{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:03:57Z","timestamp":1789718637007,"version":"4.0.1"},"reference-count":28,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GMR23T2157"],"award-info":[{"award-number":["GMR23T2157"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004462","name":"Consiglio Nazionale delle Ricerche","doi-asserted-by":"publisher","award":["DSB.AD006.371\u2010InvAt\u2010FOE2022"],"award-info":[{"award-number":["DSB.AD006.371\u2010InvAt\u2010FOE2022"]}],"id":[{"id":"10.13039\/501100004462","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Hereditary Spastic Paraplegia (HSP) comprises a group of rare genetic diseases characterized by length\u2010dependent axonal degeneration of the corticospinal tracts and dorsal columns, whose main clinical feature is spastic gait. Pathogenic variants in the\n                      <jats:italic>SPG4<\/jats:italic>\n                      gene cause Spastic Paraplegia Type 4 (SPG4\u2010HSP), the most common form of HSP.\n                      <jats:italic>SPG4\/SPAST<\/jats:italic>\n                      encodes spastin, a protein involved in microtubule regulation and lipid droplet behavior. SPG4\u2010HSP shows extreme heterogeneity in both clinical manifestations and genetics. Although no cure is currently available, several strategies aimed at restoring spastin levels are emerging; however, SPG4\u2010HSP still lacks accessible cellular readouts for clinical studies. This study evaluates a cell\u2010imaging approach that quantifies the distance between nucleus and cell centroid (dcnc) in peripheral blood mononuclear cells (PBMCs) in a genetically and clinically heterogeneous SPG4\u2010HSP cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PBMCs from 48 molecularly confirmed SPG4\u2010HSP patients and 21 healthy controls (HC) were analyzed by automated cell imaging. Dcnc and additional cytoskeletal and lipid droplet\u2010related parameters were measured. Patient\u2010level discrimination was assessed via cross\u2010validated classification; correlations with molecular and clinical features were explored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At the patient level, dcnc distinguishes SPG4\u2010HSP from HC, independently of mutation type and disease severity, supporting robust cross\u2010validated classification and inverse correlation with spastin protein levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Dcnc is a robust, non\u2010invasive, and mutation\u2010independent cellular candidate biomarker for SPG4\u2010HSP. It also offers preliminary evidence consistent with spastin target engagement supporting evaluation in future clinical trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70482","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T04:20:26Z","timestamp":1788409226000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Validation of a Cellular Imaging\u2010Based Method as a Potential Biomarker for SPG4 Hereditary Spastic Paraplegia"],"prefix":"10.1002","author":[{"given":"Gaia","family":"Fattorini","sequence":"first","affiliation":[{"name":"IBPM\u2010CNR  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Licursi","sequence":"additional","affiliation":[{"name":"IBPM\u2010CNR  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianmarco Dalla","family":"Zanna","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6447-4585","authenticated-orcid":false,"given":"Flavio","family":"Dal Canto","sequence":"additional","affiliation":[{"name":"Molecular Medicine, IRCCS Fondazione Stella Maris  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Barghigiani","sequence":"additional","affiliation":[{"name":"Molecular Medicine, IRCCS Fondazione Stella Maris  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunzio","family":"Setola","sequence":"additional","affiliation":[{"name":"Molecular Medicine, IRCCS Fondazione Stella Maris  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Funcis","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo M.","family":"Santorelli","sequence":"additional","affiliation":[{"name":"Molecular Medicine, IRCCS Fondazione Stella Maris  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Silvestri","sequence":"additional","affiliation":[{"name":"Department of Neurosciences Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"},{"name":"Department of Neurosciences, Sensory Organs and Thorax Fondazione Policlinico Universitario A. Gemelli IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Casali","sequence":"additional","affiliation":[{"name":"Sapienza University of Rome  Latina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6474-2079","authenticated-orcid":false,"given":"Francesca","family":"Sardina","sequence":"additional","affiliation":[{"name":"IBPM\u2010CNR  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6124-762X","authenticated-orcid":false,"given":"Cinzia","family":"Rinaldo","sequence":"additional","affiliation":[{"name":"IBPM\u2010CNR  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1115-8"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab386"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2021.07.005"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.01544"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000820"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201902061"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005149"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1008665"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202000715"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2005.06.009"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7007-6-31"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.55.5.702"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy285"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000664"},{"key":"e_1_2_11_16_1","volume-title":"GeneReviews","author":"Hedera P.","year":"1993"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.51518"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac155"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.15841"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt644"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202000799"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2021.5051"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.15756"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae095"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-025-02333-y"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000228242.53336.90"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2023.1073516"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-025-13155-4"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-025-13251-5"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70482","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.70482","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70482","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T07:36:40Z","timestamp":1789717000000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.70482"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,2]]},"references-count":28,"alternative-id":["10.1002\/acn3.70482"],"URL":"https:\/\/doi.org\/10.1002\/acn3.70482","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,2]]},"assertion":[{"value":"2026-03-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"acn3.70482"}}