Preview

Neurology, Neuropsychiatry, Psychosomatics

Advanced search

Sporadic cerebral non-amyloid microangiopathy: pathogenesis, diagnosis, and features of treatment policy

https://doi.org/10.14412/2074-2711-2018-4-13-22

Full Text:

Abstract

The paper is devoted to the most common variant of cerebral small-vessel disease Р sporadic cerebral non-amyloid microangiopathy (SCNAMA) in the context of acute and chronic cerebral circulatory disorders. It highlights the topical issues of neuropathology and pathogenesis of the disease. The paper presents the current neuroimaging markers of SCNAMA with a detailed discussion of lacunar infarcts, cerebral microinfarctions, and microbleeds. It considers the clinical manifestations of the chronic form of the disease, including cognitive impairment. The problem in the differential diagnosis of SCNAMA and cerebral amyloid angiopathy is highlighted. The current possibilities of minimizing risks and improving the efficiency of treatment in this category of patients are discussed.

About the Authors

A. A. Kulesh
Acad. E.A. Vagner Perm State Medical University, Ministry of Health of Russia
Russian Federation

Aleksey Aleksandrovich Kulesh

Perm, 26, Petropavlovskaya St., Perm 614990



V. E. Drobakha
Acad. E.A. Vagner Perm State Medical University, Ministry of Health of Russia
Russian Federation

Perm, 26, Petropavlovskaya St., Perm 614990



V. V. Shestakov
Acad. E.A. Vagner Perm State Medical University, Ministry of Health of Russia
Russian Federation

Perm, 26, Petropavlovskaya St., Perm 614990



References

1. Charidimou A, Pantoni L, Love S. The concept of sporadic cerebral small vessel disease: A road map on key definitions and current concepts. Int JStroke. 2016 Jan;11(1):6-18. doi: 10.1177/1747493015607485.

2. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010; 9(7): 689-701.

3. Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013 May;12(5):483-97. doi: 10.1016/S1474-4422(13)70060-7.

4. Parfenov VA. Diagnosis and treatment of chronic cerebrovascular disease, use of pentoxifylline. Nevrologiya, neiropsikhia-triya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2016;8(3):4-9. (In Russ.). doi: 10.14412/2074-2711-2016-3-4-9

5. Ihara M, Yamamoto Y. Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease. Stroke. 2016 Feb;47(2):554-60. doi: 10.1161/STROKEAHA.115.009627. Epub 2016 Jan 7.

6. Kulesh AA, Kaileva NA, Gorst NKh, Shestakov VV. A relationship between the integrated assessment of magnetic resonance imaging markers for cerebral small vessel disease and the clinical and functional status in the acute period of ischemic stroke. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2018;10(1):24-31. (In Russ.). doi: 10.14412/2074-2711-2018-1-24-31

7. Lammie GA, Brannan F, Slattery J, Warlow C. Nonhypertensive cerebral small-vessel disease. An autopsy study. Stroke. 1997 Nov;28(11):2222-9.

8. Kalaria RN, Akinyemi R, Ihara M. Does vascular pathology contribute to Alzheimer changes? J Neurol Sci. 2012 Nov 15;322(1-2): 141-7. doi: 10.1016/jjns.2012.07.032. Epub 2012 Aug 11.

9. Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, the Stroke Genetics Network (SiGN), and the International Stroke Genetics Consortium (ISGC). Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 2016 Jun;15(7):695-707. doi: 10.1016/ S1474-4422(16)00102-2. Epub 2016 Apr 7.

10. Woo D, Falcone GJ, Devan WJ, et al. International Stroke Genetics Consortium. Meta-analysis of genome-wide association studies identifies 1q22 as a susceptibility locus for intracerebral hemorrhage. Am J Hum Genet. 2014 Apr 3;94(4):511-21. doi: 10.1016/j.ajhg.2014.02.012. Epub 2014 Mar 20.

11. Rannikma e K, Sivakumaran V, Millar H, et al. Stroke Genetics Network (SiGN), METASTROKE Collaboration, and International Stroke Genetics Consortium (ISGC). COL4A2 is associated with lacunar ischemic stroke and deep ICH: meta-analyses among 21,500 cases and 40,600 controls. Neurology. 2017 Oct 24; 89(17):1829-1839. doi: 10.1212/WNL.000000 0000004560. Epub 2017 Sep 27.

12. Traylor M, Malik R, Nalls MA, et al. METASTROKE, UK Young Lacunar DNA Study, NINDS Stroke Genetics Network, Neurology Working Group of the CHARGE Consortium; International Stroke Genetics Consortium. Genetic variation at 16q24.2 is associated with small vessel stroke. Ann Neurol. 2017 Mar;81(3):383-394. doi: 10.1002/ana.24840.

13. Schmidt H, Zeginigg M, Wiltgen M, et al. CHARGE Consortium Neurology Working Group. Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease. Brain. 2011 Nov;134(Pt 11):3384-97. doi: 10.1093/brain/awr252. Epub 2011 Oct 17.

14. Di Donato I, Bianchi S, Gallus GN, et al. Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease. CNSNeurosci Ther. 2017 Sep;23(9):759-765. doi: 10.1111/cns.12722. Epub 2017 Aug 6.

15. Bailey E, Wardlaw J, Graham D, et al. Cerebral small vessel endothelial structural changes predate hypertension in stroke prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5-to 21-week old rats. Neuropathol Appl Neurobiol. 2011 Dec;37(7):711-26. doi: 10.1111/j.1365-2990.2011.01170.x.

16. Bailey EL, Smith C, Sudlow CLM, Wardlaw JM. Is the spontaneously hypertensive stroke prone rat a pertinent model of subcortical ischaemic stroke? A systematic review. Int J Stroke. 2011 Oct;6(5):434-44. doi: 10.1111/j.1747-4949.2011.00659.x.

17. Dickinson KM, Clifton PM, Keogh JB. Endothelial function is impaired after a high-salt meal in healthy subjects. Am J Clin Nutr. 2011 Mar;93(3):500-5. doi: 10.3945/ajcn.110.006155. Epub 2011 Jan 12.

18. Rosenberg GA. Binswanger's disease: biomarkers in the inflammatory form of vascular cognitive impairment and dementia. J Neuro-chem. 2018 Mar;144(5):634-643. doi: 10.1111/jnc.14218. Epub 2017 Nov 6.

19. Carare RO, Hawkes CA, Jeffrey M, et al. Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy. Neuropathol Appl Neurobiol. 2013 Oct; 39(6):593-611. doi: 10.1111/nan.12042.

20. Schley D, Carare-Nnadi R, Please CP, et al. Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol. 2006 Feb 21;238(4):962-74. Epub 2005 Aug 22.

21. Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest. 2015 Mar 2;125(3):926-38. doi: 10.1172/JCI76304. Epub 2015 Feb 17.

22. Lee YL, Hu HY, Huang N, et al. Dental prophylaxis and periodontal treatment are protective factors to ischemic stroke. Stroke. 2013 Apr;44(4):1026-30. doi: 10.1161/STROKEAHA.111.000076. Epub 2013 Feb 19.

23. Miyatani F, Kuriyama N, Watanabe I, et al. Relationship between Cnm-positive Streptococcus mutans and cerebral microbleeds in humans. OralDis. 2015 Oct;21(7):886-93. doi: 10.1111/odi.12360. Epub 2015 Sep 1.

24. Wardlaw JM, Valdes Hernandez MC, Munoz-Maniega S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J Am Heart Assoc. 2015 Jun 23;4(6):001140. doi: 10.1161/JAHA.114.001140.

25. Maniega SM, Valdes Hernandez MC, Clayden JD, et al. White matter hyperintensities and normal-appearing white matter integrity in the aging brain. Neurobiol Aging. 2015 Feb;36(2):909-18. doi: 10.1016/j.neurobiolag-ing.2014.07.048. Epub 2014 Oct 13.

26. Hinman JD, Lee MD, Tung S, et al. Molecular disorganization of axons adjacent to human lacunar infarcts. Brain. 2015 Mar;138 (Pt 3):736-45. doi: 10.1093/brain/awu398. Epub 2015 Jan 21.

27. Summers PM, Hartmann DA, Hui ES, et al. Functional deficits induced by cortical microinfarcts. J Cereb Blood Flow Metab. 2017 Nov;37(11): 3599-3614. doi: 10.1177/0271678X16685573. Epub 2017 Jan 16.

28. Ter Telgte A, Van Leijsen EMC, Wiegertjes K, et al. Cerebral small vessel disease: from a focal to a global perspective. Nat Rev Neurol. 2018 Jul;14(7):387-398. doi: 10.1038/s41582-018-0014-y.

29. Kulesh AA, Drobakha VE, Shestakov VV, et al. Neuroinflammatory, neurodegenerative and structural cerebral markers of the main clinical variants of post-stroke cognitive disorders in the acute period of ischemic stroke. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk. 2016;71(4):304-12. In Russ.).

30. Duering M, et al. Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts. Neurology. 2015; 84: 1685-1692.

31. Tuladhar AM, Reid AT, Shumskaya E, et al. Relationship between white matter hyperintensities, cortical thickness, and cognition. Stroke. 2015 Feb;46(2):425-32. doi:10.1161/STROKE-AHA.114.007146. Epub 2015 Jan 8.

32. Lawrence AJ, Chung AW, Morris RG, et al. Structural network efficiency is associated with cognitive impairment in small-vessel disease. Neurology. 2014 Jul 22;83(4):304-11. doi: 10.1212/WNL.0000000000000612. Epub 2014 Jun 20.

33. Tuladhar AM, Lawrence A, Norris DG, et al. Disruption of rich club organisation in cerebral small vessel disease. Hum Brain Mapp. 2017 Apr;38(4):1751-1766. doi: 10.1002/hbm.23479. Epub 2016 Dec 9.

34. Fornito A, Zalesky A, Breakspear M. The connectomics of brain disorders. Nat Rev Neurosci. 2015 Mar;16(3):159-72. doi: 10.1038/nrn3901.

35. Loos CMJ, Makin SDJ, Staals J, et al. Long-Term Morphological Changes of Symptomatic Lacunar Infarcts and Surrounding White Matter on Structural Magnetic Resonance Imaging. Stroke. 2018 May;49(5): 1183-1188. doi: 10.1161/STROKEA-HA.117.020495. Epub 2018 Mar 22.

36. Norrving B. Evolving Concept of Small Vessel Disease through Advanced Brain Imaging. J Stroke. 2015 May;17(2):94-100. doi: 10.5853/jos.2015.17.2.94. Epub 2015 May 29.

37. Petrone L, Nannoni S, Del Bene A, et al. Branch Atheromatous Disease: A Clinically Meaningful, Yet Unproven Concept. Cerebrovasc Dis. 2016;41(1-2):87-95. doi: 10.1159/000442577. Epub 2015 Dec 16.

38. Duering M, Csanadi E, Gesierich B, et al. Incident lacunes preferentially localize to the edge of white matter hyperintensities: insights into the pathophysiology of cerebral small vessel disease. Brain. 2013 Sep;136(Pt 9):2717-26. doi: 10.1093/brain/awt184. Epub 2013 Jul 17.

39. Potter G, Doubal F, Jackson C, et al. Associations of clinical stroke misclassification (‘clinical-imaging dissociation’) in acute ischemic stroke. Cerebrovasc Dis. 2010;29(4): 395-402. doi: 10.1159/000286342. Epub 2010 Feb 19.

40. Molad J, Ben-Assayag E, Korczyn AD, et al. Clinical and radiological determinants of transient symptoms associated with infarction (TSI). J Neurol Sci. 2018 Jul 15;390:195-199. doi: 10.1016/j.jns.2018.04.038. Epub 2018 Apr 24.

41. Van Veluw SJ, Shih AY, Smith EE, et al. Detection, risk factors, and functional consequences of cerebral microinfarcts. Lancet Neurol. 2017 Sep;16(9):730-740. doi: 10.1016/S1474-4422(17)30196-5. Epub 2017 Jul 14.

42. Westover MB, Bianchi MT, Yang C, et al. Estimating cerebral microinfarct burden from autopsy samples. Neurology. 2013 Apr 9;80(15): 1365-9. doi: 10.1212/WNL.0b013e31828c2f52. Epub 2013 Mar 13.

43. Auriel E, Westover MB, Bianchi MT, et al. Estimating total cerebral microinfarct burden from diffusion-weighted imaging. Stroke. 2015 Aug;46(8):2129-35. doi: 10.1161/STROKEA-HA.115.009208. Epub 2015 Jul 9.

44. Saini M, Suministrado MS, Hilal S, et al. Prevalence and risk factors of acute incidental infarcts. Stroke. 2015 Oct;46(10):2722-7. doi: 10.1161/STROKEAHA.115.009963. Epub 2015 Aug 20.

45. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013 Aug; 12(8):822-38. doi: 10.1016/S1474-4422(13)70124-8.

46. Van Veluw SJ, Hilal S, Kuijf HJ, et al. Cortical microinfarcts on 3T MRI: clinical correlates in memory-clinic patients. Alzheimers Dement. 2015 Dec;11(12):1500-1509. doi: 10.1016/j.jalz.2014.12.010. Epub 2015 May 5.

47. Kulesh AA, Drobakha VE, Shestakov VV. Hemorrhagic manifestations of cerebral amyloid angiopathy: from pathogenesis to clinical significance. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2018;10(3):4-11. (In Russ.). Doi: 10.14412/2074-2711-2018-3-4-11

48. Yates PA, Villemagne VL, Ellis KA, et al. Cerebral microbleeds: a review of clinical, genetic, and neuroimaging associations. Front Neurol. 2014 Jan 6;4:205. doi: 10.3389/fneur.2013.00205.eCollection 2014 Jan 6.

49. Werring DJ, Gregoire SM, Cipolotti L. Cerebral microbleeds and vascular cognitive impairment. J Neurol Sci. 2010 Dec 15;299 (1-2):131-5. doi: 10.1016/j.jns.2010.08.034. Epub 2010 Sep 17.

50. Wilson D, Charidimou A, Ambler G, et al. Recurrent stroke risk and cerebral microbleed burden in ischemic stroke and TIA: A metaanalysis. Neurology. 2016 Oct 4;87(14): 1501-1510. Epub 2016 Sep 2.

51. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002 Jan 12;324(7329):71-86.

52. Charidimou A, Shoamanesh A. Clinical relevance of microbleeds in acute stroke thrombolysis: Comprehensive meta-analysis. International META-MICROBLEEDS Initiative. Neurology. 2016 Oct 11;87(15):1534-1541. Epub 2016 Sep 14.

53. Kulesh AA, Shestakov VV. Vascular cognitive impairment, no dementia: diagnosis, prognosis, treatment, and prevention. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2017;9(3):68-75. (In Russ.). doi: 10.14412/2074-2711-2017-3-68-75

54. Wang Z, Van Veluw SJ, Wong A, et al. Risk factors and cognitive relevance of cortical cerebral microinfarcts in patients with ischemic stroke or transient ischemic attack. Stroke. 2016 Oct;47(10):2450-5. doi: 10.1161/STROKEA-HA.115.012278. Epub 2016 Aug 18.

55. Hilal S, Sikking E, Shaik MA, et al. Cortical cerebral microinfarcts on 3T MRI: a novel marker of cerebrovascular disease. Neurology. 2016 Oct 11;87(15):1583-1590. Epub 2016 Sep 2.

56. Parfenov VA, Neverovskii DV. Outpatient management of patients with dyscir-culatory encephalopathy. Nevrologiya, neirop-sikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2015;7(1): 37-42. (In Russ.). doi: 10.14412/2074-2711-2015-1-37-42

57. Greenberg SM, Charidimou A. Diagnosis of Cerebral Amyloid Angiopathy: Evolution of the Boston Criteria. Stroke. 2018 Feb;49(2):491-497. doi: 10.1161/STROKEAHA.117.016990. Epub 2018 Jan 15.

58. Rodrigues MA, Samarasekera N, Lerpini-ere C, et al. The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage associated with cerebral amyloid angiopathy: model development and diagnostic test accuracy study. Lancet Neurol. 2018 Mar; 17(3):232-240. doi: 10.1016/S1474-4422(18)30006-1. Epub 2018 Jan 10.

59. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018 Mar;49(3):e46-e110. doi: 10.1161/STR.0000000000000158. Epub 2018 Jan 24.

60. Ostroumova TM, Parfenov VA, Ostroumova OD. Hypertension and cognitive impairment: the standpoint of evidence-based medicine. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2017;9(4):70—6. (In Russ.). doi: 10.14412/2074-2711-2017-4-70-76

61. Parfenov VA, Ostroumova TM, Ostroumova OD, et al. Diffusion tensor magnetic resonance imaging in the diagnosis of white matter lesion in middle-aged patients with uncomplicated essential hypertension. Nevrologiya, neiropsikhi-atriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2018;10(2):20-6. (In Russ.). doi: 10.14412/2074-2711-2018-2-20-26

62. Ostroumova TM, Parfenov VA, Ostroumova OD, et al. Possibilities of contrast-free magnetic resonance perfusion imaging for the detection of early brain damage in essential hypertension. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2018;10(1):17-23. (In Russ.). doi: 10.14412/2074-2711-2018-1-17-23

63. Kernan WN, Ovbiagele B, Black HR, et al; American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014 Jul;45(7):2160-236. doi: 10.1161/STR.0000000000000024. Epub 2014 May 1.

64. Dufouil C, Chalmers J, Coskun O, et al; PROGRESS MRI Substudy Investigators. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy. Circulation. 2005 Sep 13;112(11):1644-50. Epub 2005 Sep 6.

65. Muller M, Sigurdsson S, Kjartansson O, et al. Joint effect of mid- and late-life blood pressure on the brain: the Ages-Reykjavik study. Neurology. 2014 Jun 17;82(24):2187-95. doi: 10.1212/WNL.0000000000000517. Epub 2014 Jun 4.

66. Van Middelaar T, Argillander TE, Schreuder FHBM, et al. Effect of Antihypertensive Medication on Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis. Stroke. 2018 Jun;49(6):1531-1533. doi: 10.1161/STROKE-AHA.118.021160. Epub 2018 May 8.

67. Croall ID, Tozer DJ, Moynihan B, et al. Effect of Standard vs Intensive Blood Pressure Control on Cerebral Blood Flow in Small Vessel Disease: The PRESERVE Randomized Clinical Trial. JAMA Neurol. 2018 Jun 1;75(6):720-727. doi: 10.1001/jamaneurol.2017.5153.

68. SPS Investigators, Benavente OR, Hart RG, McClure LA, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012 Aug 30;367(9):817-25. doi: 10.1056/NEJMoa1204133.

69. Johnston SC, Easton JD, Farrant M, et al; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018 Jul 19;379(3):215-225. doi: 10.1056/NEJMoa1800410. Epub 2018 May 16.

70. Jing J, Meng X, Zhao X, et al. Dual Antiplatelet Therapy in Transient Ischemic Attack and Minor Stroke With Different Infarction Patterns: Subgroup Analysis of the CHANCE Randomized Clinical Trial. JAMA Neurol. 2018 Jun 1;75(6):711-719. doi: 10.1001/jamaneurol.2018.0247.

71. Qiu J, Ye H, Wang J, et al. Antiplatelet Therapy, Cerebral Microbleeds, and Intracerebral Hemorrhage: A Meta Analysis. Stroke. 2018 Jul;49(7):1751-1754. doi: 10.1161/STROKEAHA.118.021789. Epub 2018 May 24.

72. Lau KK, Lovelock CE, Li L, et al. Antiplatelet Treatment After Transient Ischemic Attack and Ischemic Stroke in Patients With Cerebral Microbleeds in 2 Large Cohorts and an Updated Systematic Review. Stroke. 2018 Jun;49(6):1434-1442. doi: 10.1161/STROKEA-HA.117.020104. Epub 2018 May 10.

73. Bath PM, Wardlaw JM. Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions. Int J Stroke. 2015 Jun;10(4):469-78. doi: 10.1111/ijs.12466. Epub 2015 Mar 2.

74. Amarenco P, Benavente O, Goldstein LB, et al. Results of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) trial by stroke subtypes. Stroke. 2009 Apr;40(4):1405-9. doi: 10.1161/STROKEA-HA.108.534107. Epub 2009 Feb 19.

75. Ji T, Zhao Y, Wang J, et al. Effect of Low-Dose Statins and Apolipoprotein E Genotype on Cerebral Small Vessel Disease in Older Hypertensive Patients: A Subgroup Analysis of a Randomized Clinical Trial. J Am Med Dir Assoc. 2018 Nov;19(11):995-1002.e4. doi: 10.1016/j.jamda.2018.05.025. Epub 2018 Jul 10.


Review

For citations:


Kulesh A.A., Drobakha V.E., Shestakov V.V. Sporadic cerebral non-amyloid microangiopathy: pathogenesis, diagnosis, and features of treatment policy. Neurology, Neuropsychiatry, Psychosomatics. 2018;10(4):13-22. (In Russ.) https://doi.org/10.14412/2074-2711-2018-4-13-22

Views: 1513


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 2074-2711 (Print)
ISSN 2310-1342 (Online)