Деменция вследствие поражения мелких церебральных сосудов: современные представления о патогенезе и терапии

В настоящее время при рассмотрении цереброваскулярной патологии, приводящей к когнитивным расстройствам (КН), все большее внимание уделяется деменции, обусловленной поражением мелких сосудов. Одним из наиболее значимых факторов риска (ФР) возникновения сосудистых КН, включая сосудистую деменцию, является инсульт. Перенесенный инсульт в три раза увеличивает риск возникновения деменции. В генезе сосудистых КН важную роль играют диффузные изменения белого вещества полушарий головного мозга (лейкоареоз), в большинстве случаев обусловленные колебаниями артериального давления (АД) и поражением мелких церебральных сосудов. Ведущими в клинической картине субкортикальной сосудистой деменции являются нарушения исполнительных функций, нередко сочетающиеся с замедлением скорости психомоторных процессов. Выраженные нарушения памяти для субкортикальной деменции, особенно для ее начальных этапов, не характерны. В основе патогенеза КН лежит феномен разобщения, заключающийся в нарушении связей лобных отделов с субкортикальными структурами и другими отделами коры головного мозга. Более 1/4 случаев развития деменции у пожилых обусловлены неадекватной коррекцией артериальной гипертензии в среднем возрасте. Выявление и последующее устранение сосудистых ФР позволяет уменьшить риск развития деменции в пожилом и старческом возрасте. Коррекция повышенного АД в среднем возрасте рассматривается как эффективный метод предотвращения развития деменции в будущем, а вот у пожилых – на фоне присущего этой категории больных снижения АД – гипотензивной терапии большого значения не придается Для лечения широко используются лекарственные средства, действующие на ФР, а также препараты, способные улучшать церебральный метаболизм и кровоток, включая ницерголин.

1. Kuller LH, Lopez OL, Jagust WJ, et al. Determinants of vascular dementia in the Cardiovascular Health Cognition Study. Neurology. 2005;64:1548–52. DOI: http://dx.doi.org/10.1212/01.WNL. 0000160115.55756.DE.

2. Tullberg M, Fletcher E, DeCarli C, et al. White matter lesions impair frontal lobe function regardless of their location. Neurology. 2004;63:246–53. DOI: http://dx.doi.org/10.1212/01.WNL.0000130530.55104.B5.

3. Kaffashian S, Dugravot A, Brunner EJ, et al. Midlive stroke risk and cognitive decline: a 10-year follow-up of the Whitehall II cohort study. Alzheim Dement. 2013;9:572–9. DOI: http://dx.doi.org/10.1016/j.jalz.2012.07.001.

4. Cumming TB, Marshall RS, Lazar RM. Stroke, cognitive deficits, and rehabilitation: still an incomplete picture. Int J Stroke.2013;8:38–45. DOI: http://dx.doi.org/10.1111/j.1747-4949.2012.00972.x.

5. De Haan EH, Nys GM, van Zandvoort MJ. Cognitive function following stroke and vascular cognitive impairment. Curr Opin Neurol. 2006;19:559–64. DOI: http://dx.doi.org/10.1097/01.wco.0000247612.21235.d9.

6. Murphy TH, Corbett D. Plasticity during stroke recovery: from synapse to behaviour. Nature Rev Neurosci. 2009;10:861–72. DOI: http://dx.doi.org/10.1038/nrn2735.

7. Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline. New Engl J Med. 2003;348:1215–22. DOI:http://dx.doi.org/10.1056/NEJMoa022066.

8. Fein G, Di Sclafani V, Tanabe J, et al. Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease. Neurology. 2000;55:1626–35. DOI:http://dx.doi.org/10.1212/WNL.55.11.1626.

9. Blass JP, Ratan RR. «Silent» strokes and dementia. New Engl J Med. 2003;348(13): 1277–8. DOI: http://dx.doi.org/10.1056/NEJMe030017.

10. Werring DJ, Coward LJ, Losseff NA, et al. Cerebral microbleeds are common in ischemic stroke but rare in TIA. Neurology. 2005;65:1914–8. DOI: http://dx.doi.org/10. 1212/01.wnl.0000188874.48592.f7.

11. Wardlaw JM. What causes lacunar stroke? J Neurol Neurosurg Psychiatry. 2005;76:617–9. DOI: http://dx.doi.org/10.1136/jnnp.2004.039982.

12. Alexander MP, Stuss DT. Disorders of frontal lobe functioning. Sem Neurol. 2000;20(40):427–37. DOI: http://dx.doi.org/10.1055/s-2000-13175.

13. Kwan LT, Reed BR, Eberling JL, et al. Effects of subcortical cerebral infarction on cortical glucose metabolism and cognitive function. Arch Neurol. 1999;56:809–14. DOI: http://dx.doi.org/10.1001/archneur.56.7.809.

14. Reed BR, Eberling JL, Mungas D, et al. Effects of white matter lesions and lacunes on cortical function. Arch Neurol. 2004;61:1545–50. DOI: http://dx.doi.org/10.1001/archneur. 61.10.1545.

15. Reed BR, Eberling JL, Mungas D, et al. Frontal lobe hypometabolism predicts cognitive decline in patients with lacunar infarctions. Arch Neurol. 2001;58:494–7. DOI: http://dx.doi.org/10.1001/archneur.58.3.493.

16. De Leeuw FE, van Gijn J. Vascular dementia. Pract Neurol. 2003;3:86–91. DOI: http://dx.doi.org/10.1046/j.1474-7766.2003.04132.x.

17. Walha K, Ricolfi F, Bejot Y, et al. Hippocampus: a «forgotten» border zone of brain ischemia. J Neuroimag. 2013;23:98–101. DOI: http://dx.doi.org/10.1111/j.1552-6569.2011.00610.x.

18. Charidimoi A, Krishnan A, Werring DJ, Jager HR. Cerebral microbleedings: a guide to detection and clinical relevance in different disease settings. Neuroradiol. 2013;55:655–74. DOI: http://dx.doi.org/10.1007/s00234-013-1175-4.

19. Cordonnier C. Brain microbleedens: more evidence, but still a clinical dilemma. Curr Opin Neurol. 2011;24:69–74. DOI: http://dx.doi.org/10.1097/WCO.0b013e328341f8c0.

20. De Leeuw FE, de Groot JC, Oudkerk M, et al. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain. 2002;125:765–72. DOI: http://dx.doi.org/ 10.1093/brain/awf07721.

21. Goldstein IB, Bartzokis G, Guthrie D, Shapiro D. Ambulatory blood pressure and the brain. A 5-year follow-up. Neurology. 2005;64:1846–52. DOI: http://dx.doi.org/10.1212/01.WNL.0000164712.24389.BB.

22. Bonoczk P, Panczel G, Nagy Z. Vasoreactivity in patients with periventricular white matter lucency. Acta Neurologica Scand. 2004;110 (4): 254–6. DOI: http://dx.doi.org/10.1111/j.1600-0404.2004.00316.x.

23. Pantoni L, Poggesi A, Inzitari D. The relation between white-matter lesions and cognition. Curr Opin Neurol. 2007;20:390–7. DOI: http://dx.doi.org/10.1097/WCO.0b013e328172d661.

24. Udaka F, Sawada H, Kameyama M. White matter lesions and dementia: MRI-pathologicalcorrelations. Ann NY Acad Sci. 2002;977:411–5. DOI: http://dx.doi.org/10.1111/j.1749-6632.2002.tb04845.x.

25. Guermazi A, Miaux Y, Rovira-Canellas A, et al. Neuroradiological findings in vascular dementia. Neuroradiol. 2007;49:1–22. DOI: http://dx.doi.org/10.1007/s00234-006-0156-2.

26. Yamauchi H. Ischemic white matter damage and cognitive impairment. Psychogeriatrics. 2003;3:11–6. DOI: http://dx.doi.org/10. 1046/j.1479-8301.2003.00003.x.

27. Kril JJ, Patel S, Harding AJ, Halliday GM. Patients with vascular dementia due to microvascular pathology have significant hippocampal neuronal loss. J Neurol Neurosurg Psychiatry. 2002;72:747–51. DOI: http://dx.doi.org/10.1136/jnnp.72.6.747.

28. Righart R, Duering M, Gonik M, et al. Impact of regional cortical and subcortical changes on processing speed in cerebral small vessel disease. Neuroimage Clin. 2013;2:854–61. DOI: http://dx.doi.org/10.1016/j.nicl.2013. 06.006.

29. Capizzano AA, Schuff N, Amend DL, et al. Subcortical ischemic vascular dementia: assessment with quantitative MR imaging and 1H MR spectroscopy. Am J Neuroradiol. 2000;21(4):621–30.

30. Greener M. Clarifying the link between Alzheimer's and vascular disease. Progress in Neurology and Psychiatry. 2013;March/April:27–8. DOI: http://dx.doi.org/10.1002/pnp.276.

31. Benarroch EE. Microglia: Multiple roles in surveillance, circuit shaping, and response to injury. Neurology. 2013;81:1079–88. DOI: http://dx.doi.org/10.1212/WNL.0b013e3182a4a577.

32. Meyer JS, Xu G, Thornby G, et al. Is mild cognitive impairment prodromal for vascular dementia like Alzheimer's disease? Stroke. 2002;33:1981–5. DOI: http://dx.doi.org/10. 1161/01.STR.0000024432.34557.10.

33. Poels MMF, Steyerberg EW, Wieberdink RG, et al. Assessment of cerebral small vessel disease predicts individual stroke risk. J Neurol Neurosurg Psychiatry. 2012;83:1174–9. DOI: http://dx.doi.org/10.1136/jnnp-2012-302381.

34. Elkins JS, O'Meara ES, Longstreth WT, et al. Stroke risk factors and loss of high cognitive function. Neurology. 2004;63:793–9.DOI: http://dx.doi.org/10.1212/01.WNL. 0000137014.36689.7F.

35. Imfeld P, Bodmer M, Schuerch M, et al. Risk of incident stroke in patients with Alzheimer disease or vascular dementia. Neurology. 2013;81:910–9. DOI: http://dx.doi.org/10.1212/WNL.0b013e3182a35151.

36. Вахнина НВ. Сосудистые когнитивные нарушения. Неврологuя, нейропсихиатрия, психосоматика. 2014;(1):74–9. [Vakhnina NV. Vascular cognitive impairment. Nevrologuya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2014;(1):74–9. (In Russ.)]. DOI: http://dx.doi.org/10.14412/2074-2711-2014-1-74-79.

37. Stewart R. Vascular dementia: a diagnosis running out of time. Br J Psychiatry. 2002;180:152–6. DOI: http://dx.doi.org/10. 1192/bjp.180.2.152

38. Sachdev PS, Brodaty H, Valenzuela MJ, et al. The neuropsychological profile of vascular cognitive impairment in stroke and TIA patients. Neurology. 2004;62:912–9. DOI: http://dx.doi.org/10.1212/01.WNL. 0000115108.65264.4B.

39. Alvarez JA, Emory E. Executive function and the frontal lobes: a meta-analytic review. Neuropsychol Rev. 2006;16(1):17–42. DOI: http://dx.doi.org/10.1007/s11065-006-9002-x.

40. Jurado MB, Rosselli M. The elusive nature of executive functions: a review of our current understanding. Neuropsychol Rev. 2007;17:213–33. DOI: http://dx.doi.org/ 10.1007/s11065-007-9040-z41.

41. Nachev P. Cognition and medial frontal cortex in health and disease. Curr Opin Neurol. 2006;19:586–92. DOI: http://dx.doi.org/10. 1097/01.wco.0000247609.36482.ae.

42. Cummings JL, Trimble MR. Concise guide to neuropsychiatry and behavioral neurology. 2nd ed. Washington, London: American Psychiatric Publishing, Inc.; 2002. 275 p.

43. Della Sala S, Gray C, Spinnler H, Trivelly C. Frontal lobe function in man: the riddle revisited. Arch Clin Neuropsychol. 1998;13(8):663–82.

44. Nonaka H, Akima M, Hatori T, et al. Microvasculature of the human cerebral white matter: Arteries of the deep white matter. Neuropathology. 2003;23:111–8. DOI: http://dx.doi.org/10.1046/j.1440-1789.2003.00486.x.

45. Hirono N, Kitagaki H, Kazui H, et al. Impact of white matter changes on clinical manifestation of Alzheimer's disease: a quantitative study. Stroke. 2000;31:2182–8. DOI: http://dx.doi.org/10.1161/01.STR.31.9.2182.

46. Oostrman JM, de Vries K, Scherder EJA. Executive ability in relation to blood pressure in residents of homes for the elderly. Arch Clinic Neuropsychol. 2007;22:731–8. DOI: http://dx.doi.org/10.1016/j.acn.2007.06.001.

47. Den Heijer T, Launer LJ, Prins ND, et al. Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe. Neurology. 2005;64:263–7. DOI: http://dx.doi.org/10.1212/01.WNL. 0000149641.55751.2E.

48. Gelber RP, Ross GW, Petrovitch H, et al.Antihypertensive medication use and risk of cognitive impairment: the Honolulu-Asia Aging Study. Neurology. 2013;81:888–95. DOI: http://dx.doi.org/10.1212/WNL. 0b013e3182a351d4.

49. Alagiakrishnan K, McCracken P, Feldman H. Treating vascular risk factors and maintaining vascular health: Is this the way towards successful cognitive ageing and preventing cognitive decline? Postgrad Med J. 2006; 82:101–5. DOI: http://dx.doi.org/10.1136/pgmj.2005.035030.

50. Seshadri S. Delaying dementia: can antihypertensives prevent Alzheimer dementia? Neurology. 2013;81:860–2. DOI: http://dx.doi.org/10.1212/WNL. 0b013e3182a35296.

51. Hill MD, Mitchell JR. White matter lesions and cognition. It's time for randomized trials to preserve intelligence. Neurology. 2006;66:470–1. DOI: http://dx.doi.org/10.1212/01.wnl.0000203412.56752.88.

52. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000;355(9207):865–72. DOI: http://dx.doi.org/10.1016/S0140-6736(99)07330-4.

53. Feigin V, Ratnasabapathy Y, Anderson C. Does blood pressure lowering treatment prevents dementia or cognitive decline in patients with cardiovascular and cerebrovascular disease? J Neurol Sci. 2005;229–230:151–5. DOI: http://dx.doi.org/10.1016/j.jns.2004.11.020.

54. Pandita-Gunawardena ND, Clarke SEM. Amlodipine lowers blood pressure without affecting cerebral blood flow as measured by single photon emission computed tomography in elderly hypertensive subjects. Age Ageing. 1999;28:451–7. DOI: http://dx.doi.org/10.1093/ageing/28.5.451.

55. Calero MD, Navarro E. Relationship between plasticity, mild cognitive impairment and cognitive decline. Arch Clin Neuropsychol. 2004;19:653–60. DOI:http://dx.doi.org/10.1016/j.acn.2003.08.008.

56. Farfel JM, Nitrini R, Suemoto CK, et al. Very low levels of education and cognitive reserve: a clinicopathologic study. Neurology. 2013;81:650–7. DOI: http://dx.doi.org/10.1212/WNL.0b013e3182a08f1b.

57. Преображенская ИС. Деменция – эпидемиология, клиническая картина, диагностика, подходы к терапии. Неврология, нейропсихиатрия, психосоматика. 2013;(4):71–7. [Preobrazhenskaya IS. Dementia: epidemiology, clinical picture, diagnosis, approaches to therapy. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2013;(4):71–7. (In Russ.)]. DOI: http://dx.doi.org/10. 14412/2074-2711-2013-2459.

58. Van Spronsen M, Hoogenraad C. Synapse pathology in psychiatric and neurologic disease. Curr Neurol Neurosci Rep. 2010;10:207–14. DOI: http://dx.doi.org/10.1007/s11910-010-0104-8.

59. Максимова МЮ, Домашенко МА, Танашян ММ. Современные подходы к профилактике и лечению хронических нарушений мозгового кровообращения. Неврология, нейропсихиатрия, психосоматика. 2012;(4):88–91. [Maksimova MYu, Domashenko MA, Tanashyan MM. Current approaches to preventing and treating chronic cerebral circulatory disorder. Nevrologiya, neiropsikhiatriya, psikhosomatika = Neurology, Neuropsychiatry, Psychosomatics. 2012;(4):88–91. (In Russ.)].

60. DOI: http://dx.doi.org/10.14412/2074-2711-2012-429.

61. Парфенов ВА. Антигипертензивная терапия в профилактике инсульта и когнитивных расстройств. Неврологический журнал. 2006;11(4):31–5. [Parfenov VA. Antihipertensiv

62. therapy in prevention of a stroke and cognitive frustration. Nevrologicheskii zhurnal. 2006;11(4):31–5. (In Russ.)]

63. Стаховская ЛВ, Скворцова ВИ, Чазова ИЕ. Вторичная профилактика ишемического инсульта. Consilium Medicum. 2003;5(8):473–6. [Stakhovskaya LV, Skvortsova VI, Chazova IE. Secondary prevention of an ischemic stroke. Consilium Medicum. 2003;5(8):473–6. (In Russ.)]

64. Gould DB, Phalan FC, van Mil SE, et al. Role of COL4A1 in small-vessel disease and hemorrhagic stroke. New Engl J Med. 2006;354(14):1489–96. DOI: http://dx.doi.org/10.1056/NEJMoa053727.

65. Greenberg SM. Small vessels, big problems. New Engl J Med. 2006;354(14):1451–3. DOI: http://dx.doi.org/10.1056/NEJMp068043.

66. Vahedi K, Boukobza M, Massin P, et al. Clinical and brain MRI follow-up study of a family with COL4A1 mutation. Neurology. 2007;69:1564–8. DOI: http://dx.doi.org/10.1212/01.wnl.0000295994.46586.e7.

67. Hassan A, Hunt BJ, O'Sullivan M, et al. Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain. 2003;126(2):424–32. DOI: http://dx.doi.org/10.1093/brain/awg040.

68. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J. 2002;324:71–86. DOI: http://dx.doi.org/10.1136/bmj.324.7329.71.

69. Winblad B, Carfagna N, Bonura L, et al. Nicergoline in dementia. A review of its pharmacological properties and therapeutic potential. CNS Drugs. 2000;14:267–87. DOI: http://dx.doi.org/10.2165/00023210-200014040-00003.

70. Winblad B, Fioravanti M, Dolezal T, et al. Therapeutic use of nicergoline. Clin Drug Invest. 2008;28:533–52. DOI: http://dx.doi.org/10.2165/00044011-200828090-00001.

71. Cattabeni F. Protein kinase C in synaptic plasticity: A molecular target in the treatment of cognitive disorders. Dement Geriatr Cogn Disord. 1997;8 Suppl 1:6–11.

72. Одинак ММ, Емелин АЮ, Лобзин ВЮ. Нарушения когнитивных функций при цереброваскулярной патологии. Санкт-Петербург: ВМедА; 2006. 158 с. [Odinak MM, Emelin AYu,

73. Lobzin VYu. Narusheniya kognitivnykh funktsii pritserebrovaskulyarnoi patologii [Violations of cognitive functions at cerebrovasculyar pathology] . St-Petersburg: VMedA; 2006. 158 p.]

74. Caraci F, Chisari M, Frasca G, et al. Nicergoline, a drug used for age-dependent cognitive impairment, protects cultured neurons against β-amyloid toxicity. Brain Res. 2005;1047:30–7.

75. DOI: http://dx.doi.org/10.1016/j.brainres. 2005.04.004.

76. Giardino L, Giuliani A, Battaglia A, et al. Neuroprotection and aging of the cholinergic system: A role for the ergoline derivative nicergoline (Sermion). Neurosci. 2002;109:487–97.

77. DOI: http://dx.doi.org/10.1016/S0306-4522(01)00470-5.

78. Crook TH. Nicergoline: Parallel evolution of clinical trial methodology and drug development in dementia. Dement Geriatr Cogn Disord. 1997;8 Suppl 1:22–6. DOI: http://dx.doi.org/10.1159/000106667.