Skip to main content

Advertisement

SpringerLink
Log in

Amyloid and Tau as cerebrospinal fluid biomarkers in anti-N-Methyl-D-aspartate receptor encephalitis

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Introduction

Neuroinfection is associated with the deposition of amyloid-beta (Aβ) peptides, and subsequent decrease in cerebrospinal fluid (CSF) amyloid levels. However, whether autoimmune encephalitis involves extracellular deposition of Aβ peptides in the brain is unreported.

Methods

We examined CSF amyloid and tau values in adults with anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E). Forty-two patients with NMDAR-E, 35 patients with viral and bacterial neuroinfections, and 16 controls were included. We measured CSF Aβ1–42 (cAβ1–42), Aβ1–40 (cAβ1–40), t-Tau (ct-Tau), and p-Tau181 (cp-Tau181) levels and assessed their efficacies regarding differential diagnosis and predicting prognosis.

Results

NMDAR-E patients had lower cAβ1–42 levels; however, they were higher than those of patients with bacterial meningitis. ct-Tau levels in NMDAR-E patients were lower than those in patients with neuroinfections. No changes were observed in controls. cAβ1–42 and ct-Tau were combined as an excellent marker to distinguish NMDAR-E from neuroinfections. cAβ1–42 levels in NMDAR-E patients were positively correlated with Montreal Cognitive Assessment scores. We observed an inverse relationship between cAβ1–42 levels and modified Rankin Scale scores. Patients with poor outcomes exhibited low cAβ1–42 levels and high levels of several blood parameters. cAβ1–42 was the highest quality biomarker for assessing NMDAR-E prognosis. Correlations were found between cAβ1–42 and some inflammatory indicators.

Conclusion

cAβ1–42 was decreased in NMDAR-E patients. cAβ1–42 levels indicated NMDAR-E severity and acted as a biomarker for its prognosis. Combining cAβ1–42 and ct-Tau levels could serve as a novel differential diagnostic marker for NMDAR-E.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

The original data underlying our research are available within this article.

References

  1. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15(4):391–404. https://doi.org/10.1016/S1474-4422(15)00401-9

    Article  PubMed  PubMed Central  Google Scholar 

  2. Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12(2):157–165. https://doi.org/10.1016/S1474-4422(12)70310-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lancaster E, Dalmau J (2012) Neuronal autoantigens–pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 8(7):380–390. https://doi.org/10.1038/nrneurol.2012.99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ho ACC, Mohammad SS, Pillai SC, Tantsis E, Jones H, Ho R, Lim M, Hacohen Y, Vincent A, Dale RC (2017) High sensitivity and specificity in proposed clinical diagnostic criteria for anti-N-methyl-D-aspartate receptor encephalitis. Dev Med Child Neurol 59(12):1256–1260. https://doi.org/10.1111/dmcn.13579

    Article  PubMed  Google Scholar 

  5. Balu R, McCracken L, Lancaster E, Graus F, Dalmau J, Titulaer MJ (2019) A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology 92(3):e244–e252. https://doi.org/10.1212/WNL.0000000000006783

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hansen HC, Klingbeil C, Dalmau J, Li W, Weissbrich B, Wandinger KP (2013) Persistent intrathecal antibody synthesis 15 years after recovering from anti-N-methyl-D-aspartate receptor encephalitis. JAMA Neurol 70(1):117–119. https://doi.org/10.1001/jamaneurol.2013.585

    Article  PubMed  PubMed Central  Google Scholar 

  7. Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8(6):595–608. https://doi.org/10.15252/emmm.201606210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6(3):131–144. https://doi.org/10.1038/nrneurol.2010.4

    Article  CAS  PubMed  Google Scholar 

  9. Leng F, Edison P (2021) Neuroinflammation and microglial activation in Alzheimer’s disease: where do we go from here? Nat Rev Neurol 17(3):157–172. https://doi.org/10.1038/s41582-020-00435-y

    Article  PubMed  Google Scholar 

  10. Heppner FL, Ransohoff RM, Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16(6):358–372. https://doi.org/10.1038/nrn3880

    Article  CAS  PubMed  Google Scholar 

  11. Lövheim H, Gilthorpe J, Adolfsson R, Nilsson LG, Elgh F (2015) Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimers Dement 11(6):593–599. https://doi.org/10.1016/j.jalz.2014.04.522

    Article  PubMed  Google Scholar 

  12. Zhan X, Stamova B, Jin LW, Decarli C, Phinney B, Sharp FR (2016) Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology 87(22):2324–2332. https://doi.org/10.1212/WNL.0000000000003391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pisa D, Alonso R, Rábano A, Horst MN, Carrasco L (2016) Fungal enolase, β-tubulin, and chitin are detected in brain tissue from Alzheimer’s disease patients. Front Microbiol 7:1772. https://doi.org/10.3389/fmicb.2016.01772

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hur JY, Frost GR, Wu X, Crump C, Pan SJ, Wong E, Barros M, Li T, Nie P, Zhai Y, Wang JC, Tcw J, Guo L, McKenzie A, Ming C, Zhou X, Wang M, Sagi Y, Renton AE, Esposito BT, Kim Y, Sadleir KR, Trinh I, Rissman RA, Vassar R, Zhang B, Johnson DS, Masliah E, Greengard P, Goate A, Li YM (2020) The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease. Nature 586(7831):735–740. https://doi.org/10.1038/s41586-020-2681-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Abbott A (2020) Are infections seeding some cases of Alzheimer’s disease? Nature 587(7832):22–25. https://doi.org/10.1038/d41586-020-03084-9

    Article  CAS  PubMed  Google Scholar 

  16. Sühs KW, Novoselova N, Kuhn M, Seegers L, Kaever V, Müller-Vahl K, Trebst C, Skripuletz T, Stangel M, Pessler F (2019) Kynurenine is a cerebrospinal fluid biomarker for bacterial and viral central nervous system infections. J Infect Dis 220(1):127–138. https://doi.org/10.1093/infdis/jiz048

    Article  CAS  PubMed  Google Scholar 

  17. de Araujo LS, Pessler K, Sühs KW, Novoselova N, Klawonn F, Kuhn M, Kaever V, Müller-Vahl K, Trebst C, Skripuletz T, Stangel M, Pessler F (2020) Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis. J Transl Med 18(1):9. https://doi.org/10.1186/s12967-019-02179-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Krut JJ, Zetterberg H, Blennow K, Cinque P, Hagberg L, Price RW, Studahl M, Gisslén M (2013) Cerebrospinal fluid Alzheimer’s biomarker profiles in CNS infections. J Neurol 260(2):620–626. https://doi.org/10.1007/s00415-012-6688-y

    Article  CAS  PubMed  Google Scholar 

  19. Spitzer P, Lang R, Oberstein TJ, Lewczuk P, Ermann N, Huttner HB, Masouris I, Kornhuber J, Ködel U, Maler JM (2018) A specific reduction in Aβ1–42 vs. a universal loss of Aβ peptides in CSF differentiates Alzheimer’s disease from meningitis and multiple sclerosis. Front Aging Neurosci 10:152. https://doi.org/10.3389/fnagi.2018.00152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Stroffolini G, Guastamacchia G, Audagnotto S, Atzori C, Trunfio M, Nigra M, Di Stefano A, Di Perri G, Calcagno A (2021) Low cerebrospinal fluid Amyloid-βeta 1–42 in patients with tuberculous meningitis. BMC Neurol 21(1):449. https://doi.org/10.1186/s12883-021-02468-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brew BJ, Pemberton L, Blennow K, Wallin A, Hagberg L (2005) CSF amyloid beta42 and tau levels correlate with AIDS dementia complex. Neurology 65(9):1490–1492. https://doi.org/10.1212/01.wnl.0000183293.95787.b7

    Article  CAS  PubMed  Google Scholar 

  22. Di Stefano A, Alcantarini C, Atzori C, Lipani F, Imperiale D, Burdino E, Audagnotto S, Mighetto L, Milia MG, Di Perri G, Calcagno A (2020) Cerebrospinal fluid biomarkers in patients with central nervous system infections: a retrospective study. CNS Spectr 25(3):402–408. https://doi.org/10.1017/S1092852919000981

    Article  PubMed  Google Scholar 

  23. Sulik A, Toczylowski K, Kulczynska-Przybik A, Mroczko B (2022) Amyloid and Tau protein concentrations in children with meningitis and encephalitis. Viruses 14(4):725. https://doi.org/10.3390/v14040725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD (2016) Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med 8(340):340ra72. https://doi.org/10.1126/scitranslmed.aaf1059

    Article  CAS  PubMed  Google Scholar 

  25. Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, György B, Breakefield XO, Tanzi RE, Moir RD (2018) Alzheimer’s disease-associated β-amyloid is rapidly seeded by Herpesviridae to protect against brain infection. Neuron 99(1):56-63.e3. https://doi.org/10.1016/j.neuron.2018.06.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Makin S (2018) The amyloid hypothesis on trial. Nature 559(7715):S4–S7. https://doi.org/10.1038/d41586-018-05719-4

    Article  CAS  PubMed  Google Scholar 

  27. Ezzat K, Pernemalm M, Pålsson S, Roberts TC, Järver P, Dondalska A, Bestas B, Sobkowiak MJ, Levänen B, Sköld M, Thompson EA, Saher O, Kari OK, Lajunen T, Sverremark Ekström E, Nilsson C, Ishchenko Y, Malm T, Wood MJA, Power UF, Masich S, Lindén A, Sandberg JK, Lehtiö J, Spetz AL, El Andaloussi S (2019) The viral protein corona directs viral pathogenesis and amyloid aggregation. Nat Commun 10(1):2331. https://doi.org/10.1038/s41467-019-10192-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zetterberg H (2017) Review: tau in biofluids - relation to pathology, imaging and clinical features. Neuropathol Appl Neurobiol 43(3):194–199. https://doi.org/10.1111/nan.12378

    Article  CAS  PubMed  Google Scholar 

  29. Huang Q, Xie Y, Hu Z, Tang X (2020) Anti-N-methyl-D-aspartate receptor encephalitis: a review of pathogenic mechanisms, treatment, prognosis. Brain Res 1727:146549. https://doi.org/10.1016/j.brainres.2019.146549

    Article  CAS  PubMed  Google Scholar 

  30. Pietroboni AM, Schiano di Cola F, Scarioni M, Fenoglio C, Spanò B, Arighi A, Cioffi SM, Oldoni E, De Riz MA, Basilico P, Calvi A, Fumagalli GG, Triulzi F, Galimberti D, Bozzali M, Scarpini E (2017) CSF β-amyloid as a putative biomarker of disease progression in multiple sclerosis. Mult Scler 23(8):1085–1091. https://doi.org/10.1177/1352458516674566

    Article  CAS  PubMed  Google Scholar 

  31. Pietroboni AM, Caprioli M, Carandini T, Scarioni M, Ghezzi L, Arighi A, Cioffi S, Cinnante C, Fenoglio C, Oldoni E, De Riz MA, Basilico P, Fumagalli GG, Colombi A, Giulietti G, Serra L, Triulzi F, Bozzali M, Scarpini E, Galimberti D (2019) CSF β-amyloid predicts prognosis in patients with multiple sclerosis. Mult Scler 25(9):1223–1231. https://doi.org/10.1177/1352458518791709

    Article  CAS  PubMed  Google Scholar 

  32. Virgilio E, Vecchio D, Crespi I, Serino R, Cantello R, Dianzani U, Comi C (2021) Cerebrospinal tau levels as a predictor of early disability in multiple sclerosis. Mult Scler Relat Disord 56:103231. https://doi.org/10.1016/j.msard.2021.103231

    Article  CAS  PubMed  Google Scholar 

  33. Lin J, Xiang Q, Liu X, Li J (2022) Risk factors and prognosis in patients with anti-N-methyl-D-aspartate receptor encephalitis requiring prolonged mechanical ventilation. Front Neurol 13:814673. https://doi.org/10.3389/fneur.2022.814673

    Article  PubMed  PubMed Central  Google Scholar 

  34. Peng Y, Zheng D, Zhang X, Pan S, Ji T, Zhang J, Shen HY, Wang HH (2019) Cell-free mitochondrial DNA in the CSF: a potential prognostic biomarker of anti-NMDAR encephalitis. Front Immunol 10:103. https://doi.org/10.3389/fimmu.2019.00103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ciano-Petersen NL, Cabezudo-García P, Muñiz-Castrillo S, Honnorat J, Serrano-Castro PJ, Oliver-Martos B (2021) Current status of biomarkers in anti-N-methyl-D-aspartate receptor encephalitis. Int J Mol Sci 22(23):13127. https://doi.org/10.3390/ijms222313127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ma X, Lu Y, Peng F, Wang Y, Sun X, Luo W, Shen S, Liu Z, Kermode AG, Qiu W, Shu Y (2022) Serum NfL associated with anti-NMDA receptor encephalitis. Neurol Sci 43(6):3893–3899. https://doi.org/10.1007/s10072-021-05838-3

    Article  PubMed  Google Scholar 

  37. Hou JH, Ou YN, Xu W, Zhang PF, Tan L, Yu JT, Alzheimer’s Disease Neuroimaging Initiative (2022) Association of peripheral immunity with cognition, neuroimaging, and Alzheimer’s pathology. Alzheimers Res Ther 14(1):29. https://doi.org/10.1186/s13195-022-00968-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li W, Li S, Shang Y, Zhuang W, Yan G, Chen Z, Lyu J (2023) Associations between dietary and blood inflammatory indices and their effects on cognitive function in elderly Americans. Front Neurosci 17:1117056. https://doi.org/10.3389/fnins.2023.1117056

    Article  PubMed  PubMed Central  Google Scholar 

  39. Shao Y, Du J, Song Y, Li Y, Jing L, Gong Z, Duan R, Yao Y, Jia Y, Jiao S (2022) Elevated plasma D-dimer levels in patients with anti-N-methyl-D-aspartate receptor encephalitis. Front Neurol 13:1022785. https://doi.org/10.3389/fneur.2022.1022785

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wannamethee SG, Whincup PH, Lennon L, Papacosta O, Lowe GD (2014) Associations between fibrin D-dimer, markers of inflammation, incident self-reported mobility limitation, and all-cause mortality in older men. J Am Geriatr Soc 62(12):2357–2362. https://doi.org/10.1111/jgs.13133

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all the trial participants and clinical staff for their contributions and effort to the study, and the Editage team for English language editing.

Funding

This work was supported by the National Key R&D Program of China (2018YFC131400 and 2018YFC1314403) and the National Natural Science Foundation of China (NSFC 82001290).

Author information

Author notes

  1. Qianmeng Hao and Zhe Gong contributed equally to this work.

Authors and Affiliations

  1. Department of Blood Transfusion, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450053, Henan, China

    Qianmeng Hao, Yali Wang, Weiwei Meng, Wei Wu & Yulin Zhang

  2. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Zhe Gong, Yajun Song & Yanfei Li

Authors
  1. Qianmeng Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhe Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yajun Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yali Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weiwei Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yanfei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yulin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Qianmeng Hao sorted the data, conducted the analyses, and wrote the manuscript. Zhe Gong performed the experiments and collected the clinical data. Yajun Song and Yali Wang contributed to collecting the clinical data. Weiwei Meng, Wei Wu and Yanfei Li contributed to complete the manuscript. Yulin Zhang designed the study. All the authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Yulin Zhang.

Ethics declarations

Competing Interests Disclosure

The authors declare that there are no conflicts of interest in connection with this article.

Ethics Approval

This study was approved by the Ethics Committee of Zhengzhou University, China (2019-KY-018) and written informed consent was obtained from all participants.

Patient Consent Statement

Written informed consent of all the participants was obtained before grouping.

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.

Supplementary file1 (DOCX 14 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hao, Q., Gong, Z., Song, Y. et al. Amyloid and Tau as cerebrospinal fluid biomarkers in anti-N-Methyl-D-aspartate receptor encephalitis. Neurol Sci (2024). https://doi.org/10.1007/s10072-024-07341-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10072-024-07341-x

Keywords

Search

Navigation