Plaque Enhancement Grade on High-Resolution MRI and Recurrent Ischemic Events in Intracranial Stenosis: A Retrospective Cohort Study

Summary

In 381 medically managed patients with 30%–69% intracranial stenosis, higher plaque enhancement grade on high-resolution magnetic resonance imaging predicted recurrent ischemic stroke or transient ischemic attack.

Abstract

Recurrent ischemic events may occur in patients with mild-to-moderate intracranial atherosclerotic stenosis despite standardized medication; stenosis rate alone is insufficient for risk stratification, and plaque activity imaging markers are needed. Because plaque enhancement may reflect plaque activity beyond luminal narrowing, we hypothesized that higher enhancement grade would predict recurrent ischemic events of stenosis rate. This study evaluated the association between high-resolution magnetic resonance imaging (HR-MRI) plaque enhancement grading and recurrent ischemic events and examined its incremental value beyond stenosis rate. In a retrospective medication-treated cohort, patients aged 18–85 years with ischemic stroke or TIA and responsible intracranial arterial stenosis of 30%–69% completed contrast-enhanced HR-MRI within 14 days of onset and received standardized secondary prevention. Enhancement referenced to the pituitary stalk was graded 0–2 with blinded reading. The primary outcome was recurrent ischemic events (stroke or TIA) in the responsible vascular territory. Time-to-event analysis used left truncation. Kaplan–Meier and Cox models adjusted for stenosis rate, LDL-C, age, and imaging interval. Among 381 patients, loss to follow-up was 4.72%. Recurrence occurred in 52 (13.65%) patients; median event time was 171.84 days. Recurrence-free survival differed by enhancement grade (log-rank P = 0.002). Versus grade 0, grade 2 was associated with higher recurrence risk (simplified adjusted HR = 2.50, 95% CI 1.30–4.82; fully adjusted HR = 2.31, 95% CI 1.17–4.56). Per 1-grade increase, risk increased (fully adjusted HR = 1.33, 95% CI 1.07–1.65; trend P = 0.01); grade 1 vs grade 0 was not significant. For stroke recurrence, grade 2 remained associated with higher risk (aHR = 2.63, 95% CI 1.03–6.69). Higher-grade HR-MRI plaque enhancement independently predicts recurrent ischemic events in mild-to-moderate intracranial arterial stenosis and provides incremental risk stratification beyond stenosis rate, supporting the study hypothesis and identifying patients requiring intensified follow-up and risk-factor target achievement.

Introduction

Ischemic stroke remains one of the main causes of death and disability¹, and intracranial atherosclerotic stenosis is more common in Asian populations and is an important mechanism of ischemic stroke and recurrence². Standardized antiplatelet and statin therapy can reduce the risk of recurrence³, but in clinical practice, patients with mild-to-moderate stenosis may still develop recurrent events in the responsible vascular territory; such populations usually do not meet indications for revascularization⁴. Treatment strategies mainly rely on medication and risk factor management, and earlier and more accurate risk stratification tools are needed. Traditional stenosis rate assessment based on lumen imaging focuses on structural burden and cannot reflect biological instability such as intraplaque inflammatory activity, neovascularization of the intima, and impairment of the endothelial barrier, and these processes are closer to triggering links of recurrence such as artery-to-artery embolism and local perfusion decompensation⁵. High-resolution MRI vessel wall imaging makes it possible to evaluate intracranial plaque phenotype in vivo, and post-contrast plaque enhancement is associated with inflammation and vulnerable phenotype⁶. Previous studies have mostly focused on symptomatic differentiation or populations with severe stenosis; direct evidence is still lacking regarding the predictive value for recurrence in mild-to-moderate stenosis under a background of uniform medication treatment. Meanwhile, non-uniform evaluation standards for enhancement and time bias caused by differences in examination time points also limit the generalizability of conclusions⁷. Based on this, using a medication-treated cohort design, we included patients with mild-to-moderate responsible intracranial arterial stenosis who completed HR-MRI early after onset, applied a reproducible three-grade plaque enhancement system, explored the association between enhancement grading and recurrent ischemic events in the responsible vascular territory during follow-up, and controlled for the effects of stenosis rate and key clinical factors within a time-to-event framework. The purpose of this study was to clarify whether enhancement grading can provide incremental risk information beyond stenosis severity, and to provide imaging evidence for high-risk identification and follow-up management in populations with mild-to-moderate intracranial atherosclerosis. We hypothesized that, in medically managed patients with mild-to-moderate intracranial atherosclerotic stenosis, higher plaque enhancement grade on high-resolution magnetic resonance imaging would be associated with an increased risk of recurrent ischemic events in the responsible vascular territory independent of stenosis severity and key clinical factors.

Protocol

This retrospective study involving human participants complied with institutional guidelines and was approved by the Ethics Committee of Quzhou Hospital of Traditional Chinese Medicine (Approval No.: 2023-08-233). The requirement for written informed consent was waived. All included cases were de-identified before statistical analysis.

Study design

This study was a single-center retrospective medication-treated cohort study. Eligible patients who visited the Department of Neurology of our hospital between January 1, 2022 and July 31, 2024 were consecutively enrolled retrospectively, and follow-up ended on August 31, 2025 (data lock date). The study site was the Department of Neurology of this hospital. The core exposure factor was HR-MRI plaque enhancement three-grade classification (Grade 0/1/2), and the primary outcome was recurrent ischemic events in the responsible vascular territory. The overall study design and analytical workflow are summarized in Figure 1 and were implemented according to the following pre-specified steps: retrieve records of visits for ischemic stroke or transient ischemic attack within the study time window in the hospital information system, and verify in the imaging PACS whether intracranial HR-MRI vessel wall imaging and contrast-enhanced scans were completed; form the study cohort according to inclusion and exclusion criteria, and complete determination of the responsible vessel and measurement of stenosis rate; use the date of index event onset (or the date of first visit/triage, whichever was earlier) as the baseline time point to extract clinical data, laboratory indicators, and medication information; and complete HR-MRI image reading and enhancement grading within 14 days after the index event; verify outcome events according to pre-specified follow-up time points and construct time-to-event data; complete statistical analysis according to the pre-specified statistical plan.

Study participants

The study participants were patients who visited our hospital within the study time window, developed ischemic stroke or transient ischemic attack, and completed intracranial HR-MRI vessel wall imaging. A cohort was constructed by consecutive screening and enrolment of eligible patients within the study time window, and the final sample size was determined by the number of eligible cases. To ensure the stability of the multivariable Cox proportional hazards regression model, the number of covariates was pre-specified, and the EPV ≥ 10 principle was referenced⁸; the actual EPV is reported in the results.

Inclusion criteria includes: age 18–85 years; the clinical event was ischemic stroke or transient ischemic attack and could be localized to a single responsible intracranial arterial territory; responsible intracranial arterial stenosis was 30%–69%; HR-MRI vessel wall imaging and contrast-enhanced scans were completed within 14 days after the index event; standardized secondary prevention medication treatment had been initiated at baseline, with both antiplatelet therapy and statin therapy started; stenosis rate, enhancement grading, follow-up outcome information, and the time of last follow-up were complete and available.

Exclusion criteria include: evidence of a definite non-atherosclerotic mechanism for ischemic events, including definite diagnosis of cardioembolic stroke, definite diagnosis of vasculitis, and definite imaging diagnosis of arterial dissection; the responsible artery had previously received interventional treatment or surgical revascularization; HR-MRI images were not readable, defined as inability to identify the inner and outer boundaries of the vessel wall or failure of pre- and post-contrast registration leading to inability to assess enhancement; the responsible vessel could not be determined; key variables were missing, including stenosis rate, enhancement grading, outcome event information, or time of last follow-up.

Determination of the responsible vessel followed uniform rules: When acute-phase DWI showed an acute ischemic lesion in a single vascular territory, the responsible vascular territory was determined according to the correspondence between the anatomical distribution of the ischemic lesion and intracranial arterial territories, and the stenotic segment within the corresponding territory was defined as the responsible vessel. When DWI was negative and the definition of transient ischemic attack was met, the responsible vascular territory was determined according to the anatomical localization of neurological deficits and the distribution of vascular territories, and the stenotic segment within the corresponding territory was defined as the responsible vessel. When multiple stenoses were present within the same territory, the segment that best matched clinical localization and had the most severe stenosis was selected as the responsible stenotic segment.

Stenosis severity was calculated using the WASID method⁹. Stenosis rate (%) = [1 − (lumen diameter at the narrowest stenosis/proximal normal lumen diameter)] × 100%. Mild stenosis was defined as 30%–49%, and moderate stenosis was defined as 50%–69%. Stenosis rate was recorded as a continuous variable, and a mild/moderate stratification variable was also retained for descriptive statistics and model adjustment.

Clinical data and variable definitions

Baseline clinical data and variable definitions were uniformly extracted at the baseline time point and applied using a single standard. Demographic variables were age and sex. Risk factor variables were recorded as binary variables: hypertension was defined as a previous definite diagnosis of hypertension or use of antihypertensive medication at baseline; diabetes was defined as a previous definite diagnosis of diabetes or use of glucose-lowering medication at baseline; smoking was defined as being a current smoker at baseline, with the criterion of continuous smoking within the past 30 d. Baseline laboratory indicators mandatorily included low-density lipoprotein cholesterol (LDL-C). The LDL-C time window was defined as the most recent fasting lipid test result within 48 h after the index event, with the unit uniformly as mmol/L; patients without an LDL-C result within 48 h after the index event were recorded as missing. Medication treatment background variables were used only for confounding adjustment and were uniformly recorded based on the baseline prescription regimen. Antiplatelet therapy was categorized as single antiplatelet therapy (SAPT) and dual antiplatelet therapy (DAPT): SAPT was defined as aspirin 100 mg/day monotherapy or clopidogrel 75 mg/day monotherapy; DAPT was defined as aspirin 100 mg/day combined with clopidogrel 75 mg/day. Statin intensity was categorized as high-intensity and non-high-intensity: high-intensity was defined as atorvastatin 40–80 mg/day or rosuvastatin 20 mg/day; non-high-intensity was defined as statin regimens that did not meet the above dose thresholds.

HR-MRI examination and imaging assessment

All patients completed intracranial vessel wall HR-MRI and were assessed according to a unified workflow¹⁰. Scan protocol and key sequences: the scanner was a 3.0T MRI system using a 32-channel head-neck combined coil; the scan sequences mandatorily included 3D TOF-MRA, 3D T1-weighted vessel wall imaging (pre-contrast), and 3D T1-weighted vessel wall imaging (post-contrast). The contrast agent was gadopentetate dimeglumine, with a dose of 0.1 mmol/kg and an injection rate of 2.0 mL/s; the start time of post-contrast vessel wall scanning was fixed at 5 min after completion of injection. Image reconstruction used isotropic voxels of 0.6 mm, and the scan coverage included the Circle of Willis and the segments related to the responsible artery. Image quality control: the quality control criteria were fixed as clear vessel wall layers, identifiable inner and outer boundaries of the vessel wall, and consistent pre- and post-contrast registration; if any criterion was not met, the images were judged as unreadable and handled according to the exclusion criteria. Plaque identification and matching to the responsible artery: plaque was defined as focal or eccentric thickening of the wall of the responsible artery; the plaque assessment level was fixed at the level corresponding to the narrowest stenosis of the responsible artery, and extended 2 levels proximally and 2 levels distally to confirm plaque continuity; the plaque assessment range was limited to the responsible vessel segment. Plaque enhancement grading: enhancement was graded using a three-grade classification (Grade 0/1/2). Determination was made by comparing post-contrast T1 vessel wall images with pre-contrast T1 vessel wall images, with the reference structure fixed as the enhancement intensity of the pituitary stalk. Grade 0 was defined as plaque enhancement intensity ≤ the intracranial arterial wall without plaque at other sites in the same patient and lower than the pituitary stalk; Grade 1 was defined as plaque enhancement intensity > the intracranial arterial wall without plaque at other sites in the same patient and lower than the pituitary stalk; Grade 2 was defined as plaque enhancement intensity greater than or equal to the pituitary stalk¹¹. Enhancement grading was recorded as an ordinal categorical variable based on the final grade. Image reading process and consistency evaluation: image reading was independently performed by two radiologists experienced in vessel wall imaging, and the readers were blinded to clinical outcomes and follow-up information; the two readers separately provided enhancement grades, and if grades were inconsistent, a third senior physician adjudicated and determined the final grade; consistency evaluation used the weighted Kappa coefficient, and the Kappa value and its 95% CI were reported in the Results section.

Observation indicators and evaluation criteria

Data collection time points and frequency definition

This study used a collection mode of single baseline acquisition and multiple follow-up verifications. The baseline time point was defined as the date of index event onset (or the date of first visit/triage, whichever was earlier). Follow-up was set at fixed verification time points: T1 was defined as 90 ± 15 days after baseline; T2 was defined as 180 ± 15 days after baseline; T3 was defined as 365 ± 30 days after baseline. The follow-up method was fixed as verification of outpatient follow-up records and telephone follow-up verification. The follow-up termination conditions were fixed as occurrence of the primary outcome event, completion of T3 follow-up, or reaching the study end date. Loss to follow-up was defined as inability to obtain outcome information at two consecutive fixed verification time points and no outpatient records.

Time windows and evaluation criteria for each indicator

Plaque enhancement grading was assessed on the day of HR-MRI examination completed within 14 days after the index event and recorded as the baseline exposure variable. The responsible arterial stenosis rate was measured on the day of HR-MRI/TOF-MRA assessment and recorded as the baseline imaging variable. Age, sex, and risk factors (hypertension, diabetes, smoking) were collected once at baseline, sourced from admission medical records and prior diagnoses/medication records. LDL-C was collected within 48 h after the index event, sourced from fasting lipid test results in the laboratory system. The antiplatelet regimen and statin intensity were collected once at baseline.

The primary outcome was recurrent ischemic events in the responsible vascular territory, with the collection time window from baseline to follow-up termination. Outcome event information was verified at fixed time points T1, T2, and T3, and emergency or hospitalization events occurring between two verifications were additionally checked. Ischemic stroke was defined as new focal neurological deficits lasting more than 24 h and confirmed by head MRI or CT showing a new ischemic infarct consistent with symptoms. Transient ischemic attack was defined as focal neurological deficits lasting no more than 24 h and head MRI (preferably DWI) or CT showing no evidence of acute infarction consistent with symptoms¹². The rules for determining recurrence in the responsible vascular territory were fixed as recurrence events being consistent with the baseline responsible arterial territory: for stroke, determination was based on matching the distribution of the new infarct lesion with the vascular territory; for transient ischemic attack, determination was based on matching symptom localization with the vascular territory. The event date was fixed as the earlier of the imaging examination date and the emergency or hospitalization triage date; the time-to-event variable was defined as the number of days from baseline to the event date. For patients without recurrence events, the censoring time was the T3 completion date or the last available follow-up date. The interval (d) from the index event to completion of HR-MRI was also recorded for multivariable model adjustment.

Statistical analysis

Considering that exposure was obtained on the day of HR-MRI, time-to-event analysis used left truncation: the index event date was used as the time scale origin, and the time of entry into the risk set was defined as the HR-MRI completion date¹³. Recurrence occurring before HR-MRI completion was not included in the analysis. For continuous variables, the Shapiro–Wilk test was used to assess normality, and the Levene test was used to assess homogeneity of variance; continuous variables satisfying normality and homogeneity of variance were described as mean ± SD, otherwise as median (interquartile range); categorical variables were described as n and percentage. Baseline characteristics were compared by enhancement grade (Grade 0/1/2). For continuous variables satisfying normality and homogeneity of variance, one-way analysis of variance was used; otherwise, the Kruskal-Wallis test was used. Categorical variables were compared using the chi-square test.

For time-to-event analysis, the Kaplan–Meier method was used to plot recurrence-free survival curves, and the log-rank test was used to compare recurrence differences among enhancement grades. The primary association analysis used the Cox proportional hazards regression model, reporting hazard ratio (HR) and 95% CI. Given the limited number of outcome events, the main analysis was pre-specified to use a simplified adjustment model: adjusting for stenosis rate, LDL-C, the interval from the index event to HR-MRI, and age (enhancement grade entered the model as an ordinal variable). The fully adjusted model further included sex, hypertension, diabetes, smoking, antiplatelet regimen, and statin intensity on this basis as a sensitivity analysis. Using Grade 0 as the reference, HRs for Grade 1 and Grade 2 were estimated, and enhancement grade was treated as an ordinal variable for trend testing. The proportional hazards assumption was evaluated using the Schoenfeld residual test.

Sensitivity analysis was pre-specified as repeating the above Cox regression analysis using only recurrent ischemic stroke as the outcome event, to test the stability of conclusions under a stricter outcome definition. Missing data handling: patients with missing exposure factor (enhancement grade), outcome event information, or time of last follow-up were excluded; missing values of other covariates were handled by multiple imputation to complete the main analysis, and complete-case analysis was used as a sensitivity analysis. Statistical tests were two-sided, with significance level set at P < 0.05. The statistical software was fixed as R.

Results

Study participants and cohort screening

A total of 1879 stroke/TIA (transient ischemic attack) records were retrieved, and 548 patients completed HR-MRI within 14 days after the index event. Patients who did not complete HR-MRI within this 14 days window were not eligible for exposure-based time-to-event analysis. After excluding cases with non-atherosclerotic mechanisms, non-eligible stenosis range, unclear responsible vessel, prior revascularization, unreadable images, and k...

Discussion

In the context of mild-to-moderate intracranial arterial stenosis receiving standardized secondary prevention medication treatment, plaque enhancement grade could still stably distinguish the risk of recurrent ischemic events during follow-up. This finding supports the study hypothesis that higher plaque enhancement grade provides recurrence-risk information beyond luminal stenosis severity. After incorporating factors such as stenosis rate, lipid level, age, and the interval between imaging examinations into the model, ...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
3.0T MRI system	Siemens Healthineers	https://www.siemens-healthineers.com/en-ca/magnetic-resonance-imaging/3t-mri-scanner/magnetom-skyra	MAGNETOM Skyra 3T MRI system; Intracranial high-resolution vessel wall magnetic resonance imaging (MRI)
32-channel head-neck combined coil	Siemens Healthineers	https://medicine.tulane.edu/centers-institutes/taic/facilities	32-channel head/neck coil (Skyra-compatible configuration); Signal acquisition for high-resolution intracranial vessel wall imaging
Disposable syringe set for MR injector	Bayer / MEDRAD	SSQK 65/115vs; https://www.radiology.bayer.com/it/products/medrad-spectris-solaris	Qwik-Fit Syringe Kit; Contrast-agent and saline delivery for MR imaging
Gadopentetate dimeglumine injection	Bayer AG	https://www.bayer.com/sites/default/files/magnevist-smpc-may-2016.pdf	Magnevist 0.5 mmol/mL (469 mg/mL); Contrast-enhanced vessel wall imaging at 0.1 mmol/kg
MR-compatible power injector	Bayer	https://www.radiology.bayer.com/products/medrad-spectris-solaris	MEDRAD Spectris Solaris EP MR Injection System; Automated contrast-agent injection at 2.0 mL/s during contrast-enhanced MRI
Picture archiving and communication system (PACS)	Zhejiang Laida Information Technology Co., Ltd.	https://www.qzszyy.com/home/info/15410?type=003	PACS system; Image retrieval, image verification, and follow-up record checking
R statistical software	R Foundation for Statistical Computing	R version 4.3.0, RRID:SCR_001905 https://cran.r-project.org/bin/windows/base/old/4.3.0/	Statistical analysis