
==== Front
Eur J Neurol
Eur J Neurol
10.1111/(ISSN)1468-1331
ENE
European Journal of Neurology
1351-5101
1468-1331
John Wiley and Sons Inc. Hoboken

39096086
10.1111/ene.16422
ENE16422
EJoN-24-0813.R1
Original Article
Stroke
Small vessel disease burden and prognosis of recent subcortical ischaemic stroke differ by parent artery atherosclerosis
RSIS differ by parent artery atherosclerosis
Lin et al.
Lin Qian‐Qian https://orcid.org/0000-0001-5724-3087
1 2
Chen Hui‐Sheng https://orcid.org/0000-0002-7486-1992
3
Yang Yi https://orcid.org/0000-0002-9729-8522
4
Zhang Meng 5
Wu Shi‐Wen 6
Li Ming‐Li 7
Huang Yi‐Ning 8
Xu Wei‐Hai https://orcid.org/0000-0003-3874-2598
1 xuwh@pumch.cn

Stroke Imaging Package Study (SIPS) study Group
1 Department of Neurology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
2 Department of Neurology, Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology Fujian Medical University Fuzhou China
3 Department of Neurology General Hospital of Northern Theater Command Shenyang China
4 Department of Neurology The First Hospital of Jilin University Changchun China
5 Department of Neurology Army Medical Centre of PLA Chongqing China
6 Department of Neurology First Medical Centre of Chinese PLA General Hospital Beijing China
7 Department of Radiology, Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China
8 Department of Neurology, Peking University First Hospital Peking University Beijing China
* Correspondence
Wei‐Hai Xu, Department of Neurology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan 1, Dongcheng District, Beijing, 100730, China.
Email: xuwh@pumch.cn

03 8 2024
10 2024
31 10 10.1111/ene.v31.10 e1642208 7 2024
25 4 2024
14 7 2024
© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Abstract

Background and purpose

Parent artery atherosclerosis is an important aetiology of recent subcortical ischaemic stroke (RSIS). However, comparisons of RSIS with different degrees of parent artery atherosclerosis are lacking.

Methods

Prospectively collected data from our multicentre cohort (all were tertiary centres) of the Stroke Imaging Package Study between 2015 and 2017 were retrospectively reviewed. The patients with RSIS defined as a single clinically relevant diffusion‐weighted imaging positive lesion in the territory of lenticulostriate arteries were categorized into three subgroups: (1) normal middle cerebral artery (MCA) on magnetic resonance angiography and high‐resolution magnetic resonance imaging (HR‐MRI); (2) low‐grade MCA atherosclerosis (normal or <50% stenosis on magnetic resonance angiography and with MCA plaques on HR‐MRI); (3) steno‐occlusive MCA atherosclerosis (stenosis ≥50% or occlusion). The primary outcome was 90‐day functional dependence (modified Rankin Scale score >2). The clinical and imaging findings were compared between subgroups.

Results

A total of 239 patients (median age 60.0 [52.0–67.0] years, 72% male) were enrolled, including 140 with normal MCA, 64 with low‐grade MCA atherosclerosis and 35 with steno‐occlusive MCA atherosclerosis. Patients with steno‐occlusive MCA atherosclerosis had the largest infarct volume. Low‐grade MCA atherosclerosis was independently associated with cerebral microbleeding, more severe perivascular spaces in basal ganglia and higher total cerebral small vessel disease burden. Low‐grade MCA atherosclerosis was an independent determinant of 90‐day functional dependence (odds ratio 3.897; 95% confidence interval 1.309–11.604).

Conclusions

Our study suggested RSIS with varying severity of parent artery atherosclerosis exhibits distinctive clinical and neuroimaging characteristics, with low‐grade MCA atherosclerosis associating with higher cerebral small vessel disease burden and worse prognosis.

cerebral infarction
cerebral small vessel disease
intracranial atherosclerosis
magnetic resonance imaging
plaque, atherosclerotic
Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences2022‐I2M‐1‐002 Central High‐level Hospital Clinical Scientific Research Project of Peking Union Medical College Hospital2022‐PUMCH‐C‐001 the National Natural Science Foundation of China81471207 81671370 the National Science Fund for Distinguished Young Scholars82025013 source-schema-version-number2.0
cover-dateOctober 2024
details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.4.8 mode:remove_FC converted:20.09.2024
Lin Q‐Q , Chen H‐S , Yang Y , et al. Small vessel disease burden and prognosis of recent subcortical ischaemic stroke differ by parent artery atherosclerosis. Eur J Neurol. 2024;31 :e16422. doi:10.1111/ene.16422

Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02485275
==== Body
pmcINTRODUCTION

Recent subcortical ischaemic stroke (RSIS) accounts for nearly 25% of all infarctions [1, 2]. The classic mechanisms of RSIS are heterogeneous based on autopsy studies, mainly including intrinsic cerebral small vessel abnormalities and blocking of the orifice of the perforating artery by atheroma or parent artery plaque, although cardiac or artery‐to‐artery embolisms account for a small proportion of cases [3]. Due to limitations in imaging resolution, it is challenging to directly assess cerebral small vessels and perforating arteries. Most studies have characterized RSIS according to infarct size, location or shape [4, 5, 6, 7], which only provided indirect evidence for the pathogenesis. Therefore, evaluating the parent artery may offer more comprehensive information for assessing RSIS.

In the past decades, luminal imaging, including magnetic resonance angiography (MRA), computed tomography angiography and digital subtraction angiography, has been used to detect luminal stenosis as an indicator of atherosclerosis severity. Recently, the technique of high‐resolution magnetic resonance imaging (HR‐MRI) has made it possible to evaluate the intracranial arterial wall at a submillimetre level [8, 9]. Several studies have demonstrated the value of HR‐MRI in detecting non‐stenotic or low degree stenosis of intracranial plaque in RSIS, thus expanding our ability to detect atherosclerosis [10, 11, 12]. However, there have been few studies comparing RSIS with varying degrees of parent artery atherosclerosis. It remains unknown whether the clinical and neuroimaging characteristics of RSIS vary with parent artery atherosclerosis. In this study, the aim was to comprehensively classify and compare RSIS in the territory of lenticulostriate arteries with different degrees of middle cerebral artery (MCA) atherosclerosis using HR‐MRI in addition to conventional MRA.

MATERIALS AND METHODS

Study design and participants

The Stroke Imaging Package Study was a prospective, multicentre, cohort study to explore the clinical value of conventional MRI in combination with HR‐MRI in patients with acute ischaemic stroke [13]. Patients were consecutively enrolled from 16 tertiary medical centres in China and were eligible if they were aged 18–80 years and had a first‐ever stroke within 72 h of symptom onset between 1 July 2015 and 30 November 2017. Patients were excluded if they (1) had contraindications to MRI, (2) were unable to complete the required MRI sequences or had non‐interpretable images and (3) declined to participate in the study. Demographic information, traditional vascular risk factors, physical examination findings, laboratory investigations, National Institutes of Health Stroke Scale (NIHSS) scores and 90‐day functional dependence were documented. All subjects enrolled in this study were medically managed according to the guidelines [14, 15]. The patients were followed up via telephone or outpatient clinic at 90 days. The study protocol adheres to the ethical guidelines of the 1975 Declaration of Helsinki. This study was approved by the institutional review board at Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (JS‐872). Written informed consent was obtained from each patient included in the study.

In this current substudy, the data of patients with RSIS, defined by the presence of a single clinically relevant diffusion‐weighted imaging (DWI) positive lesion within the distribution of the lenticulostriate arterial territory (MCA perforators), were analysed [16]. ‘Clinically relevant’ meant that patients should present with clinical symptoms and signs corresponding to the DWI positive lesion such as hemiplegia, hemianaesthesia, slurred speech etc. These lesions were differentiated based on the medical records of patients' manifestations to prevent irrelevant DWI lesions. Patients with potential upstream embolic sources (ipsilateral internal carotid artery [both extracranial and intracranial segments] stenosis ≥50% or evidence of cardiac embolism) or other aetiologies (such as dissection, vasculitis and others) were excluded.

Imaging protocols

Participants underwent multiparametric MRI, including brain MRI (DWI, T1‐weighted imaging, T2‐weighted imaging, T2‐weighted fluid attenuated inversion recovery imaging), three‐dimensional (3D) time‐of‐flight MRA, gradient echo sequences and 3D T1‐weighted HR‐MRI. All MRI scans were conducted using 3.0 T MRI scanners from three different manufacturers (Siemens, GE, Philips). Detailed imaging protocols have been described previously [13].

Parent artery imaging and RSIS classification

The MCA ipsilateral to the infarct was defined as the parent artery. The parent artery lumen stenosis degree was measured on MRA according to Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial criteria as the diameter of the narrowest lumen divided by the diameter of the proximal widest (normal) lumen [17]. Parent artery plaque was identified as the presence of eccentric wall thickening, with the thinnest part <50% of the thickest part identified by visual inspection on 3D T1‐weighted HR‐MRI [8]. Based on parent artery imaging, the RSISs were classified as follows: (1) normal MCA on MRA and HR‐MRI (Figure 1a–d); (2) low‐grade MCA atherosclerosis (normal or the narrowest lumen <50% stenosis on MRA and with MCA plaques on HR‐MRI) (Figure 1e–h); (3) steno‐occlusive MCA atherosclerosis (the narrowest lumen ≥50% stenosis on MRA and with MCA plaques on HR‐MRI; or MCA occlusion) (Figure 1i–l).

FIGURE 1 Recent subcortical ischaemic stroke with different degrees of MCA atherosclerosis. An infarct in the right middle cerebral artery (MCA) territory (thin arrow) is shown on diffusion‐weighted imaging (DWI) (a). Magnetic resonance angiography (MRA) shows no lumen stenosis of the MCA ipsilateral to the infarct (b). Three‐dimensional T1‐weighted high‐resolution magnetic resonance imaging (3D T1 HR‐MRI) shows no plaque in the right MCA in the coronal and sagittal planes (c), (d). An infarct in the left MCA territory (thin arrow) is shown on DWI (e). MRA shows low‐grade MCA stenosis (thick arrow) ipsilateral to the infarct (f). 3D T1 HR‐MRI shows a plaque at the superior wall of the left MCA (arrowhead) in the coronal and sagittal planes (g), (h). An infarct in the left MCA territory (thin arrow) is shown on DWI (i). MRA shows >50% stenosis (thick arrow) of the MCA ipsilateral to the infarct (j). 3D T1 HR‐MRI shows a plaque mainly involving the superior and dorsal wall of the left MCA (arrowhead) in the coronal and sagittal planes (k), (l).

Given the relevance of the location of MCA plaques to the infarct, the plaques on each cross‐section were further classified based on the orientation being centred on the superior, inferior, dorsal or ventral side of the vessel [18]. MCA plaques were also categorized into three groups as proximal, middle and distal according to the equal division of the M1 segment using the curved pathway on multiplanar reformation. In this process, a dot was manually placed in the centre of the vessel lumen on continuous sagittal sections, and an associated M1 segment pathway was automatically generated (Figure S1) [19].

Brain lesion evaluation

The infarct volume was calculated by multiplying the sum of the lesion area (using the region growing technique for segmentation) in each slice by the slice thickness based on DWI with self‐developed software in MATLAB (MathWorks Inc., Natick, MA, USA) [20]. The location of the infarct lesion was also examined to assess whether the posterior limb of the internal capsule, the area with congregate and organized corticospinal tract fibres, was involved [21, 22]. This assessment was important because infarcts involving the cortical spinal tract are correlated with poor motor outcomes [21, 22].

All imaging markers of cerebral small vessel disease (CSVD) were defined according to the standards for reporting vascular changes on neuroimaging [23]. The cerebral microbleeds (CMBs) were categorized into deep or infratentorial CMBs and strictly lobar CMBs based on their location [24]. The CMB burden was classified into no to mild degree (n < 5) and severe degree (n ≥ 5) on the basis of total number. The severity of enlarged perivascular spaces (EPVSs) was rated on an established semiquantitative scale from 0 to 4 [25]. Deep and periventricular white matter hyperintensity (WMH) was rated according to the Fazekas scale from 0 to 3 [26]. The total small vessel disease (SVD) burden score was calculated based on a well‐described scale from 0 to 4 [27]. A point was counted for each marker as follows: the presence of lacunes, the presence of CMBs, moderate to severe EPVSs in the basal ganglia (grade 2–4), severe WMH (periventricular WMH grade 3 or deep WMH grade 2–3). The total SVD score was further categorized into two groups: no to slight burden (score 0–2) and moderate to severe burden (score 3–4) [28].

All image data were analysed by a radiologist (MLL) and a neurologist (QQL), both of whom were blinded to the clinical information. They utilized off‐line commercial software (OsiriX MD, v.9.02) for the analysis. In cases where their judgements conflicted, the images were reviewed and discussed until a consensus was reached between the two observers. One of the readers (QQL) independently assessed the images twice with a 1‐month interval between assessments to calculate the intra‐observer agreement.

Outcome measurements

The primary outcome was 90‐day functional dependence (modified Rankin Scale score >2, range 0 [no symptoms] to 6 [death]). The secondary outcomes were CSVD markers including lacunes, CMBs, deep WMH, periventricular WMH, perivascular space in the basal ganglia (BG‐PVS), perivascular space in the centrum semiovale (CS‐PVS) and total SVD score.

Statistical analysis

Comparisons between subgroups were conducted using the Kruskal–Wallis H test for continuous or ordinal categorical variables and the Fisher exact test for binary categorical variables. The associations of parent artery atherosclerosis (normal MCA, low‐grade MCA atherosclerosis, steno‐occlusive MCA atherosclerosis) with 90‐day functional dependence were assessed using multivariable binary logistic regression. The associations of parent artery atherosclerosis with CSVD markers were assessed with multivariable binary logistic regression for the presence of lacunes, CMBs and moderate to severe CSVD burden (proportional odds assumption was not acceptable for total SVD score), and multivariable ordinal logistic regression for WMH and EPVSs, with parent artery atherosclerosis as the independent variable (set as three‐category variable) and each CSVD marker as the outcome variable. Separate regressions were fitted for each CSVD marker. All models were adjusted for potential confounders that were clinically relevant or statistically significant (p < 0.1) in the univariate analysis. All statistical analyses were performed using SPSS 23.0. A two‐sided p value less than 0.05 was considered statistically significant, and Bonferroni correction was used for multiple pairwise comparisons. The updated statistical significance after applying Bonferroni was p < 0.017 (0.05/3) for pairwise comparison of baseline characteristics and CSVD markers amongst three groups with different degrees of MCA atherosclerosis and p < 0.025 (0.05/2) in the separate regressions for comparisons of low‐grade MCA atherosclerosis or steno‐occlusive MCA atherosclerosis with normal MCA. Cohen's κ coefficient was used to assess inter‐observer and intra‐observer agreement of the CSVD markers. A weighted κ coefficient was used to assess inter‐rater reliability for degree of MCA atherosclerosis. In the case of disagreement, a consensus was reached between the two raters. A Cohen's κ coefficient and weighted κ coefficient greater than 0.75 were considered excellent.

RESULTS

From 1 July 2015 to 30 November 2017, a total of 756 patients were enrolled in the Stroke Imaging Package Study. Amongst them, 243 patients (32.1%) were diagnosed with RSIS within the MCA territory. Four patients with potential upstream embolic sources were excluded, which included one patient with atrial fibrillation identified through electrocardiogram monitoring and three patients with ipsilateral internal carotid artery stenosis ≥50%, as determined through extracranial vessel imaging. Ultimately, 239 patients were included in the final analysis. The baseline characteristics, categorized by RSIS subtypes, are summarized in Table 1. The median age of the patients was 60.0 (52.0–67.0) years and 72% (172/239) were male. There were 140 patients (58.6%) with normal MCA, 64 (26.8%) with low‐grade MCA atherosclerosis and 35 with steno‐occlusive MCA atherosclerosis (14.6%, 31 MCA stenosis and four MCA occlusion). Amongst the three groups, patients with normal MCA were the youngest and most likely to be smokers. No significant differences were detected amongst the three groups regarding gender distribution, other vascular risk factors, time from symptoms onset to MRI, clinical severity, or treatments. The weighted κ coefficient for inter‐observer agreement was excellent (κ = 0.813) for assessing the degree of MCA atherosclerosis.

TABLE 1 Baseline characteristics of RSIS with different degree of MCA atherosclerosis.

Variable	Total patients (N = 239)	Normal MCA (group 1) (n = 140)	Low‐grade MCA atherosclerosis (group 2) (n = 64)	Steno‐occlusive MCA atherosclerosis (group 3) (n = 35)	p value	Pairwise comparison	
Age, median (IQR), years	60.0 (52.0–67.0)	59.0 (51.0–65.0)	61.0 (56.0–69.8)	62.0 (54.0–67.0)	0.013	Group 1 versus 2*; no significance for group 1 versus 3 or group 2 versus 3	
Male, n (%)	172 (72.0)	100 (71.4)	46 (71.9)	26 (74.3)	0.945	No significance	
Risk factors, n (%)	
Hypertension	174 (72.8)	101 (72.1)	46 (71.9)	27 (77.1)	0.822	No significance	
Diabetes	70 (29.3)	37 (26.4)	20 (31.3)	13 (37.1)	0.424	No significance	
Hyperlipidaemia	86 (36.0)	55 (39.3)	18 (28.1)	13 (37.1)	0.301	No significance	
Currently or previously smoking	119 (49.8)	83 (59.3)	23 (35.9)	13 (37.1)	0.002	Group 1 versus 2*; no significance for group 1 versus 3 or group 2 versus 3	
Time from symptom onset to MRI, median (IQR), h	48.0 (29.0–58.0)	46.5 (30.0–57.0)	52.0 (29.0–64.5)	34.0 (24.0–56.0)	0.208	No significance	
NIHSS score at admission, median (IQR)	4 (2–6)	3 (2–6)	4 (2–6)	4 (2–6)	0.703	No significance	
Therapy, n (%)	
Intravenous thrombolysis	21 (8.8)	12 (8.6)	7 (10.9)	2 (5.7)	0.690	No significance	
Thrombectomy	0 (0)	0 (0)	0 (0)	0 (0)	NA	No significance	
Antiplatelet	237 (99.2)	139 (99.3)	63 (98.4)	35 (100)	0.658	No significance	
Statin therapy	223 (93.3)	129 (92.1)	61 (95.3)	33 (94.3)	0.816	No significance	
Antihypertensive	94 (39.3)	58 (41.4)	24 (37.5)	12 (34.3)	0.697	No significance	
Outcomes, n (%)						No significance	
90‐day functional dependence	24 (10.0)	8 (5.7)	11 (17.2)	5 (14.3)	0.020	Group 1 versus group 2*; no significance for group 1 versus 3 or group 2 versus 3	
Abbreviations: IQR, interquartile range; MCA, middle cerebral artery; MRI, magnetic resonance imaging; NA, not available; NIHSS, National Institutes of Health Stroke Scale; RSIS, recent subcortical ischaemic stroke.

* Significant after Bonferroni correction (p < 0.017).

Imaging features of RSIS with different degrees of MCA atherosclerosis

Amongst patients with low‐grade MCA atherosclerosis (39 out of 64, 60.9%) and those with steno‐occlusive MCA atherosclerosis (23 out of 31, 74.2%), the majority had their plaques situated on the superior wall (Table S1). Specifically a significant portion of low‐grade MCA atherosclerotic plaques were located in the middle M1 segment (70.3%, 45/64), whereas steno‐occlusive plaques were predominantly found in the distal M1 segment (67.7%, 21/31).

Amongst the three groups, the patients with low‐grade MCA atherosclerosis were most likely to have an infarct involving the posterior limb of the internal capsule (normal MCA vs. low‐grade MCA atherosclerosis vs. steno‐occlusive MCA atherosclerosis: 25.7% vs. 42.2% vs. 20.0%; p = 0.024). On the other hand, patients with steno‐occlusive MCA atherosclerosis had the largest infarct volume (normal MCA vs. low‐grade MCA atherosclerosis vs. steno‐occlusive MCA atherosclerosis: 0.885 mL vs. 0.931 mL vs. 1.593 mL; p = 0.014) (Table S2).

Cerebral SVD burden of RSIS with different degrees of MCA atherosclerosis

The patients with low‐grade MCA atherosclerosis were most likely to have CMBs (especially located in the deep and infratentorial region), moderate to severe BG‐PVS, highest degree of periventricular WMH (PWMH) and the highest total CSVD burden (Table S2). After adjusting for age, sex, hypertension, diabetes mellitus, hyperlipidaemia, smoking, anti‐platelet, statin and antihypertensive treatments (Table 2), low‐grade MCA atherosclerosis was independently associated with the presence of CMBs (odds ratio [OR] 3.249; 95% confidence interval [CI] 1.586–6.656), more severe BG‐PVS (OR 2.171; 95% CI 1.182–3.987) and a higher total CSVD burden (OR 2.113; 95% CI 1.185–3.766). The Cohen's κ coefficients for inter‐observer and intra‐observer for CSVD markers are shown in Table S2.

TABLE 2 Associations between degree of MCA atherosclerosis and cerebral small vessel disease markers in recent subcortical ischaemic stroke.

Outcome variable a	Model 1	Model 2	
Adjusted OR (95% CI)	p value	Adjusted OR (95% CI)	p value	
Lacunes	
Normal MCA	1		1		
Low‐grade MCA atherosclerosis	1.127 (0.607–2.093)	0.706	1.243 (0.644–2.399)	0.517	
Steno‐occlusive MCA atherosclerosis	0.559 (0.247–1.265)	0.163	0.559 (0.240–1.303)	0.178	
CMBs	
Normal MCA	1		1		
Low‐grade MCA atherosclerosis	2.357 (1.201–4.627)	0.013*	3.249 (1.586–6.656)	0.001*	
Steno‐occlusive MCA atherosclerosis	0.969 (0.430–2.184)	0.939	0.589 (0.249–1.392)	0.228	
Deep WMH	
Normal MCA	1		1		
Low‐grade MCA atherosclerosis	1.125 (0.640–1.982)	0.681	1.331 (0.738–2.399)	0.342	
Steno‐occlusive MCA atherosclerosis	0.620 (0.305–1.259)	0.185	0.658 (0.318–1.362)	0.260	
Periventricular WMH	
Normal MCA	1		1		
Low‐grade MCA atherosclerosis	0.331 (0.087–1.259) b	0.105	1.368 (0.743–2.514)	0.315	
Steno‐occlusive MCA atherosclerosis	0.936 (0.263–3.329) b	0.919	0.716 (0.338–1.519)	0.384	
BG‐PVS	
Normal MCA	1		1		
Low‐grade MCA atherosclerosis	2.168 (1.207–3.892)	0.010*	2.171 (1.182–3.987)	0.013*	
Steno‐occlusive MCA atherosclerosis	1.372 (0.660–2.849)	0.397	1.351 (0.634–2.881)	0.435	
CS‐PVS	
Normal MCA	1		1		
Low‐grade MCA atherosclerosis	1.679 (0.950–2.968)	0.075	1.476 (0.816–2.664)	0.198	
Steno‐occlusive MCA atherosclerosis	1.889 (0.942–3.789)	0.073	1.496 (0.731–3.068)	0.271	
Total SVD score	
Normal MCA	1		1		
Low‐grade MCA atherosclerosis	2.357 (1.201–4.627) b	0.013*	2.113 (1.185–3.766)	0.01*	
Steno‐occlusive MCA atherosclerosis	0.969 (0.430–2.184) b	0.969	0.855 (0.421–1.737)	0.664	
Note: Model 1 was adjusted for age and sex. Model 2 was adjusted for age, sex, hypertension, diabetes mellitus, hyperlipidaemia, smoking, anti‐platelet, statin and antihypertensive treatments.

Abbreviations: BG‐PVS, perivascular space in basal ganglia; CI, confidence interval; CMB, cerebral microbleed; CS‐PVS, perivascular space in centrum semiovale; OR, odds ratio; MCA, middle cerebral artery; SVD, small vessel disease; WMH, white matter hyperintensity.

a There were four missing cases for lacunes, five missing cases for WMH, six missing cases for CMBs and BG‐PVS, and 12 missing cases for SVD score due to no available magnetic resonance imaging sequence.

b Because proportional odds assumption was not acceptable in model 1, periventricular WMH was divided into two groups (degree 0–2 vs. degree 3) and SVD score was divided into two groups (degree 0–1 vs. degree 2–4).

* Significant after Bonferroni correction (p < 0.025).

Stroke outcome of RSIS with different degrees of MCA atherosclerosis

The patients with low‐grade MCA atherosclerosis had the highest risk and those with normal MCA had the lowest risk of 90‐day functional dependence (normal MCA vs. low‐grade MCA atherosclerosis vs. steno‐occlusive MCA atherosclerosis: 5.7% vs. 17.2% vs. 14.3%; p = 0.02; Table 1). In the multivariable models (Table 3), only the low‐grade MCA atherosclerosis group showed a significantly increased risk of 90‐day functional dependence compared with the normal MCA group, with an OR of 3.897 (95% CI 1.309–11.604; p = 0.015) after adjusting for age and NIHSS at admission. The result still remained significant (OR 4.941; 95% CI 1.421–17.179; p = 0.012) after total SVD score was additionally adjusted for in model 2. The steno‐occlusive MCA atherosclerosis group did not independently predict 90‐day functional dependence (OR 2.700; 95% CI 0.698–10.444; p = 0.150) compared with the normal MCA group after adjusting for age and NIHSS score at admission.

TABLE 3 Association between degree of MCA atherosclerosis and stroke outcomes in recent subcortical ischaemic stroke.

Outcome variable	Crude OR (95% CI)	p value	Model 1	Model 2	
Adjusted OR (95% CI)	p value	Adjusted OR (95% CI)	p value	
90‐day functional dependence	
Normal MCA	1		1		1		
Low‐grade MCA atherosclerosis	3.425 (1.305–8.988)	0.009*	3.897 (1.309–11.604)	0.015*	4.941 (1.421–17.179)	0.012*	
Steno‐occlusive MCA atherosclerosis	2.75 (0.840–9.000)	0.171	2.700 (0.698–10.444)	0.150	3.808 (0.854–16.982)	0.08	
Note: Model 1 adjusted for age and NIHSS score at admission. Model 2 adjusted for age, NIHSS score at admission and cerebral small vessel disease burden for low‐grade MCA atherosclerosis group, and age, NIHSS score at admission and infarct volume for steno‐occlusive MCA atherosclerosis group.

Abbreviations: CI, confidence interval; MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio.

* Significant after Bonferroni correction (p < 0.025).

DISCUSSION

In our study population, RSIS with normal MCA (58.6%) was the most prevalent subtype, followed by RSIS with low‐grade MCA atherosclerosis (26.8%) and RSIS with steno‐occlusive MCA atherosclerosis (14.6%). Patients with normal MCA were the youngest and were most likely to be smokers. The patients with low‐grade MCA atherosclerosis were most likely to have an infarct involving the posterior limb of the internal capsule and coexistent CSVD imaging markers. The patients with steno‐occlusive MCA atherosclerosis had the largest infarct volume. In the multivariable analysis, low‐grade MCA atherosclerosis was identified as an independent determinant of 90‐day functional dependence.

Our data showed that patients with normal MCA were most likely to be smokers compared to patients with MCA atherosclerosis. This finding was unexpected because smoking is a well‐established risk factor for large artery atherosclerosis [29, 30]. Two possible explanations were proposed for the phenomenon. (1) Both active smoking and pre‐stroke smoking were included in the study. Currently, active smoking is recognized as a risk factor for atherosclerosis. However, the impact of pre‐stroke smoking on atherosclerosis remains controversial [31, 32], which might introduce bias into the results. Furthermore, the details of smoking such as smoking amount, age at smoking initiation, the use of filtered or mild tobacco could also influence the results. (2) Our study was based on a stroke cohort, not a community cohort of a healthy population. Therefore, the association between smoking and parent artery atherosclerosis might be influenced by other disease related risk factors.

It was observed that MCA plaques, whether low‐grade or steno‐occlusive, were commonly present in patients with RSIS. This finding was consistent with previous studies [10, 11, 12, 33]. Our finding provides stronger support to the temporal causal link between MCA plaques and RSIS, as patients with RSIS within 72 h after stroke onset were specifically enrolled. Additionally, a significant proportion of MCA plaques were located at the superior artery walls where the penetrating arteries arose, suggesting branch blockage as the stroke mechanism rather than embolism [12, 18]. Furthermore, the application of 3D HR‐MRI helped alleviate limitations related to obliqueness artefacts resulting from partial volume effects and prevented the over‐estimation of wall thickness [34].

It was observed that RSISs with different degrees of parent artery atherosclerosis exhibited distinct neuroimaging features of brain lesions. First, the normal MCA group showed a similar infarct volume to the low‐grade MCA atherosclerosis group. In contrast, the steno‐occlusive MCA atherosclerosis group had a significantly larger infarct volume. These findings are reasonable because, in the low‐grade MCA atherosclerosis group, single or a small number of perforators may be obstructed, whilst in the steno‐occlusive MCA atherosclerosis group more perforators may be obstructed or haemodynamically influenced [35, 36]. Second, patients with low‐grade MCA atherosclerosis were most likely to have an infarct involving the posterior limb of the internal capsule, which is supplied by the medial and lateral groups of the lenticulostriate arteries [19]. Interestingly, it was observed that as much as 70.3% of low‐grade MCA atherosclerotic plaque was located in the middle segment of the MCA, supporting that the relevant responsible branch arteries were blocked. Third, it was observed that the low‐grade MCA atherosclerosis group was associated with the highest CSVD burden. The findings were consistent with some previous studies [37, 38], but inconsistent with others [4, 39]. It was also noted that patients with low‐grade MCA atherosclerosis had the highest prevalence of CMBs located in the deep or infratentorial region rather than strictly the lobe, and EPVS in the basal ganglia rather than the centrum semiovale. Due to the limitations of our observational study based on neuroimaging data, our data could not provide a basis for understanding the downstream small vessel changes that are more severe in those with low grade as opposed to none or more severe MCA atherosclerosis. It is speculated that RSIS patients with low‐grade MCA atherosclerosis may have a high susceptibility of both large arteries and downstream small vessels when exposed to shared vascular risk factors, including hypertension, old age etc.

Recent subcortical ischaemic stroke with different degrees of MCA atherosclerosis had different clinical outcomes. A few previous studies showed that RSIS with parent artery atherosclerosis had worse clinical outcomes compared to those without [40, 41], whilst others found no significant differences [12, 37]. These discrepancies could be attributed to variations in evaluation criteria and imaging techniques. In our study, it was observed that patients with normal MCA had the lowest rate of 90‐day functional dependence amongst the three groups. The relatively poor outcome of the low‐grade MCA atherosclerosis group may be partially explained by the involvement of the posterior limb of the internal capsule. Acute damage to the posterior limb of the internal capsule, a symptom‐prone area with congregate and organized corticospinal tract fibres, has been proposed as an important imaging predictor of motor outcome after stroke [21, 22]. Meanwhile, the higher burden of coexistent CSVD in the low‐grade MCA atherosclerosis group may also contribute to the unfavourable outcomes [42]. The steno‐occlusive MCA atherosclerosis group with largest infarct volume also showed a tendency to predict poor functional outcome, although statistical significance was not reached due to the small sample size.

Based on the study results, it is proposed that RSISs with varying degrees of parent artery atherosclerosis may have a different pathogenesis. The pathogenesis of RSIS with normal MCA is primarily attributed to intrinsic SVD, which can account for its small infarct volume and relatively random location. However, it is essential to note that other potential aetiologies, such as perforating artery atheroma (branching artery disease), undetected cardioembolism and extracranial large artery atherosclerosis without significant stenosis, cannot be definitively excluded. RSIS with low‐grade MCA atherosclerosis may be a co‐criminal vasculopathy involving both the parent artery and its downstream small vessels given the most severe CSVD burden and the specific infarct pattern which could be explained by the common sites of the MCA plaques. It is conceivable that low‐grade MCA plaque may partially block the orifice of the perforating artery, whilst the coexisting diseased small vessels downstream cannot compensate for the reduction in perfusion. Lastly, steno‐occlusive MCA atherosclerosis may greatly influence its downstream perforators’ perfusion and obstruct more perforators, leading to RSISs with larger infarct volume.

Our study has clinical implications. First, the results indicated that RSIS with normal MCA and RSIS with MCA atherosclerosis (low‐grade or steno‐occlusive) were clearly different in terms of infarct lesion, CSVD burden and prognosis. These differences suggest the need for distinct treatment strategies. For instance, lipid‐lowering therapies aimed at preventing or reducing the progression of atherosclerosis may be more appropriate for patients with MCA atherosclerosis. Secondly, even though RSIS with low‐grade MCA atherosclerosis exhibited similar clinical severity and prognosis to the steno‐occlusive MCA atherosclerosis group, it is independently associated with cerebral microbleeding and a higher CSVD burden. Attention should be paid to whether the risk of poor outcomes including intracranial haemorrhage is different between the two subtypes in long‐term antithrombotic therapy.

Our study has several limitations. First, although HR‐MRI is valuable in detecting MCA plaques, it cannot directly identify the specific culprit penetrating artery. Moreover, enhanced 3D T1 HR‐MRI which is helpful to evaluate plaque vulnerability was not performed. Consequently, it was not possible to establish a definitive causal link between plaque, penetrating artery and the infarct. A proportion of patients with MCA involvement might also have alternative causes of RSIS, such as penetrating artery abnormalities. Secondly, the ethnic bias arising from the high prevalence of intracranial atherosclerosis in the Asian population should not be ignored [43]. Additionally, the strong male predominance, accounting for over 70% of the study population, is a relevant limitation to the study. Thus, caution should be taken when extrapolating our results to a more general population and further studies with larger sample size are warranted.

In conclusion, this prospective multicentre study revealed that RSIS with varying degrees of MCA atherosclerosis presented with distinct characteristics concerning infarct lesion, CSVD burden and prognosis, suggesting different stroke mechanisms. The assessment of the parent artery of RSIS using multiparametric MRI, including HR‐MRI, may provide valuable insights for predicting prognosis and tailoring treatment in clinical practice.

AUTHOR CONTRIBUTIONS

Qian‐Qian Lin: Writing – original draft; formal analysis; data curation; investigation. Hui‐Sheng Chen: Data curation; conceptualization. Yi Yang: Conceptualization; data curation. Meng Zhang: Conceptualization; data curation. Shi‐Wen Wu: Conceptualization; data curation. Ming‐Li Li: Formal analysis; conceptualization; methodology. Yi‐Ning Huang: Conceptualization; investigation. Wei‐Hai Xu: Conceptualization; writing – review and editing; data curation; funding acquisition; investigation; validation.

FUNDING INFORMATION

This study was supported by the Central High‐level Hospital Clinical Scientific Research Project of Peking Union Medical College Hospital (2022‐PUMCH‐C‐001); Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2022‐I2M‐1‐002); the National Science Fund for Distinguished Young Scholars (82025013); and the National Natural Science Foundation of China (81671370 and 81471207).

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflict of interest.

Supporting information

Data S1.

ACKNOWLEDGEMENTS

The authors appreciate the data collection and judgement provided by Le Fang MD, Baoquan Lu MD, Yong You MD, Beilei Chen MD, Changyun Liu MD, Min Lou MD, Hongtao Hu MD, Haifeng Li MD, Zuneng Lu MD, Ailian Du MD, Jue Zhang PhD, Yuyuan Xu MD, Xue Man MD, Yuwen Chen MD, Yao Meng MD, Yitong Liu MD, Weizhuang Yuan MD, Hanjing Kong PhD, Bo Wu MD, Chenglin Tian MD, and statistical consultation provided by Dingding Zhang PhD. The authors are grateful to the patients and their families for their participation in this study.

DATA AVAILABILITY STATEMENT

The data from this study are available from the corresponding author upon reasonable request by any qualified investigator.
==== Refs
REFERENCES

1 Ghika J , Bogousslavsky J , Regli F . Infarcts in the territory of the deep perforators from the carotid system. Neurology. 1989;39 :507‐512. doi:10.1212/wnl.39.4.507 2927674
2 Moulin T , Tatu L , Vuillier F , Berger E , Chavot D , Rumbach L . Role of a stroke data bank in evaluating cerebral infarction subtypes: patterns and outcome of 1,776 consecutive patients from the Besançon stroke registry. Cerebrovasc Dis. 2000;10 :261‐271. doi:10.1159/000016068 10878430
3 Fisher CM . Lacunar infarcts—a review. Cerebrovasc Dis. 1991;1 :311‐320. doi:10.1159/000108861
4 Nah HW , Kang DW , Kwon SU , Kim JS . Diversity of single small subcortical infarctions according to infarct location and parent artery disease: analysis of indicators for small vessel disease and atherosclerosis. Stroke. 2010;41 :2822‐2827. doi:10.1161/STROKEAHA.110.599464 20966406
5 Kvistad CE , Oygarden H , Logallo N , et al. A dark side of subcortical diffusion‐weighted lesions? Characteristics, cause, and outcome in large subcortical infarction: the Bergen Norwegian stroke cooperation study. Stroke. 2014;45 :2710‐2716. doi:10.1161/STROKEAHA.114.005781 25013025
6 Zhang C , Wang Y , Zhao X , et al. Distal single subcortical infarction had a better clinical outcome compared with proximal single subcortical infarction. Stroke. 2014;45 :2613‐2619. doi:10.1161/STROKEAHA.114.005634 25052317
7 Wilson LK , Pearce LA , Arauz A , et al. Morphological classification of penetrating artery pontine infarcts and association with risk factors and prognosis: the SPS3 trial. Int J Stroke. 2016;11 :412‐419. doi:10.1177/1747493016637366 26956031
8 Li ML , Xu YY , Hou B , et al. High‐resolution intracranial vessel wall imaging using 3D CUBE T1 weighted sequence. Eur J Radiol. 2016;85 :803‐807. doi:10.1016/j.ejrad.2016.01.014 26971427
9 Li ML , Xu WH , Song L , et al. Atherosclerosis of middle cerebral artery: evaluation with high‐resolution MR imaging at 3T. Atherosclerosis. 2009;204 :447‐452. doi:10.1016/j.atherosclerosis.2008.10.019 19041971
10 Yoon Y , Lee DH , Kang DW , Kwon SU , Kim JS . Single subcortical infarction and atherosclerotic plaques in the middle cerebral artery: high‐resolution magnetic resonance imaging findings. Stroke. 2013;44 :2462‐2467. doi:10.1161/STROKEAHA.113.001467 23847248
11 Xu WH , Li ML , Niu JW , Feng F , Jin ZY , Gao S . Intracranial artery atherosclerosis and lumen dilation in cerebral small‐vessel diseases: a high‐resolution MRI study. CNS Neurosci Ther. 2014;20 :364‐367. doi:10.1111/cns.12224 24423003
12 Jiang S , Yan Y , Yang T , et al. Plaque distribution correlates with morphology of lenticulostriate arteries in single subcortical infarctions. Stroke. 2020;51 :2801‐2809. doi:10.1161/STROKEAHA.120.030215 32757756
13 Zhang ZM , Si QQ , Chen HS , et al. High‐resolution magnetic resonance imaging of acute intracranial artery thrombus. Eur J Neurol. 2023;30 :3172‐3181. doi:10.1111/ene.15985 37452734
14 Powers WJ , Derdeyn CP , Biller J , et al. American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early Management of Patients with Acute Ischemic Stroke Regarding Endovascular Treatment: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;2015 (46 ):3020‐3035. doi:10.1161/STR.0000000000000074
15 Wang Y , Liu M , Pu C . 2014 Chinese guidelines for secondary prevention of ischemic stroke and transient ischemic attack. Int J Stroke. 2017;12 :302‐320. doi:10.1177/1747493017694391 28381199
16 Tatu L , Moulin T , Bogousslavsky J , Duvernoy H . Arterial territories of the human brain: cerebral hemispheres. Neurology. 1998;50 :1699‐1708. doi:10.1212/wnl.50.6.1699 9633714
17 Samuels OB , Joseph GJ , Lynn MJ , Smith HA , Chimowitz MI . A standardized method for measuring intracranial arterial stenosis. Am J Neuroradiol. 2000;21 :643‐646.10782772
18 Xu WH , Li ML , Gao S , et al. Plaque distribution of stenotic middle cerebral artery and its clinical relevance. Stroke. 2011;42 :2957‐2959. doi:10.1161/STROKEAHA.111.618132 21799160
19 Rosner SS , Rhoton AL Jr , Ono M , Barry M . Microsurgical anatomy of the anterior perforating arteries. J Neurosurg. 1984;61 :468‐485. doi:10.3171/jns.1984.61.3.0468 6747683
20 Adams R , Bischof L . Seeded region growing. IEEE Trans Pattern Anal Mach Intell. 1994;16 :641‐647.
21 Puig J , Pedraza S , Blasco G , et al. Acute damage to the posterior limb of the internal capsule on diffusion tensor tractography as an early imaging predictor of motor outcome after stroke. Am J Neuroradiol. 2011;32 :857‐863. doi:10.3174/ajnr.A2400 21474629
22 Shelton FN , Reding MJ . Effect of lesion location on upper limb motor recovery after stroke. Stroke. 2001;32 :107‐112. doi:10.1161/01.str.32.1.107 11136923
23 Wardlaw JM , Smith EE , Biessels GJ , et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12 :822‐838. doi:10.1016/S1474-4422(13)70124-8 23867200
24 Gregoire SM , Chaudhary UJ , Brown MM , et al. The microbleed anatomical rating scale (MARS): reliability of a tool to map brain microbleeds. Neurology. 2009;73 :1759‐1766. doi:10.1212/WNL.0b013e3181c34a7d 19933977
25 Doubal FN , MacLullich AM , Ferguson KJ , Dennis MS , Wardlaw JM . Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke. 2010;41 :450‐454. doi:10.1161/STROKEAHA.109.564914 20056930
26 Fazekas F , Chawluk JB , Alavi A , Hurtig HI , Zimmerman RA . MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging. Am J Roentgenol. 1987;149 :351‐356. doi:10.2214/ajr.149.2.351 3496763
27 Staals J , Makin SD , Doubal FN , Dennis MS , Wardlaw JM . Stroke subtype, vascular risk factors, and total MRI brain small‐vessel disease burden. Neurology. 2014;83 :1228‐1234. doi:10.1212/WNL.0000000000000837 25165388
28 Seiffge DJ , Wilson D , Ambler G , et al. Small vessel disease burden and intracerebral haemorrhage in patients taking oral anticoagulants. J Neurol Neurosurg Psychiatry. 2021;92 :805‐814. doi:10.1136/jnnp-2020-325299 33741739
29 Bermúdez‐López M , Martí‐Antonio M , Castro‐Boqué E , et al. Cumulative tobacco consumption has a dose‐dependent effect on atheromatosis burden and improves severe atheromatosis prediction in asymptomatic middle‐aged individuals: the ILERVAS study. Atherosclerosis. 2023;375 :75‐83. doi:10.1016/j.atherosclerosis.2023.05.002 37276714
30 Kelesidis T , Sharma M , Sharma E , Ruedisueli I , Tran E , Middlekauff HR . Chronic electronic cigarette use and atherosclerosis risk in young people: a cross‐sectional study—brief report. Arterioscler Thromb Vasc Biol. 2023;43 :1713‐1718. doi:10.1161/ATVBAHA.123.319172 37409529
31 Suutari‐Jääskö A , Ylitalo A , Ronkaine J , Huikuri H , Kesäniemi YA , Ukkola OH . Smoking cessation and obesity‐related morbidities and mortality in a 20‐year follow‐up study. PLoS One. 2022;17 :e0279443.36576905
32 Hahad O , Schmitt VH , Arnold N , et al. Chronic cigarette smoking is associated with increased arterial stiffness in men and women: evidence from a large population‐based cohort. Clin Res Cardiol. 2023;112 :270‐284. doi:10.1007/s00392-022-02092-1 36068365
33 Shen M , Gao P , Zhang Q , Jing L , Yan H , Li H . Middle cerebral artery atherosclerosis and deep subcortical infarction: a 3 T magnetic resonance vessel wall imaging study. J Stroke Cerebrovasc Dis. 2018;27 :3387‐3392. doi:10.1016/j.jstrokecerebrovasdis.2018.08.013 30145026
34 Qiao Y , Steinman DA , Qin Q , et al. Intracranial arterial wall imaging using three‐dimensional high isotropic resolution black blood MRI at 3.0 Tesla. J Magn Reson Imaging. 2011;34 :22‐30. doi:10.1002/jmri.22592 21698704
35 Nam KW , Kwon HM , Lee YS . Different predictive factors for early neurological deterioration based on the location of single subcortical infarction: early prognosis in single subcortical infarction. Stroke. 2021;52 :3191‐3198. doi:10.1161/STROKEAHA.120.032966 34176312
36 Kim JS , Yoon Y . Single subcortical infarction associated with parental arterial disease: important yet neglected sub‐type of atherothrombotic stroke. Int J Stroke. 2013;8 :197‐203. doi:10.1111/j.1747-4949.2012.00816.x 22568537
37 Sun LL , Li ZH , Tang WX , et al. High resolution magnetic resonance imaging in pathogenesis diagnosis of single lenticulostriate infarction with nonstenotic middle cerebral artery, a retrospective study. BMC Neurol. 2018;18 :51. doi:10.1186/s12883-018-1054-z 29699507
38 Cho HJ , Kim KH , Kim EJ , et al. Clinical implications of basilar artery plaques in the pontine infarction with n ormal basilar angiogram: a high‐resolution magnetic resonance imaging study. J Stroke Cerebrovasc Dis. 2018;27 :3591‐3598. doi:10.1016/j.jstrokecerebrovasdis.2018.08.032 30219629
39 Jiang S , Cao T , Yan Y , et al. Lenticulostriate artery combined with neuroimaging markers of cerebral small vessel disease differentiate the pathogenesis of recent subcortical infarction. J Cereb Blood Flow Metab. 2021;41 :2105‐2115. doi:10.1177/0271678X21992622 33563077
40 Yan Y , Jiang S , Yang T , et al. Lenticulostriate artery length and middle cerebral artery plaque as predictors of early neurological deterioration in single subcortical infarction. Int J Stroke. 2023;18 :95‐101. doi:10.1177/17474930221081639 35120419
41 Jeong HG , Kim BJ , Yang MH , Han MK , Bae HJ . Neuroimaging markers for early neurologic deterioration in single small subcortical infarction. Stroke. 2015;46 :687‐691. doi:10.1161/STROKEAHA.114.007466 25677600
42 Appleton JP , Woodhouse LJ , Adami A , et al. Imaging markers of small vessel disease and brain frailty, and outcomes in acute stroke. Neurology. 2020;94 :e439‐e452. doi:10.1212/WNL.0000000000008881 31882527
43 Kim JS , Bonovich D . Research on intracranial atherosclerosis from the east and west: why are the results different? J Stroke. 2014;16 :105‐113. doi:10.5853/jos.2014.16.3.105 25328869
