Phosphorylated TDP-43 Pathology in Skin and Muscle Tissue of Patients With Amyotrophic Lateral Sclerosis

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.