Imaging Muscle Denervation by Detecting Glutamate Carboxypeptidase II Expression with Positron Emission Tomography (PET)
William M Padovano, MD MPHS1, Catherine A Foss, PhD1, Aidan Weitzner, BS1, Emma Rowley, BS1, Zachary Zamore, BA2, Rachana Suresh, MBBS MPH1, 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
Introduction: Accurate identification of muscle denervation and re-innervation is necessary for optimal nerve surgical decision-making. Unfortunately, it is often difficult to ascertain the status of muscle in complex peripheral nervous system injuries. We identified glutamate carboxypeptidase II (GCPII) expression as a novel biomarker for muscle denervation. We then investigated the performance of PET radiopharmaceuticals that target GCPII, which are FDA-approved for cancer imaging, to characterize muscle denervation and re-innervation after nerve injury.
Methods: We performed serial PET/MRI in Lewis rats 4-weeks and 16-weeks after sciatic nerve transection with or without repair (n=6) using the GCPII ligand, 68Ga-PSMA-11. To further evaluate muscle uptake and assess generalizability, we performed ex-vivo biodistribution studies in 48 Lewis rats (M:F 1:1) after intravenous injection of another FDA-approved GCPII ligand, 18F-DCFPyL. 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-weeks, 4-weeks, or 16-weeks postoperative (n=5-6 per group per timepoint). Muscle uptake was calculated using an automated gamma counter and expressed as percent injected dose per gram (%ID/g). Changes in muscle GCPII expression were also examined using immunohistochemistry (n=14). To assess translational potential, a Yorkshire pig underwent 68Ga-PSMA-11 PET/CT on a clinical scanner 16-weeks after median nerve transection with repair and contralateral median nerve transection without repair.
Results: At 4-weeks postoperative, nerve-injured rats had greater 18F-DCFPyL uptake in denervated gastrocnemius muscles (unrepaired: 5.0x greater, p=0.009; repaired: 4.2x greater, p=0.016) compared to sham. At 16-weeks, muscle uptake remained high in unrepaired animals relative to sham (p=0.006) but resolved in repaired animals, consistent with muscle re-innervation (p=0.6). The same trend was identified on small animal PET/MRI, which demonstrated selective 68Ga-PSMA-11 uptake by denervated muscles. On histology, elevated muscle GCPII expression was attributed to a special population of CD68+/GCPII+ tissue macrophage. The pig PET/CT study also demonstrated clear uptake in median-nerve innervated flexor muscles with sparing of the flexor carpi ulnaris (Figure 1).
Conclusions: GCPII expression is a promising biomarker for muscle denervation. Safe, commercially available PET agents that target GCPII expression can be used to evaluate muscle denervation and re-innervation after nerve injury.
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