P184 Cutaneous TDP-43 pathology increases with proximity to diagnosis in amyotrophic lateral sclerosis

Abstract The shared embryonic origin of neural and skin tissues, alongside frequent dermatological abnormalities in neurodegeneration, supports a link between amyotrophic lateral sclerosis (ALS) and skin changes that may precede neurological symptoms. Skin affected by ALS shows a distinctive molecular and morphological phenotype that progresses with disease. TDP-43 pathology, the hallmark of around 97% of cases of LS, is detectable in both the central nervous system and skin. However, it remains unclear whether these cutaneous alterations emerge early enough to be reliably detected in the presymptomatic phase. In this study we characterized pathological TDP-43 accumulation in ante mortem skin tissue from a cohort of presymptomatic individuals who later developed ALS. Pathological TDP-43 was identified using a TDP-43 RNA aptamer in 17 individuals (25 skin sections) from various locations on the face, upper limb and upper and lower body. Sweat glands demonstrated the most consistent and robust TDP-43 pathology and so a superpixel-based segmentation was conducted on QuPath to quantify sweat gland pathology burden. A moderate negative correlation (Spearman ρ = −0.36) was observed when sweat gland TDP-43 pathology burden (H-score) was plotted against time to ALS diagnosis. Furthermore, in a single patient, minimal TDP-43 pathology burden was observed in the chest (H-score 4.6) but a markedly higher burden was found in samples from the shoulder (H-score 126) and back (H-score 127) at similar timepoints to diagnosis. Lip samples demonstrated greater burden closer to diagnosis (H-score 90.2) relative to lower pathology in samples obtained > 10 years presurgical operation (H-scores 26.8 and 33.1). Conversely, shoulder and back regions consistently exhibited high levels (H-scores > 116) irrespectively of time to diagnosis. Cutaneous sweat glands exhibit progressive peripheral accumulation of TDP-43 approaching symptomatic disease and thus raises the possibility of detecting TDP-43 pathology through sweat-gland-guided or biofluid sampling. Clinically, this could support earlier specialist referral. Thus, integrating dermatology into the multidisciplinary pathway may enable earlier recognition of ALS and reduce diagnostic delays.