of axons by neutrophils. Uniquely, these clinically relevant pathologic changes have not previously been found in other models of brain trauma. From these data, we have developed several testable hypotheses: 1) diffuse brain trauma will induce progressive Alzheimer's disease-like pathology (Abeta and tau accumulation) and Lewy body pathology (neurofilament cytoplasmic inclusions), 2) diffuse brain trauma will initiate a long- term deleterious immune response resulting in axon phagocytosis by both neutrophils and microglia, and 3) the extent of posttraumatic coma will be dependent on the angle of rotation and will correlate with the severity of brainstem injury. We propose to explore each of these hypotheses using multiple histologic and biochemical techniques, evaluating progressive neuropathologic changes over six months posttrauma. Success of these studies may reveal mechanistic links between brain trauma and neurodegenerative processes and facilitate the development of therapeutic and diagnostic techniques for diffuse brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS038104-01
Application #
2737841
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Heetderks, William J
Project Start
1999-02-15
Project End
2003-01-31
Budget Start
1999-02-15
Budget End
2000-01-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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