{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T23:19:48Z","timestamp":1785021588801,"version":"3.55.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T00:00:00Z","timestamp":1703030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Istituti Clinici Scientifici Maugeri IRCCS"},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of University and Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Over recent 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.<\/jats:p>\n               <jats:p>The aims of this study were to assess sensory involvement by applying a morpho-functional approach to a large population of ALS patients stratified according to King\u2019s stages and correlate these findings with the severity and prognosis of the disease.<\/jats:p>\n               <jats:p>We recruited 149 ALS patients and 41 healthy controls. Patients undertook clinical questionnaires for small fibre neuropathy symptoms (Small Fiber Neuropathy Symptoms Inventory Questionnaire) and underwent nerve conductions studies (NCS) and 3-mm punch skin biopsies from leg, thigh and fingertip. We assessed intraepidermal nerve fibre (IENF) and Meissner corpuscle (MC) density by applying an indirect immunofluorescence technique. Moreover, a subset of 65 ALS patients underwent a longitudinal study with repeat biopsies from the thigh at 6- and 12-month follow-ups. Serum NfL levels were measured in 40 patients.<\/jats:p>\n               <jats:p>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.<\/jats:p>\n               <jats:p>Skin biopsy showed a significant loss of IENFs and MCs in ALS compared with healthy controls (all P &amp;lt; 0.001). Across the clinical stages, we found a progressive reduction in MCs (P = 0.004) and an increase in IENFs (all P &amp;lt; 0.027). The increase in IENFs was confirmed by the longitudinal study. Interestingly, the MC density inversely correlated with NfL level (r = \u22120.424, P = 0.012), and survival analysis revealed that low MC density, higher NfL levels and increasing IENF density over time were associated with a poorer prognosis (all P &amp;lt; 0.024).<\/jats:p>\n               <jats:p>To summarize, 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.<\/jats:p>","DOI":"10.1093\/brain\/awad426","type":"journal-article","created":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T00:25:40Z","timestamp":1703031940000},"page":"1740-1750","source":"Crossref","is-referenced-by-count":32,"title":["Skin innervation across amyotrophic lateral sclerosis clinical stages: new prognostic biomarkers"],"prefix":"10.1093","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4849-1318","authenticated-orcid":false,"given":"Maria","family":"Nolano","sequence":"first","affiliation":[{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Skin Biopsy Lab, Neurological Rehabilitation Unit of Telese Terme Institute , Telese Terme, Benevento 82037 , Italy"},{"name":"Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II , Naples 80131 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1230-942X","authenticated-orcid":false,"given":"Vincenzo","family":"Provitera","sequence":"additional","affiliation":[{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Skin Biopsy Lab, Neurological Rehabilitation Unit of Telese Terme Institute , Telese Terme, Benevento 82037 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5822-7505","authenticated-orcid":false,"given":"Giuseppe","family":"Caporaso","sequence":"additional","affiliation":[{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Skin Biopsy Lab, Neurological Rehabilitation Unit of Telese Terme Institute , Telese Terme, Benevento 82037 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Fasolino","sequence":"additional","affiliation":[{"name":"Institute of Polymers, Composites and Biomaterials\u2014National Research Council (IPCB-CNR) , Naples 80125 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Borreca","sequence":"additional","affiliation":[{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Skin Biopsy Lab, Neurological Rehabilitation Unit of Telese Terme Institute , Telese Terme, Benevento 82037 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Stancanelli","sequence":"additional","affiliation":[{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Skin Biopsy Lab, Neurological Rehabilitation Unit of Telese Terme Institute , Telese Terme, Benevento 82037 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina V","family":"Iuzzolino","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II , Naples 80131 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianmaria","family":"Senerchia","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II , Naples 80131 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floriana","family":"Vitale","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II , Naples 80131 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9672-4577","authenticated-orcid":false,"given":"Stefano","family":"Tozza","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II , Naples 80131 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Ruggiero","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II , Naples 80131 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Iodice","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples Federico II , Naples 80131 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Neurology Unit, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Policlinico GB Rossi , Verona 37134 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucio","family":"Santoro","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, 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