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Despite significant advances in brain imaging techniques, clinical practice still faces challenges due to infrastructure reliance and high resource demands. This review explores the current knowledge on blood\u2010based biomarkers that indicate brain pathology, which can assist in identifying at\u2010risk patients, diagnosing patients, predicting disease progression, and treatment response. We focus on the inherited metabolic disorders X\u2010linked adrenoleukodystrophy (X\u2010ALD) and metachromatic leukodystrophy (MLD) which share remarkable phenotypic variability. Disease\u2010specific increases in the lipid metabolites lyso\u2010PC26:0 in X\u2010ALD and sulfatides in MLD might contribute to predicting clinical manifestation. Disease\u2010unspecific biomarkers for axonal damage (neurofilament light chain protein, NfL) and glial degeneration (glial fibrillary acidic protein, GFAP) are able to distinguish X\u2010ALD and MLD phenotypes at the group level. The implementation of X\u2010ALD into newborn screening programs in various countries, including several U.S. states, has increased the demand for predictive blood\u2010based biomarkers capable of detecting the early conversion from the pre\u2010symptomatic to the early neuroinflammatory cerebral form of X\u2010ALD. Among different biomarkers, NfL has proven most effective in reflecting neuroinflammation and correlating with brain lesion volume and the magnetic resonance imaging (MRI)\u2010based severity scores. We discuss how NfL has moved from initial proof\u2010of\u2010principle towards proof\u2010of\u2010concept studies in brain disorders such as multiple sclerosis and how this knowledge could be applied for the clinical implementation of NfL in rare inherited metabolic disorders such as X\u2010ALD.<\/jats:p>","DOI":"10.1002\/jimd.70032","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T01:49:26Z","timestamp":1746496166000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Blood Biomarkers Reflecting Brain Pathology\u2014From Common Grounds to Rare Frontiers"],"prefix":"10.1002","volume":"48","author":[{"given":"Isabelle","family":"Weinhofer","sequence":"first","affiliation":[{"name":"Department Pathobiology of the Nervous System, Center for Brain Research Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulus","family":"Rommer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0182-2658","authenticated-orcid":false,"given":"Johannes","family":"Berger","sequence":"additional","affiliation":[{"name":"Department Pathobiology of the Nervous System, Center for Brain Research Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,5]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207507"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/8503859"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010024\u201003499\u2010x"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1067\/mcp.2001.113989"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/1535370217750088"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207193"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jdn.10003"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.2147\/TACG.S49590"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.445445"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy299"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt361"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2013.11.023"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awy127"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974\u2010022\u201002664\u2010y"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1994.2855"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410400221"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43856\u2010024\u201000605\u20109"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200571"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2405541"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2400442"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae169"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2024.6774"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.101"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2023.107678"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2024.6771"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.23.9436"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.576221"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcyt.2024.03.487"},{"key":"e_1_2_12_30_1","first-page":"1761","article-title":"Adrenoleukodystrophy: A Scoring Method for Brain MR Observations","volume":"15","author":"Loes D. 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