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Glutamate Carboxypeptidase II Upregulation and Detection in Varying degrees of Denervated Muscles
John D Nguyen, DO
1,2, Rachana Suresh, MBBS, MPH
3, Jeffrey Khong, BS
3, Samarth Krishna, MBBS, MPH
3, Kiara Quinn, MS
1, Alec J. Chen, MS
3, Zachary Zamore, BA
3, Mohammed Shahid, MD
3, Bashar M. Alsamman, BS
4, Fares Lebbos, MD
1, Jared Z Zhang, BS
3, Jawad Khalifeh, MD
1, Catherine A Foss, PhD
3, Cameron Ghergherehchi, PhD
1, William Padovano, MD, MPHS
3; Sami H. Tuffaha, MD
3(1)Johns Hopkins University, Baltimore, MD, (2)Florida Atlantic University, Boca Raton, FL, (3)Johns Hopkins University School of Medicine, Baltimore, MD, (4)University of Rochester School of Medicine, Rochester, NY
Introduction: Peripheral nerve injuries are challenging to diagnose and manage. We recently identified glutamate carboxypeptidase II (GCPII) expression as a biomarker for muscle denervation and demonstrated that a FDA commercially available imaging agent, 18F-DCFPyl could detect changes in muscle GCPII expression. In this study, we investigate muscle GCPII expression uptake in varying degrees of nerve injuries with electrodiagnostic correlation.
Methods: 120 female Lewis rats were used for selective transection of spinal roots that contribute to the right sciatic nerve. The groups were sham and transection of either L4, L4-L5, or L4-L6.The main outcome was the differences in GCPII upregulation at the 3-week and 12-week time points. Ex-Vivo biodistribution was performed on 60 rats at 3 and 12 weeks post-surgery using radiotracer 18F-DCFPyL. An automated gamma counter computed 18F-DCFPyL uptake in the hindlimb muscles. The remaining 60 rats were used for nerve conduction studies at 3 and 12 weeks post-surgery to measure compound muscle action potential (CMAP) in the right lateral gastrocnemius muscle. Statistical analysis was performed with Kruskal Wallis and post hoc Dunn test.
Results: 3 weeks after surgery there was higher upregulation (p<0.05) of GCPII observed in the right gastrocnemius when comparing L4-L6 group to sham, L4, and L4-L5 groups. The right tibialis anterior (TA) showed increase GCPII upregulation when comparing the L4-L6 to sham and L4, L4-L5 to sham. The right extensor digitorum longus (EDL) showed higher GCPII upregulation when comparing L4-L6 to sham and L4. The 12 weeks cohort, the right gastrocnemius and TA muscle showed high upregulation of GCPII in the L4-L6 group when compared to sham and L4. While the right EDL showed higher GCPII upregulation only when comparing L4-L6 to L4.The nerve conduction study revealed that the CMAP was preserved near baseline until there was complete denervation. In the acute model, complete denervation resulted in no measurable CMAP while the chronic denervated group regain CMAP at a lower than baseline level.
Conclusion: GCPII upregulation and 18F-DCFPyL uptake may serve as a promising radiotracer for evaluating and monitoring the degree of nerve injury. At the 3-week timepoint, 18F-DCFPyL uptake appear to correspond with the degree of denervation in a stepwise fashion. While at the 12-week time point showed that 18F-DCFPyL uptake decreased, suggestive of axonal collateralization. Nerve conduction studies showed preserved CMAP until complete denervation was reached with minimal recovery of CMAP after axonal collateralization has occurred, suggestive of preserved function despite partial nerve injury.
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