Metabolic Characterization of Cerebrospinal Fluid for Patients With Autoimmune Encephalitis: A Preliminary Study

Overview

Journal CNS Neurosci Ther

Specialties Neurology
Pharmacology

Date 2025 Jan 3

PMID 39749658

Authors

Xiaolong Li

Xiaoxiao Qin

Yuan Xie

Lingyun Wang

Jinwen Wang

Shushen Ji

Huihui Jiang

Qun Wang

Affiliations

Soon will be listed here.

Abstract

Background: Metabolomics offers promise in uncovering potential biomarkers and understanding the pathophysiology of autoimmune encephalitis (AE), which is a cluster of disorders with the host immune system targeting self-antigens expressed in the central nervous system (CNS). In this research, our objective was to explore metabolic characterization in cerebrospinal fluid (CSF) from individuals with AE, aiming to shed light on the pathophysiology of AE.

Methods: A targeted approach was applied using an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system to study CSF metabolites in patients with AE (n = 18), and control subjects without neurological diseases (n = 17).

Results: A total of 21 potential biomarkers were acquired by getting the intersection of the differential metabolites from univariate statistics and multidimensional statistics between the AE (cell-based assay panel, CBA-panel) group and the control group. Specifically, the levels of pyruvic acid and oxoglutaric acid were notably elevated in the AE(CBA-panel) group compared to those in the control group, indicating that the dysregulated TCA cycle may play a pivotal role in the progression of AE(CBA-panel). Interestingly, 27 potential biomarkers were acquired by getting the intersection of the differential metabolites from univariate statistics and multidimensional statistics between the anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) group and the control group, suggesting that the disparities between patients with greater homogeneity and the controls are amplified. In addition, seven differential metabolites were identified by the univariate statistics between the AE (tissue-based assay, TBA) group and the control group, including alpha-linolenic acid and gamma-linolenic acid, suggesting that dysregulated biosynthesis of unsaturated fatty acids and alpha-linolenic acid metabolism might be crucial in the AE(TBA) disease course.

Conclusion: Collectively, distinct metabolic profiles were evident in the CSF of the AE group compared to the control group, notably involving metabolites associated with mitochondrial dysfunction, which helped to elucidate the pathophysiology of AE.

References

Solmaz I, Kaplan O, Celebier M, Lay I, Anlar B . A combination of Q-TOF LC/MS and LC-MS/MS based metabolomics in pediatric-onset multiple sclerosis demonstrates potential biomarkers for unclassified patients. Turk J Med Sci. 2022; 52(4):1299-1310. PMC: 10387893. DOI: 10.55730/1300-0144.5436. View

Luo Y, Mohn N, Skripuletz T, Senel M, Tumani H, Pessler F . Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway. Ann Clin Transl Neurol. 2021; 8(12):2228-2234. PMC: 8670317. DOI: 10.1002/acn3.51383. View

Datta I, Zahoor I, Ata N, Rashid F, Cerghet M, Rattan R . Utility of an Untargeted Metabolomics Approach Using a 2D GC-GC-MS Platform to Distinguish Relapsing and Progressive Multiple Sclerosis. Metabolites. 2024; 14(9). PMC: 11434588. DOI: 10.3390/metabo14090493. View

Irani S, Bera K, Waters P, Zuliani L, Maxwell S, Zandi M . N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain. 2010; 133(Pt 6):1655-67. PMC: 2877907. DOI: 10.1093/brain/awq113. View

Abboud H, Probasco J, Irani S, Ances B, Benavides D, Bradshaw M . Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry. 2021; 92(7):757-768. PMC: 8223680. DOI: 10.1136/jnnp-2020-325300. View

Miller A, Koeneman S, Arakkal A, Cavanaugh J, Polgreen P . Incidence, Duration, and Risk Factors Associated With Missed Opportunities to Diagnose Herpes Simplex Encephalitis: A Population-Based Longitudinal Study. Open Forum Infect Dis. 2021; 8(9):ofab400. PMC: 8415533. DOI: 10.1093/ofid/ofab400. View

Binks S, Klein C, Waters P, Pittock S, Irani S . LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes. J Neurol Neurosurg Psychiatry. 2017; 89(5):526-534. PMC: 5909759. DOI: 10.1136/jnnp-2017-315720. View

Shaw W . Elevated Urinary Glyphosate and Clostridia Metabolites With Altered Dopamine Metabolism in Triplets With Autistic Spectrum Disorder or Suspected Seizure Disorder: A Case Study. Integr Med (Encinitas). 2017; 16(1):50-57. PMC: 5312745. View

Dalmau J, Graus F . Antibody-Mediated Encephalitis. N Engl J Med. 2018; 378(9):840-851. DOI: 10.1056/NEJMra1708712. View

10.

Funchal C, Latini A, Jacques-Silva M, Santos A, Buzin L, Gottfried C . Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int. 2006; 49(7):640-50. DOI: 10.1016/j.neuint.2006.05.007. View

11.

Quist-Paulsen E, Aukrust P, Kran A, Dunlop O, Ormaasen V, Stiksrud B . High neopterin and IP-10 levels in cerebrospinal fluid are associated with neurotoxic tryptophan metabolites in acute central nervous system infections. J Neuroinflammation. 2018; 15(1):327. PMC: 6260858. DOI: 10.1186/s12974-018-1366-3. View

12.

Titulaer M, McCracken L, Gabilondo I, Armangue T, Glaser C, Iizuka T . Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013; 12(2):157-65. PMC: 3563251. DOI: 10.1016/S1474-4422(12)70310-1. View

13.

Royds J, Timperley W, Taylor C . Levels of enolase and other enzymes in the cerebrospinal fluid as indices of pathological change. J Neurol Neurosurg Psychiatry. 1981; 44(12):1129-35. PMC: 491233. DOI: 10.1136/jnnp.44.12.1129. View

14.

Cohen J, Sotoca J, Gandhi S, Yeshokumar A, Gordon-Lipkin E, Geocadin R . Autoimmune encephalitis: A costly condition. Neurology. 2019; 92(9):e964-e972. DOI: 10.1212/WNL.0000000000006990. View

15.

Nissen M, Ryding M, Meyer M, Blaabjerg M . Autoimmune Encephalitis: Current Knowledge on Subtypes, Disease Mechanisms and Treatment. CNS Neurol Disord Drug Targets. 2020; 19(8):584-598. DOI: 10.2174/1871527319666200708133103. View

16.

Taschetto L, Scaini G, Zapelini H, Ramos A, Strapazzon G, Andrade V . Acute and long-term effects of intracerebroventricular administration of α-ketoisocaproic acid on oxidative stress parameters and cognitive and noncognitive behaviors. Metab Brain Dis. 2017; 32(5):1507-1518. DOI: 10.1007/s11011-017-0035-z. View

17.

Ratuszny D, Suhs K, Novoselova N, Kuhn M, Kaever V, Skripuletz T . Identification of Cerebrospinal Fluid Metabolites as Biomarkers for Enterovirus Meningitis. Int J Mol Sci. 2019; 20(2). PMC: 6359617. DOI: 10.3390/ijms20020337. View

18.

Halestrap A, Brand M, Denton R . Inhibition of mitochondrial pyruvate transport by phenylpyruvate and alpha-ketoisocaproate. Biochim Biophys Acta. 1974; 367(1):102-8. DOI: 10.1016/0005-2736(74)90140-0. View

19.

Amaral A, Leipnitz G, Fernandes C, Seminotti B, Schuck P, Wajner M . Alpha-ketoisocaproic acid and leucine provoke mitochondrial bioenergetic dysfunction in rat brain. Brain Res. 2010; 1324:75-84. DOI: 10.1016/j.brainres.2010.02.018. View

20.

Kepa L . [Acid-base equilibrium of cerebrospinal fluid in inflammatory diseases of the central nervous system]. Pol Tyg Lek. 1994; 49(20-22):475-9. View