Imaging Macrophages to Evaluate Peripheral Nerve Injuries
William M Padovano, MD MPHS1, Catherine A Foss, PhD1, Aidan Weitzner, BS1, Emma Rowley, BS1, Zachary Zamore, BA2, Rachana Suresh, MBBS MPH1, Erica B Lee, MS1, Zohra V Aslami, BA1, Martin G Pomper, MD PhD1 and Sami H Tuffaha, MD2, 1Johns Hopkins University School of Medicine, Baltimore, MD, 2Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
Background: No clinical imaging modality can reliably determine the status of axons within injured nerves or localize the regenerating front of axons after nerve repair. To address this problem, we hypothesized that imaging macrophage content along a nerve could provide an inverse image of nerve regeneration. We investigated the translocator protein (TSPO), which is highly expressed by activated macrophages, as a biomarker for peripheral nerve injury. We also evaluated DPA713, a clinical-stage investigational TSPO ligand used to image inflammation with positron emission tomography (PET), as a novel nerve imaging agent.
Methods: We performed near-infrared (NIR) imaging using fluorescently-labeled DPA713 in Lewis rats at 2-weeks, 4-weeks, and 16-weeks after sciatic nerve injury (n=12). To quantify nerve uptake, ex-vivo biodistribution studies were performed in 49 Lewis rats (M:F 1:1) using radiolabeled 124I-iodo-DPA713. Animals were divided into 3 surgical groups (sciatic nerve transection without repair, sciatic nerve transection with repair, or sham surgery) and underwent tissue harvests at 2-, 4-, or 16-weeks postoperative (n=5-7 per group per timepoint). To examine differential uptake along the sciatic nerve, the nerve was divided into 4 segments and uptake for each segment was calculated using an automated gamma counter. Nerve TSPO expression was also assessed using immunohistochemistry (n=14). To evaluate translational potential, a Yorkshire pig underwent dynamic 124I-iodo-DPA713 PET/CT on a clinical scanner 16-weeks after median nerve transection with repair and contralateral median nerve transection without repair.
Results: Injured sciatic nerves demonstrated significantly higher tracer uptake around the injury site (segments 2 and 3) and in the distalmost nerve segment when compared to sham at 2-weeks postop (unrepaired: 3.0x greater uptake, p<0.05; repaired: 3.2x greater uptake, p<0.05). Nerve uptake remained elevated at 16-weeks postop in the unrepaired group, but it resolved by 4-weeks postop in the repaired group with axonal regeneration through the sciatic nerve (Figure 1). The same trend was identified on NIR imaging studies (Figure 2). The pig PET/CT study also demonstrated 124I-iodo-DPA713 uptake in the distal median nerve.
Conclusions: TSPO expression is a novel biomarker for Wallerian degeneration in injured peripheral nerves. DPA713 has promise as a nerve imaging agent, such as in PET/MRI or NIR-guided surgery.
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