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Neuroimaging Cerebrovascular Function and Diffuse Axonal Injury after Traumatic Brain Injury and Response to Sildenafil Treatment
Uniformed Services University of the Health Sciences Bethesda United States
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Damage to the cerebral microvasculature and diffuse axonal injury DAI are two well recognized end ophenotypes of traumatic brain injury TBI which significantly contribute to neuropsychological sequelae 40 61 110. Patients who have suffered mild TBI show acute disruptions in cerebrovascular reactivity 73 and chronic regional deficits in cerebral blood flow CBF that are concordant with neuropsychiatric localization 18. Furthermore, compelling evidence indicates that enhancing angiogenesis may attenuate secondary injury and improve functional recovery 21 77 121 122 136. Although diffuse axonal injury has similarly been linked to neurologic outcome 70, the relationship of microvascular disease and axonal injury after TBI remains unknown. The present study establishes a method to efficiently and non-invasively quantify traumatic cerebral microvascular injury after TBI and response to therapeutic intervention, using sildenafil as a model. Young adult male rats were assessed over a 30-day period following moderate fluid percussion injury through multimodal magnetic resonance imaging. Cerebrovascular reactivity to hypercapnia was measured using arterial spin labeling. Diffusion tensor imaging was employed to assess microstructural alterations, including axonal injury. Neurobehavioral outcome was assessed by the Neurological Severity Score, Morris Water Maze, Rotarod, and Open Field Test. Animals were euthanized 30 days after injury for histological measures of astrogliosis GFAP, microgliosis Iba-1 and vascular recovery RECA-1. The effectiveness of sildenafil Viagra, Revatio as a cytoprotective treatment was also evaluated using these methods. Regional deficits in cerebrovascular function were concordant with regions of increased astrogliosis and microglial activation GFAP and Iba-1 increased in auditory cortex, each p0.001.
APPROVED FOR PUBLIC RELEASE