Abstract
Serum neurofilament light chain (NfL) and chitinase 3-like 1 (CHI3L1, also called YKL-40) concentrations are attractive candidate biomarkers for neurodegenerative disorders, which include amyotrophic lateral sclerosis (ALS) and parkinsonian disorders. We aimed to assess the diagnostic power of serum NfL and CHI3L1 concentrations with regard to the early diagnosis of ALS and Parkinson’s disease (PD). We studied 157 individuals, which included 41 healthy controls, 8 patients with ALS mimics, 18 patients initially diagnosed with ALS (ID-ALS), 32 patients late-diagnosed with ALS (LD-ALS), 29 patients with PD, 12 patients with PD mimics, and 17 patients initially diagnosed with atypical parkinsonian disorders (ID-APDs) at the initial stage of diagnosis. Electrochemiluminescence was used to measure the concentrations of serum NfL and CHI3L1, the diagnostic performance of which was assessed using the area under the receiver operating curves (AUCs). The AUCs of serum NfL were 0.90 for discriminating ALS mimics from LD-ALS at the initial stage of diagnosis and 0.89 for discriminating ALS mimics from ALS (LD/ID-ALS). The AUCs of serum NfL were 0.76 for discriminating PD from PD mimics at the initial stage of diagnosis, and 0.80 for discriminating PD from APD. No significant difference existed in serum CHI3L1 concentrations between individuals with suspected ALS or parkinsonism (p = 0.14, and p = 0.44, respectively). Serum NfL had excellent and almost good diagnostic performances for patients with ALS and PD, respectively, at the initial stage of diagnosis, whereas no significant difference existed in serum CHI3L1 between any groups.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alagaratnam J, von Widekind S, De Francesco D, Underwood J, Edison P, Winston A, Zetterberg H, Fidler S (2021) Correlation between CSF and blood neurofilament light chain protein: a systematic review and meta-analysis. BMJ Neurol Open 3(1):e000143. https://doi.org/10.1136/bmjno-2021-000143
Alcolea D, Vilaplana E, Suárez-Calvet M, Illán-Gala I, Blesa R, Clarimón J, Lladó A, Sánchez-Valle R, Molinuevo JL, García-Ribas G, Compta Y, Martí MJ, Piñol-Ripoll G, Amer-Ferrer G, Noguera A, García-Martín A, Fortea J, Lleó A (2017) CSF sAPPβ, YKL-40, and neurofilament light in frontotemporal lobar degeneration. Neurology 89(2):178–188. https://doi.org/10.1212/wnl.0000000000004088
Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B, Boxer AL, Dickson DW, Grossman M, Hallett M, Josephs KA, Kertesz A, Lee SE, Miller BL, Reich SG, Riley DE, Tolosa E, Troster AI, Vidailhet M, Weiner WJ (2013) Criteria for the diagnosis of corticobasal degeneration. Neurology 80(5):496–503. https://doi.org/10.1212/WNL.0b013e31827f0fd1
Benatar M, Wuu J, Andersen PM, Lombardi V, Malaspina A (2018) Neurofilament light: a candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion. Ann Neurol 84(1):130–139. https://doi.org/10.1002/ana.25276
Benatar M, Wuu J, Lombardi V, Jeromin A, Bowser R, Andersen PM, Malaspina A (2019) Neurofilaments in pre-symptomatic ALS and the impact of genotype. Amyotroph Lateral Scler Front Degener 20(7–8):538–548. https://doi.org/10.1080/21678421.2019.1646769
Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 169(1–2):13–21
Costa J, Swash M, de Carvalho M (2012) Awaji criteria for the diagnosis of amyotrophic lateral sclerosis:a systematic review. Arch Neurol 69(11):1410–1416. https://doi.org/10.1001/archneurol.2012.254
Di Rosa M, Distefano G, Zorena K, Malaguarnera L (2016) Chitinases and immunity: ancestral molecules with new functions. Immunobiology 221(3):399–411. https://doi.org/10.1016/j.imbio.2015.11.014
Feneberg E, Oeckl P, Steinacker P, Verde F, Barro C, Van Damme P, Gray E, Grosskreutz J, Jardel C, Kuhle J, Koerner S, Lamari F, Amador MDM, Mayer B, Morelli C, Muckova P, Petri S, Poesen K, Raaphorst J, Salachas F, Silani V, Stubendorff B, Turner MR, Verbeek MM, Weishaupt JH, Weydt P, Ludolph AC, Otto M (2018) Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis. Neurology 90(1):e22–e30. https://doi.org/10.1212/wnl.0000000000004761
Forsaa EB, Larsen JP, Wentzel-Larsen T, Alves G (2010) What predicts mortality in Parkinson disease?: a prospective population-based long-term study. Neurology 75(14):1270–1276. https://doi.org/10.1212/WNL.0b013e3181f61311
Gaetani L, Blennow K, Calabresi P, Di Filippo M, Parnetti L, Zetterberg H (2019) Neurofilament light chain as a biomarker in neurological disorders. J Neurol Neurosurg Psychiatry 90(8):870–881. https://doi.org/10.1136/jnnp-2018-320106
Gaiani A, Martinelli I, Bello L, Querin G, Puthenparampil M, Ruggero S, Toffanin E, Cagnin A, Briani C, Pegoraro E, Sorarù G (2017) Diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis: neurofilament light chain levels in definite subtypes of disease. JAMA Neurol 74(5):525–532. https://doi.org/10.1001/jamaneurol.2016.5398
Gille B, De Schaepdryver M, Dedeene L, Goossens J, Claeys KG, Van Den Bosch L, Tournoy J, Van Damme P, Poesen K (2019) Inflammatory markers in cerebrospinal fluid: independent prognostic biomarkers in amyotrophic lateral sclerosis? J Neurol Neurosurg Psychiatry 90(12):1338–1346. https://doi.org/10.1136/jnnp-2018-319586
Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71(9):670–676. https://doi.org/10.1212/01.wnl.0000324625.00404.15
Gray E, Thompson AG, Wuu J, Pelt J, Talbot K, Benatar M, Turner MR (2020) CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis. Ann Clin Transl Neurol. https://doi.org/10.1002/acn3.51114
Hall S, Janelidze S, Surova Y, Widner H, Zetterberg H, Hansson O (2018) Cerebrospinal fluid concentrations of inflammatory markers in Parkinson’s disease and atypical parkinsonian disorders. Sci Rep 8(1):13276. https://doi.org/10.1038/s41598-018-31517-z
Hansson O, Janelidze S, Hall S, Magdalinou N, Lees AJ, Andreasson U, Norgren N, Linder J, Forsgren L, Constantinescu R, Zetterberg H, Blennow K (2017) Blood-based NfL: a biomarker for differential diagnosis of parkinsonian disorder. Neurology 88(10):930–937. https://doi.org/10.1212/wnl.0000000000003680
Hoglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, Mollenhauer B, Muller U, Nilsson C, Whitwell JL, Arzberger T, Englund E, Gelpi E, Giese A, Irwin DJ, Meissner WG, Pantelyat A, Rajput A, van Swieten JC, Troakes C, Antonini A, Bhatia KP, Bordelon Y, Compta Y, Corvol JC, Colosimo C, Dickson DW, Dodel R, Ferguson L, Grossman M, Kassubek J, Krismer F, Levin J, Lorenzl S, Morris HR, Nestor P, Oertel WH, Poewe W, Rabinovici G, Rowe JB, Schellenberg GD, Seppi K, van Eimeren T, Wenning GK, Boxer AL, Golbe LI, Litvan I (2017) Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord 32(6):853–864. https://doi.org/10.1002/mds.26987
Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55(3):181–184. https://doi.org/10.1136/jnnp.55.3.181
Illán-Gala I, Alcolea D, Montal V, Dols-Icardo O, Muñoz L, de Luna N, Turón-Sans J, Cortés-Vicente E, Sánchez-Saudinós MB, Subirana A, Sala I, Blesa R, Clarimón J, Fortea J, Rojas-García R, Lleó A (2018) CSF sAPPβ, YKL-40, and NfL along the ALS-FTD spectrum. Neurology 91(17):e1619–e1628. https://doi.org/10.1212/wnl.0000000000006383
Kempster PA, O’Sullivan SS, Holton JL, Revesz T, Lees AJ (2010) Relationships between age and late progression of Parkinson’s disease: a clinico-pathological study. Brain 133(Pt 6):1755–1762. https://doi.org/10.1093/brain/awq059
Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T, Barro C, Kappos L, Comabella M, Fazekas F, Petzold A, Blennow K, Zetterberg H, Kuhle J (2018) Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol 14(10):577–589. https://doi.org/10.1038/s41582-018-0058-z
Kouli A, Horne CB, Williams-Gray CH (2019) Toll-like receptors and their therapeutic potential in Parkinson’s disease and α-synucleinopathies. Brain Behav Immun 81:41–51. https://doi.org/10.1016/j.bbi.2019.06.042
Kuhle J, Barro C, Andreasson U, Derfuss T, Lindberg R, Sandelius Å, Liman V, Norgren N, Blennow K, Zetterberg H (2016) Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa. Clin Chem Lab Med 54(10):1655–1661. https://doi.org/10.1515/cclm-2015-1195
Lin CH, Li CH, Yang KC, Lin FJ, Wu CC, Chieh JJ, Chiu MJ (2019) Blood NfL: a biomarker for disease severity and progression in Parkinson disease. Neurology 93(11):e1104–e1111. https://doi.org/10.1212/wnl.0000000000008088
Lu CH, Macdonald-Wallis C, Gray E, Pearce N, Petzold A, Norgren N, Giovannoni G, Fratta P, Sidle K, Fish M, Orrell R, Howard R, Talbot K, Greensmith L, Kuhle J, Turner MR, Malaspina A (2015) Neurofilament light chain: a prognostic biomarker in amyotrophic lateral sclerosis. Neurology 84(22):2247–2257. https://doi.org/10.1212/wnl.0000000000001642
Magdalinou N, Lees AJ, Zetterberg H (2014) Cerebrospinal fluid biomarkers in parkinsonian conditions: an update and future directions. J Neurol Neurosurg Psychiatry 85(10):1065–1075. https://doi.org/10.1136/jnnp-2013-307539
Marques TM, van Rumund A, Oeckl P, Kuiperij HB, Esselink RAJ, Bloem BR, Otto M, Verbeek MM (2019) Serum NFL discriminates Parkinson disease from atypical parkinsonisms. Neurology 92(13):e1479–e1486. https://doi.org/10.1212/wnl.0000000000007179
Ng ASL, Tan YJ, Yong ACW, Saffari SE, Lu Z, Ng EY, Ng SYE, Chia NSY, Choi X, Heng D, Neo S, Xu Z, Keong NCH, Tay KY, Au WL, Tan LCS, Tan EK (2020) Utility of plasma Neurofilament light as a diagnostic and prognostic biomarker of the postural instability gait disorder motor subtype in early Parkinson’s disease. Mol Neurodegener 15(1):33. https://doi.org/10.1186/s13024-020-00385-5
Olsson B, Constantinescu R, Holmberg B, Andreasen N, Blennow K, Zetterberg H (2013) The glial marker YKL-40 is decreased in synucleinopathies. Mov Disord 28(13):1882–1885. https://doi.org/10.1002/mds.25589
Rissin DM, Kan CW, Campbell TG, Howes SC, Fournier DR, Song L, Piech T, Patel PP, Chang L, Rivnak AJ, Ferrell EP, Randall JD, Provuncher GK, Walt DR, Duffy DC (2010) Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol 28(6):595–599. https://doi.org/10.1038/nbt.1641
Sako W, Murakami N, Izumi Y, Kaji R (2015) Neurofilament light chain level in cerebrospinal fluid can differentiate Parkinson’s disease from atypical parkinsonism: evidence from a meta-analysis. J Neurol Sci 352(1–2):84–87. https://doi.org/10.1016/j.jns.2015.03.041
Sanfilippo C, Longo A, Lazzara F, Cambria D, Distefano G, Palumbo M, Cantarella A, Malaguarnera L, Di Rosa M (2017) CHI3L1 and CHI3L2 overexpression in motor cortex and spinal cord of sALS patients. Mol Cell Neurosci 85:162–169. https://doi.org/10.1016/j.mcn.2017.10.001
Thompson AG, Gray E, Thézénas ML, Charles PD, Evetts S, Hu MT, Talbot K, Fischer R, Kessler BM, Turner MR (2018) Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis. Ann Neurol 83(2):258–268. https://doi.org/10.1002/ana.25143
Venezia S, Kaufmann WA, Wenning GK, Stefanova N (2021) Toll-like receptor 4 deficiency facilitates α-synuclein propagation and neurodegeneration in a mouse model of prodromal Parkinson’s disease. Parkinsonism Relat Disord 91:59–65. https://doi.org/10.1016/j.parkreldis.2021.09.007
Verde F, Steinacker P, Weishaupt JH, Kassubek J, Oeckl P, Halbgebauer S, Tumani H, von Arnim CAF, Dorst J, Feneberg E, Mayer B, Müller HP, Gorges M, Rosenbohm A, Volk AE, Silani V, Ludolph AC, Otto M (2019) Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 90(2):157–164. https://doi.org/10.1136/jnnp-2018-318704
Vu L, An J, Kovalik T, Gendron T, Petrucelli L, Bowser R (2020) Cross-sectional and longitudinal measures of chitinase proteins in amyotrophic lateral sclerosis and expression of CHI3L1 in activated astrocytes. J Neurol Neurosurg Psychiatry 91(4):350–358. https://doi.org/10.1136/jnnp-2019-321916
Wennström M, Surova Y, Hall S, Nilsson C, Minthon L, Hansson O, Nielsen HM (2015) The inflammatory marker YKL-40 is elevated in cerebrospinal fluid from patients with Alzheimer’s but not Parkinson’s disease or Dementia with Lewy bodies. PLoS ONE 10(8):e0135458. https://doi.org/10.1371/journal.pone.0135458
Wilson DH, Rissin DM, Kan CW, Fournier DR, Piech T, Campbell TG, Meyer RE, Fishburn MW, Cabrera C, Patel PP, Frew E, Chen Y, Chang L, Ferrell EP, von Einem V, McGuigan W, Reinhardt M, Sayer H, Vielsack C, Duffy DC (2016) The Simoa HD-1 analyzer: a novel fully automated digital immunoassay analyzer with single-molecule sensitivity and multiplexing. J Lab Autom 21(4):533–547. https://doi.org/10.1177/2211068215589580
Acknowledgements
We would like to thank Dr. Takahiro Furukawa for contribution to establishment of dataset of the present study.
Funding
This study was supported by Japan Society for Promotion of Science (JSPS) KAKENHI Grant Number 20K12670, Japan Intractable Disease (Nanbyo) Research Foundation, and Grants-in Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, the Ministry of Health, Labour and Welfare, Japan.
Author information
Authors and Affiliations
Contributions
WS conceived the idea for this research. WS, SH, and NM designed the experiments. WS, YO, and YI recruited the patients. NM measured concentrations of NfL and CHI3L1. SH analyzed the data. WS wrote the first draft of the manuscript, with important contributions from SH, NM, YO, and YI. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing interests.
Ethical approval
This study was approved by the ethics committee of Tokushima University Hospital (#2572).
Consent to participate
Written informed consent was obtained from all patients prior to participating in the study.
Consent for publication
All the authors of the manuscript have read the paper and agree to its submission.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
702_2022_2470_MOESM1_ESM.tif
Supplementary file 1 Figure S1. A–F NfL was not correlated with CHI3L1 in other groups (all subjects, rho = 0.16, p = 0.04; Ctr, rho = 0.00, p = 0.99; suspected ALS, rho = 0.12, p = 0.37; ALS mimics, rho = 0.05. p = 0.93; ID-ALS, rho = 0.40, p = 0.10; LD-ALS, rho = 0.04, p = 0.84). G–J NfL was correlated with CHI3L1 in parkinsonism (parkinsonism, rho = 0.46, p < 0.001; PD, rho = 0.48. p = 0.01; LD-APD, rho = 0.64, p = 0.03; ID-APD, rho = 0.53, p = 0.03). (TIF 329 KB)
702_2022_2470_MOESM2_ESM.tif
Supplementary file 2 Figure S2. The ROC curve analysis results of serum CHI3L1. A, B The AUCs are not significant for ALS mimics versus LD-ALS or ALS (LD/ID ALS). C, D The AUCs are not significant and around 0.6 for PD versus PD mimics (LD-APD) or APD (PD mimics/ID-APD). AUCs area under the curves; CHI3L1 chitinase 3-like 1; ID-ALS initially diagnosed with amyotrophic lateral sclerosis; ID-APD initially diagnosed with atypical parkinsonian disorders; LD-ALS late diagnosed with amyotrophic lateral sclerosis; LD-APD late diagnosed with atypical parkinsonian disorders; NfL neurofilament light chain; PD Parkinson’s disease; ROC, receiver operating characteristic. (TIF 789 KB)
702_2022_2470_MOESM3_ESM.tif
Supplementary file 3 Figure S3. The ROC curve analysis results of serum NfL and the combination of NfL and CHI3L1. Solid line indicates the ROC curve results of serum NfL, and dotted line indicates those of the combination of NfL and CHI3L1. A The AUCs of NfL and the combination of NfL and CHI3L1 were 0.90 and 0.89 for discriminating ALS mimics from LD-ALS at the initial stage of diagnosis (p = 0.48). B The AUCs of NfL only and the combination of NfL and CHI3L1 were 0.89 and 0.88 for discriminating ALS mimics from ALS (p = 0.57). C The AUCs of NfL only and the combination of NfL and CHI3L1 were 0.76 and 0.80 for discriminating PD from PD mimics at the initial stage of diagnosis (p = 0.36). D The AUCs of NfL only and combination of NfL and CHI3L1 were 0.80 and 0.83 for discriminating PD from APD (p = 0.39). The combination of NfL and CHI3L1 did not improve diagnostic performance in ALS and PD. (TIF 310 KB)
Rights and permissions
About this article
Cite this article
Haji, S., Sako, W., Murakami, N. et al. Serum NfL and CHI3L1 for ALS and parkinsonian disorders in the process of diagnosis. J Neural Transm 129, 301–309 (2022). https://doi.org/10.1007/s00702-022-02470-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-022-02470-z