Патогенетические механизмы развития болезни мелких сосудов головного мозга

Цереброваскулярная патология занимает лидирующие позиции среди причин смертности и длительного периода восстановления после нетрудоспособности населения в странах с разным уровнем дохода, что свидетельствует о необходимости поиска новых стратегических направлений по профилактике этих заболеваний. Сегодня среди наиболее распространенных форм цереброваскулярных заболеваний выделяют острый ишемический инсульт и сосудистые когнитивные нарушения, в частности, сосудистую деменцию. В патогенезе обоих этих состояний значительную роль играет повреждение мелких сосудов головного мозга. Статья посвящена анализу данных литературы по изучению цереброваскулярных заболеваний. В базе данных PubMed отобраны статьи по ключевым словам: болезни мелких сосудов, гиперинтенсивность белого вещества головного мозга, лакуны, расширенные периваскулярные пространства, атрофия мозга, сосудистые когнитивные нарушения. Заключение. Изучение патогенетических механизмов развития церебральной микроангиопатии, или болезни мелких сосудов позволит выработать направления в клинических и научных исследованиях на поиск генетически обоснованного лечения и стратегии профилактики, что крайне важно для пациентов пожилого возраста.

1. Li Q.,Yang Y., Reis C. et al. Cerebral small vessel disease. Cell. Transplant. 2018;27(12):1711–1722. DOI: 10.1177/0963689718795148

2. Chojdak-Ukasiewicz J., Dziadkowiak E., Zimny A., Paradowski B. Cerebral small vessel disease: A review. Adv. Clin. Exp. Med. 2021;30(3):349–356. DOI: 10.17219/acem/131216.

3. Wardlaw J.M., Smith C., Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013;12(5):483–497. DOI: 10.1016/S1474-4422(13)70060-7

4. Khan U., Porteous L., Hassan A., Markus H.S. Risk factor profile of cerebral small vessel disease and its subtypes. J. Neurol. Neurosurg. Psychiatry. 2007;78(7):702–706. DOI: 10.1136/jnnp.2006.103549

5. Aribisala B.S., Morris Z., Eadie E. et al. Blood pressure, internal carotid artery flow parameters, and age-related white matter hyperintensities. Hypertension. 2014;63(5):1011–1018. DOI: 10.1161/HYPERTENSIONAHA.113.02735

6. Boulouis G., Charidimou A., Auriel E. et al. Intracranial atherosclerosis and cerebral small vessel disease in intracerebral hemorrhage patients. J. Neurol. Sci. 2016;369:324–329. DOI: 10.1016/j.jns.2016.08.049

7. Brisset M., Boutouyrie P., Pico F. et al. Large-vessel correlates of cerebral small-vessel disease. Neurology. 2013;80(7):662–669. DOI: 10.1212/WNL.0b013e318281ccc2

8. Hannawi Y. Cerebral small vessel disease: a review of the pathophysiological mechanisms. Transl. Stroke Res. 2023. DOI: 10.1007/s12975-023-01195-9

9. Kitamura A., Saito S., Maki T. et al. Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory. J. Cereb. Blood Flow Metab. 2016;36(9):1592–1602. DOI: 10.1177/0271678X15606717

10. Poels M.M., Zaccai K., Verwoert G.C. et al. Arterial stiffness and cerebral small vessel disease: the Rotterdam Scan Study. Stroke. 2012;43(10):2637–2642. DOI: 10.1161/STROKEAHA.111.642264

11. 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

12. Gomes J., Wachsman A.M. Types of stroke. In: Corrigan ML, Escuro A.A., Kirby D.F. editors. Handbook of Clinical Nutrition and Stroke. Totowa (NJ): Humana Press; 2013:15–32. DOI: 10.1007/978-1-62703-380-0_2

13. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9(7):689–701. DOI: 10.1016/S1474-4422(10)70104-6

14. Van Veluw S.J., Shih A.Y., Smith E.E. et al. Detection, risk factors, and functional consequences of cerebral microinfarcts. Lancet Neurol. 2017;16(9):730–740. DOI: 10.1016/S1474-4422(17)30196-5

15. Wardlaw J.M., Smith E.E., Biessels G.J. et al.; STandards for ReportIng Vascular changes on nEuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12(8):822–838. DOI: 10.1016/S1474-4422(13)70124-8

16. Debette S., Schilling S., Duperron M.G., Larsson S.C., Markus H.S. Clinical significance of magnetic resonance imaging markers of vascular brain injury: a systematic review and meta-analysis. JAMA Neurol. 2019;76(1):81–94. DOI: 10.1001/jamaneurol.2018.3122

17. Georgakis M.K., Duering M., Wardlaw J.M., Dichgans M. WMH and long-term outcomes in ischemic stroke: A systematic review and metaanalysis. Neurology. 2019;92(12):e1298–e1308. DOI: 10.1212/WNL.0000000000007142

18. Poggesi A., Pasi M., Pescini F., Pantoni L., Inzitari D. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review. J. Cereb. Blood Flow Metab. 2016;36(1):72–94. DOI: 10.1038/jcbfm.2015.116

19. Wardlaw J.M., Sandercock P.A., Dennis M.S., Starr J. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke. 2003;34(3):806–812. DOI: 10.1161/01.STR.0000058480.77236.B3

20. Huisa B.N., Caprihan A., Thompson J., Prestopnik J., Qualls C.R., Rosenberg GA. Long-Term Blood-Brain Barrier Permeability Changes in Binswanger Disease. Stroke. 2015;46(9):2413–2418. DOI: 10.1161/STROKEAHA.115.009589

21. Tao W., Cheng Y., Guo W. et al. Clinical features and imaging markers of small vessel disease in symptomatic acute subcortical cerebral microinfarcts. BMC Neurol. 2022;23;22(1):311. DOI: 10.1186/s12883-022-02824-w

22. Wardlaw J.M., Doubal F., Armitage P. et al. Lacunar stroke is associated with diffuse blood-brain barrier dysfunction. Ann. Neurol. 2009;65(2):194–202. DOI: 10.1002/ana.21549

23. Wardlaw J.M., Makin S.J., Vald s Hernndez M.C. et al. Bloodbrain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study. Alzheimers Dement. 2017;13(6):634–643. DOI: 10.1016/j.jalz.2016.09.006

24. Zhang C.E., Wong S.M., Van de Haar H.J., et al. Blood-brain barrier leakage is more widespread in patients with cerebral small vessel disease. Neurology. 2017;88(5):426–432. DOI: 10.1212/WNL.0000000000003556

25. Farrall A.J., Wardlaw J.M. Blood-brain barrier: ageing and microvascular disease--systematic review and meta-analysis. Neurobiol. Aging. 2009;30(3):337–352. DOI: 10.1016/j.neurobiolaging.2007.07.015

26. Ihara M., Yamamoto Y. Emerging evidence for pathogenesis of sporadic cerebral small vessel disease. Stroke. 2016;47(2):554–560. DOI: 10.1161/STROKEAHA.115.009627

27. Rajani R.M., Williams A. Endothelial cell-oligodendrocyte interactions in small vessel disease and aging. Clin. Sci. (Lond.). 2017;131(5):369–379. DOI: 10.1042/CS20160618

28. Deplanque D., Lavallee P.C., Labreuche J. et al.; Lacunar-BICHAT Investigators. Cerebral and extracerebral vasoreactivity in symptomatic lacunar stroke patients: a case-control study. Int. J. Stroke. 2013;8(6):413–421. DOI: 10.1111/j.1747-4949.2011.00755.x

29. Young V.G., Halliday G.M., Kril J.J. Neuropathologic correlates of white matter hyperintensities. Neurology. 2008;71(11):804–811. DOI: 10.1212/01.wnl.0000319691.50117.54

30. Markus H.S., Hunt B., Palmer K., Enzinger C., Schmidt H., Schmidt R. Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke Prevention Study. Stroke. 2005;36(7):1410–1414. DOI: 10.1161/01.STR.0000169924.60783.d4

31. Fornage M., Chiang Y.A., O’Meara E.S. et al. Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study. Stroke. 2008;39(7):1952–1959. DOI: 10.1161/STROKEAHA.107.508135

32. Satizabal C.L., Zhu Y.C., Mazoyer B., Dufouil C., Tzourio C. Circulating IL-6 and CRP are associated with MRI findings in the elderly: the 3C-Dijon Study. Neurology. 2012;78(10):720–727. DOI: 10.1212/WNL.0b013e318248e50f

33. Van Dijk E.J., Prins N.D., Vermeer S.E. et al. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation. 2005;112(6):900–905. DOI: 10.1161/CIRCULATIONAHA.104.506337

34. Notsu Y., Nabika T., Bokura H. et al. Evaluation of asymmetric dimethylarginine and homocysteine in microangiopathy-related cerebral damage. Am. J. Hypertens. 2009;22(3):257–262. DOI: 10.1038/ajh.2008.346

35. Pikula A., Bger R.H, Beiser A.S., et al. Association of plasma ADMA levels with MRI markers of vascular brain injury: Framingham offspring study. Stroke. 2009;40(9):2959–2964. DOI: 10.1161/STROKEAHA.109.557116

36. Kim Y., Kim Y.K., Kim N.K., Kim S.H., Kim O.J., Oh S.H. Circulating matrix metalloproteinase-9 level is associated with cerebral white matter hyperintensities in non-stroke individuals. Eur. Neurol. 2014;72(3–4):234–240. DOI: 10.1159/000362876

37. Rouhl R.P., Damoiseaux J.G., Lodder J. et al. Vascular inflammation in cerebral small vessel disease. Neurobiol. Aging. 2012;33(8):1800–1806. DOI: 10.1016/j.neurobiolaging.2011.04.008

38. Rudilosso S., Mena L., Esteller D. et al. Higher Cerebral Small Vessel Disease Burden in Patients with White Matter Recent Small Subcortical Infarcts. J. Stroke Cerebrovasc. Dis. 2021;30(7):105824. DOI: 10.1016/j.jstrokecerebrovasdis.2021.105824

39. Pescini F., Cesari F., Giusti B. et al. Bone marrow-derived progenitor cells in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke. 2010;41(2):218–223. DOI: 10.1161/STROKEAHA.109.563726

40. Kloppenborg R.P., Nederkoorn P.J., Van der Graaf Y., Geerlings M.I. Homocysteine and cerebral small vessel disease in patients with symptomatic atherosclerotic disease. The SMART-MR study. Atherosclerosis. 2011;216(2):461-466. DOI: 10.1016/j.atherosclerosis.2011.02.027

41. Sachdev P., Parslow R., Salonikas C. et al. Homocysteine and the brain in midadult life: evidence for an increased risk of leukoaraiosis in men. Arch. Neurol. 2004;61(9):1369–1376. DOI: 10.1001/arch-neur.61.9.1369

42. Vermeer S.E., Van Dijk E.J., Koudstaal P.J. et al. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study. Ann. Neurol. 2002;51(3):285–289. DOI: 10.1002/ana.10111

43. Arsava E.M., Yilmaz E., Topcuoglu M.A. Incidental DWI Lesions in Patients with Recent Small Subcortical Infarctions. J. Stroke Cerebrovasc. Dis. 2022;31(4):106304. DOI: 10.1016/j.jstrokecerebrovas-dis.2022.106304

44. Bridges L.R., Andoh J., Lawrence A.J. et al. Blood-brain barrier dysfunction and cerebral small vessel disease (arteriolosclerosis) in brains of older people. J. Neuropathol. Exp. Neurol. 2014;73(11):1026–1033. DOI: 10.1097/NEN.0000000000000124

45. Knottnerus I.L., Winckers K., Ten Cate H. et al. Levels of heparin-releasable TFPI are increased in first-ever lacunar stroke patients. Neurology. 2012;78(7):493–498. DOI: 10.1212/WNL.0b013e318246d6b7

46. Simpson J.E., Fernando M.S., Clark L. et al.; MRC Cognitive Function and Ageing Neuropathology Study Group. White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responses. Neuropathol. Appl. Neurobiol. 2007;33(4):410–419. DOI: 10.1111/j.1365-2990.2007.00828.x

47. Skoog I., Wallin A., Fredman P. et al. A population study on blood-brain barrier function in 85-year-olds: relation to Alzheimer’s disease and vascular dementia. Neurology. 1998;50(4):966–971. DOI: 10.1212/wnl.50.4.966

48. Pantoni L., Inzitari D., Pracucci G. et al. Cerebrospinal fluid proteins in patients with leucoaraiosis: possible abnormalities in blood-brain barrier function. J. Neurol. Sci. 1993;115(2):125–131. DOI: 10.1016/0022-510x(93)90214-j

49. Vogels S.C., Emmelot-Vonk M.H., Verhaar H.J., Koek H.L. The association of chronic kidney disease with brain lesions on MRI or CT: a systematic review. Maturitas. 2012;71(4):331–336. DOI: 10.1016/j.maturitas.2012.01.008

50. Stehouwer C.D., Smulders Y.M. Microalbuminuria and risk for cardiovascular disease: Analysis of potential mechanisms. J. Am. Soc. Nephrol. 2006;17(8):2106–2111. DOI: 10.1681/ASN.2005121288

51. Uiterwijk R., Van Oostenbrugge R.J., Huijts M., De Leeuw P.W., Kroon A.A., Staals J. Total Cerebral Small Vessel Disease MRI Score Is Associated with Cognitive Decline in Executive Function in Patients with Hypertension. Front Aging Neurosci. 2016;8:301. DOI: 10.3389/fnagi/2016/00301

52. Gattringer T., Pinter D., Enzinger C. et al. Serum neurofilament light is sensitive to active cerebral small vessel disease. Neurology. 2017;89(20):2108–2114. DOI: 10.1212/WNL.0000000000004645

53. Armulik A., Abramsson A., Betsholtz C. Endothelial/pericyte interactions. Circ. Res. 2005;97(6):512–523. DOI: 10.1161/01.RES.0000182903.16652.d7

54. Rajashekhar G., Willuweit A., Patterson C.E. et al. Continuous endothelial cell activation increases angiogenesis: evidence for the direct role of endothelium linking angiogenesis and inflammation. J. Vasc. Res. 2006;43(2):193–204. DOI: 10.1159/000090949

55. Vermeer S.E., Longstreth W.T. Jr, Koudstaal P.J. Silent brain infarcts: a systematic review. Lancet Neurol. 2007;6(7):611–619. DOI: 10.1016/S1474-4422(07)70170-9

56. Norrving B. Evolving Concept of Small Vessel Disease through Advanced Brain Imaging. J. Stroke. 2015;17(2):94–100. DOI: 10.5853/jos.2015.17.2.94

57. Staals J., Makin S.D., Doubal F.N., Dennis M.S., Wardlaw J.M. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology. 2014;83(14):1228–1234. DOI: 10.1212/WNL.0000000000000837

58. Lyoubi-Idrissi A.L., Jouvent E., Poupon C., Chabriat H. Diffusion magnetic resonance imaging in cerebral small vessel disease. Rev. Neurol. (Paris). 2017;173(4):201–210. DOI: 10.1016/j.neurol.2017.03.005

59. Blair G.W., Thrippleton M.J., Shi Y. et al. Intracranial hemodynamic relationships in patients with cerebral small vessel disease. Neurology. 2020;94(21):e2258–e2269. DOI: 10.1212/WNL.0000000000009483

60. De Guio F., Mangin J.F., Duering M., Ropele S., Chabriat H., Jouvent E. White matter edema at the early stage of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Stroke. 2015;46(1):258–261. DOI: 10.1161/STROKEAHA.114.007018

61. Rost N.S., Cougo P., Lorenzano S. et al. Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke. J. Cereb. Blood Flow Metab. 2018;38(1):75–86. DOI: 10.1177/0271678X17706449

62. Sam K., Crawley A.P., Conklin J. et al. Development of White Matter Hyperintensity Is Preceded by Reduced Cerebrovascular Reactivity. Ann. Neurol. 2016;80(2):277–285. DOI: 10.1002/ana.24712

63. Shi Y., Thrippleton M.J., Blair G.W. et al. Small vessel disease is associated with altered cerebrovascular pulsatility but not resting cerebral blood flow. J. Cereb. Blood Flow Metab. 2020;40(1):85–99. DOI: 10.1177/0271678X18803956

64. Esther MC van Leijsen, Ingeborg WM van Uden, Ghafoorian M. et al. Nonlinear temporal dynamics of cerebral small vessel disease: The RUN DMC study. Neurology. 2017;89(15):1569–1577. DOI: 10.1212/WNL.0000000000004490

65. Kario K., Matsuo T., Kobayashi H., Hoshide S., Shimada K. Hyperinsulinemia and hemostatic abnormalities are associated with silent lacunar cerebral infarcts in elderly hypertensive subjects. J. Am. Coll. Cardiol. 2001;37(3):871–877. DOI: 10.1016/s0735-1097(00)01172-4