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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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Cites
DeLong, E. R., DeLong, D. M., & Clarke-Pearson, D. L. (1988) · Biometrics · doi:10.2307/2531595 · Cited by 22,649
Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., et al. (2006) · Science · doi:10.1126/science.1134108 · Cited by 6,576
El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis
Brooks, B. R., Miller, R. G., Swash, M., & Munsat, T. L. (2000) · Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders · doi:10.1080/146608200300079536 · Cited by 5,433
Kiernan, M. C., Vucic, S., Cheah, B. C., Turner, M. R., Eisen, A., Hardiman, O., Burrell, J. R., & Zoing, M. C. (2011) · The Lancet · doi:10.1016/s0140-6736(10)61156-7 · Cited by 2,603
Self-citationMarked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease.
Hollak, C. E., van Weely, S., van Oers, M. H., & Aerts, J. M. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117084 · Cited by 896
Turner, M. R., Cagnin, A., Turkheimer, F. E., Miller, C. C. J., Shaw, C. E., Brooks, D. J., Leigh, P. N., & Banati, R. B. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2003.12.012 · Cited by 737
Self-citationPerry, V. H., & Teeling, J. L. (2013) · Seminars in Immunopathology · doi:10.1007/s00281-013-0382-8 · Cited by 638
The natural history of primary lateral sclerosis
Gordon, P. H., Cheng, B., Katz, I., Pinto, M., Hays, A. P., Mitsumoto, H., & Rowland, L. P. (2006) · Neurology · doi:10.1212/01.wnl.0000200962.94777.71 · Cited by 370
Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis
Comabella, M., Fernández, M., Martinꝉ, R., Rivera-Vallvé, S., Borràs, E., Chiva, C., Julià, E., Rovira, À., Cantó, E., Alvarez-Cermeño, J. C., et al. (2010) · Brain · doi:10.1093/brain/awq035 · Cited by 304
Brettschneider, J., Toledo, J. B., Van Deerlin, V. M., Elman, L., McCluskey, L., Lee, V. M.-Y., & Trojanowski, J. Q. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039216 · Cited by 268
Keilhauer, E. C., Hein, M. Y., & Mann, M. (2014) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m114.041012 · Cited by 260
Menke, R., Körner, S., Filippini, N., Douaud, G., Knight, S., Talbot, K., & Turner, M. R. (2014) · Brain · doi:10.1093/brain/awu162 · Cited by 194
Self-citationA CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis
Mitchell, R. M., Freeman, W. M., Randazzo, W. T., Stephens, H., Beard, J. L., Simmons, Z., & Connor, J. R. (2008) · Neurology · doi:10.1212/01.wnl.0000333251.36681.a5 · Cited by 184
Biobanking of CSF: International standardization to optimize biomarker development
Teunissen, C. E., Tumani, H., Engelborghs, S., & Mollenhauer, B. (2014) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2013.12.024 · Cited by 137
Steinacker, P., Verde, F., Fang, L., Feneberg, E., Oeckl, P., Roeber, S., Anderl-Straub, S., Danek, A., Diehl-Schmid, J., Fassbender, K., et al. (2018) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp-2017-317138 · Cited by 129
Xu, Z., Henderson, R. D., David, M., & McCombe, P. (2016) · PLoS ONE · doi:10.1371/journal.pone.0164625 · Cited by 118
Chitinases and immunity: Ancestral molecules with new functions
Rosa, M. D., Distefano, G., Zorena, K., & Malaguarnera, L. (2015) · Immunobiology · doi:10.1016/j.imbio.2015.11.014 · Cited by 118
The role of statistical power analysis in quantitative proteomics
Levin, Y. (2011) · PROTEOMICS · doi:10.1002/pmic.201100033 · Cited by 117
Chitotriosidase - a putative biomarker for sporadic amyotrophic lateral sclerosis
Varghese, A. M., Sharma, A., Mishra, P. S., Vijayalakshmi, K., Harsha, H. C., Sathyaprabha, T. N., Bharath, S., Nalini, A., Alladi, P. A., & Raju, T. R. (2013) · Clinical Proteomics · doi:10.1186/1559-0275-10-19 · Cited by 109
Rentzos, M., Rombos, A., Nikolaou, C., Zoga, M., Zouvelou, V., Dimitrakopoulos, A., Alexakis, T., Tsoutsou, A., Samakovli, A., Michalopoulou, M., et al. (2010) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.2010.01333.x · Cited by 104
Collins, M. A., An, J., Hood, B. L., Conrads, T. P., & Bowser, R. P. (2015) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5b00804 · Cited by 101
Evaluation of CHI3L-1 and CHIT-1 Expression in Differentiated and Polarized Macrophages
Rosa, M. D., Malaguarnera, G., Gregorio, C. D., Drago, F., & Malaguarnera, L. (2012) · Inflammation · doi:10.1007/s10753-012-9569-8 · Cited by 100
Glial activation colocalizes with structural abnormalities in amyotrophic lateral sclerosis
Alshikho, M. J., Zürcher, N. R., Loggia, M. L., Cernasov, P., Chonde, D. B., Izquierdo‐Garcia, D., Yasek, J. E., Akeju, O., Catana, C., Rosen, B. R., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000003427 · Cited by 90
Myelin imaging in amyotrophic and primary lateral sclerosis
Kolind, S., Sharma, R., Knight, S., Johansen‐Berg, H., Talbot, K., & Turner, M. R. (2013) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.3109/21678421.2013.794843 · Cited by 70
Self-citationCHI3L1 and CHI3L2 overexpression in motor cortex and spinal cord of sALS patients
Sanfilippo, C., Longo, A., Lazzara, F., Cambria, D., Distefano, G., Palumbo, M., Cantarella, A., Malaguarnera, L., & Rosa, M. D. (2017) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2017.10.001 · Cited by 69
Møllgaard, M. V., Degn, M., Sellebjerg, F. T., Frederiksen, J. L., & Modvig, S. (2016) · European Journal of Neurology · doi:10.1111/ene.12960 · Cited by 67
Ensuring continued progress in biomarkers for amyotrophic lateral sclerosis
Turner, M. R., & Benatar, M. G. (2014) · Muscle & Nerve · doi:10.1002/mus.24470 · Cited by 58
Self-citation
Research works printed but not linked: 1
- R Core Team, 2015, R: A language and environment for statistical computing. 3.2.3 ed
Cited by
Sorted by citations
Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189
“[422], presumably due to increased CNS microglia or their activation, as suggested by positron emission tomography”
BackgroundProteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease
Karayel, Ö., Winter, S. V., Padmanabhan, S., Kuras, Y. I., Vu, D. T., Tuncali, I., Merchant, K., Wills, A.-M. A., Scherzer, C. R., & Mann, M. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100661 · Cited by 161
Non-neuronal cells in amyotrophic lateral sclerosis — from pathogenesis to biomarkers
Vahsen, B. F., Gray, E., Thompson, A. G., Ansorge, O., Anthony, D. C., Cowley, S. A., Talbot, K., & Turner, M. R. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-021-00487-8 · Cited by 147
Self-citationLiguori, M., Nuzziello, N., Introna, A., Consiglio, A., Licciulli, F., D’Errico, E., Scarafino, A., Distaso, E., & Simone, I. L. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00288 · Cited by 131
Humphrey, J., Venkatesh, S., Hasan, R., Herb, J. T., de Paiva Lopes, K., Küçükali, F., Byrska-Bishop, M., Evani, U. S., Narzisi, G., Fagegaltier, D., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01205-3 · Cited by 138
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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