The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis

Stéphanie Debette, H S Markus, Stéphanie Debette, H S Markus

Abstract

Objectives: To review the evidence for an association of white matter hyperintensities with risk of stroke, cognitive decline, dementia, and death.

Design: Systematic review and meta-analysis.

Data sources: PubMed from 1966 to 23 November 2009.

Study selection: Prospective longitudinal studies that used magnetic resonance imaging and assessed the impact of white matter hyperintensities on risk of incident stroke, cognitive decline, dementia, and death, and, for the meta-analysis, studies that provided risk estimates for a categorical measure of white matter hyperintensities, assessing the impact of these lesions on risk of stroke, dementia, and death.

Data extraction: Population studied, duration of follow-up, method used to measure white matter hyperintensities, definition of the outcome, and measure of the association of white matter hyperintensities with the outcome.

Data synthesis: 46 longitudinal studies evaluated the association of white matter hyperintensities with risk of stroke (n=12), cognitive decline (n=19), dementia (n=17), and death (n=10). 22 studies could be included in a meta-analysis (nine of stroke, nine of dementia, eight of death). White matter hyperintensities were associated with an increased risk of stroke (hazard ratio 3.3, 95% confidence interval 2.6 to 4.4), dementia (1.9, 1.3 to 2.8), and death (2.0, 1.6 to 2.7). An association of white matter hyperintensities with a faster decline in global cognitive performance, executive function, and processing speed was also suggested.

Conclusion: White matter hyperintensities predict an increased risk of stroke, dementia, and death. Therefore white matter hyperintensities indicate an increased risk of cerebrovascular events when identified as part of diagnostic investigations, and support their use as an intermediate marker in a research setting. Their discovery should prompt detailed screening for risk factors of stroke and dementia.

Conflict of interest statement

Competing interests: All authors have completed the unified competing interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that: (1) SD was supported by a grant from the European Neurological Society, a Fulbright grant, and an award from the Bettencourt-Schueller and the Lilly foundations; (2) SD and HSM have no relationship with companies that might have an interest in the submitted work in the previous 3 years; (3) that their spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and (4) that they have no non-financial interests that may be relevant to the submitted work.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4787843/bin/debs751180.f1_default.jpg
Fig 1 White matter hyperintensities on magnetic resonance imaging (axial fluid attenuated inversion recovery sequence) in two 80 year old patients: (left) minor white matter hyperintensities; (right) extensive white matter hyperintensities predominating in periventricular region. White matter lesions are considered present if hyperintense on T2 weighted, fluid attenuated inversion recovery, and proton density images, without prominent hypointensity on T1 weighted images
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4787843/bin/debs751180.f2_default.jpg
Fig 2 Inverse variance meta-analysis of studies testing association of white matter hyperintensities with incident stroke
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4787843/bin/debs751180.f3_default.jpg
Fig 3 Inverse variance meta-analysis of studies testing association of white matter hyperintensities with incident dementia
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4787843/bin/debs751180.f4_default.jpg
Fig 4 Inverse variance meta-analysis of studies testing association of white matter hyperintensities with mortality

References

    1. Ylikoski A, Erkinjuntti T, Raininko R, Sarna S, Sulkava R, Tilvis R. White matter hyperintensities on MRI in the neurologically nondiseased elderly. Analysis of cohorts of consecutive subjects aged 55 to 85 years living at home. Stroke 1995;26:1171-7.
    1. Garde E, Mortensen EL, Krabbe K, Rostrup E, Larsson HB. Relation between age-related decline in intelligence and cerebral white-matter hyperintensities in healthy octogenarians: a longitudinal study. Lancet 2000;356:628-34.
    1. Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke 1997;28:652-9.
    1. Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 1993;43:1683-9.
    1. Van Swieten JC, van den Hout JH, van Ketel BA, Hijdra A, Wokke JH, van Gijn J. 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.
    1. O’Sullivan M, Lythgoe DJ, Pereira AC, Summers PE, Jarosz JM, Williams SC, et al. Patterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis. Neurology 2002;59:321-6.
    1. Topakian R, Barrick TR, Howe FA, Markus HS. Blood-brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis. J Neurol Neurosurg Psychiatry 2010;81:192-7.
    1. Launer LJ. Epidemiology of white matter lesions. Top Magn Reson Imaging 2004;15:365-7.
    1. Schmidt R, Scheltens P, Erkinjuntti T, Pantoni L, Markus HS, Wallin A, et al. White matter lesion progression: a surrogate endpoint for trials in cerebral small-vessel disease. Neurology 2004;63:139-44.
    1. Lechner H, Schmidt R, Bertha G, Justich E, Offenbacher H, Schneider G. Nuclear magnetic resonance image white matter lesions and risk factors for stroke in normal individuals. Stroke 1988;19:263-5.
    1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed. APA, 1987.
    1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. APA, 1994.
    1. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939-44.
    1. Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43:250-60.
    1. Bokura H, Kobayashi S, Yamaguchi S, Iijima K, Nagai A, Toyoda G, et al. Silent brain infarction and subcortical white matter lesions increase the risk of stroke and mortality: a prospective cohort study. J Stroke Cerebrovasc Dis 2006;15:57-63.
    1. Yamauchi H, Fukuda H, Oyanagi C. Significance of white matter high intensity lesions as a predictor of stroke from arteriolosclerosis. J Neurol Neurosurg Psychiatry 2002;72:576-82.
    1. Firbank MJ, Burton EJ, Barber R, Stephens S, Kenny RA, Ballard C, et al. Medial temporal atrophy rather than white matter hyperintensities predict cognitive decline in stroke survivors. Neurobiol Aging 2007;28:1664-9.
    1. Symons MJ, Moore DT. Hazard rate ratio and prospective epidemiological studies. J Clin Epidemiol 2002;55:893-9.
    1. Wong TY, Klein R, Sharrett AR, Couper DJ, Klein BE, Liao DP, et al. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 2002;288:67-74.
    1. Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke 2003;34:1126-9.
    1. Kuller LH, Longstreth WT Jr, Arnold AM, Bernick C, Bryan RN, Beauchamp NJ Jr. White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke. Stroke 2004;35:1821-5.
    1. Smith EE, Gurol ME, Eng JA, Engel CR, Nguyen TN, Rosand J, et al. White matter lesions, cognition, and recurrent hemorrhage in lobar intracerebral hemorrhage. Neurology 2004;63:1606-12.
    1. Appelros P, Samuelsson M, Lindell D. Lacunar infarcts: functional and cognitive outcomes at five years in relation to MRI findings. Cerebrovasc Dis 2005;20:34-40.
    1. Gerdes VE, Kwa VI, ten Cate H, Brandjes DP, Buller HR, Stam J. Cerebral white matter lesions predict both ischemic strokes and myocardial infarctions in patients with established atherosclerotic disease. Atherosclerosis 2006;186:166-72.
    1. Fu JH, Lu CZ, Hong Z, Dong Q, Luo Y, Wong KS. Extent of white matter lesions is related to acute subcortical infarcts and predicts further stroke risk in patients with first ever ischaemic stroke. J Neurol Neurosurg Psychiatry 2005;76:793-6.
    1. Naka H, Nomura E, Takahashi T, Wakabayashi S, Mimori Y, Kajikawa H, et al. Combinations of the presence or absence of cerebral microbleeds and advanced white matter hyperintensity as predictors of subsequent stroke types. AJNR Am J Neuroradiol 2006;27:830-5.
    1. Kobayashi S, Okada K, Koide H, Bokura H, Yamaguchi S. Subcortical silent brain infarction as a risk factor for clinical stroke. Stroke 1997;28:1932-9.
    1. Longstreth WT Jr, Diehr P, Manolio TA, Beauchamp NJ, Jungreis CA, Lefkowitz D. Cluster analysis and patterns of findings on cranial magnetic resonance imaging of the elderly: the Cardiovascular Health Study. Arch Neurol 2001;58:635-40.
    1. Debette S, Beiser A, DeCarli C, Au R, Himali JJ, Kelly-Hayes M, et al. Association of MRI markers of vascular brain injury with incident stroke, mild cognitive impairment, dementia and mortality: the Framingham Offspring Study. Stroke 2010;41:600-6.
    1. Buyck JF, Dufouil C, Mazoyer B, Maillard P, Ducimetiere P, Alperovitch A, et al. Cerebral white matter lesions are associated with the risk of stroke but not with other vascular events: the 3-City Dijon Study. Stroke 2009;40:2327-31.
    1. Kuller LH, Lopez OL, Newman A, Beauchamp NJ, Burke G, Dulberg C, et al. Risk factors for dementia in the cardiovascular health cognition study. Neuroepidemiology 2003;22:13-22.
    1. Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Koudstaal PJ, Oudkerk M, et al. Cerebral white matter lesions and the risk of dementia. Arch Neurol 2004;61:1531-4.
    1. Meguro K, Ishii H, Kasuya M, Akanuma K, Meguro M, Kasai M, et al. Incidence of dementia and associated risk factors in Japan: the Osaki-Tajiri Project. J Neurol Sci 2007;260:175-82.
    1. Steffens DC, MacFall JR, Payne ME, Welsh-Bohmer KA, Krishnan KR. Grey-matter lesions and dementia. Lancet 2000;356:1686-7.
    1. Korf ES, Wahlund LO, Visser PJ, Scheltens P. Medial temporal lobe atrophy on MRI predicts dementia in patients with mild cognitive impairment. Neurology 2004;63:94-100.
    1. DeCarli C, Mungas D, Harvey D, Reed B, Weiner M, Chui H, et al. Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia. Neurology 2004;63:220-7.
    1. Geroldi C, Rossi R, Calvagna C, Testa C, Bresciani L, Binetti G, et al. Medial temporal atrophy but not memory deficit predicts progression to dementia in patients with mild cognitive impairment. J Neurol Neurosurg Psychiatry 2006;77:1219-22.
    1. Steffens DC, Potter GG, McQuoid DR, MacFall JR, Payne ME, Burke JR, et al. Longitudinal magnetic resonance imaging vascular changes, apolipoprotein E genotype, and development of dementia in the neurocognitive outcomes of depression in the elderly study. Am J Geriatr Psychiatry 2007;15:839-49.
    1. Smith EE, Egorova S, Blacker D, Killiany RJ, Muzikansky A, Dickerson BC, et al. Magnetic resonance imaging white matter hyperintensities and brain volume in the prediction of mild cognitive impairment and dementia. Arch Neurol 2008;65:94-100.
    1. Tapiola T, Pennanen C, Tapiola M, Tervo S, Kivipelto M, Hanninen T, et al. MRI of hippocampus and entorhinal cortex in mild cognitive impairment: a follow-up study. Neurobiol Aging 2008;29:31-8.
    1. Bombois S, Debette S, Bruandet A, Delbeuck X, Delmaire C, Leys D, et al. Vascular subcortical hyperintensities predict conversion to vascular and mixed dementia in MCI patients. Stroke 2008;39:2046-51.
    1. Van Straaten EC, Harvey D, Scheltens P, Barkhof F, Petersen RC, Thal LJ, et al. Periventricular white matter hyperintensities increase the likelihood of progression from amnestic mild cognitive impairment to dementia. J Neurol 2008;255:1302-8.
    1. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215-22.
    1. Rosano C, Aizenstein HJ, Wu M, Newman AB, Becker JT, Lopez OL, et al. Focal atrophy and cerebrovascular disease increase dementia risk among cognitively normal older adults. J Neuroimaging 2007;17:148-55.
    1. Kuller LH, Lopez OL, Jagust WJ, Becker JT, DeKosky ST, Lyketsos C, et al. Determinants of vascular dementia in the Cardiovascular Health Cognition Study. Neurology 2005;64:1548-52.
    1. Dufouil C, Godin O, Chalmers J, Coskun O, MacMahon S, Tzourio-Mazoyer N, et al. Severe cerebral white matter hyperintensities predict severe cognitive decline in patients with cerebrovascular disease history. Stroke 2009;40:2219-21.
    1. Kantarci K, Weigand SD, Przybelski SA, Shiung MM, Whitwell JL, Negash S, et al. Risk of dementia in MCI: combined effect of cerebrovascular disease, volumetric MRI, and 1H MRS. Neurology 2009;72:1519-25.
    1. Jokinen H, Kalska H, Ylikoski R, Madureira S, Verdelho A, van der Flier WM, et al. Longitudinal cognitive decline in subcortical ischemic vascular disease—the LADIS Study. Cerebrovasc Dis 2009;27:384-91.
    1. Staekenborg SS, Koedam EL, Henneman WJ, Stokman P, Barkhof F, Scheltens P, et al. Progression of mild cognitive impairment to dementia: contribution of cerebrovascular disease compared with medial temporal lobe atrophy. Stroke 2009;40:1269-74.
    1. Kuller LH, Shemanski L, Manolio T, Haan M, Fried L, Bryan N, et al. Relationship between ApoE, MRI findings, and cognitive function in the Cardiovascular Health Study. Stroke 1998;29:388-98.
    1. De Groot JC, De Leeuw FE, Oudkerk M, Van Gijn J, Hofman A, Jolles J, et al. Periventricular cerebral white matter lesions predict rate of cognitive decline. Ann Neurol 2002;52:335-41.
    1. Schmidt R, Ropele S, Enzinger C, Petrovic K, Smith S, Schmidt H, et al. White matter lesion progression, brain atrophy, and cognitive decline: the Austrian stroke prevention study. Ann Neurol 2005;58:610-6.
    1. Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Jolles J, Koudstaal PJ, et al. Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain 2005;128:2034-41.
    1. Mungas D, Reed BR, Jagust WJ, DeCarli C, Mack WJ, Kramer JH, et al. Volumetric MRI predicts rate of cognitive decline related to AD and cerebrovascular disease. Neurology 2002;59:867-73.
    1. Van der Flier WM, van der Vlies AE, Weverling-Rijnsburger AW, de Boer NL, Admiraal-Behloul F, Bollen EL, et al. MRI measures and progression of cognitive decline in nondemented elderly attending a memory clinic. Int J Geriatr Psychiatry 2005;20:1060-6.
    1. Mungas D, Harvey D, Reed BR, Jagust WJ, DeCarli C, Beckett L, et al. Longitudinal volumetric MRI change and rate of cognitive decline. Neurology 2005;65:565-71.
    1. Van den Heuvel DM, ten Dam VH, de Craen AJ, Admiraal-Behloul F, Olofsen H, Bollen EL, et al. Increase in periventricular white matter hyperintensities parallels decline in mental processing speed in a non-demented elderly population. J Neurol Neurosurg Psychiatry 2006;77:149-53.
    1. Debette S, Bombois S, Bruandet A, Delbeuck X, Lepoittevin S, Delmaire C, et al. Subcortical hyperintensities are associated with cognitive decline in patients with mild cognitive impairment. Stroke 2007;38:2924-30.
    1. Schmidt R, Fazekas F, Kapeller P, Schmidt H, Hartung HP. MRI white matter hyperintensities: three-year follow-up of the Austrian Stroke Prevention Study. Neurology 1999;53:132-9.
    1. Longstreth WT Jr, Arnold AM, Beauchamp NJ Jr, Manolio TA, Lefkowitz D, Jungreis C, et al. Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 2005;36:56-61.
    1. Kramer JH, Mungas D, Reed BR, Wetzel ME, Burnett MM, Miller BL, et al. Longitudinal MRI and cognitive change in healthy elderly. Neuropsychology 2007;21:412-8.
    1. Van Dijk EJ, Prins ND, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM. Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke 2008;39:2712-9.
    1. Silbert LC, Howieson DB, Dodge H, Kaye JA. Cognitive impairment risk: white matter hyperintensity progression matters. Neurology 2009;73:120-5.
    1. Kuller LH, Arnold AM, Longstreth WT Jr, Manolio TA, O’Leary DH, Burke GL, et al. White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study. Neurobiol Aging 2007;28:1307-15.
    1. Ikram MA, Vernooij MW, Vrooman HA, Hofman A, Breteler MM. Brain tissue volumes and small vessel disease in relation to the risk of mortality. Neurobiol Aging 2009;30:450-6.
    1. Kerber KA, Whitman GT, Brown DL, Baloh RW. Increased risk of death in community-dwelling older people with white matter hyperintensities on MRI. J Neurol Sci 2006;250:33-8.
    1. Oksala NK, Oksala A, Pohjasvaara T, Vataja R, Kaste M, Karhunen PJ, et al. Age related white matter changes predict stroke death in long term follow-up. J Neurol Neurosurg Psychiatry 2009;80:762-6.
    1. Levy RM, Steffens DC, McQuoid DR, Provenzale JM, MacFall JR, Krishnan KR. MRI lesion severity and mortality in geriatric depression. Am J Geriatr Psychiatry 2003;11:678-82.
    1. Longstreth WT Jr, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. Stroke 1996;27:1274-82.
    1. Dufouil C, de Kersaint-Gilly A, Besancon V, Levy C, Auffray E, Brunnereau L, et al. Longitudinal study of blood pressure and white matter hyperintensities: the EVA MRI Cohort. Neurology 2001;56:921-6.
    1. Jeerakathil T, Wolf PA, Beiser A, Massaro J, Seshadri S, D’Agostino RB, et al. Stroke risk profile predicts white matter hyperintensity volume: the Framingham Study. Stroke 2004;35:1857-61.
    1. Nordahl CW, Ranganath C, Yonelinas AP, Decarli C, Fletcher E, Jagust WJ. White matter changes compromise prefrontal cortex function in healthy elderly individuals. J Cogn Neurosci 2006;18:418-29.
    1. Zlokovic BV. Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci 2005;28:202-8.
    1. Alonso A, Mosley TH Jr, Gottesman RF, Catellier D, Sharrett AR, Coresh J. Risk of dementia hospitalisation associated with cardiovascular risk factors in midlife and older age: the Atherosclerosis Risk in Communities (ARIC) study. J Neurol Neurosurg Psychiatry 2009;80:1194-201.
    1. Kovari E, Gold G, Herrmann FR, Canuto A, Hof PR, Michel JP, et al. Cortical microinfarcts and demyelination significantly affect cognition in brain aging. Stroke 2004;35:410-4.
    1. Greenberg SM, Gurol ME, Rosand J, Smith EE. Amyloid angiopathy-related vascular cognitive impairment. Stroke 2004;35:2616-9.
    1. Yoshita M, Fletcher E, Harvey D, Ortega M, Martinez O, Mungas DM, et al. Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD. Neurology 2006;67:2192-8.
    1. Chui HC, Zarow C, Mack WJ, Ellis WG, Zheng L, Jagust WJ, et al. Cognitive impact of subcortical vascular and Alzheimer’s disease pathology. Ann Neurol 2006;60:677-87.
    1. Bots ML, van Swieten JC, Breteler MM, de Jong PT, van Gijn J, Hofman A, et al. Cerebral white matter lesions and atherosclerosis in the Rotterdam Study. Lancet 1993;341:1232-7.
    1. Kapeller P, Barber R, Vermeulen RJ, Ader H, Scheltens P, Freidl W, et al. Visual rating of age-related white matter changes on magnetic resonance imaging: scale comparison, interrater agreement, and correlations with quantitative measurements. Stroke 2003;34:441-5.
    1. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, et al. Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis 2007;23:75-80.
    1. Dufouil C, Chalmers J, Coskun O, Besancon V, Bousser MG, Guillon P, 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;112:1644-50.
    1. Atwood LD, Wolf PA, Heard-Costa NL, Massaro JM, Beiser A, D’Agostino RB, et al. Genetic variation in white matter hyperintensity volume in the Framingham Study. Stroke 2004;35:1609-13.
    1. Carmelli D, DeCarli C, Swan GE, Jack LM, Reed T, Wolf PA, et al. Evidence for genetic variance in white matter hyperintensity volume in normal elderly male twins. Stroke 1998;29:1177-81.
    1. Aharon-Peretz J, Daskovski E, Mashiach T, Tomer R. Natural history of dementia associated with lacunar infarctions. J Neurol Sci 2002;203-4:53-5.
    1. Fazekas F, Ropele S, Schmidt R. Can small-vessel disease-related cerebral abnormalities be used as a surrogate marker for vascular dementia trials? J Neural Transm Suppl 2002:61-7.
    1. Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003;163:1069-75.

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