Traumatic brain injury (TBI) afflicts approximately three million Americans every year with a high rate of long-term neurocognitive and behavioral morbidity. The true incidence of TBI likely approaches 10 million as many mild cases go unreported. It is now recognized that repetitive mild TBI, or concussions, may lead to the insidious onset of TBI-related neurodegeneration, a process termed Chronic Traumatic Encephalopathy (CTE) which is now linked to Alzheimer’s Disease Related Dementias (ADRD). TBI and CTE are of particular concern among athletes engaged in contact sports and military personnel exposed to concussive injuries resulting from explosions. In fact, it has been estimated that roughly 15–20% of deployed US military personnel have sustained a blast-related TBI. While rodent work has provided initial information on the effects of blast injury and recovery, translation from rodents into human TBI patients has been challenging secondary to the gross differences in brain anatomy and physiology. The human brain is gyrencephalic, containing extensive sulci and gyri whereas the rodent brain is lissencephalic lacking surface convolutions and containing a much lower volume of white matter. This is an important distinction as the presence of gyri greatly influences the movement of the brain within the skull upon impact with greater deformation in gyrencephalic brains as compared to lissencephalic brains. In addition, sulci and gyri influence the points of maximum mechanical stress in the brain during angular acceleration. In lissencephalic brains the smooth brain surface distributes stress fields uniformly while in a gyrencephalic brain maximal stress is focused at the base of the sulci. In fact, this is the precise location where pathologic phosphorylated tau protein is maximally distributed in human CTE cases. Thus, current rodent models are inadequate and lack biofidelity with the human condition. In the current proposal, we aim to develop the ferret as a small mammalian model system with a well gyrated brain specifically for the study of TBI-associated neurodegeneration. The gyrated brain of the ferret model approximates the gross anatomy of the human brain much more closely than rodent models while avoiding the high costs associated with larger animal models such as non-human primates, canines and swine. Taken together, we hypothesize that a ferret model of repetitive, mild, blast-induced TBI will recapitulate the initiation and progression of human CTE with a high degree of biofidelity as compared to a standard mouse model. To test this hypothesis we will determine whether ferrets exposed to sham, single blast, or repeated blast-induced TBI develop deficits in learning, memory, and skill acquisition benchmarked to a standard mouse model. We will also correlate these neurocognitive findings with neuroanatomic, neurometabolic, and neuropathologic outcomes using longitudinal diffusion, dynamic contrast-enhanced, 3D-MRI, 18F-FDG PET, and standard neurohistopathology. Collectively, these experiments will challenge the current paradigm that rodent models of CTE can recapitulate the spectrum of neuropathology seen in human patients.
|Effective start/end date||9/1/20 → 8/31/22|
- National Institute of Neurological Disorders and Stroke (1R21NS116638-01A1)