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Despite efforts to carefully define and stratify ALS patients according to their clinical and genetic features, prognosis prediction still remains unreliable. Biomarkers that reflect changes in the central nervous system would be useful, but the physical impossibility of direct sampling and analysis of the nervous system makes them challenging to validate. A highly explored option is the identification of neuronal-specific markers that could be analyzed in peripheral biofluids. This review focuses on the description of the physical and biological barriers to the central nervous system and of the composition of biofluids in which ALS disease biomarkers are actively searched. Finally, we comment on already validated biomarkers, such as the neurofilament light chain, and show the potential of extracellular vesicles (EVs) and cell-free DNA as additional biomarkers for disease prediction.<\/jats:p>","DOI":"10.3390\/cells14110848","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T05:49:22Z","timestamp":1749102562000},"page":"848","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Barriers in the Nervous System: Challenges and Opportunities for Novel Biomarkers in Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"14","author":[{"given":"Lorena","family":"Pisoni","sequence":"first","affiliation":[{"name":"Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0667-2396","authenticated-orcid":false,"given":"Luisa","family":"Donini","sequence":"additional","affiliation":[{"name":"Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3652-6173","authenticated-orcid":false,"given":"Paola","family":"Gagni","sequence":"additional","affiliation":[{"name":"Consiglio Nazionale delle Ricerche, Istituto di Scienze e Tecnologie Chimiche \u201cGiulio Natta\u201d (SCITEC-CNR), 20131 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8634-0767","authenticated-orcid":false,"given":"Maria","family":"Pennuto","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"},{"name":"Veneto Institute of Molecular Medicine (VIMM), 35129 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Ratti","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"},{"name":"Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20145 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Verde","sequence":"additional","affiliation":[{"name":"Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20145 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, \u201cDino Ferrari\u201d Center, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5963-7426","authenticated-orcid":false,"given":"Nicola","family":"Ticozzi","sequence":"additional","affiliation":[{"name":"Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, 20145 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, \u201cDino Ferrari\u201d Center, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9244-9782","authenticated-orcid":false,"given":"Jessica","family":"Mandrioli","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Ospedale Civile Baggiovara, Azienda Ospedaliero Universitaria di Modena, 41126 Modena, Italy"},{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5122-7243","authenticated-orcid":false,"given":"Andrea","family":"Calvo","sequence":"additional","affiliation":[{"name":"ALS Centre, \u201cRita Levi Montalcini\u201d Department of Neuroscience, University of Torino, 10120 Torino, Italy"},{"name":"Azienda Ospedaliero-Universitaria Citt\u00e0 della Salute e della Scienza di Torino, SC Neurologia 1U, 10120 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Basso","sequence":"additional","affiliation":[{"name":"Department of Cellular, Computational and Integrative Biology-CIBIO, University of Trento, 38123 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s00401-018-1816-0","article-title":"Cluster: Barriers of the 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