Abstract
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Introduction: <h2>Muscle denervation caused by peripheral nerve injury significantly impedes the recovery of function and carries a risk of secondary disabilities. Needle electromyography is considered a standard method to diagnose muscle denervation [1]. However, needle electromyography is an invasive and painful procedure for patients, and interpretation of the results is subjective [2]. Previous studies have reported increased expression of the nicotinic acetylcholine receptor (nAChR) in denervated muscle [3, 4]. This phenomenon is thought to be associated with electrophysiologic acetylcholine supersensitivity after muscle denervation [5]. F-18-ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-F-18-fluorodibenzo[b,d]thiophene 5,5-dioxide), alpha7-nAChR targeting positron emission tomography (PET) radiotracer [6, 7], was recently developed for the investigation of brain diseases [8, 9]. Here, we investigated F-18-ASEM PET/magnetic resonance imaging (MRI) as a new diagnostic method for evaluating muscle denervation.</h2>
Methods: <h2>Ten-week-old C57BL/6 male mice were utilized in this study (n = 11). The mice were anesthetized, and the left sciatic nerve was exposed by splitting the gluteal muscle [10]. A nerve segment of 5 mm size was resected from the proximal portion of the left sciatic nerve before its bifurcation into the common peroneal and tibial nerves. A sham operation, exposing the sciatic nerve without resection, was performed on the opposite side as a control. One week after the denervation, PET/MRI was acquired using hybrid small animal scanner (nanoScan PET/MRI; 1T, Mediso, Hungary). After intravenous injection of F-18-ASEM via tail vein [0.44 ± 0.07 mCi (range = 0.39–0.61 mCi)], MRI was performed for 10 minutes, then PET imaging was obtained for 20 minutes. The lower leg muscles were visually assessed, and maximum and mean standardized uptake values (SUVmax and SUVmean) were measured for the denervated muscles (lesion) and the control muscles. All the mice were immediately sacrificed after imaging studies, and the tibialis anterior muscles were harvested. Autoradiographic evaluation was performed to measure the mean counts of the denervated and control tibialis anterior muscles. In addition, immunohistochemistry was used to identify alpha7-nAChR-positive areas in denervated and control tibialis anterior muscles (n = 6). Statistical analysis was performed using the Wilcoxon signed-rank test; P < 0.05 was considered statistically significant.</h2>
Results: <h2>F-18-ASEM PET showed higher uptake in the denervated lower leg muscles compared to the control muscles in all the mice, matching the signal change on MRI. The SUVmax of the denervated muscle [0.90 (0.85 – 1.31); median (interquartile range)] showed a significantly higher uptake than that of the control muscle [0.76 (0.44 – 0.88)] (P = 0.0033). In addition, the lesion-to background ratio (LBR; denervated muscle SUVmax/control muscle SUVmean) of the denervated muscle [2.08 (1.84 – 2.22)] was significantly higher than that of the control muscle [1.00 (1.00 – 1.00)] (P = 0.0033). Furthermore, the mean count ratio by autoradiography (denervated muscle mean count/control muscle mean count) for the denervated muscle [1.18 (1.13 – 1.35)] was significantly higher than that of the control muscle [1.00 (1.00 – 1.00)] (P = 0.0033). Finally, immunohistochemistry revealed a significantly greater alpha7-nAChR-positive area in the denervated muscle [25.45% (22.95 – 27.38%)] than in the control muscle [8.64% (4.91 – 10.89%)] (P = 0.0277).</h2>
Conclusions: <h2>F-18-ASEM PET/MRI showed significantly increased alpha7-nAChR expression in denervated muscle than in control muscle in a mouse model of sciatic nerve injury. Thus, F-18-ASEM PET/MRI can be a potential noninvasive imaging modality for the evaluation of muscle denervation after nerve injury. To our knowledge, this is the first study to investigate the use of F-18-ASEM in peripheral neuromuscular disorders.</h2>
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