The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis
Abstract
Objective: The neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is a heterogeneous clinical syndrome involving multiple molecular pathways. The development of biomarkers for use in therapeutic trials is a priority. We sought to use a high‐throughput proteomic method to identify novel biomarkers in individual cerebrospinal fluid (CSF) samples. Methods: Liquid chromatography/tandem mass spectrometry with label‐free quantification was used to identify CSF proteins using samples from a well‐characterized longitudinal cohort comprising patients with ALS (n = 43), the upper motor neuron variant, primary lateral sclerosis (PLS; n = 6), and cross‐sectional healthy (n = 20) and disease controls (Parkinsons' disease, n = 20; ALS mimic disorders, n = 12). Results: Three macrophage‐derived chitinases showed increased abundance in ALS: chitotriosidase (CHIT1), chitinase‐3‐like protein 1 (CHI3L1), and chitinase‐3‐like protein 2 (CHI3L2). Elevated CHI3L1 was common to ALS and PLS, whereas CHIT1 and CHI3L2 levels differed. Chitinase levels correlated with disease progression rate (CHIT1, r = 0.56, p < 0.001; CHI3L1, r = 0.31; p = 0.028; CHI3L2, r = 0.29, p = 0.044). CHIT1, CHI3L1, and CHI3L2 levels correlated with phosphorylated neurofilament heavy chain (pNFH; r = 0.62, p < 0.001; r = 0.49, p < 0.001; r = 0.41, p < 0.001). CHI3L1 levels, but not CHIT1 or CHI3L2, increased over time in those with low initial levels (gradient = 0.005 log abundance units/month, p = 0.001). High CHIT1 was associated with shortened survival (hazard ratio [HR] 2.84; p = 0.009). Inclusion of pNFH in survival models left only an association of pNFH and survival (HR 1.26; p = 0.019). Interpretation: Neuroinflammatory mechanisms have been consistently implicated through various experimental paradigms. These results support a key role for macrophage activity in ALS pathogenesis, offering novel target engagement and pharmacodynamic biomarkers for neuroinflammation‐focused ALS therapy. Ann Neurol 2018;83:258–268
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“ALS patients exhibit elevated macrophage markers in their CSF compared to unaffected controls [422]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [422]
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Self-citationMarked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease.
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Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis
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Items 101–130 of 130
Serum chitotriosidase-1 (CHIT1) as candidate biomarker for mitochondriopathies
Foerster, L., Scholle, L. M., Mayer, T., Schneider, I., Stoltenburg, G., Delank, K.-S., Kraya, T., Hahn, A., Strube, D., Koelsch, A. K., et al. (2025) · Journal of Neurology · doi:10.1007/s00415-025-12916-5 · Cited by 2
Adler, G. L., Kiernan, M. C., & Tan, R. H. (2025) · Annals of Neurology · doi:10.1002/ana.27300 · Cited by 2
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Xie, X., Wu, P. S., Wen, T., Jia, R., Zhang, R., Hu, F., Jin, J., Qin, X., & Chen, Q. Y. (2025) · Journal of Molecular Neuroscience · doi:10.1007/s12031-025-02416-6 · Cited by 2
“Elevated CSF total protein is often used as a biomarker for blood–brain barrier dysfunction, and is associated with various neurodegenerative disorders including ALS (Fautsch et al. 2023; Rushkevich et al. 2018; Thompson et al. 2018, 2019; Zhao et al. 2020; Agnello et al. 2021).”
Arslan, D., Ergul-Ulger, Z., Gökşen, S., İnan, B., Esendağlı, G., Erdem‐Özdamar, S., Tan, E., & Bekircan‐Kurt, C. E. (2025) · Neurological Sciences · doi:10.1007/s10072-025-08724-4 · Cited by 2
Fluid-based biomarkers of amyotrophic lateral sclerosis: recent advances and future prospects
Jiang, Y., Hu, S., Yang, B., Zhang, L., Wang, ·., Yang, G., & Zhang, H. (2026) · Brain Research · doi:10.1016/j.brainres.2026.150395 · Cited by 2
Wei, C., Zhu, Y., Li, S., Chen, W., Li, C., Jiang, S., & Xu, R. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.993424 · Cited by 2
“To date, numerous studies have identified a few biomarkers to distinguish ALS from healthy individuals, frontal temporal dementia, and other neurodegenerative diseases (Thompson et al., 2018; Calvo et al., 2019; Yamada et al., 2021); furthermore, biomarkers developed by some of these studies, are of complexity and dif…”
BackgroundGuo, N., Huang, W., Huang, J., Liu, Y., Zhu, K., & Gao, W. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1588968 · Cited by 4
Dols‐Icardo, O., Montal, V., Sirisi, S., López‐Pernas, G., Cervera‐Carles, L., Querol‐Vilaseca, M., Muñoz, L., Belbin, O., Alcolea, D. A., Molina‐Porcel, L., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.07.938662 · Cited by 2
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“Of note, the well-established ALS microglial marker CHIT-1 was . elevated in CSF of SOD1-ALS patients as previously described [26,27], but did not show a response to tofersen treatment.”
ResultMass Spectrometry-Based Proteomic Analysis in Neurodegenerative Disorders’ Research
Bulska, E., Bicka, M., Gawor, A., Karpiński, A., & Konopka, A. (2022) · Springer eBooks · doi:10.1007/978-3-030-63957-0_2-1 · Cited by 1
Extending the Interpretation of Biomarker Dynamics in SOD1 ‐ ALS Proteomics
Khan, H., & Khan, M. M. (2025) · Annals of Neurology · doi:10.1002/ana.78089 · Cited by 1
Mass Spectrometry-Based Proteomic Analysis in Neurodegenerative Disorders’ Research
Bulska, E., Bicka, M., Gawor, A., Karpiński, A., & Konopka, A. (2022) · Springer eBooks · doi:10.1007/978-3-030-95660-8_2 · Cited by 1
Amyotrophic Lateral Sclerosis: Neurochemical Biomarkers
Verde, F., & Ticozzi, N. (2022) · Springer eBooks · doi:10.1007/978-3-031-06731-0_16 · Cited by 1
Khorshidi, Z., Adibi, I., & Ghasemi, M. (2024) · Hormone Molecular Biology and Clinical Investigation · doi:10.1515/hmbci-2024-0007 · Cited by 1
Biofluid Biomarkers of Amyotrophic Lateral Sclerosis
Holdom, C. J., Steyn, F. J., Henderson, R. D., McCombe, P., Rogers, M., & Ngo, S. T. (2021) · Neuromethods · doi:10.1007/978-1-0716-1712-0_11 · Cited by 1
Introduction to Novel Motor Neuron Disease
Sibat, H. F., & Valdés, L. D. F. I. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.91921
“[12] used a high-throughput proteomic process to distinguish new biomarkers in patient’s cerebrospinal fluid (CSF), and they found that three macrophage-derived chitinases had increased concentration in ALS: chitinase-3-like protein 1, chitotriosidase, and chitinase-3-like protein 2.”
MethodDevelopment of Sandwich Assays for Potential Protein Biomarkers in Neurodegenerative Diseases
Yousef, J. (2020) · KTH Publication Database DiVA (KTH Royal Institute of Technology)
Clinical Controversies in Amyotrophic Lateral Sclerosis
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(2022) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2022.2120682
Current challenges in primary lateral sclerosis diagnosis
Santos, M. O., Swash, M., & de Carvalho, M. A. (2023) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2023.2295010
“The few biochemical studies aiming to differentiate between PLS and ALS based on CSF neurofilaments [68,69] and chit-inase proteins [70,71] have shown conflicting results.”
ResultBioinformatic Applications in Neuroscience
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Développement et mise au point de nouveaux outils analytiques dans une approche métabolomique
Bruno, C. (2021) · theses.fr (ABES) · doi:10.70675/7a97b7f4z8520z4ec0za3d6z3808bd39b633
Tran, C., Reddy, N., Thomas, J. K., Venugopal, V., & Bowser, R. P. (2026) · BMJ Neurology Open · doi:10.1136/bmjno-2025-001225 · Cited by 2
“Prior studies have reported increased levels of Chit-1 and CHI3L1 (YKL-40) in the CSF of ALS and other neurodegenerative diseases and specific glial subtypes that express either Chit-1 or CHI3L1.”
Multiplex Panel Detects Glial and Inflammatory Biomarker Signatures in Sporadic and C9orf72-ALS
Baskar, K., Steffke, C., Bernsen, S., Elmas, Z., Hesebeck‐Brinckmann, J., Schuster, J., Meyer, T., Weydt, P., Weishaupt, J. H., Brenner, D., et al. (2026) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000200618
Metadata
- Authors
- Thompson, A. G., Gray, E., Thézénas, M., Charles, P. D., Evetts, S., Hu, M. T., Talbot, K., Fischer, R., Kessler, B. M., & Turner, M. R.
- Affiliations
- University of Oxford (GB)
- Nuffield Department of Clinical Neurosciences University of Oxford United Kingdom
- Corresponding author
- Kessler, Benedikt M.
- Turner, Martin R.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2018-02
- Volume
- 83
- Issue
- 2
- Pages
- 258-268
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2794716002
- Cited by
- 130
- References
- 27
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 7 · 2023: 13 · 2022: 20 · 2021: 22 · 2020: 20 · 2019: 16 · 2018: 16
- FWCI
- 12.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council (MR/K01014X/1)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Keywords
- amyotrophic lateral sclerosis, cerebrospinal fluid biomarkers, chitotriosidase, YKL-40, primary lateral sclerosis, disease progression, survival prediction, neuroinflammation, proteomics
- MeSH terms
- Amyotrophic Lateral Sclerosis, Chitinases, Cross-Sectional Studies, Female, Humans, Macrophages, Male, Middle Aged, Cohort Studies, Biomarkers, Disease Progression, Proteomics
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