Silent brain infarctions and cognition decline: systematic review and meta-analysis

  • Feeha Azeem
  • Romella Durrani
  • Charlotte Zerna
  • Eric E. SmithEmail author
Original Communication



Silent brain infarction (SBI) may be associated with cognitive decline in the general population. We systematically reviewed prior literature on: (1) SBI and cognition cross-sectionally; (2) baseline SBI and future cognitive decline and risk for cognitive disorders including dementia, and (3) incident SBI and the emergence of cognitive decline or cognitive disorders.


The MEDLINE and EMBASE databases were searched for relevant studies. Data were independently extracted by two reviewers. Quality was assessed using the Newcastle Ottawa Scale. Data were pooled using a random effects model when more than two comparable estimates were found.


Thirty relevant studies were identified: 17 had a cross-sectional design, 10 evaluated the association of baseline SBI with future cognitive decline, and 5 evaluated the association of incident SBI with cognitive decline. Most cross-sectional studies reported lower cognitive performance in persons with SBI. The pooled risk for incident dementia in persons with SBI was 1.48 (95% CI 1.12–1.97), but there was significant heterogeneity (p = 0.009); removing one outlier eliminated the heterogeneity (p = 0.53), giving a lower but still significant estimate (hazard ratio 1.27, 95% CI 1.06–1.51). The pooled risk for incident MCI was not increased in persons with SBI (hazard ratio 0.83, 95% CI 0.40 to 1.72), but there was significant heterogeneity (p < 0.001). The appearance of new SBI was associated with steeper rate of cognitive decline and the appearance of dementia.


SBI are associated with worse cognition and increased risk for dementia. More standardization of cognitive assessment methods would facilitate future cross-study comparisons.


Stroke Mild cognitive impairment Dementia Magnetic resonance imaging 



The work was funded by the Katthy Taylor Chair in Vascular Dementia (University of Calgary), held by Dr. Smith. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr. Smith has had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The study dataset will be made available to other researchers on request to Dr. Smith.

Compliance with ethical standards

Conflicts of interest

Dr. Smith reports funding from the Canadian Institutes of Health Research and Brain Canada for studies of biomarkers of cerebral small vessel disease, and consulting fees from Portola Pharmaceuticals and Alnylam Pharmaceuticals for activities outside the submitted work. The other authors report no relevant financial conflicts of interest.

Ethical standard statement

Approval by an Institutional Review Board was not needed because this was a systematic review based on published work, with no interactions with study participants.

Supplementary material

415_2019_9534_MOESM1_ESM.pdf (118 kb)
Supplementary file1 (PDF 118 kb)


  1. 1.
    Bangen KJ, Preis SR, Delano-Wood L, Wolf PA, Libon DJ, Bondi MW, Au R, DeCarli C, Brickman AM (2018) Baseline white matter hyperintensities and hippocampal volume are associated with conversion from normal cognition to mild cognitive impairment in the Framingham Offspring Study. Alzheimer Dis Assoc Disord 32:50–56PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Bangen KJ, Preis SR, Delano-Wood L, Wolf PA, Libon DJ, Bondi MW, Au R, DeCarli C, Brickman AM (2017) Baseline white matter hyperintensities and hippocampal volume are associated with conversion from normal cognition to mild cognitive impairment in the Framingham offspring study. Alzheimer Dis Assoc Disord 03:03Google Scholar
  3. 3.
    Bos D, Wolters FJ, Darweesh SKL, Vernooij MW, de Wolf F, Ikram MA, Hofman A (2018) Cerebral small vessel disease and the risk of dementia: a systematic review and meta-analysis of population-based evidence. Alzheimer's Dementia J Alzheimer's Assoc 14:1482–1492CrossRefGoogle Scholar
  4. 4.
    Brundel M, de Bresser J, van Dillen JJ, Kappelle LJ, Biessels GJ (2012) Cerebral microinfarcts: a systematic review of neuropathological studies. J Cereb Blood Flow Metab 32:425–436PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Carey CL, Kramer JH, Josephson SA, Mungas D, Reed BR, Schuff N, Weiner MW, Chui HC (2008) Subcortical lacunes are associated with executive dysfunction in cognitively normal elderly. Stroke 39:397–402PubMedCrossRefGoogle Scholar
  6. 6.
    De Bruijn R, Akoudad S, Cremers L, Hofman A, Niessen WJ, Van Der Lugt A, Koudstaal PJ, Vernooij MW, Ikram MA (2014) Determinants, MRI-correlates, and prognosis of mild cognitive impairment: the Rotterdam study. Alzheimer's and Dementia 10:P582–P583CrossRefGoogle Scholar
  7. 7.
    Debette S, Beiser A, DeCarli C, Au R, Himali JJ, Kelly-Hayes M, Romero JR, Kase CS, Wolf PA, Seshadri S (2010) Association of MRI markers of vascular brain injury with incident stroke, mild cognitive impairment, dementia, and mortality: the Framingham Offspring study. Stroke 41:600–606PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Debette S, Markus HS (2010) The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 341:c3666PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Debette S, Schilling S, Duperron MG, Larsson SC, Markus HS (2018) Clinical significance of magnetic resonance imaging markers of vascular brain injury: a systematic review and meta-analysis. JAMA Neurol 76:81–94PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Ding D, Xiong Y, Zhao Q, Guo Q, Chu S, Chu WWC, Luo J, Liang X, Zheng L, Hong Z, Wong LKS, Mok VCT (2018) White matter hyperintensity predicts the risk of incident cognitive decline in community dwelling elderly. JAD 61:1333–1341PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Elnimr EM, Kondo T, Suzukamo Y, Satoh M, Oouchida Y, Hara A, Ohkubo T, Kikuya M, Hirano M, Hosokawa A, Hosokawa T, Imai Y, Izumi SI (2012) Association between white matter hyperintensity and lacunar infarction on MRI and subitem scores of the Japanese version of mini-mental state examination for testing cognitive decline: the Ohasama study. Clin Exp Hypertens 34:541–547PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Glazer H, Dong C, Yoshita M, Rundek T, Elkind MSV, Sacco RL, Decarli C, Stern Y, Wright CB (2015) Subclinical cerebrovascular disease inversely associates with learning ability. Neurology 84:2362–2367PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Hugo J, Ganguli M (2014) Dementia and cognitive impairment: epidemiology, diagnosis, and treatment. Clin Geriatr Med 30:421–442PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Kaffashian S, Soumare A, Zhu YC, Mazoyer B, Debette S, Tzourio C (2016) Long-term clinical impact of vascular brain lesions on magnetic resonance imaging in older adults in the population. Stroke J Cereb Circ 47:2865–2869CrossRefGoogle Scholar
  15. 15.
    Knopman DS, Griswold ME, Lirette ST, Gottesman RF, Kantarci K, Sharrett AR, Jack CR Jr, Graff-Radford J, Schneider AL, Windham BG, Coker LH, Albert MS, Mosley TH, Aric Neurocognitive I (2015) Vascular imaging abnormalities and cognition: mediation by cortical volume in nondemented individuals: atherosclerosis risk in communities-neurocognitive study. Stroke 46:433–440PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Kuller LH, Lopez OL, Newman A, Beauchamp NJ, Burke G, Dulberg C, Fitzpatrick A, Fried L, Haan MN (2003) Risk factors for dementia in the cardiovascular health cognition study. Neuroepidemiology 22:13–22PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Longstreth WT Jr, Bernick C, Manolio TA et al (1998) Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the cardiovascular health study. Arch Neurol 55:1217–1225PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Longstreth WT Jr, Dulberg C, Manolio TA, Lewis MR, Beauchamp NJ Jr, O'Leary D, Carr J, Furberg CD (2002) Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 33:2376–2382PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Lopez OL, Jagust WJ, Dulberg C, Becker JT, DeKosky ST, Fitzpatrick A, Breitner J, Lyketsos C, Jones B, Kawas C, Carlson M, Kuller LH (2003) Risk factors for mild cognitive impairment in the cardiovascular health study cognition study: part 2. Arch Neurol 60:1394–1399PubMedCrossRefGoogle Scholar
  20. 20.
    Lopez OL, Jagust WJ, Dulberg C et al (2003) Risk factors for mild cognitive impairment in the cardiovascular health study cognition study: Part 2. Arch Neurol 60:1394–1399PubMedCrossRefGoogle Scholar
  21. 21.
    Maeshima S, Moriwaki H, Ozaki F, Okita R, Yamaga H, Ueyoshi A (2002) Silent cerebral infarction and cognitive function in middle-aged neurologically healthy subjects. Acta Neurol Scand 105:179–184PubMedCrossRefGoogle Scholar
  22. 22.
    Matsubayashi K, Shimada K, Kawamoto A, Ozawa T (1992) Incidental brain lesions on magnetic resonance imaging and neurobehavioral functions in the apparently healthy elderly. Stroke J Cereb Circ 23:175–180CrossRefGoogle Scholar
  23. 23.
    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151(264–269):W264Google Scholar
  24. 24.
    Ngandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, Antikainen R, Backman L, Hanninen T, Jula A, Laatikainen T, Lindstrom J, Mangialasche F, Paajanen T, Pajala S, Peltonen M, Rauramaa R, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M (2015) A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 385:2255–2263PubMedCrossRefGoogle Scholar
  25. 25.
    Nylander R, Kilander L, Ahlstrom H, Lind L, Larsson EM (2018) Small vessel disease on neuroimaging in a 75-year-old cohort (PIVUS): Comparison with cognitive and executive tests. Front Aging Neurosci 10:217PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Price TR, Manolio TA, Kronmal RA, Kittner SJ, Yue NC, Robbins J, Anton-Culver H, O'Leary DH (1997) Silent brain infarction on magnetic resonance imaging and neurological abnormalities in community-dwelling older adults: the cardiovascular health study. Stroke 28:1158–1164PubMedCrossRefGoogle Scholar
  27. 27.
    Prins ND, van Dijk EJ, den Heijer T, Vermeer SE, Jolles J, Koudstaal PJ, Hofman A, Breteler MM (2005) Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain 128:2034–2041PubMedCrossRefGoogle Scholar
  28. 28.
    Riba-Llena I, Koek M, Verhaaren BFJ, Vrooman HA, van der Lugt A, Hofman A, Ikram MA, Vernooij MW (2015) Small cortical infarcts: Prevalence, determinants, and cognitive correlates in the general population. Int J Stroke 10:18–24PubMedCrossRefGoogle Scholar
  29. 29.
    Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, Elkind MS, George MG, Hamdan AD, Higashida RT, Hoh BL, Janis LS, Kase CS, Kleindorfer DO, Lee JM, Moseley ME, Peterson ED, Turan TN, Valderrama AL, Vinters HV, American Heart Association Stroke Council CoCS, Anesthesia, Council on Cardiovascular R, Intervention, Council on C, Stroke N, Council on E, Prevention, Council on Peripheral Vascular D, Council on Nutrition PA, Metabolism (2013) An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke J Cereb Circ 44:2064–2089PubMedCrossRefGoogle Scholar
  30. 30.
    Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA (2009) The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol 66:200–208PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Sedille-Mostafaie N, Zehetmayer S, Krampla W, Krugluger W, Fischer P (2015) Influence of vascular risk factors on executive function among an age-homogeneous elderly cohort. Journal of neural transmission (Vienna, Austria: 1996) 122:1323–1328Google Scholar
  32. 32.
    Sharma M, Hart RG, Smith EE, Bosch J, Yuan F, Casanova A, Eikelboom JW, Connolly SJ, Wong G, Diaz R, Lopez-Jaramillo P, Ertl G, Stork S, Dagenais GR, Lonn EM, Ryden L, Tonkin AM, Varigos JD, Bhatt DL, Branch KR, Probstfield JL, Kim JH, Ha JW, O'Donnell M, Vinereanu D, Fox KA, Liang Y, Liu L, Zhu J, Pogosova N, Maggioni AP, Avezum A, Piegas LS, Keltai K, Keltai M, Cook Bruns N, Berkowitz S, Yusuf S (2018) Rationale, design, and baseline participant characteristics in the MRI and cognitive substudy of the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial. Int J Stroke 1747493018784478Google Scholar
  33. 33.
    Sigurdsson S, Aspelund T, Kjartansson O, Gudmundsson EF, Jonsdottir MK, Eiriksdottir G, Jonsson PV, van Buchem MA, Gudnason V, Launer LJ (2017) Incidence of brain Infarcts, cognitive change, and risk of dementia in the general population: The AGES-Reykjavik Study (Age Gene/Environment Susceptibility-Reykjavik Study). Stroke J Cereb Circ 48:2353–2360CrossRefGoogle Scholar
  34. 34.
    Skoog I, Nilsson L, Palmertz B, Andreasson LA, Svanborg A (1993) A population-based study of dementia in 85-year-olds. N Engl J Med 328:153–158PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Smith EE, O'Donnell M, Dagenais G, Lear SA, Wielgosz A, Sharma M, Poirier P, Stotts G, Black SE, Strother S, Noseworthy MD, Benavente O, Modi J, Goyal M, Batool S, Sanchez K, Hill V, McCreary CR, Frayne R, Islam S, DeJesus J, Rangarajan S, Teo K, Yusuf S, Pure I (2015) Early cerebral small vessel disease and brain volume, cognition, and gait. Ann Neurol 77:251–261PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Smith EE, Saposnik G, Biessels GJ, Doubal FN, Fornage M, Gorelick PB, Greenberg SM, Higashida RT, Kasner SE, Seshadri S, American Heart Association Stroke C, Council on Cardiovascular R, Intervention, Council on Functional G, Translational B, Council on H (2017) Prevention of stroke in patients with silent cerebrovascular disease: A scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke J Cereb Circ 48:e44–e71Google Scholar
  37. 37.
    Squarzoni P, Tamashiro-Duran JH, Duran FLS, Leite CC, Wajngarten M, Scazufca M, Menezes PR, Lotufo PA, Alves T, Busatto GF (2017) High frequency of silent brain infarcts associated with cognitive deficits in an economically disadvantaged population. Clinics (Sao Paulo, Brazil) 72:474–480CrossRefGoogle Scholar
  38. 38.
    Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Thong JYJ, Hilal S, Wang Y, Soon HW, Dong Y, Collinson SL, Anh TT, Ikram MK, Wong TY, Venketasubramanian N, Chen C, Qiu A (2013) Association of silent lacunar infarct with brain atrophy and cognitive impairment. J Neurol Neurosurg Psychiatry 84:1219–1225PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    van Dijk EJ, Prins ND, Vrooman HA, Hofman A, Koudstaal PJ, Breteler MM (2008) Progression of cerebral small vessel disease in relation to risk factors and cognitive consequences: Rotterdam Scan study. Stroke 39:2712–2719PubMedCrossRefGoogle Scholar
  41. 41.
    Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM (2003) Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 348:1215–1222PubMedCrossRefGoogle Scholar
  42. 42.
    Vibha D, Tiemeier H, Mirza SS, Adams HHH, Niessen WJ, Hofman A, Prasad K, van der Lugt A, Vernooij MW, Ikram MA (2018) Brain volumes and longitudinal cognitive change: a population-based study. Alzheimer Dis Assoc Disord 32:43–49PubMedCrossRefGoogle Scholar
  43. 43.
    Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O'Brien JT, Barkhof F, Benavente OR, Black SE, Brayne C, Breteler M, Chabriat H, Decarli C, de Leeuw FE, Doubal F, Duering M, Fox NC, Greenberg S, Hachinski V, Kilimann I, Mok V, Oostenbrugge R, Pantoni L, Speck O, Stephan BC, Teipel S, Viswanathan A, Werring D, Chen C, Smith C, van Buchem M, Norrving B, Gorelick PB, Dichgans M (2013) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12:822–838PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Warren MW, King KS, Weiner MF (2013) White matter hyperintensity and lacunar infarct effects on cognition. Am J Geriatr Psychiatry 1:S76CrossRefGoogle Scholar
  45. 45.
    Wright CB, Festa JR, Paik MC, Schmiedigen A, Brown TR, Yoshita M, DeCarli C, Sacco R, Stern Y (2008) White matter hyperintensities and subclinical infarction: associations with psychomotor speed and cognitive flexibility. Stroke J Cereb Circ 39:800–805CrossRefGoogle Scholar
  46. 46.
    Yao H, Araki Y, Takashima Y, Uchino A, Yuzuriha T, Hashimoto M (2017) Chronic Kidney Disease and Subclinical Brain Infarction Increase the Risk of Vascular Cognitive Impairment: The Sefuri Study. J Stroke Cerebrovasc Dis 26:420–424PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Neurology, Department of Clinical NeurosciencesUniversity of CalgaryCalgaryCanada
  2. 2.Hotchkiss Brain InstituteCalgaryCanada
  3. 3.Calgary Stroke ProgramCalgaryCanada
  4. 4.Department of Community Health SciencesUniversity of CalgaryCalgaryCanada

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