Maria Nolano, Vincenzo Provitera, Giuseppe Caporaso, Arianna Rita Areniello, Ilaria Borreca, Annamaria Stancanelli, Gianmaria Senerchia, Valentina Virginia Iuzzolino, Ines Fasolino, Floriana Vitale, Giuseppina Ciccarelli, Domenico Dell’Aversana, Francesca Masciarelli, Stefano Tozza, Rosa Iodice, Lucio Santoro, Fiore Manganelli, Raffaele Dubbioso
BACKGROUND AND OBJECTIVES: Phosphorylated TAR DNA-binding protein 43 (pTDP-43) is the pathologic hallmark of amyotrophic lateral sclerosis (ALS), yet no peripheral premortem biomarker is available. We evaluated pTDP-43 distribution in skin and tongue tissues and its association with ALS and clinical stage. METHODS: This cross-sectional case-control study included patients with ALS meeting revised El Escorial criteria who underwent skin and tongue biopsies. Control groups included healthy controls (HC), patients with non-ALS neuropathy or neuronopathy (NANN), and patients with burning mouth syndrome (BMS). pTDP-43 was quantified in Meissner corpuscles (MC) and keratinocytes using standardized immunofluorescence. In MC, PGP (%), pTDP-43 (%), and the pTDP-43/PGP ratio were assessed. A subset of skin samples underwent western blot analysis. ALS severity was classified using King's staging system. Diagnostic performance was evaluated using receiver operating characteristic analysis. RESULTS: < 0.001). Tongue biopsies showed pTDP-43 aggregates in intramuscular nerves, denervated endplates, and muscle fibers. DISCUSSION: Peripheral pTDP-43 deposition distinguishes ALS from controls and reflects disease stage, supporting its potential role as a biomarker of ALS and disease severity. Larger and longitudinal studies are required for validation.