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