Abstract
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Objectives: Traumatic brain injury (TBI) results from energy transmission to the brain, disrupting its normal function1. While clinical TBI is markedly heterogenous, the primary injury is typically characterized by damage to neurons, glial cells and blood vessels. After the initial injury, a complex secondary injury which may last months can be observed by metabolic, cellular and molecular changes that lead to cell death, tissue damage and atrophy. White matter degeneration as a result of this secondary injury involves demyelination has been observed in postmortem human tissues and histopathological studies in animal models of TBI2-4.Assessing myelin content via PET imaging can shed light on the role of demyelination in TBI, providing better understanding of the disease and improvement in diagnosis and treatment monitoring. PET is particularly suitable to image demyelination, as it can provide quantitative images with high sensitivity and biochemical specificity for this process. For example, [18F]3F4AP, a novel radiotracer based on the FDA-approved drug for multiple sclerosis (MS) 4-aminopyridine, has been used to image demyelinated lesions in models of MS in rodents5. The goal of this study was to evaluate the ability of [18F]3F4AP to detect demyelination in TBI in a rodent model.
Methods: Animal model: Controlled cortical impact (CCI), a well-established model of TBI, was used in mice in combination with microPET studies and ex-vivo examination of the brains. Briefly, a small craniotomy was performed while keeping the dura intact. A controlled injury was then induced with a flat-tipped impactor placed on the dural surface, the incision was sutured, and animals were imaged over a 2 week period following the injury. Imaging: [18F]3F4AP was synthesized according to previous reports.5 Dynamic PET data was acquired for at least 30 min after IV injection of ~200 µCi of [18F]3F4AP. CT was acquired for attenuation correction and identification of the craniotomy site. Post mortem analysis: gamma counting, immunoblotting and histochemical staining was performed on a subset of animals at day 7.
Results: Longitudinal PET imaging after CCI showed increased [18F]3F4AP uptake after TBI with a peak 7 days post injury (35 ± 6% increase in SUV0-1h in the injury site compared to the contralateral control area, n = 5). Sham animals showed no changes in [18F]3F4AP uptake. Gamma counting of the left vs. right side of the brain showed a 40% increase in radiotracer concentration on the injured side compared to the contralateral side consistent with the PET findings. Preliminary histochemical staining with myelin-specific Luxol Fast Blue showed reduced staining on the injured side consistent with demyelination.Conclusions: In summary, [18F]3F4AP showed high sensitivity to TBI in mice after CCI. The time course of the changes in [18F]3F4AP signal was consistent with the expected time course of demyelination after CCI. Histological evaluation at peak of disease was also indicative of demyelination.. This study shows that [18F]3F4AP is a potential tracer for imaging demyelination in TBI and a possible noninvasive method for disease diagnosis and monitoring.