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Vessel wall magnetic resonance imaging of symptomatic middle cerebral artery atherosclerosis: A systematic review and meta-analysis

Open AccessPublished:August 04, 2022DOI:https://doi.org/10.1016/j.clinimag.2022.08.001

      Highlights

      • Symptomatic MCA plaques were significantly associated with T1 hyperintensity
      • Plaque enhancement was statistically significantly associated with symptomatic MCA plaques
      • VWI has become a potential noninvasive vascular imaging tool for the management of intracranial atherosclerotic plaques

      Abstract

      Objective

      A comprehensive understanding of atherosclerotic middle cerebral artery (MCA) plaques aids physicians in diagnosis and treatment of ischemic stroke. High-resolution magnetic resonance imaging (MRI) has been used to identify imaging biomarkers of symptomatic MCA plaque. We performed this systematic review and meta-analysis to evaluate which characteristics of MCA plaque are markers of culprit lesions.

      Materials and methods

      The PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched for publications up to March 2022. Two independent reviewers extracted data on study design, high-resolution MRI parameters, and imaging end points. Odds ratios (ORs) for the prevalence of stroke with atherosclerotic MCA plaque features were pooled in the meta-analysis by using a random-effects model. Subgroup analysis, sensitivity analysis, and evaluation of publication bias were also conducted.

      Results

      Seventeen articles were included in this review. Symptomatic MCA plaques were significantly associated with contrast enhancement (OR, 9.4; 95 % CI, 4.3–20.4) and T1 hyperintensity (OR, 6.2; 95 % CI, 2.7–14.3). However, there was no association between symptomatic plaques and T2 hyperintensity (OR, 1.4; 95 % CI, 0.8–2.3). Plaque enhancement was significantly associated with downstream ischemic events in subgroup analyses based on different study designs and MR sequence types.

      Conclusion

      Based on current evidence, contrast enhancement and T1 hyperintensity on high-resolution MRI have high potential as imaging biomarkers of patients with MCA plaques at risk of ischemic events. Future prospective, longitudinal studies of intracranial-plaque high-resolution MRI are required to improve decision-making for the management of intracranial atherosclerotic plaques.

      Keywords

      1. Introduction

      Ischemic stroke is one of the leading causes of death and the leading cause of disability in the world.
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      Executive summary: heart disease and stroke statistics–2014 update: a report from the American Heart Association.
      Intracranial atherosclerosis (ICAS) has been recognized as the most common cause of ischemic stroke worldwide,
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      Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier.
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      • et al.
      Prevalence and outcomes of symptomatic intracranial large artery stenoses and occlusions in China: the chinese intracranial atherosclerosis (CICAS) study.
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      and is more prevalent in Asian than in Western populations.
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      • et al.
      Postmortem study of validation of low signal on fat-suppressed T1-weighted magnetic resonance imaging as marker of lipid Core in middle cerebral artery atherosclerosis.
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      • Chang H.M.
      • Wong M.C.
      South asian patients with ischemic stroke: intracranial large arteries are the predominant site of disease.
      In approximately 40–70% of Asian patients with ICAS, the affected vessel is the middle cerebral artery (MCA).
      • Kim J.S.
      • Kang D.W.
      • Kwon S.U.
      Intracranial atherosclerosis: incidence, diagnosis and treatment.
      In addition, patients with symptomatic MCA stenosis in one study had an overall stroke risk of 12.5% per year, compared to that of only 2.85% in patients with asymptomatic MCA disease.
      • Kern R.
      • Steinke W.
      • Daffertshofer M.
      • Prager R.
      • Hennerici M.
      Stroke recurrences in patients with symptomatic vs asymptomatic middle cerebral artery disease.
      For many years, the degree of MCA atherosclerotic stenosis was thought to be the most accurate reflection of the ischemic stroke risk.
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      • Steen H.
      Prediction of coronary artery disease by a systemic atherosclerosis score index derived from whole-body MR angiography.
      However, accumulating evidence suggests that stenotic grade does not really differ between symptomatic and asymptomatic groups of patients with moderate to severe MCA stenosis.
      • Shi M.C.
      • Wang S.C.
      • Zhou H.W.
      • et al.
      Compensatory remodeling in symptomatic middle cerebral artery atherosclerotic stenosis: a high-resolution MRI and microemboli monitoring study.
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis.
      Thus, a shift took place toward the vessel wall imaging (VWI) for the assessment of atherosclerotic plaque features.
      • Leng X.
      • Wong K.S.
      • Liebeskind D.S.
      Evaluating intracranial atherosclerosis rather than intracranial stenosis.
      • Teng Z.
      • Peng W.
      • Zhan Q.
      • et al.
      An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery.
      • Wu F.
      • Song H.
      • Ma Q.
      • et al.
      Hyperintense plaque on intracranial Vessel Wall magnetic resonance imaging as a predictor of artery-to-artery embolic infarction.
      Meanwhile, high-resolution magnetic resonance imaging (hr-MRI) has emerged as a novel diagnostic tool to assess both the coronary and extracranial carotid stenosis.
      • Millon A.
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      • et al.
      Clinical and histological significance of gadolinium enhancement in carotid atherosclerotic plaque.
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      • Jarvik G.P.
      • Hatsukami T.S.
      MR imaging of adventitial vasa vasorum in carotid atherosclerosis.
      However, VWI is not yet as commonly used for MCA stenosis owing to technical limitations in the imaging of small structures and the lack of in vivo histological results for comparison.
      To successfully image the intracranial vessel wall, the black blood technique was used by suppressing the MRI signal arising from luminal blood and cerebrospinal fluid (CSF) to obtain a high contrast-to-noise ratio (CNR). Blood and CSF suppression may be attained using spin-echo imaging, pre-regional saturation pulse, or a double-inversion recovery-based sequence.
      • Zhu X.J.
      • Wang W.
      • Liu Z.J.
      High-resolution magnetic resonance vessel wall imaging for intracranial arterial stenosis.
      However, the most common method is the three-dimensional (3D) turbo spin-echo sequences with variable flip angle refocusing pulses.
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      • Qiao Y.
      • et al.
      Intracranial Vessel Wall MRI: principles and expert consensus recommendations of the american Society of Neuroradiology.
      • Lindenholz A.
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      • Hendrikse J.
      The use and pitfalls of intracranial vessel wall imaging: how we do it.
      Recently, numerous imaging studies on MCA plaques have been published, suggesting that, in addition to the degree of stenosis, radiological characteristics may be an important predictor of plaque vulnerability.
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      • Jahng G.H.
      • Kim E.J.
      • Choi W.S.
      • Yang D.M.
      High resolution wall and lumen MRI of the middle cerebral arteries at 3 tesla.
      • Zhao D.L.
      • Deng G.
      • Xie B.
      • et al.
      High-resolution MRI of the vessel wall in patients with symptomatic atherosclerotic stenosis of the middle cerebral artery.
      As many of the studies had small sample sizes and as the relationship between MCA plaque morphology and the risk of stroke is unclear, we performed this meta-analysis to quantitatively synthesize existing evidence and evaluate the strengths of association of commonly investigated imaging features of symptomatic MCA plaques.

      2. Materials and methods

      This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      Institutional Review Board approval and written informed consent were not required because this study was retrospective. This protocol is registered on PROSPERO (registration number is CRD42022316417).

      2.1 Literature search strategy

      The PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched for publications up to March 2022. The following search terms were used in relevant combinations using the Boolean operators “OR” and “AND”: “middle cerebral artery,” “plaque, atherosclerotic,” “magnetic resonance imaging,” “high resolution,” and “gadolinium contrast” (Supplemental material: Search Strategy). In addition, we screened the reference lists of the included articles for further relevant studies.

      2.2 Eligibility criteria

      Two researchers independently screened studies, and disagreements were resolved by consensus. Inclusion criteria were as follows: (1) studies in which patients with atherosclerotic stenosis of the MCA were recruited; (2) studies in which patients who underwent hr-MRI of the MCA were included; and (3) studies in which imaging features were compared between symptomatic and asymptomatic atherosclerotic plaques of the MCA. We excluded studies in which (1) there was insufficient raw data, (2) duplicate data were reported, (3) only continuous variables were assessed as imaging end points, (4) <10 participants were included, and that (5) were cohort studies, conference abstracts, or letters.

      2.3 Quality assessment

      The quality of the selected studies was independently evaluated by two investigators using the “Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies,” provided by the National Institutes of Health.
      National Heart Lung and Blood Institute
      Data from: quality assessment tool for observational cohort and cross-sectional studies.

      2.4 Data extraction

      Two reviewers independently extracted data from the eligible studies, and discrepancies were resolved by consensus. The following data were collected: study characteristics (e.g., first author's name, public-cation year, patient enrollment design, country in which the study was conducted, demographic data, and prevalence of stroke risk factors), MRI protocols (e.g., MR scanner, magnetic field strength, coil type, hr-MRI sequences, and certain sequence parameters), and MRI analysis (e.g., reader characteristics, imaging end point criteria).

      2.5 Statistical analysis

      Demographic characteristics and extracted variables were described using standard descriptive statistics. Categorical variables were expressed as frequencies and percentages, and continuous variables were expressed as means with standard deviations.
      In the present meta-analysis, the association between the ischemic event and the plaque imaging feature was measured by estimating the odds ratios (ORs) and corresponding 95 % confidence intervals (CIs). Pooled ORs for dichotomous variables were estimated using a random-effects (DerSimonian-Laird) model with the assumption that individual studies did not have the same effect size. Forest plots were generated when the imaging feature of interest was present in at least three studies. These included plaque T1 hyperintensity, T2 hyperintensity, contrast enhancement, eccentricity, and positive remodeling. In order to calculate ORs for studies in which the degree of contrast enhancement was classified with a three-level grading system (0: enhancement was less than or equal to that of intracranial arterial walls without plaque, 1: less enhancement than the pituitary stalk, 2: enhancement greater than or equal to that of the pituitary stalk), we dichotomized the three-level grading system as negative (grade 0) and positive (grade 1 to 2). A continuity correction of 0.5 was applied to studies with zero cell frequencies.
      Heterogeneity among studies was tested using I2 statistics,
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      with values higher than 50% considered to indicate substantial heterogeneity. We explored factors that may account for heterogeneity by conducting subgroup analysis according to any binary variables that may have affected the consistency of a result across the enrolled studies. We further conducted sensitivity analysis with the “leave-one-out” method to assess the robustness of the results. Publication bias was assessed with a funnel plot and Egger's test; a P-value < 0.05 was considered to indicate publication bias.
      All statistical analyses were implemented using STATA statistical software: release 16 (StataCorp LLC, College Station, TX).

      3. Results

      3.1 Literature search

      A flow chart summarizing the literature search is presented in Fig. 1. A total of 543 studies were identified during the initial search, of which 53 were selected after title and abstract screening. After reviewing the full texts, 17 studies met the inclusion criteria for our systematic review.
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis.
      • Teng Z.
      • Peng W.
      • Zhan Q.
      • et al.
      An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery.
      • Zhao D.L.
      • Deng G.
      • Xie B.
      • et al.
      High-resolution MRI of the vessel wall in patients with symptomatic atherosclerotic stenosis of the middle cerebral artery.
      • Zhang D.F.
      • Wu X.Y.
      • Zhang W.D.
      • Wang M.
      • Yin X.
      • Chen Y.C.
      The relationship between patterns of remodeling and degree of enhancement in patients with atherosclerotic middle cerebral artery stenosis: a high-resolution MRI study.
      • Zhang D.F.
      • Chen Y.C.
      • Chen H.
      • et al.
      A high-resolution MRI study of relationship between remodeling patterns and ischemic stroke in patients with atherosclerotic middle cerebral artery stenosis.
      • Zhang D.
      • Wang M.
      • Wu L.
      • et al.
      Assessing the characteristics and diagnostic value of plaques for patients with acute stroke using high-resolution magnetic resonance imaging.
      • Yang W.Q.
      • Huang B.
      • Liu X.T.
      • Liu H.J.
      • Li P.J.
      • Zhu W.Z.
      Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3T.
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      Middle cerebral artery intraplaque hemorrhage: prevalence and clinical relevance.
      • Xu P.
      • Lv L.
      • Li S.
      Use of high-resolution 3.0-T magnetic resonance imaging to characterize atherosclerotic plaques in patients with cerebral infarction.
      • Shi Z.
      • Li J.
      • Zhao M.
      • et al.
      Quantitative histogram analysis on intracranial atherosclerotic plaques: a high-resolution magnetic resonance imaging study.
      • Meng Y.
      • Li M.
      • Yu Y.
      • et al.
      Quantitative score of the vessel morphology in middle cerebral artery atherosclerosis.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • Xie J.
      • Shi H.B.
      • Hong X.N.
      Plaque distribution and characteristics in low-grade middle cerebral artery stenosis and its clinical relevance: a 3-dimensional high-resolution magnetic resonance imaging study.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • et al.
      MRI of plaque characteristics and relationship with downstream perfusion and cerebral infarction in patients with symptomatic middle cerebral artery stenosis.
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      • Lin G.H.
      • Song J.X.
      • Fu N.X.
      • Huang X.
      • Lu H.X.
      Quantitative and qualitative analysis of atherosclerotic stenosis in the middle cerebral artery using high-resolution magnetic resonance imaging.
      • Liang J.
      • Guo J.
      • Liu D.
      • Shi C.
      • Luo L.
      Application of high-resolution CUBE sequence in exploring stroke mechanisms of atherosclerotic stenosis of middle cerebral artery.
      • Chung G.H.
      • Kwak H.S.
      • Hwang S.B.
      • Jin G.Y.
      High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis.

      3.2 Quality assessment

      The risk of bias of the studies is summarized in the Supplemental table. The results were satisfactory, with all the studies except one
      • Liang J.
      • Guo J.
      • Liu D.
      • Shi C.
      • Luo L.
      Application of high-resolution CUBE sequence in exploring stroke mechanisms of atherosclerotic stenosis of middle cerebral artery.
      rated “good” or “fair.” As all the included studies were cross-sectional analyses, the answer to Questions 5–7 of the assessment guidance was “no.”

      3.3 Characteristics of included studies

      The basic demographic data and the prevalence of risk factors of the 17 studies are summarized in Table 1. In total, 1192 MCA atherosclerotic plaques of 1165 patients were eligible for the meta-analysis. The 17 included studies were all based on the Asian population: 16 were from China
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis.
      • Teng Z.
      • Peng W.
      • Zhan Q.
      • et al.
      An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery.
      • Zhao D.L.
      • Deng G.
      • Xie B.
      • et al.
      High-resolution MRI of the vessel wall in patients with symptomatic atherosclerotic stenosis of the middle cerebral artery.
      • Zhang D.F.
      • Wu X.Y.
      • Zhang W.D.
      • Wang M.
      • Yin X.
      • Chen Y.C.
      The relationship between patterns of remodeling and degree of enhancement in patients with atherosclerotic middle cerebral artery stenosis: a high-resolution MRI study.
      • Zhang D.F.
      • Chen Y.C.
      • Chen H.
      • et al.
      A high-resolution MRI study of relationship between remodeling patterns and ischemic stroke in patients with atherosclerotic middle cerebral artery stenosis.
      • Zhang D.
      • Wang M.
      • Wu L.
      • et al.
      Assessing the characteristics and diagnostic value of plaques for patients with acute stroke using high-resolution magnetic resonance imaging.
      • Yang W.Q.
      • Huang B.
      • Liu X.T.
      • Liu H.J.
      • Li P.J.
      • Zhu W.Z.
      Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3T.
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      Middle cerebral artery intraplaque hemorrhage: prevalence and clinical relevance.
      • Xu P.
      • Lv L.
      • Li S.
      Use of high-resolution 3.0-T magnetic resonance imaging to characterize atherosclerotic plaques in patients with cerebral infarction.
      • Shi Z.
      • Li J.
      • Zhao M.
      • et al.
      Quantitative histogram analysis on intracranial atherosclerotic plaques: a high-resolution magnetic resonance imaging study.
      • Meng Y.
      • Li M.
      • Yu Y.
      • et al.
      Quantitative score of the vessel morphology in middle cerebral artery atherosclerosis.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • Xie J.
      • Shi H.B.
      • Hong X.N.
      Plaque distribution and characteristics in low-grade middle cerebral artery stenosis and its clinical relevance: a 3-dimensional high-resolution magnetic resonance imaging study.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • et al.
      MRI of plaque characteristics and relationship with downstream perfusion and cerebral infarction in patients with symptomatic middle cerebral artery stenosis.
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      • Lin G.H.
      • Song J.X.
      • Fu N.X.
      • Huang X.
      • Lu H.X.
      Quantitative and qualitative analysis of atherosclerotic stenosis in the middle cerebral artery using high-resolution magnetic resonance imaging.
      • Liang J.
      • Guo J.
      • Liu D.
      • Shi C.
      • Luo L.
      Application of high-resolution CUBE sequence in exploring stroke mechanisms of atherosclerotic stenosis of middle cerebral artery.
      and one from South Korea.
      • Chung G.H.
      • Kwak H.S.
      • Hwang S.B.
      • Jin G.Y.
      High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis.
      Eight
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis.
      • Zhao D.L.
      • Deng G.
      • Xie B.
      • et al.
      High-resolution MRI of the vessel wall in patients with symptomatic atherosclerotic stenosis of the middle cerebral artery.
      • Zhang D.F.
      • Wu X.Y.
      • Zhang W.D.
      • Wang M.
      • Yin X.
      • Chen Y.C.
      The relationship between patterns of remodeling and degree of enhancement in patients with atherosclerotic middle cerebral artery stenosis: a high-resolution MRI study.
      • Zhang D.F.
      • Chen Y.C.
      • Chen H.
      • et al.
      A high-resolution MRI study of relationship between remodeling patterns and ischemic stroke in patients with atherosclerotic middle cerebral artery stenosis.
      • Zhang D.
      • Wang M.
      • Wu L.
      • et al.
      Assessing the characteristics and diagnostic value of plaques for patients with acute stroke using high-resolution magnetic resonance imaging.
      • Xu P.
      • Lv L.
      • Li S.
      Use of high-resolution 3.0-T magnetic resonance imaging to characterize atherosclerotic plaques in patients with cerebral infarction.
      • Liang J.
      • Guo J.
      • Liu D.
      • Shi C.
      • Luo L.
      Application of high-resolution CUBE sequence in exploring stroke mechanisms of atherosclerotic stenosis of middle cerebral artery.
      • Chung G.H.
      • Kwak H.S.
      • Hwang S.B.
      • Jin G.Y.
      High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis.
      and nine
      • Teng Z.
      • Peng W.
      • Zhan Q.
      • et al.
      An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery.
      • Yang W.Q.
      • Huang B.
      • Liu X.T.
      • Liu H.J.
      • Li P.J.
      • Zhu W.Z.
      Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3T.
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      Middle cerebral artery intraplaque hemorrhage: prevalence and clinical relevance.
      • Shi Z.
      • Li J.
      • Zhao M.
      • et al.
      Quantitative histogram analysis on intracranial atherosclerotic plaques: a high-resolution magnetic resonance imaging study.
      • Meng Y.
      • Li M.
      • Yu Y.
      • et al.
      Quantitative score of the vessel morphology in middle cerebral artery atherosclerosis.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • Xie J.
      • Shi H.B.
      • Hong X.N.
      Plaque distribution and characteristics in low-grade middle cerebral artery stenosis and its clinical relevance: a 3-dimensional high-resolution magnetic resonance imaging study.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • et al.
      MRI of plaque characteristics and relationship with downstream perfusion and cerebral infarction in patients with symptomatic middle cerebral artery stenosis.
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      • Lin G.H.
      • Song J.X.
      • Fu N.X.
      • Huang X.
      • Lu H.X.
      Quantitative and qualitative analysis of atherosclerotic stenosis in the middle cerebral artery using high-resolution magnetic resonance imaging.
      studies were prospective and retrospective cross-sectional studies, respectively.
      Table 1Demographics and risk factors of enrolled studies.
      StudyStudy designCountryNo. of subjects (plaques)Age (years)Male (%)HTN (%)DM (%)Dyslipidemia (%)Smoking (%)
      Xu et al
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      Middle cerebral artery intraplaque hemorrhage: prevalence and clinical relevance.
      RetroChina104 (109)56.7 ± 12.881.367.330.844.961.7
      Chung et al
      • Chung G.H.
      • Kwak H.S.
      • Hwang S.B.
      • Jin G.Y.
      High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis.
      ProSouth Korea30 (30)65.8 ± 9.763.356.746.770.043.3
      Xu et al
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis.
      ProChina61 (54)62.4 ± 11.663.968.929.531.136.1
      Yang et al
      • Yang W.Q.
      • Huang B.
      • Liu X.T.
      • Liu H.J.
      • Li P.J.
      • Zhu W.Z.
      Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3T.
      RetroChina73 (65)63.0 ± 11.363.0N/AN/AN/AN/A
      Xu et al
      • Xu P.
      • Lv L.
      • Li S.
      Use of high-resolution 3.0-T magnetic resonance imaging to characterize atherosclerotic plaques in patients with cerebral infarction.
      ProChina32 (32)65.8 ± 13.146.978.128.159.434.4
      Zhao et al
      • Zhao D.L.
      • Deng G.
      • Xie B.
      • et al.
      High-resolution MRI of the vessel wall in patients with symptomatic atherosclerotic stenosis of the middle cerebral artery.
      ProChina51 (51)67.4 ± 8.858.864.735.3NR31.4
      Teng et al
      • Teng Z.
      • Peng W.
      • Zhan Q.
      • et al.
      An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery.
      RetroChina139 (165)57.1 ± 10.464.771.234.5NR29.5
      Zhang et al.
      • Zhang D.F.
      • Chen Y.C.
      • Chen H.
      • et al.
      A high-resolution MRI study of relationship between remodeling patterns and ischemic stroke in patients with atherosclerotic middle cerebral artery stenosis.
      ProChina33 (33)68.1 ± 11.881.881.851.5NR57.6
      Lin et al
      • Lin G.H.
      • Song J.X.
      • Fu N.X.
      • Huang X.
      • Lu H.X.
      Quantitative and qualitative analysis of atherosclerotic stenosis in the middle cerebral artery using high-resolution magnetic resonance imaging.
      RetroChina53 (53)53.6 ± 9.777.464.220.854.726.4
      Lu et al
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • Xie J.
      • Shi H.B.
      • Hong X.N.
      Plaque distribution and characteristics in low-grade middle cerebral artery stenosis and its clinical relevance: a 3-dimensional high-resolution magnetic resonance imaging study.
      RetroChina46 (53)60.7 ± 12.669.676.139.134.832.6
      Meng et al
      • Meng Y.
      • Li M.
      • Yu Y.
      • et al.
      Quantitative score of the vessel morphology in middle cerebral artery atherosclerosis.
      RetroChina192 (196)57 0.0 ± 12.969.466.830.144.934.7
      Shi et al
      • Shi Z.
      • Li J.
      • Zhao M.
      • et al.
      Quantitative histogram analysis on intracranial atherosclerotic plaques: a high-resolution magnetic resonance imaging study.
      RetroChina88 (88)N/AN/AN/AN/AN/AN/A
      Zhang et al
      • Zhang D.
      • Wang M.
      • Wu L.
      • et al.
      Assessing the characteristics and diagnostic value of plaques for patients with acute stroke using high-resolution magnetic resonance imaging.
      ProChina65 (65)68.1 ± 13.176.973.866.2N/A56.9
      Zhang et al
      • Zhang D.F.
      • Wu X.Y.
      • Zhang W.D.
      • Wang M.
      • Yin X.
      • Chen Y.C.
      The relationship between patterns of remodeling and degree of enhancement in patients with atherosclerotic middle cerebral artery stenosis: a high-resolution MRI study.
      ProChina38 (38)66.7 ± 12.378.965.857.9N/A52.6
      Liang et al
      • Liang J.
      • Guo J.
      • Liu D.
      • Shi C.
      • Luo L.
      Application of high-resolution CUBE sequence in exploring stroke mechanisms of atherosclerotic stenosis of middle cerebral artery.
      ProChina47 (47)58.6 ± 8.844.76663.838.329.8
      Liu et al
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      RetroChina67 (67)58.0 ± 12.461.261.222.438.838.8
      Lu et al
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • et al.
      MRI of plaque characteristics and relationship with downstream perfusion and cerebral infarction in patients with symptomatic middle cerebral artery stenosis.
      RetroChina46 (46)56.1 ± 15.167.476.128.347.828.3
      SD, standard deviation; HTN, hypertension; DM, diabetes mellitus; N/A, data not available.
      In all the included studies, VWI was performed on 3.0 Tesla scanner using different types of coils. Hr-MR protocols used two-dimensional (2D),
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis.
      • Teng Z.
      • Peng W.
      • Zhan Q.
      • et al.
      An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery.
      • Zhang D.F.
      • Wu X.Y.
      • Zhang W.D.
      • Wang M.
      • Yin X.
      • Chen Y.C.
      The relationship between patterns of remodeling and degree of enhancement in patients with atherosclerotic middle cerebral artery stenosis: a high-resolution MRI study.
      • Zhang D.F.
      • Chen Y.C.
      • Chen H.
      • et al.
      A high-resolution MRI study of relationship between remodeling patterns and ischemic stroke in patients with atherosclerotic middle cerebral artery stenosis.
      • Zhang D.
      • Wang M.
      • Wu L.
      • et al.
      Assessing the characteristics and diagnostic value of plaques for patients with acute stroke using high-resolution magnetic resonance imaging.
      • Yang W.Q.
      • Huang B.
      • Liu X.T.
      • Liu H.J.
      • Li P.J.
      • Zhu W.Z.
      Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3T.
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      Middle cerebral artery intraplaque hemorrhage: prevalence and clinical relevance.
      • Xu P.
      • Lv L.
      • Li S.
      Use of high-resolution 3.0-T magnetic resonance imaging to characterize atherosclerotic plaques in patients with cerebral infarction.
      • Shi Z.
      • Li J.
      • Zhao M.
      • et al.
      Quantitative histogram analysis on intracranial atherosclerotic plaques: a high-resolution magnetic resonance imaging study.
      • Meng Y.
      • Li M.
      • Yu Y.
      • et al.
      Quantitative score of the vessel morphology in middle cerebral artery atherosclerosis.
      • Chung G.H.
      • Kwak H.S.
      • Hwang S.B.
      • Jin G.Y.
      High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis.
      3D,
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • Xie J.
      • Shi H.B.
      • Hong X.N.
      Plaque distribution and characteristics in low-grade middle cerebral artery stenosis and its clinical relevance: a 3-dimensional high-resolution magnetic resonance imaging study.
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      • Lin G.H.
      • Song J.X.
      • Fu N.X.
      • Huang X.
      • Lu H.X.
      Quantitative and qualitative analysis of atherosclerotic stenosis in the middle cerebral artery using high-resolution magnetic resonance imaging.
      • Liang J.
      • Guo J.
      • Liu D.
      • Shi C.
      • Luo L.
      Application of high-resolution CUBE sequence in exploring stroke mechanisms of atherosclerotic stenosis of middle cerebral artery.
      or both 2D and 3D sequences.
      • Zhao D.L.
      • Deng G.
      • Xie B.
      • et al.
      High-resolution MRI of the vessel wall in patients with symptomatic atherosclerotic stenosis of the middle cerebral artery.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • et al.
      MRI of plaque characteristics and relationship with downstream perfusion and cerebral infarction in patients with symptomatic middle cerebral artery stenosis.
      All but two studies
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      • Lin G.H.
      • Song J.X.
      • Fu N.X.
      • Huang X.
      • Lu H.X.
      Quantitative and qualitative analysis of atherosclerotic stenosis in the middle cerebral artery using high-resolution magnetic resonance imaging.
      involved more than one reader evaluating plaque images for MCA stenosis (Table 2).
      Table 2HR-MR images protocol and review.
      StudyMR scannerField strength (T)Coil type (channel)Image protocolSequence to detect plaqueField of view (cm)MatrixImage criterion of plaqueNo. of MR readers
      Xu et al
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      Middle cerebral artery intraplaque hemorrhage: prevalence and clinical relevance.
      GE Signa, VH/i3.082D FSE T1W/T2WN/AProtocol 1: 13 × 13

      Protocol 2: 16 × 16
      Proto1: 256 × 256

      Proto2: 384 × 224
      N/A2
      Chung et al
      • Chung G.H.
      • Kwak H.S.
      • Hwang S.B.
      • Jin G.Y.
      High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis.
      Siemens, Verio3.082D BB T1W/T2W/PDWN/A10 × 12.5256 × 204N/A2
      Xu et al
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis.
      GE Signa, VH/i3.082D FSE-T2W; DIR-T1WT2W13 × 13256 × 256Eccentric or focal wall thickening2
      Yang et al
      • Yang W.Q.
      • Huang B.
      • Liu X.T.
      • Liu H.J.
      • Li P.J.
      • Zhu W.Z.
      Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3T.
      GE Signa, Excite HD3.082D BB pre/post T1W; 2D FSE T2WT2W13 × 13256 × 256Eccentric or focal wall thickening2
      Xu et al
      • Xu P.
      • Lv L.
      • Li S.
      Use of high-resolution 3.0-T magnetic resonance imaging to characterize atherosclerotic plaques in patients with cerebral infarction.
      GE, Piscataway3.0162D PDW; pre/post T1WN/A12 × 12256 × 256N/A2
      Zhao et al
      • Zhao D.L.
      • Deng G.
      • Xie B.
      • et al.
      High-resolution MRI of the vessel wall in patients with symptomatic atherosclerotic stenosis of the middle cerebral artery.
      Siemens, Magnetom Verio3.082D BB T1W/T2W/PDW; 3D SPACE T1WN/A2D:14 × 14

      3D:20 × 17.5
      2D: 256 × 256

      2D: 225 × 256
      N/A2
      Teng et al
      • Teng Z.
      • Peng W.
      • Zhan Q.
      • et al.
      An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery.
      GE, HDx3.082D BB FSE T2W, pre/post T1W;T2W10 × 10320 × 256PB >40%3
      Zhang et al
      • Zhang D.F.
      • Chen Y.C.
      • Chen H.
      • et al.
      A high-resolution MRI study of relationship between remodeling patterns and ischemic stroke in patients with atherosclerotic middle cerebral artery stenosis.
      Philips, Ingenia3.082D BB T1W/T2W/PDWPDW0.8 × 0.8180 × 144N/A2
      Lin et al
      • Lin G.H.
      • Song J.X.
      • Fu N.X.
      • Huang X.
      • Lu H.X.
      Quantitative and qualitative analysis of atherosclerotic stenosis in the middle cerebral artery using high-resolution magnetic resonance imaging.
      Siemens, Magnetom Skyra3.0203D SPACE pre/post T1WT1W20 × 17.8N/AN/A1
      Lu et al
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • Xie J.
      • Shi H.B.
      • Hong X.N.
      Plaque distribution and characteristics in low-grade middle cerebral artery stenosis and its clinical relevance: a 3-dimensional high-resolution magnetic resonance imaging study.
      Siemens, Skyra3.0203D BB SPACE pre/post T1WT1W24 × 21.6N/AFocal wall thickening2
      Meng et al
      • Meng Y.
      • Li M.
      • Yu Y.
      • et al.
      Quantitative score of the vessel morphology in middle cerebral artery atherosclerosis.
      GE Signa, VH/I; Discovery MR7503.082D FSE T2WT2W13 × 13225 × 256Eccentric or concentric wall thickening2
      Shi et al
      • Shi Z.
      • Li J.
      • Zhao M.
      • et al.
      Quantitative histogram analysis on intracranial atherosclerotic plaques: a high-resolution magnetic resonance imaging study.
      GE, Signa; Siemens, Skyra3.08/202D FSE T2W, pre/post T1WT2W10 × 10320 × 256Eccentric or focal wall thickening with PB > 40%2
      Zhang et al
      • Zhang D.
      • Wang M.
      • Wu L.
      • et al.
      Assessing the characteristics and diagnostic value of plaques for patients with acute stroke using high-resolution magnetic resonance imaging.
      Philips, Ingenia3.082D BB PDW, pre/post T1WPDW0.8 × 0.8180 × 144N/A2
      Zhang et al
      • Zhang D.F.
      • Wu X.Y.
      • Zhang W.D.
      • Wang M.
      • Yin X.
      • Chen Y.C.
      The relationship between patterns of remodeling and degree of enhancement in patients with atherosclerotic middle cerebral artery stenosis: a high-resolution MRI study.
      Philips, Ingenia3.082D BB PDW, pre/post T1WPDW0.8 × 0.8180 × 144N/A2
      Liang et al
      • Liang J.
      • Guo J.
      • Liu D.
      • Shi C.
      • Luo L.
      Application of high-resolution CUBE sequence in exploring stroke mechanisms of atherosclerotic stenosis of middle cerebral artery.
      GE, MR7503.083D FSE pre/post T1WT1W23 × 18.4480 × 320N/AN/A
      Liu et al
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      Siemens, MAGNETOM3643D IR-SPACE PDW, pre/post T1WN/AN/AN/APB > 40%3
      Lu et al
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • et al.
      MRI of plaque characteristics and relationship with downstream perfusion and cerebral infarction in patients with symptomatic middle cerebral artery stenosis.
      Siemens, Verio/Skyra3.032/163D BB SPACE PDW, pre/post T1W; 2D BB TSE T2W/TIWT1W3D PDW: 16 × 13

      3D T1W: 24 × 21.6

      2D: 13 × 13
      2D: 320 × 320N/A2
      HR-MR, high-resolution magnetic resonance; T1W, T1-weighted; T2W, T2-weighted; PD, proton density; 2D, two dimensional; 3D, three dimensional; BB, black blood; FSE, fast spin echo; SPACE, sampling perfection with application optimized contrasts using different flip angle evolution; PB: plaque burden; DIR, double inversion recovery; IR, inversion recovery; DSC, dynamic susceptibility contrast; PWI, perfusion-weighted imaging; N/A, data not available.

      3.4 Data synthesis and statistical analysis

      We included 533 plaques in eight studies
      • Teng Z.
      • Peng W.
      • Zhan Q.
      • et al.
      An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery.
      • Zhang D.
      • Wang M.
      • Wu L.
      • et al.
      Assessing the characteristics and diagnostic value of plaques for patients with acute stroke using high-resolution magnetic resonance imaging.
      • Yang W.Q.
      • Huang B.
      • Liu X.T.
      • Liu H.J.
      • Li P.J.
      • Zhu W.Z.
      Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3T.
      • Xu P.
      • Lv L.
      • Li S.
      Use of high-resolution 3.0-T magnetic resonance imaging to characterize atherosclerotic plaques in patients with cerebral infarction.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • Xie J.
      • Shi H.B.
      • Hong X.N.
      Plaque distribution and characteristics in low-grade middle cerebral artery stenosis and its clinical relevance: a 3-dimensional high-resolution magnetic resonance imaging study.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • et al.
      MRI of plaque characteristics and relationship with downstream perfusion and cerebral infarction in patients with symptomatic middle cerebral artery stenosis.
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      • Liang J.
      • Guo J.
      • Liu D.
      • Shi C.
      • Luo L.
      Application of high-resolution CUBE sequence in exploring stroke mechanisms of atherosclerotic stenosis of middle cerebral artery.
      and 540 MCA atherosclerotic plaques in six studies
      • Teng Z.
      • Peng W.
      • Zhan Q.
      • et al.
      An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery.
      • Yang W.Q.
      • Huang B.
      • Liu X.T.
      • Liu H.J.
      • Li P.J.
      • Zhu W.Z.
      Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3T.
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      Middle cerebral artery intraplaque hemorrhage: prevalence and clinical relevance.
      • Shi Z.
      • Li J.
      • Zhao M.
      • et al.
      Quantitative histogram analysis on intracranial atherosclerotic plaques: a high-resolution magnetic resonance imaging study.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • et al.
      MRI of plaque characteristics and relationship with downstream perfusion and cerebral infarction in patients with symptomatic middle cerebral artery stenosis.
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      in the meta-analyzed for plaque contrast enhancement and T1 hyperintensity, respectively. Symptomatic plaques were significantly associated with contrast enhancement (OR, 9.4; 95 % CI, 4.3–20.4; I2 = 49.3%; P < 0.001) and T1 hyperintensity (OR, 6.2; 95 % CI, 2.7–14.3; I2 = 10.7%; P < 0.001) (Fig. 2A, B).
      Fig. 2
      Fig. 2Forest plots of imaging features of symptomatic plaque. Forest plots of pooled data are graphically shown for 3 imaging features. Squares represent point estimates of a study's effect size and their sizes are proportional to the sample sizes. Horizontal lines show the corresponding 95 % confidence intervals (CIs). The vertical line represents an odds ratio of 1 (no effect). Diamonds represent pooled estimates with the diamond width representing 95 % CIs.
      In terms of plaque T2 hyperintensity, 411 plaques in six studies
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis.
      • Teng Z.
      • Peng W.
      • Zhan Q.
      • et al.
      An assessment on the incremental value of high-resolution magnetic resonance imaging to identify culprit plaques in atherosclerotic disease of the middle cerebral artery.
      • Zhao D.L.
      • Deng G.
      • Xie B.
      • et al.
      High-resolution MRI of the vessel wall in patients with symptomatic atherosclerotic stenosis of the middle cerebral artery.
      • Yang W.Q.
      • Huang B.
      • Liu X.T.
      • Liu H.J.
      • Li P.J.
      • Zhu W.Z.
      Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3T.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • Xie J.
      • Shi H.B.
      • Hong X.N.
      Plaque distribution and characteristics in low-grade middle cerebral artery stenosis and its clinical relevance: a 3-dimensional high-resolution magnetic resonance imaging study.
      • Chung G.H.
      • Kwak H.S.
      • Hwang S.B.
      • Jin G.Y.
      High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis.
      provided data that were eligible for the meta-analysis. Symptomatic plaques were not significantly associated with T2 hyperintensity (OR, 1.4; 95 % CI, 0.8–2.3; I2 = 0%; P = 0.19) (Fig. 2C).
      Eight
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis.
      • Zhao D.L.
      • Deng G.
      • Xie B.
      • et al.
      High-resolution MRI of the vessel wall in patients with symptomatic atherosclerotic stenosis of the middle cerebral artery.
      • Zhang D.F.
      • Wu X.Y.
      • Zhang W.D.
      • Wang M.
      • Yin X.
      • Chen Y.C.
      The relationship between patterns of remodeling and degree of enhancement in patients with atherosclerotic middle cerebral artery stenosis: a high-resolution MRI study.
      • Zhang D.F.
      • Chen Y.C.
      • Chen H.
      • et al.
      A high-resolution MRI study of relationship between remodeling patterns and ischemic stroke in patients with atherosclerotic middle cerebral artery stenosis.
      • Zhang D.
      • Wang M.
      • Wu L.
      • et al.
      Assessing the characteristics and diagnostic value of plaques for patients with acute stroke using high-resolution magnetic resonance imaging.
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      • Lin G.H.
      • Song J.X.
      • Fu N.X.
      • Huang X.
      • Lu H.X.
      Quantitative and qualitative analysis of atherosclerotic stenosis in the middle cerebral artery using high-resolution magnetic resonance imaging.
      • Chung G.H.
      • Kwak H.S.
      • Hwang S.B.
      • Jin G.Y.
      High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis.
      and seven
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      In vivo high-resolution MR imaging of symptomatic and asymptomatic middle cerebral artery atherosclerotic stenosis.
      • Yang W.Q.
      • Huang B.
      • Liu X.T.
      • Liu H.J.
      • Li P.J.
      • Zhu W.Z.
      Reproducibility of high-resolution MRI for the middle cerebral artery plaque at 3T.
      • Xu P.
      • Lv L.
      • Li S.
      Use of high-resolution 3.0-T magnetic resonance imaging to characterize atherosclerotic plaques in patients with cerebral infarction.
      • Meng Y.
      • Li M.
      • Yu Y.
      • et al.
      Quantitative score of the vessel morphology in middle cerebral artery atherosclerosis.
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • et al.
      MRI of plaque characteristics and relationship with downstream perfusion and cerebral infarction in patients with symptomatic middle cerebral artery stenosis.
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      • Chung G.H.
      • Kwak H.S.
      • Hwang S.B.
      • Jin G.Y.
      High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis.
      studies were meta-analyzed for eccentricity and positive remodeling, respectively. However, the results were not pooled because we observed significant heterogeneity in the analysis.

      3.5 Subgroup analyses and sensitivity analysis

      Because plaque contrast enhancement was the most frequently studied imaging feature (n = 8 studies) and the pooled results had a moderate heterogeneity (I2 = 49.3%), subgroup analysis was performed based on the (1) patient enrollment design (retrospective vs. prospective), (2) MRI sequence type (2D vs. 3D), and (3) grading scheme of the degree of contrast enhancement (two vs. three levels).
      Plaque enhancement had a significantly higher (P < 0.001) association with downstream ischemic events in retrospective studies (OR, 12.4; 95 % CI, 3.2–47.7) than in prospective studies (OR, 8.5; 95 % CI, 3.7–19.9). The association was also significantly higher (P < 0.001) when a two-level grading system was employed to evaluate enhancement (OR, 15.6; 95 % CI, 2.6–93.6) than when a three-level grading system was used (OR, 7.6; 95 % CI, 3.1–18.6). The strength of the association did not differ based on MRI sequence type for plaque enhancement (P = 0.56) (Table 3).
      Table 3Results of subgroup analyses of contrast enhancement of symptomatic plaque.
      CategorySubgroupStudies no.Odds ratio (95 % CI)I2 (%)P value
      Subject enrollment designRetrospective enrollment512.4 (3.2, 47.7)68.9<0.001
      Prospective enrollment38.5 (3.7, 19.9)0
      MR sequence type2D sequence412.0 (3.9, 37.2)63.70.56
      3D sequence47.4 (2.0, 27.0)44.5
      Degree of contrast enhancementTwo grading315.6 (2.6, 93.6)75.5<0.001
      Three grading57.6 (3.1–18.6)29.2
      MR, magnetic resonance; no., number; CI, confidence interval.
      Sensitivity analysis revealed that our results were robust (Fig. 3).
      Fig. 3
      Fig. 3Sensitivity analysis using a leave-one-out method.

      3.6 Publication bias

      The funnel plot for plaque enhancement and an Egger's test (P = 0.09) suggested no obvious publication bias (Fig. 4).
      Fig. 4
      Fig. 4Funnel plot of studies evaluating plaque enhancement.

      4. Discussion

      It is important to improve the diagnostic confidence that an MCA atherosclerotic plaque is the cause of a patient's ischemic stroke because it can help guide effective stroke prevention and treatment strategies. Our results indicate that MCA plaques with contrast enhancement and T1 hyperintensity are related to downstream ischemia. Unlike two previously published meta-analyses,
      • Lee H.N.
      • Ryu C.W.
      • Yun S.J.
      Vessel-Wall magnetic resonance imaging of intracranial atherosclerotic plaque and ischemic stroke: a systematic review and meta-analysis.
      • Song J.W.
      • Pavlou A.
      • Xiao J.
      • Kasner S.E.
      • Fan Z.
      • Messé S.R.
      Vessel Wall magnetic resonance imaging biomarkers of symptomatic intracranial atherosclerosis: a meta-analysis.
      we only included studies in which VWI was used to evaluate atherosclerotic plaques of the MCA, rather than those of all intracranial arteries.
      Based on previous postmortem MCA, carotid artery, and coronary artery pathological control studies,
      • Chen X.Y.
      • Wong K.S.
      • Lam W.W.
      • Zhao H.L.
      • Ng H.K.
      Middle cerebral artery atherosclerosis: histological comparison between plaques associated with and not associated with infarct in a postmortem study.
      • Degnan A.J.
      • Gallagher G.
      • Teng Z.
      • Lu J.
      • Liu Q.
      • Gillard J.H.
      MR angiography and imaging for the evaluation of middle cerebral artery atherosclerotic disease.
      T1 hyperintensity of hr-MRI may be due to both recent and fresh intraplaque hemorrhages (IPH). IPH is mostly attributed to fragile and leaky neovascularity with endothelial disruption and large local deformation.
      • Teng Z.
      • He J.
      • Degnan A.J.
      • et al.
      Critical mechanical conditions around neovessels in carotid atherosclerotic plaque may promote intraplaque hemorrhage.
      It is closely linked to plaque progression, thin or ruptured fibrous caps, and clinical symptoms.
      • Ota H.
      • Yu W.
      • Underhill H.R.
      • et al.
      Hemorrhage and large lipid-rich necrotic cores are independently associated with thin or ruptured fibrous caps: an in vivo 3T MRI study.
      • Sun J.
      • Underhill H.R.
      • Hippe D.S.
      • Xue Y.
      • Yuan C.
      • Hatsukami T.S.
      Sustained acceleration in carotid atherosclerotic plaque progression with intraplaque hemorrhage: a long-term time course study.
      • Takaya N.
      • Yuan C.
      • Chu B.
      • et al.
      Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: a high-resolution magnetic resonance imaging study.
      • Virmani R.
      • Kolodgie F.D.
      • Burke A.P.
      • et al.
      Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage.
      A meta-analysis revealed that T1 hyperintensity is a reliable predictor of subsequent stroke or transient ischemic attack for patients with extracranial carotid plaques.
      • Gupta A.
      • Baradaran H.
      • Schweitzer A.D.
      • et al.
      Carotid plaque MRI and stroke risk: a systematic review and meta-analysis.
      In our meta-analysis, T1 hyperintensity was more common in patients with symptomatic atherosclerotic stenosis than in those with asymptomatic plaques, which suggests that MCA atherosclerosis may share a common potential pathophysiology with carotid atherosclerosis. A major limitation to the use of T1 hyperintensity in intracranial plaques is that it has a low prevalence at the site of the stenosis due to the small size and deep location of the target vessel.
      • Xu W.H.
      • Li M.L.
      • Gao S.
      • et al.
      Middle cerebral artery intraplaque hemorrhage: prevalence and clinical relevance.
      However, Lu et al
      • Lu S.S.
      • Ge S.
      • Su C.Q.
      • et al.
      MRI of plaque characteristics and relationship with downstream perfusion and cerebral infarction in patients with symptomatic middle cerebral artery stenosis.
      and Liu et al
      • Liu S.
      • Tang R.
      • Xie W.
      • et al.
      Plaque characteristics and hemodynamics contribute to neurological impairment in patients with ischemic stroke and transient ischemic attack.
      improved the T1 hyperintensity rates in symptomatic MCA stenoses to 30% and 55.6%, respectively, using 3D sequences.
      Plaque contrast enhancement, being a very attractive imaging marker of plaque vulnerability in both extracranial and intracranial arteries, is thought to be related to active inflammation, neovascularity, and increased endothelial permeability.
      • Chung G.H.
      • Kwak H.S.
      • Hwang S.B.
      • Jin G.Y.
      High resolution MR imaging in patients with symptomatic middle cerebral artery stenosis.
      A postmortem study found that neovascularity in MCA atherosclerotic plaque was associated with ipsilateral infarction.
      • Chen X.Y.
      • Wong K.S.
      • Lam W.W.
      • Zhao H.L.
      • Ng H.K.
      Middle cerebral artery atherosclerosis: histological comparison between plaques associated with and not associated with infarct in a postmortem study.
      In our study, plaque enhancement was statistically significantly associated with symptomatic MCA plaques, and some of the included studies revealed that such enhancement may be independent of the degree of stenosis. Infarction was approximately 10 times more likely to occur in patients with an enhancing MCA stenosis than in those with a non-enhancing MCA stenosis.
      In the subgroup analysis for the patient enrollment design, the association between contrast enhancement and symptomatic plaques was higher for retrospective studies than for prospective studies, which may be because of selection bias. The association was also higher in studies in which a two-level grading system was used rather than a three-level grading system, probably because of increased measurement variability. Finally, although the strength of the association did not differ between studies in which 2D-sequences were used and those in which 3D-sequences were used, there was an increased association between plaque enhancement and symptomatic plaques in studies in which 2D-sequences were used. A possible explanation is that a relatively low spatial resolution may be sufficient to detect enhancement of a lesion as a result of an increase in CNR caused by the contrast uptake.
      • Dieleman N.
      • van der Kolk A.G.
      • Zwanenburg J.J.
      • et al.
      Imaging intracranial vessel wall pathology with magnetic resonance imaging: current prospects and future directions.
      In addition, Balu et al revealed that 3D-sequences improve small plaque component visualization of the carotid artery, while providing poor image quality caused by motion artifacts.
      • Balu N.
      • Chu B.
      • Hatsukami T.S.
      • Yuan C.
      • Yarnykh V.L.
      Comparison between 2D and 3D high-resolution black-blood techniques for carotid artery wall imaging in clinically significant atherosclerosis.
      Plaque hyperintensity on T2-weighted images has been documented to reflect plaque components, such as fibrous caps, IPH, or thrombi.
      • Chu B.
      • Ferguson M.S.
      • Underhill H.
      • et al.
      Images in cardiovascular medicine. Detection of carotid atherosclerotic plaque ulceration, calcification, and thrombosis by multicontrast weighted magnetic resonance imaging.
      • Kampschulte A.
      • Ferguson M.S.
      • Kerwin W.S.
      • et al.
      Differentiation of intraplaque versus juxtaluminal hemorrhage/thrombus in advanced human carotid atherosclerotic lesions by in vivo magnetic resonance imaging.
      In our study, T2 hyperintensity was not seen to be significantly associated with symptomatic plaques, which suggests that the T2 hyperintensity alone may not be a high-risk imaging biomarker.

      4.1 Limitations

      There are several limitations to this study. First, most of the included studies had small sample sizes, with limited power for subgroup analyses. Second, all included studies were from Asian populations, which may cause publication bias. This is because ICAS accounts for 30–50% and 10% of ischemic cerebrovascular events in Asian and Western populations, respectively.
      • De Silva D.A.
      • Woon F.P.
      • Lee M.P.
      • Chen C.P.
      • Chang H.M.
      • Wong M.C.
      South asian patients with ischemic stroke: intracranial large arteries are the predominant site of disease.
      • Kim J.S.
      • Bonovich D.
      Research on intracranial atherosclerosis from the east and west: why are the results different?.
      Especially in Chinese populations, it accounts for approximately 33–50% of stroke and 45% of TIA, which is far more than in other Asian countries.
      • Thomas G.N.
      • Lin J.W.
      • Lam W.W.
      • et al.
      Increasing severity of cardiovascular risk factors with increasing middle cerebral artery stenotic involvement in type 2 diabetic chinese patients with asymptomatic cerebrovascular disease.
      • Leung S.Y.
      • Ng T.H.
      • Yuen S.T.
      • Lauder I.J.
      • Ho F.C.
      Pattern of cerebral atherosclerosis in Hong Kong Chinese. Severity in intracranial and extracranial vessels.
      Third, the wide CIs suggest low statistical power, leading to imprecise effect estimates. Finally, different methodologies were used in the included studies. Although the statistical analysis of heterogeneity in effect sizes showed homogeneity among studies, the methodological diversity may have led to misinterpretation of the pooled estimates.

      5. Conclusion

      In this study, by pooling the available evidence, we identified two imaging markers for symptomatic MCA plaques: contrast enhancement and plaque T1 hyperintensity. These imaging features may help clinicians to improve patient diagnosis and treatment decisions. Future prospective, longitudinal studies of patients with ischemia are required to validate the utility of these imaging features as predictive markers.

      Declaration of competing interest

      None.

      Acknowledgments

      This work was supported by the National Natural Science Foundation of China [grant numbers 81860222 , 82060226 , 81960220 ]; and the Natural Science Foundation of Guangxi Province [grant numbers 2019GXNSFDA185008 , 2019GXNSFAA185029 ].

      Appendix A. Supplementary data

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