Annals of Clinical and Experimental NeurologyAnnals of Clinical and Experimental NeurologyАнналы клинической и экспериментальной неврологии2075-54732409-2533Eco-Vector82710.54101/ACEN.2022.2.9ReviewsОбзорыReview ArticleMorphology and pathogenesis of white matter changes in chronic cerebrovascular diseaseМорфология и патогенез изменений белого вещества при хронической цереброваскулярной патологииhttps://orcid.org/0000-0003-2970-8136GulevskayaTatyana S.ГулевскаяТатьяна Сергеевна
Russian Federation

D. Sci. (Med.), Prof., chief researcher, Laboratory of neuromorphology

д.м.н., профессор, г.н.с. лаб. нейроморфологии

anufriev@neurology.ruhttps://orcid.org/0000-0002-5327-2275AnufrievPavel L.АнуфриевПавел Лазаревич
Russian Federation

Cand. Sci. (Med.), senior researcher, Laboratory of neuromorphology

к.м.н., с.н.с. лаб. нейроморфологии

anufriev@neurology.ruhttps://orcid.org/0000-0002-5883-8119TanashyanМarine М.ТанашянМаринэ Мовсесовна
Russian Federation

D. Sci. (Med.), Prof., Corresponding member of RAS, Deputy Director for science, Head, 1st Neurological department

д.м.н., профессор, член-корреспондент РАН, зам. директора по научной работе, руководитель 1-го неврологического отделения

anufriev@neurology.ruResearch Center of NeurologyФГБНУ «Научный центр неврологии»3006202216278880203202214032022Copyright ©; 2022, Gulevskaya T.S., Anufriev P.L., Tanashyan М.М.Copyright ©; 2022, Гулевская Т.С., Ануфриев П.Л., Танашян М.М.2022Gulevskaya T.S., Anufriev P.L., Tanashyan М.М.Гулевская Т.С., Ануфриев П.Л., Танашян М.М.https://creativecommons.org/licenses/by/4.0https://annaly-nevrologii.com/pathID/article/view/827

This review contains up-to-date information on the fundamentals and clinical aspects of white matter disease in chronic progressive cerebrovascular disease with cognitive impairment, the leading risk factors for which are hypertension and cerebral atherosclerosis. Highly informative methods of neuroimaging have contributed significantly to the study of this problem, confirming the important role of white matter changes in the development and progression of cognitive impairment. The full range of the morphological changes in white matter, typical of vascular encephalopathy and cognitive dysfunction, is presented. Chronic hypoperfusion and white matter ischaemia play a leading role in the pathogenesis of white matter changes in vascular dementia development, but alternative hypotheses are also emerging. Further fundamental morphological and clinical studies will help to determine the leading mechanisms of white matter damage in patients with vascular and other age-related forms of dementia. This is necessary for the development of effective methods of treatment and prevention.

В обзоре освещены современные представления о фундаментальных и клинических аспектах патологии белого вещества (БВ) при хронических прогрессирующих цереброваскулярных заболеваниях c когнитивными нарушениями, ведущими факторами риска которых являются артериальная гипертония и церебральный атеросклероз. Отмечается вклад в изучение этой проблемы высокоинформативных методов нейровизуализации, благодаря которым подтверждена важная роль изменений БВ в развитии и прогрессировании когнитивных нарушений. Представлен весь комплекс морфологических изменений БВ, характерных для дисциркуляторной энцефалопатии с когнитивной дисфункцией. В патогенезе поражения БВ при развивающейся сосудистой деменции ведущая роль отводится хронической гипоперфузии и ишемии БВ, активно разрабатываются альтернативные гипотезы. Дальнейшие фундаментальные морфологические и клинические исследования помогут решить вопрос о ведущих механизмах поражения БВ у больных с сосудистой и другими возрастзависимыми формами деменции, что необходимо для разработки эффективных методов лечения и профилактики.

white matter diseasehypertensioncerebral atherosclerosiswhite matter hyperintensitycognitive impairmentBinswanger's diseaseпатология белого вещества головного мозгаартериальная гипертонияцеребральный атеросклерозгиперинтенсивность белого веществакогнитивные нарушениядеменция бинсвангеровского типаPantoni L., Gorelick P. Cerebral small vessel disease. Cambridge; 2014. 371 р. DOI: 10.1017/CBO9781139382694Ostergaard L., Engedal T., Moreton F. et al. Cerebral small vessel disease: Capillary pathways to stroke and cognitive decline. J. Cereb. Blood Flow Metab. 2016; 36(2): 302–325. DOI: 10.1177/0271678X15606723Добрынина Л.А. Нейроваскулярное взаимодействие и церебральная перфузия при старении, церебральной микроангиопатии и болезни Альцгеймера. Анналы клинической и экспериментальной неврологии. 2018; (12): 87–94. Dobrynina L.A. Neurovascular coupling and cerebral perfusion in aging, cerebral microangiopathy and Alzheimer’s disease. Annals of Clinical and Experimental Neurology. 2018; (12): 87–94. (In Russ.) DOI: 10.25692/ACEN.2018.5.11Калашникова Л.А., Гулевская Т.С., Добрынина Л.А. Актуальные проблемы патологии головного мозга при церебральной микроангиопатии. Журнал неврологии и психиатрии им. С.С. Корсакова. 2018; 118(2): 90–99. Kalashnikova L.A., Gulevskaya T.S., Dobrynina L.A. Actual problems of brain pathology in cerebral microangiopathy. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova. 2018; 118(2): 90–99. (In Russ.) DOI: 10.17116/jnevro20181182190-99Гнедовская Е.В., Добрынина Л.А., Кротенкова М.В., Сергеева А.Н. МРТ в оценке прогрессирования церебральной ангиопатии. Анналы клинической и экспериментальной неврологии. 2018; 12(1): 61–68. Gnedovskaya E.V., Dobrynina L.A., Krotenkova M.V., Sergeeva A.N. MRI in the assessment of cerebral small vessel disease. Annals of Clinical and Experimental Neurology. 2018; 12(1): 61–68. (In Russ.) DOI: 10.25692/ACEN.2018.1.9Суслина З.А., Гулевская Т.С., Максимова М.Ю., Моргунов В.А. Нарушения мозгового кровообращения. Диагностика, лечение, профилактика. М.; 2016. 536 с. Suslina Z.A, Gulevskaya T.S., Maksimova M.Yu., Morgunov V.A. Cerebrovascular diseases: diagnosis, treatment, prevention. Moscow; 2016. 536 p. (In Russ.)Верещагин Н.В., Калашникова Л.А., Гулевская Т.С., Миловидов Ю.К. Болезнь Бинсвангера и проблема сосудистой деменции: к 100-летию первого описания. Журнал неврологии и психиатрии им. С.С. Корсакова. 1995; (1): 98–103. Vereshchagin N.V., Kalashnikova L.A., Gulevskaia T.S., Milovidov Yu.K. Binswanger’s disease and the problem of vascular dementia: on the centenary of its first description. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova. 1995; (1): 98–103. (In Russ.)Калашникова Л.А., Гулевская Т.С. Сосудистая деменция бинсвангеровского типа: клинико-морфологическое исследование. Журн. неврол. и психиатр. им. С.С. Корсакова. Приложение «Инсульт», спецвыпуск. 2007: 364. Kalashnikova L.A., Gulevskaya T.S. Vascular dementia of the Binswanger type: clinic-morphological study. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova. Prilozhenie «Insult» (special issue). 2007: 364. (In Russ.)Шмырёв В.И., Мартынов А.И., Гулевская Т.С. и др. Поражение белого вещества головного мозга (лейкоареоз): частота, факторы риска, патогенез, клиническая значимость. Неврологический журнал. 2000; 5(3): 47–54. Shmyryov V.I., Martynov A.I., Gulevskaya T.S. et al. White matter lesions (leukoaraiosis): incidence, risk factors, pathogenesis, and clinical implication. Nevrologicheskiy Zhurnal. 2000; 5(3): 47–54. (In Russ.)Яхно Н.Н., Левин О.С., Дамулин И.В. Сопоставление клинических и МРТ-данных при дисциркуляторной энцефалопатии. Сообщение 2: когнитивные нарушения. Неврологический журнал. 2001; 6(3): 10–19. Yahno N.N., Levin O.S., Damulin I.V. Comparison of clinical and MRI data in discirculatory encephalopathy. Message 2: cognitive impairment. Nevrologicheskiy Zhurnal. 2001; 6(3): 10–19. (In Russ.)Schmidt R., Petrovic K., Ropele S. et al. Progression of leukoaraiosis and cognition. Stroke. 2007; 38(9): 2619–2625. DOI: 10.1161/STROKEAHA.107.489112Black S., Gao F., Bilbao J. Understanding white matter disease: ima- ging-pathological correlations in vascular cognitive impairment. Stroke. 2009; 40(3 suppl): 48–52. DOI: 10.1161/STROKEAHA.108.537704Pantoni L., Gorelick P. Advances in vascular cognitive impairment 2010. Stroke. 2011; 42(2): 291–293. DOI: 10.1161/STROKEAHA.110.605097Merino J. White matter hyperintensities on magnetic resonance imaging: what is a clinician to do? Mayo Clin. Proc. 2019; 94(3): 380–382. DOI: 10.1016/j.mayocp.2019.01.016Wardlaw J., Smith E., Biessels G. et al. 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)70124-8Wardlaw J., Smith C., Dichgans M. Mechanisms underlying sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013; 12(6): 532–559. DOI: 10.1016/S1474-4422(13)70060-7Shim Y., Yang D., Roe C. et al. Pathological correlates of white matter hypertensities on MRI. Dement. Geriatr. Cogn. Disord. 2015; 39(1–2): 92–104. DOI: 10.1159/000366411Wardlaw J.M. William M. Feinberg Award for excellence in clinical stroke: small vessel disease; a big problem, but fixable. Stroke. 2018; 49(7): 1770–1775. DOI: 10.1161/STROKEAHA.118.021184Liu Y., Dong Y., Lyu P. et al. Hypertension-Induced Cerebral Small Vessel Disease Leading to Cognitive Impairment. Clin. Med. J. (Engl). 2018; 131(5): 615–619. DOI: 10.4103/0366-6999.226069Сuadrado-Godia E., Dwivedi P., Sharma S. et al. Cerebral Small vessel disease: a review focusing on pathophysiology, biomarkers, and machine learning strategies. J. Stroke. 2018; 20(3): 302–320. DOI: 10.5853/jos.2017.02922Li Q., Yang Y., Res C. et al. Cerebral small vessel disease. Cell Transplant. 2018; 27(2): 1711–1722. DOI: 10.1177/0963689718795148Hakim A. Small vessel disease. Front. Neurol. 2019; 10: 1020. DOI: 10.3389/fneur.2019.01020Gurol M., Biessels G., Polimeni J. Advanced neuroimaging to unravel mechanisms of cerebral small vessel diseases. Stroke. 2020; 51(1): 29–37. DOI: 10.1161/STROKEAHA.119.024149Pasi M., Cordonnier C. Clinical relevance of cerebral small vessel diseases. Stroke. 2020; 51(1): 47–53. DOI: 10.1161/STROKEAHA.119.024148Meissner A. Hypertension and the brain: a risk factor for more than heart disease. Cerebrovasc. Dis. 2016; 42(3–4): 255–262. DOI: 10.1159/000446082Гулевская Т.С., Моргунов В.А. Патологическая анатомия нарушений мозгового кровообращения при атеросклерозе и артериальной гипертонии. Руководство для врачей. М.; 2009. 295 с. Gulevskaya T.S., Morgunov V.A. Pathological anatomy of cerebral circulation disorders in atherosclerosis and arterial hypertension. A guide for doctors. Moscow; 2009. 295 p. (In Russ.).Колтовер А.Н., Людковская И.Г., Гулевская Т.С. и др. Гипертоническая ангиоэнцефалопатия в патологоанатомическом аспекте. Журнал невропатологии и психиатрии им. С.С. Корсакова. 1984; 84(7): 1016–1020. Koltover A.N., Liudkovskaia I.G., Gulevskaia T.S. et al. Hypertonic angioencephalopathy in its pathomorphological aspect. Zh. Nevropatol. Psikhiatr. Im. S. S. Korsakova. 1984; 84(7): 1016–1020. (In Russ.)Колтовер А.Н., Моргунов В.А., Людковская И.Г. и др. Гипертоническая ангиопатия головного мозга. Архив патологии. 1986; 48(11): 34–39. Koltover A.N., Morgunov V.A., Liudkovskaya I.G. et al. Hypertensive angiopathy of the brain. Arkhiv Patologii. 1986; 48(11): 34–39. (In Russ.)Людковская И.Г., Гулевская Т.С., Моргунов В.А. Деструктивные изменения средней оболочки интрацеребральных артерий при артериальной гипертензии. Архив патологии. 1982; 44(9): 66–72. Liudkovskaia I.G., Gulevskaia T.S., Morgunov V.A. Destructive changes in the media of intracerebral arteries in arterial hypertension. Arkhiv Patologii. 1982; 44(9): 66–72. (In Russ.)Верещагин Н.В., Моргунов В.А., Гулевская Т.С. Патология головного мозга при атеросклерозе и артериальной гипертонии. М.; 1997. 288 с. Vereshchagin N.V., Gulevskaya T.S., Morgunov V.A. Brain pathology in atherosclerosis and arterial hypertension. Moscow; 1997. 288 p. (In Russ.)Гулевская Т.С., Людковская И.Г. Артериальная гипертония и патология белого вещества головного мозга. Архив патологии. 1992; (2): 53–59. Gulevskaya T.S., Liudkovskaia I.G. Arterial hypertension and pathology of cerebral white matter. Arkhiv Patologii. 1992; (2): 53–59. (In Russ.)Гулевская Т.С., Людковская И.Г. Особенности изменений сосудов коры и белого вещества полушарий головного мозга при артериальной гипертонии. Журнал невропатологии и психиатрии им. С.С. Корсакова. 1985; (7): 979–985. Gulevskaia T.S., Liudkovskaia I.G. Features of changes in vessels of the cortex and white matter of the cerebral hemispheres in arterial hypertension. Zh. Nevro- patol. Psikhiatr. Im. S. S. Korsakova. 1985; 85(7): 979–985. (In Russ.)Людковская И.Г., Гулевская Т.С. К морфологии и патогенезу изменений белого вещества полушарий головного мозга при артериальной гипертонии. Журнал невропатологии и психиатрии им. С.С. Корсакова. 1988; 88(7): 25–32. Liudkovskaya I.G., Gulevskaia T.S. Morphology and pathogenesis of changes in the substantia alba of the cerebral hemispheres in arterial hypertension. Zh. Nevropatol. Psikhiatr. Im. S. S. Korsakova. 1988; 88(7): 25–32. (In Russ.)Moody D.M., Brown W.R., Challa V.R. et al. Periventricular venous collagenosis: association with leukoaraiosis. Radiology. 1995; 194(2): 469–476. DOI: 10.1148/radiology.194.2.7824728Калашникова Л.А. Субкортикальная артериосклеротическая энцефалопатия (клинико-морфологическое исследование). Неврологический журнал. 1998; 3(2): 7–13. Kalashnikova L.A. Subcortical arteriosclerotic encephalopathy (clinico-morphological examination). Nevrologicheskiy Zhurnal. 1998; 3(2): 7–13. (In Russ.)Левина Г.Я., Гулевская Т.С. Прогрессирующая субкортикальная артериосклеротическая энцефалопатия (болезнь Бинсвангера). Архив патологии. 1985; 47(8): 70–73. Levina G.Ya., Gulevskaia T.S. Progressive subcortical arteriosclerotic encephalopathy (Binswanger’s disease). Arkhiv Patologii. 1985; 47(8): 70–73. (In Russ.)Babikian V., Ropper A. Binswanger’s disease: a review. Stroke. 1987; 18(1): 2–12. DOI: 10.1161/01.str.18.1.2Roman G. Senile dementia of the Binswanger type. A vascular form of dementia in the elderly. JAMA. 1987; 258(13): 1782–1788. DOI: 10.1001/jama.1987.03400130096040Fisher C. Binswanger’s encephalopathy: a review. J. Neurol. 1989; 236(2): 65–79. DOI: 10.1007/BF00314400Yamanouchi H., Sugiura S., Schimada H. Loss of nerve fibres in the corpus callosum of progressive subcortical vascular encephalopathy. J. Neurol. 1990; 237(1): 39–41. DOI: 10.1007/BF00319666Yamauchi H., Fukuyama H., Shio H. Corpus callosum atrophy in patients with leukoaraiosis may indicate global cognitive impairment. Stroke. 2000; 31(7): 1515–1520. DOI: 10.1161/01.str.31.7.1515Hachinski V. Binswanger’s disease: neither Binswanger’s nor a disease. J. Neurol. Sci. 1991; 103(1): 1. DOI: 10.1016/0022-510x(91)90274-bMcQuinn B.A., O’Leary D.H. White matter lucencies on computed tomography, subacute arteriosclerotic encephalopathy (Binswanger’s disease), and blood pressure. Stroke. 1987; 18(5): 900–905. DOI: 10.1161/01.str.18.5.900Hachinski V., Potter P., Merskey H. Leuko-araiosis. Arch. Neurol. 1987; 44(1): 21–23. DOI: 10.1001/archneur.1987.00520130013009Pantoni L. Leukoaraiosis: from an ancient term to an actual marker of poor prognosis. Stroke. 2008; 39(5): 1401–1403. DOI: 10.1161/STROKEAHA.107.505602Hase Y., Horsburgh K., Ihara M., Kalaria R. White matter degeneration in vascular and other ageing — related dementias. J. Neurochem. 2018; 144(5): 617–633. DOI: 10.1111/jnc.14271Bastin M., Clayden J., Pattie A. et al. Diffusion tensor and magnetization transfer MRI measurements of periventricular white matter hyperintensities in old age. Neurobiol. Aging. 2009; 30(1): 125–136. DOI: 10.1016/j.neurobiolaging.2007.05.013Dai W., Lopez O., Carmichael O. Abnormal regional cerebral blood flow in cognitively normal elderly subjects with hypertension. Stroke. 2008; 39(2): 349–354. DOI: 10.1161/STROKEAHA.107.495457Meguro K., Hatazawa J., Yamaguchi T. et al. Cerebral circulation and oxygen metabolism associated with subclinical periventricular hyperintensity as shown by magnetic resonance imaging. Ann. Neurol. 1990; 28(3): 378–383. DOI: 10.1002/ana.410280313Wallin A., Gottfries C., Karlsson I., Svennerholm L. Decreased myelin lipid in Alzheimer,s disease and vascular dementia. Acta Neurol. Scand. 1989; 80(4): 319–323. DOI: 10.1111/j.1600-0404.1989.tb03886.xLin J., Tomimoto H., Akiguchi I. et al. Vascular cell components of the medullary arteries in Binswanger’s disease brains. A morphometric and immunoelectron microscopic study. Stroke. 2000; 31(8): 1838–1842. DOI: 10.1161/01.str.31.8.1838Brown W., Moody D., Thore C. et al. Microvascular changes in the white matter in dementia. J. Neurol. Sci. 2009; 283(1–2): 28–31. DOI: 10.1016/j.jns.2009.02.328Goldberg M., Ransom R. New light on white matter. Stroke. 2003; 34(3): 330–332. DOI: 10.1161/01.str.0000054048.22626.b9Jones D., Lythgoe D., Horsfield M. et al. Characterization of white matter damage in ischemic leukoaraiosis with diffusion tensor MRI. Stroke. 1999; 30(2): 393–397. DOI: 10.1161/01.str.30.2.393Okeda R., Arima K., Kawai M. Arterial changes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) in relation to pathogenesis of diffuse myelin loss of cerebral white matter. Examination of cerebral medullary arteries by reconstruction of serial sections of an autopsy case. Stroke. 2002; 33(11): 2565–2569. DOI: 10.1161/01.str.0000032620.91848.1cFazekas F., Kleinert R., Offenbacher H. et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993; 43(9): 1683–1689. DOI: 10.1212/wnl.43.9.1683Fernando M., Simpson J., Matthews F. et al. White matter lesions in an unselected cohort of the elderly. Molecular pathology suggests origin from chronic hypoperfusion injury. Stroke. 2006; 37(6): 1391–1398. DOI: 10.1161/01.STR.0000221308.94473.14De Reuck J., Crevits L., De Coster W. et al. Pathogenesis of Binswanger chronic progressive subcortical encephalopathy. Neurology. 1980; 30(9): 920–928. DOI: 10.1212/wnl.30.9.920Oishi M., Mochizuki Y., Takasu T. Blood flow differences between leukoaraiosis with and without lacunar infarction. Can. J. Neurol. Sci. 1998; 25(1): 70–75. DOI: 10.1017/s0317167100033527Akiguchi I., Tomimoto H., Suenaga T. et al. Alterations in glia and axons in brains of Binswanger’s disease patients. Stroke. 1997; 28(7): 1423–1429. DOI: 10.1161/01.str.28.7.1423Rosenberg G., Sullivan N., Esiri M. White matter damage is associated with matrix metalloproteinases in vascular dementia. Stroke. 2001; 32(5): 1162–1168. DOI: 10.1161/01.str.32.5.1162Nakaji K., Ihara M., Takahashi C. et al. Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents. Stroke. 2006; 37(11): 2816–2823. DOI: 10.1161/01.STR.0000244808.17972.55Candelario-Jalil E., Thompson J., Taheri S. et al. Matrix metalloproteinases are associated with increased blood-brain barrier opening in vascular cognitive impairment. Stroke. 2011; 42(5): 1345–1350. DOI: 10.1161/STROKEAHA.110.600825Jung K., Stephens K., Yochim K. et al. Heterogenety of cerebral white matter lesions and clinical correlates in older adults. Stroke. 2021; 52(2): 620–630. DOI: 10.1161/STROKEAHA.120.031641Yu X., Yin X., Hong H. et al. Increased extracellular fluid is associated with white matter fiber degeneration in CADASIL: in vivo evidence from diffusion magnetic resonance imaging. Fluids Barriers CNS. 2021; 18(1): 29. DOI: 10.1186/s12987-021-00264-1Bradley W.G., Whittemore A.R., Watanabe A.S. et al. Association of deep white matter infarction with chronic communicating hydrocephalus: implications regarding the possible origin of normal-pressure hydrocephalus. Am. J. Neuro- radiol. 1991; 12(1): 31–39.Maclullich A., Ferguson K., Reid L. et al. Higher systolic blood pressure is associated with increased water diffusivity in normal-appearing white matter. Stroke. 2009; 40(12): 3869–3871. DOI: 10.1161/STROKEAHA.109.547877Zhang R., Huang P., Jiaerken Y. et al. Venous disruption affects white matter integrity through increased interstitial fluid in cerebral small vessel disease. J. Cereb. Blood Flow Metab. 2021; 41(1): 157–165. DOI: 10.1177/0271678X20904840Mestre H., Kostrikov S., Mehta R., Nedergaard M. Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clin. Sci (Lond). 2017; 131(17): 2257–2274. DOI: 10.1042/CS20160381Wardlaw J., Benveniste H., Nedergaard M. et al. Perivascular spaces in the brain: anatomy, physiology and pathology. Nat. Rev. Neurol. 2020; 16(3): 137–153. DOI: 10.1038/s41582-020-0312-zHuang P., Zhang R., Jiaerken Y. et al. Deep white matter hyperintensity is associated with the dilation of perivascular space. J. Cereb. Blood. Flow. Metab. 2021; 41(9): 2370–2380. DOI: 10.1177/0271678X211002279Weller R., Hawkes C., Kalaria R. et al. White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol. 2015; 25(1): 63–78. DOI: 10.1111/bpa.12218Ihara M., Yamamoto Y. Emerging evidence for pathogenesis of sporadic cerebral small vessel disease. Stroke. 2016; 47(2): 554–560. DOI: 10.1161/STROKEAHA.115.009627Poggesi A., Pasi M., Pescini F. et al. 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.2015.116Rosenberg G., Wallin A., Wardlaw J. et al. Consensus statement for diagnosis of subcortical small vessel disease. J. Cereb. Blood Flow Metab. 2016; 36(1): 6–25. DOI: 10.1038/jcbfm.2015.172Dalkara T. Pericytes: a novel target to improve success of recanalization therapies. Stroke. 2019; 50(10): 2985–2991. DOI: 10.1161/STROKEAHA.118.023590Kalman J., Juhasz A., Csaszar A. et al. Increased apolipoprotein E4 allele frequency is associated with vascular dementia in the Hungarian population. Acta Neurol. Scand. 1998; 98(3): 166–168. DOI: 10.1111/j.1600-0404.1998.tb07288.xGodin O., Tzourio C., Maillard P. et al. Apolipoprotein E genotype is related to progression of white matter lesion load. Stroke. 2009; 40(10): 3186–3190. DOI: 10.1161/STROKEAHA.109.555839Amar K., Macgowan S., Wilcock G. et al. Are genetic factors important in the aetiology of leukoaraiosis? Results from a memory clinic population. Int. J. Geriatr. Psychiatry. 1998; 13(9): 585–590. DOI: 10.1002/(sici)1099-1166(199809)13:9 < 585::aid-gps825 > 3.0.co;2-0Chabriat H., Vahedi K. et al. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet. 1995; 346(8980): 934–939. DOI: 10.1016/s0140-6736(95)91557-5Abib-Samii P., Brice G., Martin R., Markus H. Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype. Study in 200 consecutively recruited individuals. Stroke. 2010; 41(4): 630–634. DOI: 10.1161/STROKEAHA.109.568402Jouvent E., Duering M., Chabriat H. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: lessons from neuroimaging. Stroke. 2020; 51(1): 21–28. DOI: 10.1161/STROKEAHA.119.024152Максимова М.Ю., Гулевская Т.С. Лакунарный инсульт. Журнал неврологии и психиатрии им. С.С. Корсакова. 2019; 119(8, вып. 2): 13–27. Maksimova M.Yu., Gulevskaya T.S. Lacunar stroke. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova. 2019; 119(8, Vyp. 2): 13–27. (In Russ.) DOI: 10.17116/jnevro201911908213Arboix A., Blanco-Rojas L., Marti-Vilalta JL. Advancements in understanding the mechanisms of symptomatic lacunar ischemic stroke: translation of knowledge to prevention strategies. Expert Rev. Neurother. 2014; 14(3): 261–276. DOI: 10.1586/14737175.2014.884926Ungvary Z., Tarantini S., Kirpatrick A. et al. Cerebral microhemorrhages: mechanisms, consequences, and prevention. Am. J. Physiol. Heart Circ. Physiol. 2017; 312(6): H1128–H1143. DOI: 10.1152/ajpheart.00780.2016Duperron M., Tzourio C., Sargurupremraj M. et al. Burden of dilated perivascular spaces, an emerging marker of cerebral small vessel disease, is heritable. Stroke. 2018; 49(2): 282–287. DOI: 10.1161/STROKEAHA.117.019309Riba-Liena J., Jimenez-Balado J., Castane X. et al. Arterial stiffness is associated with basal ganglia enlarged perivascular spaces and cerebral small vessel disease load. Stroke. 2018; 49(5): 1279–1281. DOI: 10.1161/STROKEAHA.118.020163Ishii N., Nishihara Y., Imamura T. Why do frontal lobe symptoms predominate in vascular dementia with lacunes? Neurology. 1986; 36(3): 340–345. DOI: 10.1212/wnl.36.3.340Norrving B. Evolving concept of small vessel disease through brain imaging. J. Stroke. 2015; 17(2): 94–100. DOI: 10.5853/jos.2015.17.2.94Gupta A., Giambrone A., Gialdini G. et al. Silent brain infarction and risk of future stroke: a systematic review and meta-analysis. Stroke. 2016; 47(3): 719–725. DOI: 10.1161/STROKEAHA.115.011889Loos C., Makin S., Staals J. et al. Long-term morphological changes of symptomatic lacunar infarcts and surrounding white matter on structural magnetic resonance imaging. Stroke. 2018; 49(5): 1183–1188. DOI: 10.1161/STROKEAHA.117.020495Hinman J., Lee M., Tung S. et al. Molecular disorganization of axons adjacent to human lacunar infarcts. Brain. 2015; 138(Pt 3): 736–745. DOI: 10.1093/brain/awu398Gregoire S., Brown M., Kallis C. et al. MRI detection of new microbleeds in patients with ischemic stroke: five-year cohort follow-up study. Stroke. 2010; 41(1): 184–186. DOI: 10.1161/STROKEAHA.109.568469Staals J., Oostenbrugge R., Knottnerus I. et al. Brain microbleeds relate to higher ambulatory blood pressure levels in first-ever lacunar stroke patiens. Stroke. 2009; 40(10): 3264–3268. DOI: 10.1161/STROKEAHA.109.558049Thijs V., Lemmens R., Schoofs C. et al. Microbleeds and the risk of recurrent stroke. Stroke. 2010; 41(9): 2005–2009. DOI: 10.1161/STROKEAHA.110.588020Benjamin P., Tippier S., Lawrence A. et al. Lacunar infarcts, but not perivascular spaces, are predictors of cognitive decline in cerebral small-vessel disease. Stroke. 2018; 49(3): 586–593. DOI: 10.1161/STROKEAHA.117.017526Potter G., Doubal F., Jackson C. et al. Enlarged perivascular spaces and cerebral small vessel disease. Int. J. Stroke. 2015; 10(3): 376–381. DOI: 10.1111/ijs.12054Brown R., Benveniste H., Bkack S. et al. Understanding the role of the perivascular space in cerebral small vessel disease. Cardiovasc. Res. 2018; 114(11): 1462–1473. DOI: 10.1093/cvr/cvy113Geurts L., Zwanenburg J., Klijn C. et al. Higher pulsatility in cerebral perforating arteries in patients with small vessel disease related stroke, a 7T MRI study. Stroke. 2019; 50(1): 62–68. DOI: 10.1161/STROKEAHA.118.022516Esten-Lyons D., Woltjer R., Kaye J. et al. Neuropathologic basis of white matter hypertensity accumulation with advanced age. Neurology. 2013; 81(11): 977–983. DOI: 10.1212/WNL.0b013e3182a43e45Hasan T., Barrett K., Brott T. et al. Severity of white matter hyperintensities and effects on all-cause mortality in the Mayo Clinic Florida Familian Cerebrovascular Diseases Registry. Mayo Clin. Proc. 2019; 94(3): 408–416. DOI: 10.1016/j.mayocp.2018.10.024