The diagnostic value of NR2 antibodies level in patients with chronic cerebral ischemia

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Introduction. Hypertension, diabetes mellitus, atherosclerosis, and other risk factors for cardiovascular disease (CVD) contribute to the development of cerebral hypoperfusion and neurotoxicity, leading to recurrent transient ischemic attacks and cerebral infarctions. These processes are accompanied by the release of the NR2 peptide into the bloodstream and the production of antibodies to it. The use of NR2 antibodies to identify and assess the severity of chronic cerebral ischemia (CCI) and the risk of stroke can improve the quality of care for patients with risk factors for CVD.

Aim of the study. To examine the NR2 antibody levels in patients with different CVD risk factors and CCI of varying severity.

Materials and methods. In 107 patients (mean age 60.1 ± 7.9 years, 62 women and 45 men), 1.5T magnetic resonance imaging in the T1, T2, and T2 FLAIR sequences was performed. White matter hyperintensity was assessed using the Fazekas scale, and the size of individual hyperintensity lesions was also estimated. Enzyme immunoassay was used to measure the serum level of NR2 antibodies.

Results. In patients with signs of CCI, serum NR2 antibody levels were significantly higher compared to the patients without cerebrovascular brain disease (p < 0.05). That trend was observed both in compensated cerebral ischemia (p = 0.005) and in decompensated cerebral ischemia (p = 0.001).

Conclusion. The study results indicate that elevated NR2 antibody levels (>2 ng/ml) can be considered a marker associated with the development and progression of cerebral ischemia in patients with risk factors for CVD. Further study of the NR2 peptide and NR2 antibodies in patients with CCI will help optimize the indications for magnetic resonance imaging and improve the interpretation of its results.

About the authors

Igor A. Voznyuk

St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care;
S.M. Kirov Military Medical Academy

Russian Federation, St. Petersburg

Grigory V. Ponomarev

Pavlov First Saint Petersburg State Medical University

Author for correspondence.
Russian Federation, St. Petersburg

Tatyana V. Kharitonova

St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care

Russian Federation, St. Petersburg

Ekaterina A. Gogoleva

St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care

Russian Federation, St. Petersburg

Oksana A. Ovdienko

War Veterans’ Hospital

Russian Federation, St. Petersburg

Tatyana V. Sergeeva

St. Elizabeth City Hospital;
Saint Petersburg State University;
Saint Petersburg State Pediatric Medical University

Russian Federation, St. Petersburg

Lyudmila V. Lipatova

AVA-PETER Ltd, «Scandinavia» Clinic

Russian Federation, St. Petersburg

Natalia A. Sivakova

V.M. Bekhterev National Research Medical Center for Psychiatry and Neurology

Russian Federation, St. Petersburg

Svetlana A. Dambinova

Emory Decatur Hospital

United States, Decatur, GA

Alexander A. Skoromets

Pavlov First Saint Petersburg State Medical University

Russian Federation, St. Petersburg


  1. Fedin A.I. Diagnosis and treatment of chronic cerebral ischemia. Consilium Medicum 2016; 18(2): 8–12. doi: 10.26442/2075-1753_2016.2.8-12. (In Russ.)
  2. Kadykov A.S., Manvelov L.S., Shahparonova N.V. [Chronic vascular diseases of the brain]. Moscow: GEOTAR-Media; 2006. (In Russ.)
  3. Tanashyan M.M., Maksimova M.Yu., Domashenko M.A. [Dyscirculatory encephalopathy. A guide to medical appointment]. Terapevticheskiy spravochnik. 2015; 2: 1–25. (In Russ.)
  4. Levin O.S. Distsirkulatorny encephalopathy: anachronism or clinical reality? Sovremennaya terapiya v psikhiatrii i nevrologii 2012; 3: 40–46. (In Russ.)
  5. Tanashyan M.M., Shabalina A.A., Lagoda O.V. et al. Multimodal approach to treatment of neurological complications of chronic brain ischemia. Ter Arkh. 2018; 90(12): 61–67. doi: 10.26442/00403660.2018.12.000010. PMID: 30701835.
  6. Sladojevic N., Stamatovic S.M., Johnson A.M. et al. Claudin-1-dependent destabilization of the blood-brain barrier in chronic stroke. J Neurosci. 2019; 39(4): 743–757. doi: 10.1523/JNEUROSCI.1432-18.2018. PMID: 30504279.
  7. Akpinar M.B., Sahin V., Sahin N. et al. Previous chronic cerebral infarction is predictive for new cerebral ischemia after carotid endarterectomy. J Cardiothorac Surg. 2015;10:141. doi: 10.1186/s13019-015-0367-x. PMID: 26525737
  8. Shi Y., Thrippleton M.J., Marshall I. et al. Intracranial pulsatility in patients with cerebral small vessel disease: a systematic review. Clin Sci (Lond). 2018;132(1):157‐171. doi: 10.1042/CS20171280. PMID: 29229867.
  9. Dobrynina L.A., Shamtieva K.V., Kremneva E.I., et al. Daily profile of arterial pressure and brain microstructural changes in patients with hypertension-related cerebral small vessel disease. Annals of clinical and experimental neurology. 2019; 13(1): 36–46. doi: 10.25692/ACEN.2019.1.5. (In Russ.).
  10. Wardlaw J.M., Smith C., Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol. 2019; 18(7): 684–696. doi: 10.1016/S1474-4422(19)30079-1. PMID: 31097385.
  11. Warlow C., Sudlow C., Dennis M. et al. Stroke. The Lancet. 2003; 362(9391): 1211–1224. doi: 10.1016/s0140-6736(03)14544-8. PMID: 14568745.
  12. Venkat P., Chopp M., Chen J. Blood-brain barrier disruption, vascular impairment, and ischemia/reperfusion damage in diabetic stroke. J Am Heart Assoc. 2017; 6(6): e005819. doi: 10.1161/JAHA.117.005819. PMID: 28572280.
  13. Seiler A., Kammerer S., Gühl A. et al. Revascularization of high-grade carotid stenosis restores global cerebral energy metabolism. Stroke. 2019; 50(7): 1742–1750. doi: 10.1161/STROKEAHA.118.023559. PMID: 31164069.
  14. Zhang S., Zhang W., Zhou G. Extended risk factors for stroke prevention. J Natl Med Assoc. 2019; 111(4): 447–456. doi: 10.1016/j.jnma.2019.02.004. PMID: 30878142.
  15. Washida K., Hattori Y., Ihara M. Animal models of chronic cerebral hypoperfusion: from mouse to primate. Int J Mol Sci. 2019; 20(24): 6176. doi: 10.3390/ijms20246176. PMID: 31817864.
  16. Liu Q., Radwanski R., Babadjouni R. et al. Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood-brain barrier permeability in the corpus callosum. J Cereb Blood Flow Metab. 2019; 39(2): 240–250. doi: 10.1177/0271678X17743670. PMID: 29192539.
  17. Glushakova O.Y., Glushakov A.V., Miller E.R. et al. Biomarkers for acute diagnosis and management of stroke in neurointensive care units. Brain Circ. 2016; 2(1): 28–47. doi: 10.4103/2394-8108.178546. PMID: 30276272.
  18. Esenwa C.C., Elkind M.S. Inflammatory risk factors, biomarkers and associated therapy in ischaemic stroke. Nat Rev Neurol. 2016; 12(10): 594–604. doi: 10.1038/nrneurol.2016.125. PMID: 27615422.
  19. Ng G.J.L., Quek A.M.L., Cheung C. et al. Stroke biomarkers in clinical practice: a critical appraisal. Neurochem Int. 2017; 107: 11–22. doi: 10.1016/j.neuint.2017.01.005. PMID: 28088349.
  20. Kato H., Isohashi K., Shimosegawa E. et al. Increase in extraction of I-123 iomazenil in patients with chronic cerebral ischemia. PLoS One. 2018; 13(1): e0190720. doi: 10.1371/journal.pone.0190720. PMID: 29324813.
  21. Dambinova S.A., Aliev K.T., Bondarenko E.V. et al. The biomarkers of cerebral ischemia as a new method for the validation of the efficacy of cytoprotective therapy. Zh Nevrol Psikhiatr im S S Korsakova. 2017; 117(5): 62–67. doi: 10.17116/jnevro20171175162-67. (In Russ.)
  22. González-García S., González-Quevedo A., Hernandez-Diaz Z. et al. Circulating autoantibodies against the NR2 peptide of the NMDA receptor are associated with subclinical brain damage in hypertensive patients with other pre-existing conditions for vascular risk. J Neurol Sci. 2017; 375: 324–330. doi: 10.1016/j.jns.2017.02.028. PMID: 28320161.
  23. Dambinova S.A., Khounteev G.A., Skoromets A.A. Multiple panel of biomarkers for TIA/stroke evaluation. Stroke. 2002; 33(5): 1181–1182. doi: 10.1161/01.str.0000014922.83673.86. PMID: 11988587.
  24. Sharp C.D., Fowler M., Jackson T.H. 4th et al. Human neuroepithelial cells express NMDA receptors. BMC Neurosci. 2003; 4: 28. doi: 10.1186/1471-2202-4-28. PMID: 14614784.
  25. Dambinova S.A., Skoromets A.A., Skoromets A.P. [Biomarkers of cerebral ischemia (development, research, and practical applications)]. St. Petersburg: IPK KOSTA, 2013. 336 p. (In Russ.)
  26. Dambinova S.A., Khounteev G.A., Izykenova G.A. et al. Blood test detecting autoantibodies to N-methyl-D-aspartate neuroreceptors for evaluation of patients with transient ischemic attack and stroke. Clin Chem. 2003; 49(10): 1752–1762. doi: 10.1373/49.10.1752. PMID: 14500616.
  27. Bokesch P.M., Izykenova G.A., Justice J.B. et al. NMDA receptor antibodies predict adverse neurological outcome after cardiac surgery in high-risk patients. Stroke. 2006; 37(6): 1432–1436. doi: 10.1161/01.STR.0000221295.14547.c8. PMID: 16627793.
  28. Weissman J.D., Khunteev G.A., Heath R. et al. NR2 antibodies: Risk assessment of transient ischemic attack (TIA)/stroke in patients with history of isolated and multiple cerebrovascular events. J Neurol Sci. 2011; 300(1–2): 97–102. doi: 10.1016/j.jns.2010.09.023. PMID: 20934192.
  29. Dambinova S.A., Bettermann K., Glynn T. et al. Diagnostic potential of the NMDA receptor peptide assay for acute ischemic stroke. PloS One. 2012; 7(7): e42362. doi: 10.1371/journal.pone.0042362. PMID: 22848761.
  30. Dolmans L.S., Rutten F.H., Koenen N.C.T. et al. Candidate biomarkers for the diagnosis of transient ischemic attack: a systematic review. Cerebrovasc Dis. 2019; 47(5–6): 207–216. doi: 10.1159/000502449. PMID: 31473737.

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Copyright (c) 2021 Voznyuk I.A., Ponomarev G.V., Kharitonova T.V., Gogoleva E.A., Ovdienko O.A., Sergeeva T.V., Lipatova L.V., Sivakova N.A., Dambinova S.A., Skoromets A.A.

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