<scp>TSPO</scp> Expression and [18 <scp>F</scp> ] <scp>DPA</scp> ‐714 <scp>PET</scp> / <scp>CT</scp> Imaging as Pathogenetic and Diagnostic Biomarkers in Symptomatic Stages of Skeletal Muscle Fiber Degeneration in <scp>SOD</scp> 1‐ <scp>G</scp> 93 <s

Emerging evidence highlights the involvement of skeletal muscle in the pathogenesis of amyotrophic lateral sclerosis (ALS), through mechanisms involving inflammation and mitochondrial dysfunction in skeletal muscle fibers. The 18 kDa translocator protein (TSPO) is primarily expressed on the outer mitochondrial membrane, is implicated in inflammation, and serves as both a biomarker and a therapeutic target for neuroinflammation. This study investigated whether PET imaging targeting the TSPO, immunohistochemistry, and confocal microscopy can characterize skeletal muscle inflammation and muscular fiber damage in SOD1-G93A ALS transgenic mice. High-resolution PET/CT imaging with [18F]DPA-714 was employed to assess TSPO expression in the triceps brachii of SOD1-G93A mice at mild (age range: 98-112 days; Clinical Score (CS) range:1-1.5) and moderate-severe (age range: 120-137 days; CS range: 2-4) symptomatic stages. To support PET data, TSPO was analyzed by immunohistochemistry and confocal microscopy in the triceps skeletal muscle obtained from mild and moderate-severe SOD1-G93A mice. Inflammatory and anti-inflammatory macrophage cells in skeletal muscle tissues were detected by immunofluorescence. PET/CT revealed a progressive, significant increase of [18F]DPA-714 uptake in SOD1-G93A triceps brachii in mild and moderate-severe stages. Immunohistochemistry and confocal microscopy confirmed increased TSPO expression in the degenerating muscle fibers and in infiltrating macrophage cells. In vivo studies of TSPO expression in ALS-affected skeletal muscles may provide valuable insights into muscle inflammation and mitochondrial involvement during disease progression. In addition, TSPO and PET/CT imaging with [18F]DPA-714 might represent a noninvasive and promising diagnostic biomarker for detecting early muscle pathology in ALS.