Skin innervation across amyotrophic lateral sclerosis clinical stages: new prognostic biomarkers.

In the last decades, peripheral sensory abnormalities, including the evidence of cutaneous denervation, have been reported among the non-motor manifestations in amyotrophic lateral sclerosis (ALS). However, a correlation between cutaneous innervation and clinical features has not been found. Aims of this study were to assess sensory involvement by applying a morpho-functional approach on a large population of ALS patients stratified according to King's stages and to correlate these findings with the severity and prognosis of the disease. We recruited 149 ALS patients and 41 healthy controls (HC). Patients underwent clinical questionnaires for small fiber neuropathy symptoms (SFN-siq), nerve conductions studies (NCS) and 3mm-punch skin biopsy from leg, thigh and fingertip. We assessed intraepidermal nerve fibers (IENF) and Meissner corpuscles (MC) density by applying indirect immunofluorescence technique. Moreover, a subset of 65 ALS patients underwent a longitudinal study with repeat skin biopsies from the thigh at 6- and 12-months follow-up. Serum Neurofilament light chain (NfL) levels were measured in forty patients. Sensory symptoms and sensory NCS abnormalities were present in 32.2% and 24% of patients, respectively, and increased across clinical stages. Analogously, we observed a progressive reduction in amplitude of the sensory and motor ulnar nerve potential from stage 1 to stage 4. Skin biopsy showed a significant loss of IENF and MC in ALS compared with HC (all P < 0.001). Across the clinical stages, we found a progressive reduction in MC (P = 0.004) and an increase in IENF (all P < 0.027). The increase in IENF was also confirmed by the longitudinal study. Interestingly, the MC density inversely correlated with NfL level (r = -0.424, P = 0.012), and survival analysis revealed that low MC density, higher NfL levels, and increasing IENF over time were associated with a poorer prognosis (all P < 0.024). In patients with ALS, peripheral sensory involvement worsens in parallel with motor disability. Furthermore, the correlation between skin innervation and disease activity may suggest the use of skin innervation as a putative prognostic biomarker.