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Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and β, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPβ and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS., Competing Interests: Declaration of competing interest HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). MA has served at scientific advisory boards and lectures for Biogen, Merck, Sanofi and Genzyme. KB has served as a consultant and at advisory boards for Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd., Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. Authors are required to disclose financial or non-financial interests that are directly or indirectly related to the work submitted for publication., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Huntington's disease (HD) is a hereditary neurodegenerative disease, currently lacking disease-modifying treatments. Biomarkers are needed for objective assessment of disease progression. Evidence supports both complex protein aggregation and astrocyte activation in HD. This study assesses the 42 amino acid long amyloid beta (Aβ42) and glial fibrillary acidic protein (GFAP) as potential biomarkers in the cerebrospinal fluid (CSF) of HD mutation carriers., Methods: CSF from participants was obtained from three sites in Sweden. Clinical symptoms were graded with the composite Unified Huntington's disease rating scale (cUHDRS). Protein concentrations were measured using ELISA. Pearson correlations were calculated to assess disease progression association. Results were adjusted for age and collection site., Results: The study enrolled 28 manifest HD patients (ManHD), 13 premanifest HD gene-expansion carriers (PreHD) and 20 controls. Aβ42 levels did not differ between groups and there was no correlation with measures of disease progression. GFAP concentration was higher in ManHD (424 ng/l, SD 253) compared with both PreHD (266 ng/l, SD 92.4) and controls (208 ng/l, SD 83.7). GFAP correlated with both cUHDRS (r = -0.77, p < 0.001), and 5-year risk of disease onset (r = 0.70, p = 0.008)., Conclusion: We provide evidence that indicates CSF Aβ42 has limited potential as a biomarker for HD. GFAP is a potential biomarker of progression in HD. Validation in larger cohorts measuring GFAP in blood and CSF would be of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)