Annals of Clinical and Experimental NeurologyAnnals of Clinical and Experimental NeurologyАнналы клинической и экспериментальной неврологии2075-54732409-2533Eco-Vector51510.25692/ACEN.2018.1.9ReviewsОбзорыUnknownMRI in the assessment of cerebral small vessel diseaseМРТ в оценке прогрессирования церебральной микроангиопатииGnedovskayaElena V.ГнедовскаяЕлена Владимировна
Russian Federation
lavrentevan@mail.ruhttps://orcid.org/0000-0001-9929-2725DobryninaLarisa A.ДобрынинаЛариса Анатольевна
Russian Federation

D. Sci. (Med.), Head, 3rd Neurology department

д.м.н., г.н.с., рук. 3-го неврологического отделения

lavrentevan@mail.ruhttps://orcid.org/0000-0003-3820-4554KrotenkovaMarina V.КротенковаМарина Викторовна
Russian Federation

D. Sci. (Med.), Head, Neuroradiology department

д.м.н., рук. отд. лучевой диагностики

lavrentevan@mail.ruSergeevaAnastasiya N.СергееваАнастасия Н.
Russian Federation
lavrentevan@mail.ruResearch Center of NeurologyФГБНУ «Научный центр неврологии»28032018121616828032018Copyright ©; 2018, Gnedovskaya E.V., Dobrynina L.A., Krotenkova M.V., Sergeeva A.N.Copyright ©; 2018, Gnedovskaya E.V., Dobrynina L.A., Krotenkova M.V., Sergeeva A.N.2018Gnedovskaya E.V., Dobrynina L.A., Krotenkova M.V., Sergeeva A.N.Gnedovskaya E.V., Dobrynina L.A., Krotenkova M.V., Sergeeva A.N.https://creativecommons.org/licenses/by/4.0https://annaly-nevrologii.com/pathID/article/view/515

Abstract

Cerebral small vessel disease (cSVD) is a leading cause of vascular cognitive impairment and dementia, cerebral hemorrhages, and lacunar strokes. It is considered to be the most common clinically silent vascular brain disorder. Major forms of cSVD are age- and hypertension-associated arteriolosclerosis and cerebral amyloid angiopathy. For most types of cSVD causes and mechanisms of disease development and progression remain unknown. Detailed research of cSVD is hindered by lack of technical approaches to an in vivo assessment of microvasculature. MRI equivalents of pathological changes in cSVD might serve as surrogate markers of vascular damage and might be associated with clinical signs and symptoms. We review studies that demonstrated clinical significance of the primary MR signs of cSVD, i.e. white matter hyperintensity (formerly known as leukoareosis), lacunes, enlarged perivascular spaces and cerebral microbleeds, as well as their role in the disease progression. Recently introduced STRIVE standards established MRI changes as diagnostic criteria for cSVD. These standards may significantly improve our understanding of the role of various factors in the development of cSVD and its heterogeneity. However, individual prognostication and assessment of short-term and long-term treatment efficacy is still lacking. The use of diffusion-weighted MRI techniques for the assessment of microstructural changes of visually normal bran tissue might be helpful. Strong association between microstructural changes and clinical manifestation of cSVD supports the need for multimodal MRI studies for the assessment of pathophysiological mechanisms of the disease progression even on preclinical stages.

Резюме

Церебральная микроангиопатия (ЦМА) (cerebral small vessel disease (cSVD)) признана ведущей причиной сосудистых когнитивных нарушений и деменции, кровоизлияний и лакунарных инсультов, наиболее распространенной формой асимптомного сосудистого поражения головного мозга. Ее основными формами являются связанный с возрастом и артериальной гипертензией артериолосклероз и церебральная амилоидная ангиопатия. Для большого числа ЦМА (cSVD), как причины, так и механизмы развития и прогрессирования не известны. Значительные сложности в изучении патологии обусловлены техническими ограничениями в прижизненной оценке сосудов данного калибра. Уточнение МРТ эквивалентов морфологических проявлений ЦМА (cSVD) и использование их в качестве суррогатного маркера повреждения мелких сосудов, позволило установить закономерности прогрессирования заболевания и их связь с клиническими проявлениями. В настоящем обзоре приводятся результаты исследований, показавших клиническую значимость и роль в оценке прогрессирования заболевания, ведущих МРТ признаков ЦМА (cSVD) - гиперинтенсивности белого вещества (ГИБВ) (ранее применявшийся термин - лейкоареоз), лакун, расширенных периваскулярных пространств и микрокровоизлияний. Признание МРТ признаков в качестве диагностических для ЦМА (cSVD) было закреплено международными экспертами в виде критериев STRIVE (STandards for ReportIng Vascular changes on nEuroimaging). Несмотря на огромную важность данной стандартизации в улучшении представлений о значимости различных факторов в ее развитии и понимании гетерогенности ее форм, данная категоризация признаков не может обеспечить прогнозирование течения заболевания у конкретного больного, как и оценивать эффективность лечения в коротко- и среднесрочной перспективе. Одним из подходов к решению проблемы стало использование диффузионных методик в оценке микроструктурного поражения визуально неизмененного вещества головного мозга. Полученная устойчивая связь в выраженности микроструктурных и клинических нарушений обосновывает целесообразность мультимодальных МРТ исследований, направленных на оценку патофизиологических механизмов прогрессирования заболевания, начиная с этапа субклинического поражения головного мозга.

cerebral small vessel diseasewhite matter hyperintensitylacunar strokemicrobleedperivascular spacesцеребральная микроангиопатияболезнь малых сосудовгиперинтенсивность белого веществалакунарные инфарктымикрокровоизлиянияпериваскулярные пространстваPantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010; 9(7): 689–701. PMID: 20610345 DOI10.1016/S1474-4422(10)70104-6Pasi M., van Uden I.W., Tuladhar A.M. et al. White matter microstructural damage on diffusion tensor imaging in cerebral small vessel disease: clinical consequences. Stroke. 2016; 47(6): 1679–84. PMID: 27103015 DOI10.1161/STROKEAHA.115.012065Wardlaw J.M., Smith C., Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol. 2013; 12(5): 483-97. PMID: 23602162 DOI:10.1016/S1474-4422(13)70060-7.Gorelick P.B., Scuteri A., Black S.E. et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011; 42: 2672–713. PMID: 21778438 DOI: 10.1161/STR.0b013e3182299496Charidimou A., Pantoni L., Love S. The concept of sporadic cerebral small vessel disease: A road map on key definitions and current concepts. Int J Stroke. 2016; 11(1): 6-18. PMID: 26763016 DOI: 10.1177/1747493015607485Qureshi A.I., Mendelow A.D., Hanley D.F. Intracerebral haemorrhage. Lancet. 2009 9; 373(9675): 1632-44. PMID: 19427958 DOI: 10.1016/S0140-6736(09)60371-8.Sudlow C.L., Warlow C.P. Comparable studies of the incidence of stroke and its pathological types. Results from an international collaboration. Stroke. 1997; 28: 491–9. PMID: 9056601.Biessels G.J. Diagnosis and treatment of vascular damage in dementia. Biochim Biophys Acta. 2016; 1862(5): 869-77. PMID: 26612719 DOI: 10.1016/j.bbadis.2015.11.009.Smallwood A., Oulhaj A., Joachim C., et al. Cerebral subcortical small vessel disease and its relation to cognition inelderly subjects: a pathological study in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Neuropathol Appl Neurobiol. 2012; 38: 337–43. PMID: 21951164 DOI: 10.1111/j.1365-2990.2011.01221.xVerhaaren B.F., Vernooij M.W., de Boer R. et al. High blood pressure and cerebral white matter lesion progression in the general population. Hypertension. 2013; 61: 1354–9. PMID: 23529163 DOI: 10.1161/HYPERTENSIONAHA.111.00430Wardlaw J.M., Smith E.E, Biessels G.J. et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013; 12(8): 822–38. PMID: 23867200 DOI: 10.1016/S1474-4422(13)70124-8Raina А., Zhao X., Grove M.L. et al. Cerebral white matter hyperintensities on MRI and acceleration of epigenetic aging: the atherosclerosis risk in communities study. Clinical Epigenetics. 2017; 14; 9: 21. PMID: 28289478 DOI: 10.1186/s13148-016-0302-6Barkhofa F., Scheltensb P. Imaging of White Matter Lesions, Cerebrovasc Dis 2002; 13(suppl 2): 21–30. PMID: 11901239 DOI: 10.1159/000049146Fazekas F., Chawluk J.B., Alavi A. et al. MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging, AJR Am J Roentgenol. 1987; 149(2): 351-6. PMID: 3496763 DOI: 10.2214/ajr.149.2.351de Leeuw F.E., de Groot J.C., Achten E. et al. Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry. 2001; 70: 9–14. PMID: 11118240Scheltens P., Barkhof F., Leys D. et al. A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. Journal of the Neurological Sciences. 1993; 114(1): 7-12. PMID: 8433101Wahlund L.O., Agartz I., Almqvist O. et al. The brain in healthy aged individuals: MR imaging. Radiology. 1990; 174(3 Pt 1): 675-9. PMID: 2305048 DOI:10.1148/radiology.174.3.2305048Longstreth W.T. Jr, Sonnen J.A., Koepsell T.D. et al. Associations between microinfarcts and other macroscopic vascular findings on neuropathologic examination in 2 databases. Alzheimer Dis Assoc Disord. 2009; 23: 291–4. PMID: 19812473 DOI: 10.1097/WAD.0b013e318199fc7aPrins N.D., van Straaten E.C., van Dijk E.J. et al. Measuring progression of cerebral white matter lesions on MRI: visual rating and volumetrics. Neurology. 2004; 62(9): 1533-9. PMID: 15136677Schmidt R., Schmidt H., Haybaeck J. et al. Heterogeneity in age-related white matter changes. Acta Neuropathol. 2011; 122: 171–85. PMID: 21706175 DOI: 10.1007/s00401-011-0851-xDufouil C., Chalmers J., Coskun O. et al. 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; 112(11): 1644-50. PMID: 16145004 DOI: 10.1161/CIRCULATIONAHA.104.501163Gottesman R.F., Coresh J., Catellier D.J. et al. Blood pressure and white-matter disease progression in a biethnic cohort: Atherosclerosis Risk in Communities (ARIC) study. Stroke. 2010; 41(1): 3–8. PMID: 19926835 DOI: 10.1161/STROKEAHA.109.566992Maillard P., Crivello F., Dufouil C. et al. Longitudinal follow-up of individual white matter hyperintensities in a large cohort of elderly. Neuroradiology. 2009; 51: 209–20. PMID: 19139875 DOI: 10.1007/s00234-008-0489-0Kloppenborg R.P., Nederkoorn P.J., Grool A.M. et al. Cerebral small-vessel disease and progression of brain atrophy: the SMART-MR study. Neurology. 2012; 79: 2029–36. PMID: 23115210 DOI: 10.1212/WNL.0b013e3182749f02Debette S., Markus H.S. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010; 341: c3666. PMID: 20660506 DOI: 10.1136/bmj.c3666.Wardlaw J.M., Valdés Hernández M.C., Muñoz-Maniega S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J Am Heart Assoc. 2015; 4(6): 001140. PMID: 26104658 DOI: 10.1161/JAHA.114.001140Raman M.R., Kantarci K., Murray M.E. et al. Imaging markers of cerebrovascular pathologies: Pathophysiology,clinical presentation, and risk factors. Alzheimers Dement (Amst). 2016; 5:5-14. PMID: 28054023 DOI: 10.1016/j.dadm.2016.12.006LADIS Study Group. 2001–2011: a decade of the LADIS (LeukoaraiosisAndDISability) Study: what have we learned about white matter changes and small-vessel disease? Cerebrovasc Dis. 2011; 32(6): 577–88. PMID: 22277351 DOI: 10.1159/000334498Herrmann L.L., Le Masurier M., Ebmeier K.P. White matter hyperintensities in late life depression: a systematic review. J Neurol Neurosurg Psychiatry. 2008; 79: 619–24. PMID: 17717021 DOI: 10.1136/jnnp.2007.124651Wright C.B., Dong C., Perez E.J. et al. Subclinical Cerebrovascular Disease Increases the Risk of Incident Stroke and Mortality: The Northern Manhattan Study. J Am Heart Assoc. 2017; 6(9). PMID: 28847914 DOI: 10.1161/JAHA.116.004069Windham B.G., Deere B., Griswold M.E. et al. Small brain lesions and incident stroke and mortality: a cohort study. Ann Intern Med. 2015; 163(1): 22–31. PMID: 26148278 DOI: 10.7326/M14-2057Schretlen D.J., Testa S.M., Winicki J.M. et al. Frequency and bases of abnormal performance by healthy adults on neuropsychological testing. Journal of the International Neuropsychological Society. 2008; 14(3): 436–45. PMID: 18419842 DOI: 10.1017/S1355617708080387Carmelli D., DeCarli C., Swan G.E. et al. Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke. 1998; 29(6): 1177–81. PMID: 9626291Verhaaren B.F., de Boer R., Vernooij M.W. et al. Replication study of chr17q25 with cerebral white matter lesion volume. Stroke. 2011; 42(11): 3297-9. PMID: 21868733 DOI:10.1161/STROKEAHA.111.623090Adib-Samii P., Rost N., Traylor M. et al. 17q25 Locus is associated with white matter hyperintensity volume in ischemic stroke, but not with lacunar stroke status. Stroke. 2013; 44(6): 1609-15. PMID: 23674528 DOI: 10.1161/STROKEAHA.113.679936Tabara Y., Igase M., Okada Y. et al. Association of Chr17q25 with cerebral white matter hyperintensities and cognitive impairment: the J-SHIPP study. Eur J Neurol. 2013; 20(5): 860-2. PMID: 23020117 DOI: 10.1111/j.1468-1331.2012.03879.xLin Q., Huang W.Q., Tzeng C.M. Genetic associations of leukoaraiosis indicate pathophysiological mechanisms in white matter lesions etiology. Rev. Neurosci. 2015; 26(3): 343–58. PMID: 25781674 DOI: 10.1515/revneuro-2014-0082de Leeuw F.E., de Groot J.C., Oudkerk M. et al. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain. 2002; 125(Pt 4): 765–72. PMID: 11912110Dufouil C., de Kersaint-Gilly A., Besancon V. et al. Longitudinal study on blood pressure and white matter hyperintensities. The EVA MRI cohort. Neurology. 2001; 56(7): 921–26. PMID: 11294930Dobrynina LA., Gnedovskaya E.V., Sergeeva A.N. et al. [Subclinical cerebral manifestations and changes of brain associated with newly diagnosed asymptomatic arterial hypertension]. Annals of clinical and experimental neurology. 2016; 10(3): 26-32. (In Russ.)Dobrynina LA., Gnedovskaya E.V., Sergeeva A.N. et al. [Changes in the MRI brain picture associated with newly diagnosed asymptomatic arterial hypertension]. Annals of clinical and experimental neurology. 2016; 10(3): 33-39. (In Russ.)Schmidt R., Fazekas F., Enzinger C. et al. Risk factors and progression of small vessel disease-related cerebral abnormalities. J. Neural. Transm. Suppl. 2002; 62: 47–52. PMID: 12456049Schmidt R., Enzinger C., Ropele S. et al. Progression of cerebral white matter lesions: 6-year results of the Austrian Stroke Prevention Study. Lancet. 2003; 361: 2046–8. PMID: 12814718van Leijsen E.M.C., van Uden I.W.M., Ghafoorian M. et al. The rise and fall of cerebral small vessel disease - The RUN DMC study. Eur. Stroke J. 2016Maillard P., Fletcher E., Lockhar S.N. et al. White matter hyperintensities and their penumbra lie along a continuum of injury in the aging brain. Stroke. 2014; 45(6): 1721–6. PMID: 24781079 DOI: 10.1161/STROKEAHA.113.004084Ryu W.S., Woo S.H., Schellingerhout D. et al. Grading and interpretation of white matter hyperintensities using statistical maps. Stroke. 2014; 45: 3567–75. PMID: 25388424 DOI: 10.1161/STROKEAHA.114.006662van Leijsen E.M.C., de Leeuw F.E., Tuladhar A.M. Disease progression and regression in sporadic small vessel disease–insights from neuroimaging, Clinical Science. 2017; 131(12): 1191-206. PMID: 28566448 DOI: 10.1042/CS20160384Longstreth Jr. W.T., Dulberg C., Manolio T.A. et al. Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke. 2002; 33(10): 2376-82. PMID: 12364724Gouw A.A., van der Flier W.M., Pantoni L. et al. On the etiology of incident brain lacunes: longitudinal observations from the LADIS study. Stroke. 2008; 39(11): 3083–5. PMID: 18703801 DOI: 10.1161/STROKEAHA.108.521807Duering 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; 136(Pt 9): 2717–26. PMID:23864274 DOI: 10.1093/brain/awt184Jokinen H., Gouw A.A., Madureira S. et al. Incident lacunes influence cognitive decline: the LADIS study. Neurology. 2011; 76(22): 1872–8. PMID: 21543730 DOI: 10.1212/WNL.0b013e31821d752fWright C.B., Festa J.R., Paik M.C. et al. White matter hyperintensities and subclinical infarction: associations with psychomotor speed and cognitive flexibility. Stroke. 2008; 39(3): 800–5. PMID: 18258844 DOI: 10.1161/STROKEAHA.107.484147van Dijk E.J., Prins N.D., Vrooman H.A. et al. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke. 2008; 39(10): 2712–9. PMID: 18635849 DOI: 10.1161/STROKEAHA.107.513176Schneider J.A., Aggarwal N.T., Barnes L. et al. The neuropathology of older persons with and without dementia from community versus clinic cohorts. J Alzheimers Dis. 2009; 18(3): 691–701. PMID: 19749406 DOI: 10.3233/JAD-2009-1227Brundel M., de Bresser J., van Dillen J.J. et al. Cerebral microinfarcts: a systematic review of neuropathological studies. J Cereb Blood Flow Metab. 2012; 32(3): 425–36. PMID: 22234334 DOI: 10.1038/jcbfm.2011.200van Veluw S.J., Zwanenburg J.J., Engelen-Lee J. et al. In vivo detection of cerebral cortical microinfarcts with high-resolution 7T MRI. J Cereb Blood Flow Metab. 2013; 33(3): 322–9. PMID: 23250109 DOI: 10.1038/jcbfm.2012.196Auriel E., Edlow B.L., Reijmer Y.D. et al. Microinfarct disruption of white matter structure: a longitudinal diffusion tensor analysis. Neurology. 2014; 83(8): 182–8. PMID: 24920857 DOI:10.1212/WNL.0000000000000579Deramecourt V., Slade J.Y., Oakley A.E. et al. Staging and natural history of cerebrovascular pathology in dementia. Neurology. 2012; 78(14): 1043-50. PMID: 22377814 DOI: 10.1212/WNL.0b013e31824e8e7f.Patel B., Markus H.S. Magnetic resonance imaging in cerebral small vessel disease and its use as a surrogate disease marker. International Journal of Stroke. 2011; 6(1): 47–59. PMID: 21205241 DOI: 10.1111/j.1747-4949.2010.00552.xKnudsen K.A., Rosand J., Karluk D. et al. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology. 2001; 56(4): 537-9. PMID: 11222803Iadecola C. The pathobiology of vascular dementia. Neuron. 2013; 80(4): 844–66. PMID:24267647 DOI: 10.1016/j.neuron.2013.10.008Poels M.M., Ikram M.A., van der Lugt, A. et al. Incidence of cerebral microbleeds in the general population: the Rotterdam Scan Study. Stroke. 2011; 42(3): 656–61. PMID: 21307170 DOI: 10.1161/STROKEAHA.110.607184Lee S.H., Lee S.T., Kim B.J. еt al. Dynamic temporal change of cerebral microbleeds: long-term follow-up MRI study. PloS One. 2011; 6(10): e2593. PMID: 22022473 DOI: 10.1371/journal.pone.0025930Akoudad S., Ikram M.A., Koudstaal P.J. et al. Cerebral microbleeds are associated with the progression of ischemic vascular lesions. Cerebrovasc. Dis. 2014; 37(5): 382–8. PMID: 24970709 DOI: 10.1159/000362590Vernooij M.W., van der Lugt A., Ikram M.A. et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology. 2008; 70(14): 1208–14. PMID: 18378884 DOI: 10.1212/01.wnl.0000307750.41970.d9Kim M., Bae H.J., Lee J. et al. APOE epsilon2/epsilon4 polymorphism and cerebral microbleeds on gradient-echo MRI. Neurology. 2005; 65(9): 1474–5. PMID: 16275840 DOI: 10.1212/01.wnl.0000183311.48144.7fSchmidt R., Ropele S., Ferro J. et al. Diffusion-Weighted Imaging and Cognition in the Leukoariosis and Disability in the Elderly Study. Stroke. 2010; 41(5): e402-8. PMID: 20203319 DOI: 10.1161/STROKEAHA.109.576629Goos J.D., Henneman W.J., Sluimer J.D. et al. Incidence of cerebral microbleeds: a longitudinal study in a memory clinic population. Neurology. 2010; 74(24): 1954–60. PMID: 20548041 DOI: 10.1212/WNL.0b013e3181e396eaMacLullich A.M., Wardlaw J.M., Ferguson K.J. et al. Enlarged perivascular spaces are associated with cognitive function in healthy elderly men. J Neurol Neurosurg Psychiatry. 2004; 75(11): 1519–23. PMID: 15489380 DOI: 10.1136/jnnp.2003.030858van Swieten J.C., van den Hout J.H., van Ketel B.A. et al. Periventricular lesions in the white matter on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces. Brain. 1991; 114: 761–74. PMID: 2043948Bokura H., Kobayashi S., Yamaguchi S. Distinguishing silent lacunar infarction from enlarged Virchow-Robin spaces: a magnetic resonance imaging and pathological study. J Neurol. 1998; 245(2): 116–22. PMID: 9507419Mestre H., Kostrikov S., Mehta R.I. Perivascular Spaces, Glymphatic Dysfunction, and Small Vessel Disease. Clin Sci (Lond). 2017; 131(17): 2257–74. PMID: 28798076 DOI: 10.1042/CS20160381Song S.K., Sun S.W., Ramsbottom M.J. et al. Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage. 2002; 17(3): 1429-36. PMID: 12414282Pasi M., van Uden I.W., Tuladhar A.M. et al. White Matter Microstructural Damage on Diffusion Tensor Imaging in Cerebral Small Vessel Disease Clinical Consequences. Stroke. 2016; 47(6): 1679-84. PMID: 27103015 DOI: 10.1161/STROKEAHA.115.012065Hannesdottir K., Nitkunan A., Charlton R.A. et al. Cognitive impairment and white matter damage in hypertension: a pilot study. Acta Neurol Scand. 2009; 119(4): 261–8. PMID: 18798828 DOI: 10.1111/j.1600-0404.2008.01098.xLawrence A.J., Patel B., Morris R.G. et al. Mechanisms of cognitive impairment in cerebral small vessel disease: multimodal MRI results from the St George’s cognition and neuroimaging in stroke (SCANS) study. PloS One. 2013; 8(4): e61014. PMID: 23613774 DOI: 10.1371/journal.pone.0061014de Groot M., Verhaaren B.F., de Boer R. et al. Changes in normal-appearing white matter precede development of white matter lesions. Stroke. 2013; 44(4): 1037–42. PMID: 23429507 DOI: 10.1161/STROKEAHA.112.680223