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ORIGINAL
Association between middle cerebral artery morphology andbranch atheromatous disease
Junpei Nagasawaa, Kenichi Suzukib, Sayori Hanashiroa, Masaru Yanagihashia, Takehisa Hirayamaa, Masaaki Horib,and Osamu Kanoa
Department of Neurology, Toho University Faculty of Medicine, Tokyo, Japan, bDepartment of Radiology, Toho University Faculty of Medicine, Tokyo, JapanaAbstract : Introduction : Branch atheromatous disease (BAD) is a type of cerebral infarction caused by stenosis or occlusion at the entrance of the penetrating branch due to the presence of plaque. Despite its clinicalsignificance, it is not clear how these plaques are formed. Focal geometrical characteristics are expected to be
as important as vascular risk factors in the development of atherosclerosis. This study aimed to analyze the association between middle cerebral artery (MCA) geometric features and the onset of BAD. Shear stress resultsfrom the blood flow exerting force on the inner wall of the vessels and places with low wall shear stress may beprone to atherosclerosis. At the curvature of blood vessels, the shear stress is weak on the inside of the curve andplaque is likely to form. When this is applied to the MCA M1 segment, downward type M1 is likely to form plaqueson the superior side. Because the lenticulostriate artery usually branches off from the superior side of the MCA
M1 segment, in downward type M1, a plaque is likely to be formed at the entrance of the penetrating branch,
and for that reason, BAD is likely to onset. Methods : We retrospectively reviewed hospitalized stroke patientswith BAD and investigated the morphology of their MCA using magnetic resonance imaging. The M1 segmentwas classified as straight or curved. Additionally, we compared the difference between the symptomatic and theasymptomatic side. Data regarding patients’ medical history were also collected. Results : A total of 56 patientswith lenticulostriate artery infarctions and BAD were analyzed. On the symptomatic side, downward type M1
accounted for the largest proportion at 44%, whereas on the asymptomatic side, it was the lowest, at 16%. Conclusion : A downward type MCA may be associated with the onset of BAD and the morphological characteristics
might affect the site of plaque formation. J. Med. Invest. 70 : 411-414, August, 2023
Keywords : Branch atheromatous disease, shear stress, middle cerebral artery, morphology

INTRODUCTION
Branch atheromatous disease (BAD), which accounts for
10.3%–10.8% of all cerebral infarctions (1, 2), is caused by stenosis or occlusion due to localized plaque formation at the entranceof the penetrating branch (3). Symptom exacerbation after hospitalization, such as progressive motor deficits, is seen in 17%–75%
of patients with BAD (4). Thus, early diagnosis and treatmentare crucial. Despite its clinical significance, it is not yet clear how
plaques form at the entrance of the penetrating branch.
Studies on coronary arteries have shown that arterial geometric features such as curvature and bifurcation are associatedwith altered hemodynamic flow, plaque formation, and progression, as well as ischemic events (5). Moreover, plaques tend toform at segments opposite to flow dividers (6). The relationshipbetween geometric features and plaque distribution of the middle cerebral artery (MCA) has been shown (7-9).
However, few have studied the relationship between vascularmorphology and the development of cerebral infarction.
Considering the fact that BAD is caused by occlusion at theentrance of the penetrating branch, focal geometrical characteristics are expected to be as important as vascular risk factors in
the development of atherosclerosis. In this study, we aimed toReceived for publication March 21, 2023 ; accepted June 15, 2023.
Address correspondence and reprint requests to Osamu Kano, Department of Neurology, Toho University Omori Hospital, 5-21-16
Omorinishi, Ota-ku, Tokyo, 143-8541, Japan.
E-mail : osamu.kano@med.toho-u.ac.jp

analyze the association between MCA geometric features andthe onset of BAD using magnetic resonance imaging (MRI).

MATERIALS AND METHODSWe retrospectively reviewed our single institutional databaseof hospitalized stroke patients between April 2016 and December
2020 and enrolled patients with BAD during the study period.
We diagnosed BAD by the following radiographic criteria. (a)infarcts with size more than 10 mm in diameter on axial sliceand visible for 3 or more axial slices on diffusion-weighted images (DWI) of the lenticulostriate artery (LSA) area. (b) No ≥ 50%
stenosis on the parent artery of the criminal vessel (corresponding middle cerebral artery), confirmed by magnetic resonanceangiography (MRA) or computed tomography angiography(CTA). These are based on the diagnostic criteria widely used inpast BAD studies (10, 11). BAD also develop in the pons, But inthis study, only patients with cerebral infarction in the LSA area
were included.
Patients were excluded if they had evidence of cardioembolism(atrial fibrillation, left atrial / ventricular thrombus identified byechocardiography, recent myocardial infarction within 1 month),> 50% stenosis of the responsible parent artery (internal andexternal carotid artery, MCA), multiple cerebral infarctions inlocations other than the LSA , and other determined etiologies(vasculitis, arterial dissection, Moyamoya disease, cancer-associated thrombosis, antiphospholipid antibody syndrome, etc.).
We classified infarcts in the LSA area of 2 slices or less in axial
diffusion-weighted images as lacunar and distinguished themThe Journal of Medical Investigation Vol. 70 2023

J. Nagasawa, et al. MCA morphology and BAD

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from BAD. We classified infraction lies between the tip of the anterior horn and the top of the superior limb of the insular cleft in
the coronal section of MRI diffusion weighted images as Long insular artery infraction, and distinguished them from BAD (12).
Exacerbation of symptoms is defined as an increase in NIHSS
score of 1 or more and no new cerebral infarction or intracranial
hemorrhage on MRI.
The M1 segment shape was classified as straight or curved,based on the coronal maximum intensity projection images ofthree-dimensional time-of-flight magnetic resonance angiography. We determined the direction of the M1 segment in which
the curve opened. A line was drawn from the bifurcation pointsof M1 and anterior cerebral artery to the bifurcation points of M2(shown in Fig. 1). If the vertex of the curve was above this line,
then it was classified as upward type M1, and downward typeif it was below. If there were no vertices, then it was classified
as straight type. If the M1 had more than two angles (like theS-shaped), It was classified in the direction that is the largest
angle with respect to A line.
And we investigated whether there was a shape difference
between the MCA on the symptomatic and the asymptomaticside. The symptomatic side is the side that developed BAD, andthe asymptomatic side is the MCA that did not develop BAD.
As described in the discussion, we assumed that BAD is more
likely to occur in the downward type M1, and compared the ratioof downward type M1 between the symptomatic side and theasymptomatic side. We also collected data regarding the medical
history, such as hypertension, diabetes, dyslipidemia, smoking
status, and atrial fibrillation of each patient.

Statistical Analysis
We analyzed the difference in the shape of the M1 segment
between the symptomatic and asymptomatic sides. Univariatecomparisons between categorical variables were performed
using the χ2 test, Fisher’s exact test, and unpaired t-test. All
statistical tests were 2-sided with p values of < 0.05 used todenote significance.

RESULTSA total of 846 patients with cerebral infarction were hospitalized during the study period. Among them, 56 patients (6%) had
BAD in the LSA territories.
A total of 56 patients with BAD and LSA territory infarctions
were included in this study. The M1 segment shapes are listed inTable 1. On the symptomatic side, downward type M1 accounted
for the largest proportion at 44% and was the lowest on the asymptomatic side at 16%. On the other hand, on the asymptomatic side, the upward type was the most common (64%). Patientcharacteristics, stratified by each M1 shape are summarized inTable 2. The mean age, prevalence of male sex, hypertension,diabetes, dyslipidemia and smokers were not significantly different between the each groups.

DISCUSSION / CONCLUSION
In this study, we found that the M1 shape that led to BAD wasmore often the downward type than upward or straight.
BAD is caused by stenosis or occlusion at the entrance of thepenetrating branch due to localized plaque formation. However,
it is not clear how these plaques occur. Studies on coronary arteries have shown that geometric features such as curvature and bifurcation are associated with altered hemodynamic flow, plaqueformation, and progression (5). In addition, the relationship㼏Fig 1.

a. M1 segment shape classification as straight or curved based on the coronal maximum intensity projection images of three-dimensional timeof-flight magnetic resonance angiography.
b. A line was drawn from the M1 origin to M2 bifurcation, and the vertices of the curves were evaluated based on whether they were above orbelow this line.
c. The right MCA is downward type, and the Left MCA is straight type.

Table 1. M1 segment shape classification.
symptomatic side

asymptomatic sidep-value

Downward type

25 (44%)9 (16%)

0.001

Upward type

20 (35%)36 (64%)0.004

Straight type

11 (19%)11 (19%)1

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The Journal of Medical Investigation Vol. 70 August 2023
between MCA geometric features and plaque distribution has
been reported in some studies (7-9). Shear stress is the result ofthe force that blood flow exerts on the inner walls of blood vessels. In locations where the shear stress is strong, there is antithrombotic action and plaques are hard to form. In contrast, low
shear stress may initiate the process of atherosclerosis throughendothelial dysfunction and secondary inflammation (13). At thecurvature of blood vessels, the shear stress is exerted strongly on
the outside of the curve and plaques are difficult to form, whereas on the inside, this stress is weak and plaques are more likely
to form (14, 15). When this is applied to the MCA M1 segment,
inferior side plaques are more likely to form in upward type M1,
while superior side plaques are more likely to form in downward
type M1. A previous study that investigated the relationshipbetween MCA geometric features and plaque distribution supported this finding (6).
Considering the reason for the result of this study that mostof the MCA that caused BAD were downward type, because
the LSA usually branches off from the superior side of the MCA
M1 segment (16), in downward type M1, a plaque is likely to beformed at the entrance of the penetrating branch (9), and for thatreason, BAD is likely to onset in downward type MCA in thisstudy (shown in Fig. 2).
A previous report has shown among the healthy population,
the curved MCA is the most common and the straight type isthe least (17). However, it is not yet clear what factors affect theformation of the M1 shape. In this study, the prevalence of hypertension, diabetes, and dyslipidemia was not significantly dif-ferent between the groups, whereas smoking was more prevalent
among those with a downward type M1. Smoking causes vascular endothelial injuries, which lead to functional and structuralalterations (18). Endothelial dysfunction may cause abnormal
contraction and dilation, resulting in the flexion of blood vessels.
Our study had several limitations. Firstly, the retrospective
design could introduce a systematic selection bias, thus it cannot
be used to prove causality. Moreover, the morphology of the MCA
was only evaluated in two dimensions on the coronal side. However, because the actual MCA runs in three dimensions, including the axial side, it is necessary to evaluate them for increased
accuracy. However, this is very complicated and difficult to apply
to clinical practice. Therefore, a simpler and more practical evaluation method was used in this study.
In conclusion, we found that downward type MCA may beassociated with the onset of BAD and that the morphologicalcharacteristics might affect the site of plaque formation.

FUNDING SOURCES
There no funding sources to declare.

ACKNOWLEDGEMENTS
Thanks to Editage for doing a lot of research on the grammar
and words of the article.

Table 2. Patient characteristics stratified by downward vs. non-downward type.
Downward type(n = 25)
Male, n (%)

Upward type(n = 20)

Straight type(n = 11)p-value

21 (84)16 (80)10 (90)0.92

Age (mean ± SD) years

70.6 ± 13.6

73.4 ± 10.371.0 ± 9.5

0.93

Hypertension, n (%)

21 (84)15 (75)10 (90)0.96

Dyslipidemia, n (%)

15 (60)10 (50)7 (63)

0.99

Diabetes, n (%)

9 (36)

8 (40)

3 (27)

0.99

Smoker, n (%)

15 (60)11 (55)4 (40)0.98

㻌Fig 2.

a. Upward type M1 is more likely to form plaques on the inferior side of the blood vessel.
b. Downward type M1 is more likely to form plaques on the superior side of the blood vessel and block the entrance of the penetrating branch.

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J. Nagasawa, et al. MCA morphology and BAD

AUTHOR CONTRIBUTIONS
Sayori Hanasiro and Kenichi Suzuki conceived the idea of thestudy. Masaru Yanagihashi and Takehisa Hirayama developed
the statistical analysis plan. Junpei Nagasawa draft the originalmanuscript. Osamu Kano and Masaaki Hori supervised theconduct of this study.
All authors reviewed the manuscript draft and revised critically on intellectual content. All authors approved the final
version of the manuscript to be published.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available
from the corresponding author upon reasonable request.

DECLARATIONSETHICS APPROVAL AND CONSENT TO PARTICIPATEThe study was approved by the ethics committee of Toho
University Omori Medical Center (M20187) and was conductedaccording to the Declaration of Helsinki and current legal regulations in Japan. The potential participants were given the opportunity to decline to be further enrolled in the study (opt-out).

CONSENT FOR PUBLICATION
Not applicable.

CONFLICT OF INTEREST STATEMENT
The authors have no conflicts of interest to declare.

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