Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury: A Systematic Review and Meta-analysis

Abstract

Importance: Covert vascular brain injury (VBI) is highly prevalent in community-dwelling older persons, but its clinical and therapeutic implications are debated.

Objective: To better understand the clinical significance of VBI to optimize prevention strategies for the most common age-related neurological diseases, stroke and dementia.

Data source: We searched for articles in PubMed between 1966 and December 22, 2017, studying the association of 4 magnetic resonance imaging (MRI) markers of covert VBI (white matter hyperintensities [WMHs] of presumed vascular origin, MRI-defined covert brain infarcts [BIs], cerebral microbleeds [CMBs], and perivascular spaces [PVSs]) with incident stroke, dementia, or death.

Study selection: Data were taken from prospective, longitudinal cohort studies including 50 or more adults.

Data extraction and synthesis: We performed inverse variance-weighted meta-analyses with random effects and z score-based meta-analyses for WMH burden. The significance threshold was P < .003 (17 independent tests). We complied with the Meta-analyses of Observational Studies in Epidemiology guidelines.

Main outcomes and measures: Stroke (hemorrhagic and ischemic), dementia (all and Alzheimer disease), and death.

Results: Of 2846 articles identified, 94 studies were eligible, with up to 14 529 participants for WMH, 16 012 participants for BI, 15 693 participants for CMB, and 4587 participants for PVS. Extensive WMH burden was associated with higher risk of incident stroke (hazard ratio [HR], 2.45; 95% CI, 1.93-3.12; P < .001), ischemic stroke (HR, 2.39; 95% CI, 1.65-3.47; P < .001), intracerebral hemorrhage (HR, 3.17; 95% CI, 1.54-6.52; P = .002), dementia (HR, 1.84; 95% CI, 1.40-2.43; P < .001), Alzheimer disease (HR, 1.50; 95% CI, 1.22-1.84; P < .001), and death (HR, 2.00; 95% CI, 1.69-2.36; P < .001). Presence of MRI-defined BIs was associated with higher risk of incident stroke (HR, 2.38; 95% CI, 1.87-3.04; P < .001), ischemic stroke (HR, 2.18; 95% CI, 1.67-2.85; P < .001), intracerebral hemorrhage (HR, 3.81; 95% CI, 1.75-8.27; P < .001), and death (HR, 1.64; 95% CI, 1.40-1.91; P < .001). Presence of CMBs was associated with increased risk of stroke (HR, 1.98; 95% CI, 1.55-2.53; P < .001), ischemic stroke (HR, 1.92; 95% CI, 1.40-2.63; P < .001), intracerebral hemorrhage (HR, 3.82; 95% CI, 2.15-6.80; P < .001), and death (HR, 1.53; 95% CI, 1.31-1.80; P < .001). Data on PVS were limited and insufficient to conduct meta-analyses but suggested an association of high PVS burden with increased risk of stroke, dementia, and death; this requires confirmation.

Conclusions and relevance: We report evidence that MRI markers of VBI have major clinical significance. This research prompts careful evaluation of the benefit-risk ratio for available prevention strategies in individuals with covert VBI.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Debette is supported by grant ANR-14-CE12-0016 from the French National Research Agency; grants from the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of SVD of the Brain); grants 640643, 643417, and 667375 from the European Union’s Horizon 2020 Research and Innovation Programme, the European Research Council, the European Union Joint Programme–Neurodegenerative Disease Research, supported through several funding organizations under the aegis of the Joint Programme–Neurodegenerative Disease (Australia, National Health and Medical Research Council; Austria, Federal Ministry of Science, Research and Economy; Canada, Canadian Institutes of Health Research; France, French National Research Agency; Germany, Federal Ministry of Education and Research; the Netherlands, the Netherlands Organisation for Health Research and Development; and United Kingdom, Medical Research Council); and the Initiative of Excellence of Bordeaux University. Dr Markus is supported by a National Institute for Health Research Senior Investigator award, infrastructural support from the National Institute for Health Research Cambridge University Hospitals Biomedical Research Centre, and grant 667375 from the European Union’s Horizon 2020 Research and Innovation Programme. No other disclosures were reported.

Figures

Figure 1.. Magnetic Resonance Imaging (MRI) Markers of Covert Vascular Brain Injury

A, Minor (left) and extensive (right) white matter hyperintensities of presumed vascular origin on axial fluid-attenuated inversion recovery MRI sequences.a B, Magnetic resonance imaging–defined covert brain infarct without (left) and with (right) white matter hyperintensities on axial fluid-attenuated inversion recovery MRI sequences. C, Single cerebral microbleed (left) or multiple cerebral microbleeds (right), including lobar (white arrowheads) and deep (pink arrowheads) microbleeds, on gradient echo T2-weighted axial MRI sequences. D, Perivascular spaces following the shape of deep penetrating arteries on T2-weighted MRI. aThe definitions of extensive white matter hyperintensity burden differed across studies, ie, top half, tertile, quartile, or quintile; or moderate to severe white matter hyperintensity burden (or corresponding grades) on the following visual semiquantitative rating scales: Fazekas scale, Scheltens scale, or Age-Related White Matter Changes Scale (eTables 4-6 in the Supplement).

Figure 2.. Association of Extensive White Matter Hyperintensity (WMH) Burden With Incident Stroke, Dementia, and Death

The association of extensive WMH of presumed vascular origin with incident stroke (A) (overall: I2 = 56%; P = .003; in the general population [GP]: I2 = 0%; P = .43; in high-risk populations [HRP]: I2 = 67%; P < .001), incident dementia (B) (overall: I2 = 64%; P = .001; GP: I2 = 79%; P = .003; HRP: I2 = 53%; P = .04), and mortality (C) (overall: I2 = 41%; P = .06). Results correspond to hazard ratios (HRs) with 95% CIs for each study; the meta-analysis results (inverse variance–weighted meta-analysis with random effects) are shown in diamonds. The No./total No. corresponds to the number of individuals with the outcome of interest and the total sample size.

Figure 3.. Association of Magnetic Resonance Imaging (MRI)–Defined Brain Infarct (BI) With Incident Stroke, Dementia, and Death

The association of MRI-defined covert BI with incident stroke (A) (overall: I2 = 54%; P = .01; in the general population [GP]: I2 = 45%; P = .09; in high-risk populations [HRP]: I2 = 69%; P = .01), incident dementia (B) (overall: I2 = 44%; P = .08), and mortality (C) (overall: I2 = 0%; P = .48). Results correspond to hazard ratios (HRs) with 95% CIs for each study; the meta-analysis results (inverse variance–weighted meta-analysis with random effects) are shown in diamonds. The No./total No. corresponds to the number of individuals with the outcome of interest and the total sample size.

Figure 4.. Association of Cerebral Microbleeds (CMB) With Incident Stroke, Dementia, and Death

Association of CMB with incident stroke (A) (overall: I2 = 49%; P = .005; in the general population [GP]: I2 = 71%; P = .06; in high-risk populations [HRP]: I2 = 49%; P = .008), incident dementia (B) (overall: I2 = 61%; P = .04; GP: I2 = 32%; P = .23; HRP: I2 = 86%; P = .007), and mortality (C) (overall: I2 = 0%; P = .48). Results correspond to hazard ratios (HRs) with 95% CIs for each study; the meta-analysis results (inverse variance–weighted meta-analysis with random effects) are shown in diamonds. The No./total No. corresponds to the number of individuals with the outcome of interest and the total sample size.