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NEUROSURGICAL FOCUS Neurosurg Focus 51 (3):E3, 2021 NEUROSURGICAL FOCUS Neurosurg Focus 51 (3):E3, 2021 Transcriptome-wide analysis of intracranial artery in patients with moyamoya disease showing upregulation of immune response, and downregulation of oxidative phosphorylation and DNA repair *Fumiaki Kanamori, MD,1 Kinya Yokoyama, MD, PhD,1 Akinobu Ota, PhD,2 Kazuhiro Yoshikawa, PhD,3 Sivasundaram Karnan, PhD,2 Mikio Maruwaka, MD, PhD,4 Kenzo Shimizu, MD,5 Shinji Ota, MD,6 Kenji Uda, MD, PhD,1 Yoshio Araki, MD, PhD,1 Sho Okamoto, MD, PhD,7 Satoshi Maesawa, MD, PhD,1 Toshihiko Wakabayashi, MD, PhD,1 and Atsushi Natsume, MD, PhD1 1Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya; 2Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute; 3Division of Research Creation and Biobank, Research Creation Support Center, Aichi Medical University, Nagakute; 4Department of Neurosurgery, Toyota Kosei Hospital, Toyota; 5Department of Neurosurgery, Kasugai Municipal Hospital, Kasugai; 6Department of Neurosurgery, Handa City Hospital, Handa; and 7Aichi Rehabilitation Hospital, Nishio, Japan OBJECTIVE Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive occlusion of the internal carotid artery and the secondary formation of collateral vessels. Patients with MMD have ischemic attacks or intracranial bleeding, but the disease pathophysiology remains unknown. In this study, the authors aimed to identify a gene expression profile specific to the intracranial artery in MMD. METHODS This was a single-center, prospectively sampled, retrospective cohort study. Microsamples of the middle cerebral artery (MCA) were collected from patients with MMD (n = 11) and from control patients (n = 9). Using microarray techniques, transcriptome-wide analysis was performed. RESULTS Comparison of MCA gene expression between patients with MMD and control patients detected 62 and 26 genes whose expression was significantly (p < 0.001 and fold change > 2) up- or downregulated, respectively, in the MCA of MMD. Gene set enrichment analysis of genes expressed in the MCA of patients with MMD revealed positive correlations with genes involved in antigen processing and presentation, the dendritic cell pathway, cytokine pathway, and interleukin-12 pathway, and negative correlations with genes involved in oxidative phosphorylation and DNA repair. Microarray analysis was validated by quantitative polymerase chain reaction. CONCLUSIONS Transcriptome-wide analysis showed upregulation of genes for immune responses and downregulation of genes for DNA repair and oxidative phosphorylation within the intracranial artery of patients with MMD. These findings may represent clues to the pathophysiology of MMD. https://thejns.org/doi/abs/10.3171/2021.6.FOCUS20870 KEYWORDS moyamoya disease; transcriptome-wide analysis; intracranial artery OYAMOYA disease (MMD) is a rare cerebrovascu- stenosis of proximal large intracranial arteries decreases lar disease characterized by progressive stenosis the cerebral blood flow, and the disease thus is associated of the internal carotid artery at its terminal por- with ischemic attacks. The resulting hemodynamic over- Mtion and secondary formation of collateral vessels at the stress in collateral vessels can induce pathological change, brain base; the latter are called moyamoya vessels. The leading to intracranial hemorrhage. Surgical revascular- ABBREVIATIONS cDNA = complementary DNA; DC = dendritic cell; GAPDH = glyceraldehyde 3-phosphate dehydrogenase; GSEA = gene set enrichment analysis; HIPK2 = homeodomain-interacting protein kinase 2; HUWE1 = HECT, UBA, and WWE domain containing E3 ubiquitin-protein ligase 1; IL-12 = interleukin-12; MCA = middle cerebral artery; MMD = moyamoya disease; PCR = polymerase chain reaction; qPCR = quantitative PCR; RASAL3 = RAS protein activator-like 3; RHOQ = ras homolog family member Q; RNF213 = ring finger protein 213; STA = superficial temporal artery; TSPAN2 = tetraspanin 2. SUBMITTED October 9, 2020. ACCEPTED June 18, 2021. INCLUDE WHEN CITING DOI: 10.3171/2021.6.FOCUS20870. * F. Kanamori and K. Yokoyama contributed equally to this work. ©AANS 2021, except where prohibited by US copyright law Neurosurg Focus Volume 51 • September 2021 1 Unauthenticated | Downloaded 10/10/21 11:15 PM UTC Kanamori et al. FIG. 1. A: Flow diagram of the study. B: Angiogram (anteroposterior view) obtained from a 43-year-old female with MMD. The preoperative right common carotid shows stenosis at the terminal portion of the internal carotid artery and moyamoya vessels. C: Intraoperative image of arteriotomy at the cortical segment of the MCA. A microsample was obtained from the tissue in the white circle, and this specimen was used for RNA extraction. ization, including superficial temporal artery (STA)–to– Patient Characteristics middle cerebral artery (MCA) anastomosis, is known as A total of 20 Japanese patients who received surgical an effective method to reduce the risk of subsequent stroke treatment at Nagoya University Hospital were included and rebleeding.1,2 in this study. Detailed clinical information of the patients Although the c.14576G>A variant of ring finger protein is shown in Supplemental Table 1. We obtained 11 mic- 213 (RNF213) has been identified as a susceptibility vari- rosamples of the MCA from patients with MMD and 9 ant for MMD in patients of East Asian background,3,4 little microsamples of the MCA from control patients. In the is known about the disease etiology and pathophysiology. MMD group, all patients received surgical revascular- The main histopathological characteristics of MMD are ization including STA-MCA anastomosis. In the control fibrous thickening of the intima and attenuation of the me- group, 6 patients with an internal carotid artery aneurysm dia in the terminal portion of the internal carotid artery; received aneurysm trapping or proximal ligation that re- these histopathological characteristics are also observed quired STA-MCA anastomoses as flow constructions, and 5–7 in the cortical segment of the MCA. Due to the diffi- 3 patients with medically intractable seizures received culty of extracting sufficient protein or RNA from the mi- epileptic focus resection. The control patients were en- crosamples of MCA that can be obtained during surgery, rolled in a consecutive manner, and patients with MMD few studies have examined the molecular characteristics 8 were selected to match the age, sex, and prevalence of of the intracranial artery. However, recent technological underlying diseases regarding arteriosclerosis (hyperten- advances have permitted amplification of the total RNA sion, hyperlipidemia, and diabetes mellitus) of the control from vessel microsamples, facilitating transcriptome- patients. The diagnosis of MMD was made according to wide analysis of these specimens. In the present study, we the guidelines proposed by the Ministry of Health and sought to identify the gene expression profile specific to Welfare of Japan.9 Briefly, the diagnostic criteria were the intracranial artery of MMD. We collected microsam- as follows: 1) stenosis or occlusion around the terminal ples of the MCA from patients with MMD and from con- portion of the internal carotid arteries, 2) moyamoya ves- trol patients and performed transcriptome-wide analysis sels at the brain base, and 3) exclusion of diseases with using the microarray technique. similar angiographic characteristics (e.g., arteriosclerosis, autoimmune disease, meningitis, brain neoplasm, Down Methods syndrome, neurofibromatosis type 1, head trauma, or ir- 9,10 This was a single-center, prospectively sampled, ret- radiation of the head). Figure 1B shows the angiogram rospective cohort study. The study protocol was carried obtained in one such patient with MMD. out in agreement with the Declaration of Helsinki and was approved by the IRB of the Nagoya University Graduate Collection of Vessel Samples School of Medicine. Written informed consent was ob- In each of the patients with MMD or with an inter- tained from all study participants or legal guardians. Fig- nal carotid artery aneurysm, we collected a microsample ure 1A provides a flow diagram of this study. of the MCA and a small sample of the STA during the 2 Neurosurg Focus Volume 51 • September 2021 Unauthenticated | Downloaded 10/10/21 11:15 PM UTC Kanamori et al. STA-MCA anastomosis. STA-MCA anastomosis was per- TABLE 1. Demographics of participants formed in an end-to-side fashion with 10-0 or 11-0 ny- MMD Group Control Group p Value lon threads.11–13 The vessel wall of the MCA was excised following the reported procedure.6 Tissue samples were No. of patients 11 9 washed with normal saline containing 10 U/mL heparin, Age, yrs 0.068 collected into RNAlater (Qiagen), and stored at −80°C. Median (IQR) 49 (47.5–52.0) 65 (56.0–71.0) Figure 1C shows an intraoperative image of MCA arteri- Minimum–maximum 43–52 14–79 otomy in a patient with MMD. All STA-MCA anastomo- Female sex 10 (90.9) 6 (66.7) 0.29 ses were performed successfully. In the patients with intractable seizures who received Hypertension 3 (27.3) 3 (33.3) 1.0 epileptic focus resection, the cortical arteries were dissect- Hyperlipidemia 4 (36.4) 3 (33.3) 1.0 ed from the resected tissue, washed with normal saline Diabetes mellitus 1 (9.1) 1 (11.1) 1.0 containing heparin, collected into RNAlater, and stored c.14576G>A variant (G/A) 8 (72.7) 1 (11.1) 0.0098 at −80°C. in RNF213 Values represent the number of patients (%) unless indicated otherwise. Statis- Detection of RNF213 c.14576G>A Variant
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