頭蓋内狭窄率が30%～69%で医学的管理を受けた患者381名を対象とした研究において、高解像度磁気共鳴画像法（MRI）によるプラーク造影グレードが高いほど、虚血性脳卒中または一過性脳虚血発作の再発を予測することが示された。
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頭蓋内狭窄率が30%～69%で医学的管理を受けた患者381名を対象とした研究において、高解像度磁気共鳴画像法（MRI）によるプラーク造影グレードが高いほど、虚血性脳卒中または一過性脳虚血発作の再発を予測することが示された。
標準的な薬物療法を行っているにもかかわらず、軽度から中等度の頭蓋内動脈粥状硬化性狭窄を有する患者では、虚血性イベントが再発することがあります。狭窄率のみではリスク層別化には不十分であり、プラーク活性の画像マーカーが必要です。プラークの造影効果は、管腔の狭窄を超えてプラークの活性を反映する可能性があるため、我々は、造影効果のグレードが高いほど、狭窄率よりも虚血性イベントの再発を予測しやすいという仮説を立てました。本研究では、高分解能磁気共鳴画像法（HR-MRI）によるプラーク造影効果のグレーディングと虚血性イベントの再発との関連を評価し、狭窄率に加えた際の増分価値を検討しました。薬物治療を受けたレトロスペクティブなコホートにおいて、虚血性脳卒中またはTIAを呈し、原因となる頭蓋内動脈狭窄率が30%–69%である18～85歳の患者を対象とし、発症後14日以内に造影HR-MRIを施行し、標準的な二次予防策を実施しました。下垂体茎を基準とした造影効果を、盲検読影により0～2のグレードに分類しました。主要アウトカムは、原因血管領域における虚血性イベント（脳卒中またはTIA）の再発としました。イベント発生までの時間の解析には左側切断を用いました。Kaplan–Meier法およびCoxモデルを用いて、狭窄率、LDL-C、年齢、および画像撮影の間隔で調整しました。381人の患者のうち、追跡不能は4.72%でした。52人（13.65%）に再発が認められ、イベント発生までの時間の中央値は171.84日でした。再発のない生存率は造影グレードによって異なりました（log-rank P = 0.002）。グレード0と比較して、グレード2は再発リスクの上昇と関連していました（簡易調整HR = 2.50, 95% CI 1.30–4.82; 完全調整HR = 2.31, 95% CI 1.17–4.56）。グレードが1段階上がるごとにリスクは上昇しました（完全調整HR = 1.33, 95% CI 1.07–1.65; トレンド P = 0.01）。一方、グレード1とグレード0の間では有意差はありませんでした。脳卒中の再発については、グレード2が引き続き高いリスクと関連していました（aHR = 2.63, 95% CI 1.03–6.69）。高グレードのHR-MRIプラーク造影効果は、軽度から中等度の頭蓋内動脈狭窄における虚血性イベントの再発を独立して予測し、狭窄率以上のリスク層別化を可能にします。これは本研究の仮説を支持するものであり、より強化されたフォローアップやリスク因子の目標達成が必要な患者の特定に寄与します。
虚血性脳卒中は、依然として死因および障害の主な原因の一つである。1、また、頭蓋内動脈硬化性狭窄はアジア人に多く見られ、虚血性脳卒中および再発の重要なメカニズムとなっている。2標準的な抗血小板療法およびスタチン療法により、再発のリスクを低減できる可能性がある。3しかし、臨床現場では、軽度から中等度の狭窄を有する患者においても、原因となる血管支配領域に再発イベントが発生することがあります。このような患者群は、通常、血行再建術の適応基準を満たしません。4治療戦略は主に薬物療法とリスク因子の管理に依存しており、より早期かつ正確なリスク層別化ツールが必要とされている。腔内イメージングに基づく従来の狭窄率評価は構造的な負荷に焦点を当てており、プラーク内の炎症活性、内膜の新生血管形成、内皮バリアの機能不全といった生物学的な不安定性を反映することができない。そして、これらのプロセスこそが、動脈間塞栓や局所灌流不全などの再発のトリガーとなる要因に近いものである。5高解像度MRI血管壁イメージングにより、生体内での頭蓋内プラーク表現型の評価が可能となり、造影後のプラーク増強は炎症および不安定プラーク（vulnerable phenotype）と関連している。6先行研究の多くは、有症状の鑑別や重度の狭窄がある集団に焦点を当ててきた。そのため、一律の薬物治療下における軽度から中等度の狭窄に対する再発の予測価値に関する直接的な証拠は依然として不足している。一方で、造影効果の評価基準が不統一であることや、検査時点の違いによる時間的なバイアスも、結論の汎用性を制限している。7これに基づき、薬物治療コホート設計を用いて、発症後早期にHR-MRIを完了した軽度から中等度の責任頭蓋内動脈狭窄患者を対象とした。再現性のある3段階のプラーク造影増強評価システムを適用し、追跡期間中の責任血管領域における虚血性イベントの再発と造影増強グレードとの関連を検討し、イベント発生までの時間枠の中で狭窄率および主要な臨床因子の影響を制御した。本研究の目的は、造影増強グレードが狭窄の重症度を超えて付加的なリスク情報を提供できるかを明らかにし、軽度から中等度の頭蓋内動脈硬化患者における高リスク者の特定および追跡管理のための画像的根拠を提供することであった。我々は、薬物管理を受けている軽度から中等度の頭蓋内動脈硬化性狭窄患者において、高解像度磁気共鳴画像法によるプラーク造影増強グレードが高いほど、狭窄の重症度や主要な臨床因子とは独立して、責任血管領域における虚血性イベントの再発リスクが増加するという仮説を立てた。
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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.
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研究参加者およびコホートスクリーニング
合計1879件の脳卒中/TIA（一過性脳虚血発作）の記録を抽出し、そのうち548名の患者がインデックスイベント後14日以内にHR-MRIを完了した。この14日間のウィンドウ内にHR-MRIを完了しなかった患者は、曝露ベースのイベント発生時間分析の対象外とした。事前に規定した基準に基づき、非アテローム性動脈硬化機序、不適格な狭窄範囲、責任血管が不明な例、既往の血行再建術、読影不可能な画像、および重要なデータの欠損がある症例を除外した結果、381名の患者が分析対象となり、最終的なコホートを構成した（図2）。除外カテゴリーおよびコホート構築プロセスは図2にまとめられている。
ベースラインの臨床データおよびHR-MRI画像評価
ベースライン特性を造影グレー...
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標準的な二次予防薬による治療を受けている軽度から中等度の頭蓋内動脈狭窄において、プラーク造影増強グレードは、追跡期間中の虚血性イベント再発リスクを安定して識別できる可能性がある。この知見は、プラーク造影増強グレードが高いほど、管腔狭窄の重症度を超えた再発リスク情報が得られるという研究仮説を支持している。狭窄率、脂質レベル、年齢、および画像検査の間隔などの要因をモデルに組み込んだ後でも、造影増強と再発との関連性の方向性は一貫しており、勾配的な傾向を示し、高グレードの造影増強はより明確なリスクシグナルを提示した14。造影増強の差は狭窄率では十分に説明できず、管腔の幾何学的変化だけでは再発のメカニズムを要約するには不十分であり、プラーク壁内の生物学的活性がイベント誘発のリンクに近いことが示唆された15。造影増強シグナルは、プラーク透過性の亢進と造影剤の取り込み増加を反映している可能性があり16、プラーク壁内でのより活性の高い生物学的プロセスが示唆される。これらの変化は組織因子の発現と血小板粘着を促進し...
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著者は利益相反がないことを宣言します。
著者らは、画像取得・解析、データ収集、およびフォローアップに携わったすべての患者様とそのご家族、ならびに臨床および研究スタッフに感謝いたします。本研究は、公的、商業的、または非営利セクターのいずれの資金提供機関からも、特定の助成金を受けていません。適用可能な助成金番号はありません。
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| 名前 | 会社 | カタログ番号 | コメント |
|---|---|---|---|
| 3.0T MRIシステム | Siemens Healthineers | https://www.siemens-healthineers.com/en-ca/magnetic-resonance-imaging/3t-mri-scanner/magnetom-skyra | MAGNETOM Skyra 3T MRIシステム；頭蓋内血管壁の高解像度磁気共鳴画像法（MRI） |
| 32チャンネル頭頸部複合コイル | Siemens Healthineers | https://medicine.tulane.edu/centers-institutes/taic/facilities | 32チャンネル頭頸部コイル（Skyra互換構成）；高解像度頭蓋内血管壁画像用の信号取得 |
| MRインジェクター用使い捨てシリンジセット | Bayer / MEDRAD | SSQK 65/115vs; https://www.radiology.bayer.com/it/products/medrad-spectris-solaris | Qwik-Fit Syringe Kit；MR画像用の造影剤および生理食塩水の注入 |
| ガドペンテテ酸ジメグルミン注射液 | Bayer AG | https://www.bayer.com/sites/default/files/magnevist-smpc-may-2016.pdf | Magnevist 0.5 mmol/mL (469 mg/mL)；0.1 mmol/kgでの造影血管壁画像撮影 |
| MR対応電動インジェクター | Bayer | https://www.radiology.bayer.com/products/medrad-spectris-solaris | MEDRAD Spectris Solaris EP MR Injection System；造影MRI中の2.0 mL/sでの造影剤自動注入 |
| 医用画像管理システム（PACS） | Zhejiang Laida Information Technology Co., Ltd. | https://www.qzszyy.com/home/info/15410?type=003 | PACSシステム；画像の取得、画像の検証、およびフォローアップ記録の確認 |
| R統計ソフトウェア | 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/ | 統計解析 |
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