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Cerebral microbleeds and cognition in cerebrovascular disease: An update

  • Andreas Charidimou
    Affiliations
    Stroke Research Group, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom
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  • David J. Werring
    Correspondence
    Corresponding author at: Clinical Senior Lecturer in Neurology, National Hospital for Neurology and Neurosurgery, Box 6, Queen Square, London WC1N 3BG, United Kingdom. Tel.: +44 207 829 8753.
    Affiliations
    Stroke Research Group, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom
    Search for articles by this author

      Abstract

      Sporadic cerebral small vessel disease is a major cause of cognitive impairment. MRI is an important tool for detecting and mapping cerebral small vessel disease in vivo. Lacunes and white matter changes are recognized as characteristic MRI manifestations of small vessel disease. Cerebral microbleeds (CMBs) – small, perivascular haemorrhages seen as well-demarcated, hypointense, rounded lesions on MRI sequences sensitive to magnetic susceptibility – are a more recently recognized MRI marker of small vessel pathology. CMBs are increasingly found in various patient populations and disease settings, including first-ever and recurrent ischaemic or haemorrhagic stroke, Alzheimer's disease, vascular cognitive impairment and healthy elderly individuals. Increasing evidence suggests that the anatomical distribution of CMBs (lobar or deep) may have diagnostic value in detecting small vessel disease subtypes including hypertensive arteriopathy and cerebral amyloid angiopathy. However, the relevance of CMBs for cognitive impairment remains uncertain. The study of CMBs and cognition in populations with cerebrovascular disease presents a special challenge as they coexist and correlate with other cerebrovascular pathologies. This review updates current thinking on how CMBs may be relevant in the study of cognitive impairment in populations with cerebrovascular disease, and how they can contribute in understanding the links between cerebrovascular and degenerative pathologies.

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      References

        • Werring D.J.
        • Gregoire S.M.
        • Cipolotti L.
        Cerebral microbleeds and vascular cognitive impairment.
        J Neurol Sci. 2010; 299: 131-135
        • Gorelick P.B.
        • Scuteri A.
        • Black S.E.
        • Decarli C.
        • Greenberg S.M.
        • Iadecola C.
        • 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: 2672-2713
        • Hachinski V.
        • Iadecola C.
        • Petersen R.C.
        • Breteler M.M.
        • Nyenhuis D.L.
        • Black S.E.
        • et al.
        National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards.
        Stroke. 2006; 37: 2220-2241
        • Iadecola C.
        The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia.
        Acta Neuropathol. 2010; 120: 287-296
        • Cavalieri M.
        • Schmidt R.
        New development in diagnosis of vascular cognitive impairment.
        J Neurol Sci. 2010; 299: 11-14
        • Charidimou A.
        • Werring D.J.
        Cerebral microbleeds: detection, mechanisms and clinical challenges.
        Future Neurol. 2011; 6: 587-611
        • Greenberg S.M.
        • Vernooij M.W.
        • Cordonnier C.
        • Viswanathan A.
        • Al-Shahi Salman R.
        • Warach S.
        • et al.
        Cerebral microbleeds: a guide to detection and interpretation.
        Lancet Neurol. 2009; 8: 165-174
        • Greenberg S.M.
        Small vessels, big problems.
        N Engl J Med. 2006; 354: 1451-1453
        • Pantoni L.
        Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges.
        Lancet Neurol. 2010; 9: 689-701
        • Charidimou A.
        • Gang Q.
        • Werring D.J.
        Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum.
        J Neurol Neurosurg Psychiatry. 2012; 83: 124-137
        • van Swieten J.C.
        • Staal S.
        • Kappelle L.J.
        • Derix M.M.
        • van Gijn J.
        Are white matter lesions directly associated with cognitive impairment in patients with lacunar infarcts?.
        J Neurol. 1996; 243: 196-200
        • Schmidt R.
        • Grazer A.
        • Enzinger C.
        • Ropele S.
        • Homayoon N.
        • Pluta-Fuerst A.
        • et al.
        MRI-detected white matter lesions: do they really matter?.
        J Neural Transm. 2011; 118: 673-681
        • Gouw A.A.
        • Seewann A.
        • van der Flier W.M.
        • Barkhof F.
        • Rozemuller A.M.
        • Scheltens P.
        • et al.
        Heterogeneity of small vessel disease: a systematic review of MRI and histopathology correlations.
        J Neurol Neurosurg Psychiatry. 2010;
        • Cordonnier C.
        • Al-Shahi Salman R.
        • Wardlaw J.
        Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting.
        Brain. 2007; 130: 1988-2003
        • Cordonnier C.
        • van der Flier W.M.
        Brain microbleeds and Alzheimer's disease: innocent observation or key player?.
        Brain. 2011; 134: 335-344
        • Fazekas F.
        • Kleinert R.
        • Roob G.
        • Kleinert G.
        • Kapeller P.
        • Schmidt R.
        • et al.
        Histopathologic analysis of foci of signal loss on gradient-echo T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage: evidence of microangiopathy-related microbleeds.
        AJNR Am J Neuroradiol. 1999; 20: 637-642
        • Schrag M.
        • McAuley G.
        • Pomakian J.
        • Jiffry A.
        • Tung S.
        • Mueller C.
        • et al.
        Correlation of hypointensities in susceptibility-weighted images to tissue histology in dementia patients with cerebral amyloid angiopathy: a postmortem MRI study.
        Acta Neuropathol. 2009;
        • Vernooij M.W.
        • van der Lugt A.
        • Ikram M.A.
        • Wielopolski P.A.
        • Niessen W.J.
        • Hofman A.
        • et al.
        Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study.
        Neurology. 2008; 70: 1208-1214
        • Maxwell S.S.
        • Jackson C.A.
        • Paternoster L.
        • Cordonnier C.
        • Thijs V.
        • Al-Shahi Salman R.
        • et al.
        Genetic associations with brain microbleeds: Systematic review and meta-analyses.
        Neurology. 2011; 77: 158-167
        • Dierksen G.A.
        • Skehan M.E.
        • Khan M.A.
        • Jeng J.
        • Nandigam R.N.
        • Becker J.A.
        • et al.
        Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy.
        Ann Neurol. 2010; 68: 545-548
        • Yates P.A.
        • Sirisriro R.
        • Villemagne V.L.
        • Farquharson S.
        • Masters C.L.
        • Rowe C.C.
        Cerebral microhemorrhage and brain beta-amyloid in aging and Alzheimer disease.
        Neurology. 2011; 77: 48-54
        • Werring D.J.
        • Frazer D.W.
        • Coward L.J.
        • Losseff N.A.
        • Watt H.
        • Cipolotti L.
        • et al.
        Cognitive dysfunction in patients with cerebral microbleeds on T2*-weighted gradient-echo MRI.
        Brain. 2004; 127: 2265-2275
        • Cianchetti F.A.
        • Nishimura N.
        • Schaffer C.B.
        Cortical microhaemorrhages reduce stimulus-evoked calcium responses in nearby neurons.
        J Cereb Blood Flow Metab. 2009; 29: S217-S218
        • Fotuhi M.
        • Hachinski V.
        • Whitehouse P.J.
        Changing perspectives regarding late-life dementia.
        Nat Rev Neurol. 2009; 5: 649-658
        • Snowdon D.A.
        • Greiner L.H.
        • Mortimer J.A.
        • Riley K.P.
        • Greiner P.A.
        • Markesbery W.R.
        Brain infarction and the clinical expression of Alzheimer disease. The Nun Study.
        JAMA. 1997; 277: 813-817
      1. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS).
        Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet. 2001; 357: 169-175
        • Gorelick P.B.
        • Scuteri A.
        • Black S.E.
        • Decarli C.
        • Greenberg S.M.
        • Iadecola C.
        • 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: 2672-2713
        • Hennerici M.G.
        What are the mechanisms for post-stroke dementia?.
        Lancet Neurol. 2009; 8: 973-975
        • Keage H.A.
        • Carare R.O.
        • Friedland R.P.
        • Ince P.G.
        • Love S.
        • Nicoll J.A.
        • et al.
        Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review.
        BMC Neurol. 2009; 9: 3
        • Kalaria R.N.
        • Ballard C.
        Overlap between pathology of Alzheimer disease and vascular dementia.
        Alzheimer Dis Assoc Disord. 1999; 13: S115-S123
        • Jellinger K.A.
        Alzheimer disease and cerebrovascular pathology: an update.
        J Neural Transm. 2002; 109: 813-836
        • Ellis R.J.
        • Olichney J.M.
        • Thal L.J.
        • Mirra S.S.
        • Morris J.C.
        • Beekly D.
        • et al.
        Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: the CERAD experience, Part XV.
        Neurology. 1996; 46: 1592-1596
        • Sveinbjornsdottir S.
        • Sigurdsson S.
        • Aspelund T.
        • Kjartansson O.
        • Eiriksdottir G.
        • Valtysdottir B.
        • et al.
        Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location.
        J Neurol Neurosurg Psychiatry. 2008; 79: 1002-1006
        • Mesker D.J.
        • Poels M.M.
        • Ikram M.A.
        • Vernooij M.W.
        • Hofman A.
        • Vrooman H.A.
        • et al.
        Lobar distribution of cerebral microbleeds: the rotterdam scan study.
        Arch Neurol. 2011; 68: 656-659
      2. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS).
        Lancet. MRC CFAS. 2001; 357: 169-175
        • Pfeifer L.A.
        • White L.R.
        • Ross G.W.
        • Petrovitch H.
        • Launer L.J.
        Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study.
        Neurology. 2002; 58: 1629-1634
        • Arvanitakis Z.
        • Leurgans S.E.
        • Wang Z.
        • Wilson R.S.
        • Bennett D.A.
        • Schneider J.A.
        Cerebral amyloid angiopathy pathology and cognitive domains in older persons.
        Ann Neurol. 2011; 69: 320-327
        • Smith E.E.
        • Greenberg S.M.
        Beta-amyloid, blood vessels, and brain function.
        Stroke. 2009; 40: 2601-2606
        • Gregoire S.M.
        • Charidimou A.
        • Gadapa N.
        • Dolan E.
        • Antoun N.
        • Peeters A.
        • et al.
        Acute ischaemic brain lesions in intracerebral haemorrhage: multicentre cross-sectional magnetic resonance imaging study.
        Brain. 2011; 134: 2376-2386
        • Poels M.M.
        • Vernooij M.W.
        • Ikram M.A.
        • Hofman A.
        • Krestin G.P.
        • van der Lugt A.
        • et al.
        Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study.
        Stroke. 2010; 41: S103-S106
        • Poels M.M.
        • Ikram M.A.
        • van der Lugt A.
        • Hofman A.
        • Niessen W.J.
        • Krestin G.P.
        • et al.
        Cerebral microbleeds are associated with worse cognitive function: The Rotterdam Scan Study.
        Neurology. 2012; 78: 326-333
        • Takashima Y.
        • Mori T.
        • Hashimoto M.
        • Kinukawa N.
        • Uchino A.
        • Yuzuriha T.
        • et al.
        Clinical correlating factors and cognitive function in community-dwelling healthy subjects with cerebral microbleeds.
        J Stroke Cerebrovasc Dis. 2011; 20: 105-110
        • Qiu C.
        • Cotch M.F.
        • Sigurdsson S.
        • Jonsson P.V.
        • Jonsdottir M.K.
        • Sveinbjrnsdottir S.
        • et al.
        Cerebral microbleeds, retinopathy, and dementia: the AGES-Reykjavik Study.
        Neurology. 2010; 75: 2221-2228
        • Yakushiji Y.
        • Nishiyama M.
        • Yakushiji S.
        • Hirotsu T.
        • Uchino A.
        • Nakajima J.
        • et al.
        Brain microbleeds and global cognitive function in adults without neurological disorder.
        Stroke. 2008; 39: 3323-3328
        • van Norden A.G.
        • van den Berg H.A.
        • de Laat K.F.
        • Gons R.A.
        • van Dijk E.J.
        • de Leeuw F.E.
        Frontal and Temporal Microbleeds Are Related to Cognitive Function: The Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) Study.
        Stroke. 2011; 42: 3382-3386
        • van Es A.C.
        • van der Grond J.
        • de Craen A.J.
        • Westendorp R.G.
        • Bollen E.L.
        • Blauw G.J.
        • et al.
        Cerebral microbleeds and cognitive functioning in the PROSPER study.
        Neurology. 2011; 77: 1446-1452
        • Seo S.W.
        • Hwa Lee B.
        • Kim E.J.
        • Chin J.
        • Sun Cho Y.
        • Yoon U.
        • et al.
        Clinical significance of microbleeds in subcortical vascular dementia.
        Stroke. 2007; 38: 1949-1951
        • Viswanathan A.
        • Gschwendtner A.
        • Guichard J.P.
        • Buffon F.
        • Cumurciuc R.
        • O'Sullivan M.
        • et al.
        Lacunar lesions are independently associated with disability and cognitive impairment in CADASIL.
        Neurology. 2007; 69: 172-179
        • Liem M.K.
        • Lesnik Oberstein S.A.
        • Haan J.
        • van der Neut I.L.
        • Ferrari M.D.
        • van Buchem M.A.
        • et al.
        MRI correlates of cognitive decline in CADASIL: a 7-year follow-up study.
        Neurology. 2009; 72: 143-148
        • Werring D.J.
        • O'Sullivan M.
        Cerebral microbleeds and cognitive impairment.
        in: Werring D.J. Cerebral Microbleeds: Pathophysiology to Clinical Practice. 1st ed. Cambridge University Press, 2011: 152-158
        • Pohjasvaara T.
        Dementia three months after stroke. Baseline frequency and effect of different definitions of dementia in the helsinki stroke aging memory study (sam) cohort.
        Stroke. 1997; 28: 785-792
        • Gregoire S.M.
        • Smith K.
        • Jager H.R.
        • Benjamin M.
        • Kallis C.
        • Brown M.M.
        • et al.
        Cerebral microbleeds and long-term cognitive outcome: longitudinal cohort study of stroke clinic patients.
        Cerebrovasc Dis. 2012; 33: 430-435