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Background: Long-term outcomes are unknown in patients with asymptomatic moyamoya disease. In this report, we aimed to clarify their 5-year risk of stroke and its predictors. Methods: We are conducting a multicenter, prospective cohort study (Asymptomatic Moyamoya Registry) in Japan. Participants were eligible if they were 20 to 70 years, had bilateral or unilateral moyamoya disease, experienced no episodes suggestive of TIA and stroke; and were functionally independent (modified Rankin Scale score 0–1). Demographic and radiological information was collected at enrollment. In this study, they are still followed up for 10 years. In this interim analysis, we defined the primary end point as a stroke occurring during a 5-year follow-up period. Independent predictors for stroke were also determined, using a stratification analysis method. Results: Between 2012 and 2015, we enrolled 109 patients, of whom 103 patients with 182 involved hemispheres completed the 5-year follow-up. According to the findings on DSA and MRA, 143 hemispheres were judged as moyamoya disease and 39 hemispheres as questionable manifestations (isolated middle cerebral artery stenosis). The patients with questionable hemispheres were significantly older, more often male, and more frequently had hypertension than those with moyamoya hemisphere. Moyamoya hemispheres developed 7 strokes, including 6 hemorrhagic and 1 ischemic stroke, during the first 5 years. The annual risk of stroke was 1.4% per person, 0.8% per hemisphere, and 1.0% per moyamoya hemisphere. Independent predictor for stroke was Grade-2 choroidal anastomosis (hazard ratio, 5.05 [95% CI, 1.24–20.6]; P =0.023). Furthermore, microbleeds (hazard ratio, 4.89 [95% CI, 1.13-21.3]; P =0.0342) and Grade-2 choroidal anastomosis (hazard ratio, 7.05 [95% CI, 1.62–30.7]; P =0.0093) significantly predicted hemorrhagic stroke. No questionable hemispheres developed any stroke. Conclusions: The hemispheres with asymptomatic moyamoya disease may carry a 1.0% annual risk of stroke during the first 5 years, the majority of which are hemorrhagic stroke. Grade-2 choroidal anastomosis may predict stroke, and the microbleeds and Grade-2 choroidal anastomosis may carry the risk for hemorrhagic stroke. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: UMIN000006640.

Background: Autoantibodies develop in autoimmune diseases, cancer, diabetes mellitus (DM),and atherosclerosis-related diseases. However, autoantibody biomarkers have not been successfully examined for diagnosis and therapy. Methods: Serological identification of antigens through recombinant cDNA expression cloning (SEREX) was used for primary screening of antigens. The cDNA product was expressed in bacteria and purified. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) was used to evaluate antibody levels in serum samples. Results: Phosphoenolpyruvate carboxykinase 1 (PCK1) was recognized as an antigen by serum IgG antibodies in the sera of patients with atherosclerosis. AlphaLISA showed significantly higher serum antibody levels against recombinant PCK1 protein in patients with DM and cardiovascular diseasebut not in those with acute ischemic stroke, transient ischemic attack, or obstructive sleep apnea syndrome, than in healthy donors. The area under the receiver operating characteristic curve for anti-PCK1 antibodies was 0.7024 for DM. The serum anti-PCK1 antibody levels were associated with age, platelet count, and blood pressure. Anti-PCK1-antibody-positive patients showed significantly lower overall survival than the negative patients. Conclusions: Serum anti-PCK1 antibody levels were strongly associated with DM and weakly but significantly associated with cardiovascular disease. The anti-PCK1 antibody marker is useful for predicting the overall survival of patients with DM.

The presence of disease-specific antigens and autoantibodies in the sera of patients with atherosclerosis-related diseases has been widely reported and is considered to result from inflammation of the arterial wall and the involvement of immune factors. The aim of this study was to identify a novel antibody in patients with ischemic stroke by serological identification of antigens using recombinant cDNA expression cloning from patients who had a transient ischemic attack (TIA). We identified the serpin peptidase inhibitor, clade E member 1 (SERPINE1), as a candidate antigen. The serum anti-SERPINE1 antibody levels quantified using amplified luminescent proximity homogeneous assay-linked immunosorbent assay were significantly higher in patients with ischemic stroke, including those with acute cerebral infarction (aCI), TIA, and chronic cerebral infarction, than in healthy donors. The antibody levels were strongly associated with old age, female sex, and presence of hypertension, diabetes mellitus, and cardiovascular disease. Age and intima-media thickness of the carotid artery were positively correlated with antibody levels, which suggests that SERPINE1 may reflect the progression of atherosclerosis. In a multivariate analysis, SERPINE1 antibody level was an independent predictor of aCI. Thus, the serum levels of anti-SERPINE1 antibody could potentially serve as a biomarker of atherothrombotic infarction.

We previously identified growth arrest and DNA-damage-inducible gene 34 (GADD34) as a marker of ischemic stroke. In the present study, serum levels of anti-GADD34 antibodies were found to be significantly higher in patients with acute ischemic stroke or chronic kidney disease compared to healthy donors. We then examined the biological function of GADD34 by transfection into human osteosarcoma U2OS cells. Knockdown of GADD34 by siRNA resulted in enhanced cell proliferation, which was suppressed by knockdown of MDM2. Luciferase reporter assays revealed that the transactivation ability of p53 enhanced by genotoxic anticancer drugs such as camptothecin and etoposide was further potentiated by the presence of GADD34 and attenuated by co-transfection with p53 shRNA expression plasmids. Western blotting demonstrated increased p53 protein levels after treatment with camptothecin, which was also potentiated by GADD34 but suppressed by GADD34 siRNA, ATM siRNA, and wortmannin, an ATM inhibitor. GADD34 levels increased in response to treatment with camptothecin or adriamycin, and this increase was attenuated by MDM2 siRNA. Immunoprecipitation with anti-GADD34 antibodies followed by Western blotting with anti-MDM2 antibodies indicated ubiquitination of GADD34 is mediated by MDM2. Accordingly, GADD34 may function as a ubiquitination decoy to reduce p53 ubiquitination and increase p53 protein levels. Increased neuronal death due to activation of p53 by GADD34 may account for the elevated serum levels of anti-GADD34 antibodies observed in patients with acute ischemic stroke.

Background Acute ischemic stroke (AIS) is a serious cause of mortality and disability. AIS is a serious cause of mortality and disability. Early diagnosis of atherosclerosis, which is the major cause of AIS, allows therapeutic intervention before the onset, leading to prevention of AIS. Methods Serological identification by cDNA expression cDNA libraries and the protein array method were used for the screening of antigens recognized by serum IgG antibodies in patients with atherosclerosis. Recombinant proteins or synthetic peptides derived from candidate antigens were used as antigens to compare serum IgG levels between healthy donors (HDs) and patients with atherosclerosis-related disease using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay. Results The first screening using the protein array method identified death-inducer obliterator 1 (DIDO1), forkhead box J2 (FOXJ2), and cleavage and polyadenylation specificity factor (CPSF2) as the target antigens of serum IgG antibodies in patients with AIS. Then, we prepared various antigens including glutathione S-transferase-fused DIDO1 protein as well as peptides of the amino acids 297–311 of DIDO1, 426–440 of FOXJ2, and 607–621 of CPSF2 to examine serum antibody levels. Compared with HDs, a significant increase in antibody levels of the DIDO1 protein and peptide in patients with AIS, transient ischemic attack (TIA), and chronic kidney disease (CKD) but not in those with acute myocardial infarction and diabetes mellitus (DM). Serum anti-FOXJ2 antibody levels were elevated in most patients with atherosclerosis-related diseases, whereas serum anti-CPSF2 antibody levels were associated with AIS, TIA, and DM. Receiver operating characteristic curves showed that serum DIDO1 antibody levels were highly associated with CKD, and correlation analysis revealed that serum anti-FOXJ2 antibody levels were associated with hypertension. A prospective case–control study on ischemic stroke verified that the serum antibody levels of the DIDO1 protein and DIDO1, FOXJ2, and CPSF2 peptides showed significantly higher odds ratios with a risk of AIS in patients with the highest quartile than in those with the lowest quartile, indicating that these antibody markers are useful as risk factors for AIS. Conclusions Serum antibody levels of DIDO1, FOXJ2, and CPSF2 are useful in predicting the onset of atherosclerosis-related AIS caused by kidney failure, hypertension, and DM, respectively.

Some cancers are related to atherosclerotic diseases; therefore, these two types of disease may share some antibody biomarkers in common. To investigate this, a first screening of sera was performed from patients with esophageal squamous cell carcinoma (ESCC) or acute ischemic stroke (AIS) for serological identification of antigens using recombinant cDNA expression cloning (SEREX). The amplified luminescent proximity homogeneous assay‐linked immunosorbent assay (AlphaLISA) method, which incorporates glutathione donor beads and anti‐human IgG acceptor beads, was used to evaluate serum antibody levels. SEREX screening identified low‐density lipoprotein receptor–related protein–associated protein 1 (LRPAP1) as a target antigen of serum IgG antibodies in the sera of patients with ESCC or AIS. Antigens, including recombinant glutathione S‐transferase–fused LRPAP1 protein, were prepared to examine serum antibody levels. AlphaLISA revealed significantly higher antibody levels against the LRPAP1 protein in patients with solid cancers such as ESCC and colorectal carcinoma and some atherosclerosis‐related diseases such as AIS and diabetes mellitus compared with healthy donors. Correlation analysis revealed that the elevated serum antibody levels against LRPAP1 were associated with smoking, a well‐known risk factor for both cancer and atherosclerosis. Serum LRPAP1 antibody is therefore a common marker for the early diagnosis of some cancers and atherosclerotic diseases and may reflect diseases caused by habitual smoking., Some cancers and arteriosclerosis may share some antibody biomarkers in common. To investigate this, a first screening of sera was performed from patients with esophageal squamous cell carcinoma for SEREX. Serum LRPAP1 antibody is a useful marker for the early diagnosis of some cancers and atherosclerotic diseases.

Atherosclerosis has been considered as the main cause of morbidity, mortality, and disability worldwide. The first screening for antigen markers was conducted using the serological identification of antigens by recombinant cDNA expression cloning, which has identified adaptor-related protein complex 3 subunit delta 1 (AP3D1) as an antigen recognized by serum IgG antibodies of patients with atherosclerosis. Serum antibody levels were examined using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) using a recombinant protein as an antigen. It was determined that the serum antibody levels against AP3D1 were higher in patients with acute ischemic stroke, transient ischemic attack , diabetes mellitus (DM), cardiovascular disease , chronic kidney disease (CKD), esophageal squamous cell carcinoma (ESCC), and colorectal carcinoma than those in the healthy donors. The area under the curve values of DM, nephrosclerosis type of CKD, and ESCC calculated using receiver operating characteristic curve analysis were higher than that of other diseases. Correlation analysis showed that the anti-AP3D1 antibody levels were highly associated with maximum intima-media thickness, which indicates that this marker reflected the development of atherosclerosis. The results of the Japan Public Health Center-based Prospective Study indicated that this antibody marker is deemed useful as risk factors for AIS.

Background: Numerous antibody biomarkers have been reported for cancer and atherosclerosis-related diseases. The major complications of atherosclerosis and diabetes mellitus (DM) are acute ischemic stroke (AIS), cardiovascular disease (CVD), and chronic kidney disease (CKD). Cancer development is accompanied by arterial disorders such as angiogenesis and atherosclerosis, and DM is a risk factor for certain cancers. Atherosclerosis-related diseases and cancers are therefore interrelated and could be detected by a common biomarker.Methods: We employed the protein array method for the initial screening of antigens and employed the amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) to evaluate antibody levels in serum samples.Results: The protein array identified KIAA0513 as an antigen recognized by serum IgG antibodies in the sera of patients with atherosclerosis. We then prepared recombinant glutathione S-transferase-fused KIAA0513 protein. AlphaLISA showed significantly higher serum antibody levels against KIAA0513 protein in patients with AIS, transient ischemic attack, DM, CVD, obstructive sleep apnea syndrome (OSAS), CKD, and solid cancers, such as esophageal, gastric, colon, lung, and breast cancer, than in healthy donors. A receiver operating characteristic (ROC) analysis revealed that the highest areas under the ROC curves of anti-KIAA0513 antibodies were for esophageal cancer, nephrosclerosis-type CKD, and DM. Spearman’s correlation analysis revealed that serum anti-KIAA0513 antibody levels were associated with maximum intima-media thickness and plaque score, which are indices of atherosclerosis and stenosis.Conclusion: Serum anti-KIAA0513 antibody markers appear to be useful for diagnosing AIS, TIA, DM, CVD, OSAS, CKD, and solid cancers and might reflect common arterial alterations leading to atherosclerotic and cancerous diseases.

Background: Atherosclerosis has been considered as the main cause of morbidity, mortality, premature incapacity, and disability worldwide. For early and sensitive diagnosis, development of novel biomarkers is expected and of significant practical importance.Methods: The first screening for antigen markers was conducted using the serological identification of antigens by recombinant cDNA expression cloning (SEREX). Serum antibody levels were examined using the amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) using a recombinant protein as an antigen.Results: SEREX screening has identified adaptor-related protein complex 3 subunit delta 1 (AP3D1) as an antigen recognized by serum IgG antibodies of patients with atherosclerosis. As per the results of AlphaLISA, it was determined that the serum antibody levels against AP3D1 were higher in patients with acute ischemic stroke (AIS), transient ischemic attack (TIA), diabetes mellitus (DM), cardiovascular disease (CVD), chronic kidney disease (CKD), esophageal squamous cell carcinoma (ESCC), and colorectal carcinoma than those in the healthy donors. The area under the curve values of DM, nephrosclerosis type of CKD, and ESCC calculated using receiver operating characteristic curve analysis were noted to be higher than that of other diseases. Correlation analysis showed that the anti-AP3D1 antibody levels were highly associated with maximum intima-media thickness, which indicates that this marker reflected the development of atherosclerosis. The Japan Public Health Center-based Prospective Study results have verified that the serum antibody levels against AP3D1 showed significantly higher odds ratios with the risk of AIS for persons with the third quartiles and the highest quartiles versus the lowest quartile, indicating that this antibody marker is deemed useful as risk factors for AIS.Conclusions: Serum anti-AP3D1 antibodies, which are broad-spectrum biomarkers of atherosclerotic diseases and digestive organ cancers, could be useful in predicting the onset of AIS.

Background Serum antibody markers have been increasingly identified not only for cancer and autoimmune diseases but also for atherosclerosis-related diseases such as acute ischemic stroke (AIS), acute myocardial infarction (AMI), diabetes mellitus (DM), and chronic kidney disease (CKD). Biomarkers for transient ischemic attack (TIA) and non-ST segment elevation acute coronary syndrome (NSTEACS) are potentially useful for detection of early phase of atherosclerotic changes against AIS and AMI, respectively. Methods We utilized serological identification of antigens by recombinant cDNA expression cloning (SEREX) using a human aortic endothelial cell cDNA phage library and sera from patients with TIA or NSTEACS. Serum antibody levels were measured by amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) using purified recombinant antigens. Results Screening of sera from patients with TIA identified DnaJ heat shock protein family (Hsp40) member C2 (DNAJC2) as a candidate antigen, which was also isolated by SEREX screening using sera of patients with NSTEACS. The validation cohort revealed significantly higher DNAJC2 antibody (DNAJC2-Ab) levels in the sera of patients with TIA or AIS than those in healthy donors (HDs). Multivariate logistic regression analysis indicated that the predictive odds ratios (OR) of DNAJC2-Ab levels for TIA and AIS were 2.54 (95% confidence interval [CI]: 1.36–4.74, p = 0.0034) and 2.14 (95% CI: 1.39–3.30, p = 0.0005), respectively. Serum DNAJC2-Ab levels were also higher in patients with AMI, DM, and CKD than those in HDs. Conclusion Serum DNAJC2-Ab level may be useful for early detection of atherosclerotic lesions, which lead to AIS and AMI., Cardiovascular system; Hematological system; Neurology; Neurosurgery; Clinical research; Diagnostics; Biomarkers; DNAJC2; Acute ischemic stroke; Acute myocardial infarction; Autoantibody biomarker; Atherosclerosis, Cardiology

The aim of the present study was to identify novel antibody markers for the early diagnosis of atherosclerosis in order to improve the prognosis of patients at risk for acute ischemic stroke (AIS) and acute myocardial infarction (AMI). A first screening involved the serological identification of antigens by recombinant cDNA expression cloning and identified additional sex combs‑like 2 (ASXL2) as a target antigen recognized by serum IgG antibodies in the sera of patients with atherosclerosis. Antigens, including the recombinant glutathione S‑transferase‑fused ASXL2 protein and its synthetic peptide were then prepared to examine serum antibody levels. Amplified luminescence proximity homogeneous assay‑linked immunosorbent assay, which incorporates glutathione‑donor beads and anti‑human‑IgG‑acceptor beads, revealed significantly higher serum antibody levels against the ASXL2 protein and its peptide in the patients with AIS, diabetes mellitus, AMI, chronic kidney disease, esophageal squamous cell carcinoma, or colorectal carcinoma compared with those in healthy donors. The ASXL2 antibody levels were well associated with hypertension complication, but not with sex, body mass index, habitual smoking, or alcohol intake. These results suggest that the serum ASXL2 antibody marker can discriminate between hypertension‑induced atherosclerotic AIS and AMI, as well as a number of digestive organ cancers.

Background Ischemic stroke, including transient ischemic attack (TIA) and acute-phase cerebral infarction (aCI), is a serious health problem in the aging society. Thus, this study aimed to identify TIA and aCI biomarkers. Methods In 19 patients with TIA, candidate antigens recognized by serum IgG autoantibodies were screened using a human aortic endothelial cell cDNA library. Through amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA), serum antibody levels against the candidate antigens were examined in healthy donor (HD), TIA, and aCI cohorts (n = 285, 92, and 529). The plasma antibody levels in the Japan Public Health Center-based Prospective Cohort Study (1991–1993) were also examined. Results The candidate antigens were aldolase A (ALDOA) and fumarate hydratase (FH). In AlphaLISA, patients with TIA or aCI had higher anti-ALDOA antibody (ALDOA-Ab) and anti-FH antibody (FH-Ab) levels than the HDs (P P = 0.0050) and FH-Ab (OR: 2.49, P = 0.0037) levels were independent predictors of TIA. According to the case–control study, the ALDOA-Ab (OR: 2.50, P P Conclusions ALDOA-Abs and FH-Abs can be novel potential biomarkers for predicting atherosclerotic TIA and aCI.

Background The structure and shape of the aortic arch and common carotid artery affect the level of difficulty of endovascular treatment. Changes in arterial course following thoracic surgery can make catheter guidance difficult. We report a case of extremely difficult guiding catheter settlement for coil embolization due to deformation of the aortic arch following left upper lung lobectomy. Case description A 70-year-old woman visited our hospital with headache as her chief complaint. Multiple unruptured cerebral aneurysms were incidentally detected on magnetic resonance imaging (MRI). Coil embolization was performed on an aneurysm at the bifurcation of the left internal carotid and left posterior communicating (L_IC-PC) arteries. Eleven months after coil embolization, left upper lung lobectomy was performed as treatment for lung cancer. Later, follow-up MRI revealed recanalization of L_IC-PC aneurysm due to coil compaction; therefore, we attempted to perform coil embolization again. Guiding catheter placement into the left internal carotid artery was difficult because the course of the left common carotid artery had changed following the first treatment. However, we managed to set the guiding catheter in the left internal carotid artery using a gooseneck snare via the right brachial artery, and the retreatment was successfully completed. Conclusion It is important to evaluate the access route through the femoral artery before administering endovascular treatment after prior thoracic surgery.

Transient ischemic attack (TIA) is a predictor for cerebral infarction (CI), and early diagnosis of TIA is extremely important for the prevention of CI. We set out to identify novel antibody biomarkers for TIA and CI, and detected matrix metalloproteinase 1 (MMP1), chromobox homolog 1 (CBX1), and chromobox homolog 5 (CBX5) as candidate antigens using serological identification of antigens by recombinant cDNA expression cloning (SEREX) and Western blotting to confirm the presence of serum antibodies against the antigens. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) revealed that serum antibody levels were significantly higher in patients with TIA or acute-phase CI (aCI) compared with healthy donors (P < 0.01). Spearman’s correlation analysis and multivariate logistic regression analysis demonstrated that levels of anti-MMP1, anti-CBX1, and anti-CBX5 antibodies were associated with age, cigarette-smoking habits, and blood pressure. Thus, serum levels of antibodies against MMP1, CBX1, and CBX5 could potentially serve as useful tools for diagnosing TIA and predicting the onset of aCI.

// Yoichi Yoshida 1,2,3 , Hao Wang 2,4 , Takaki Hiwasa 2 , Toshio Machida 5 , Eiichi Kobayashi 1,3 , Seiichiro Mine 5,6 , Go Tomiyoshi 2,7 , Rika Nakamura 2,7 , Natsuko Shinmen 2,7 , Hideyuki Kuroda 7 , Hirotaka Takizawa 8 , Koichi Kashiwado 9 , Ikuo Kamitsukasa 10,11 , Hideo Shin 12 , Takeshi Wada 13 , Akiyo Aotsuka 13 , Eiichiro Nishi 14 , Mikiko Ohno 14 , Minoru Takemoto 15 , Koutaro Yokote 15 , Sho Takahashi 16 , Jun Matsushima 17 , Xiao-Meng Zhang 2 , Masaki Takiguchi 2 and Yasuo Iwadate 1 1 Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan 2 Department of Biochemistry and Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan 3 Comprehensive Stroke Center, Chiba University Hospital, Chiba, Japan 4 Department of Anesthesia, The First Affiliated Hospital, Jinan University, Guangzhou, P. R. China 5 Department of Neurosurgery, Chiba Cerebral and Cardiovascular Center, Ichihara, Chiba, Japan 6 Department of Neurosurgery, Sawara Prefectural Hospital, Chiba, Japan 7 Medical Project Division, Research Development Center, Fujikura Kasei Co., Saitama, Japan 8 Port Square Kashiwado Clinic, Kashiwado Memorial Foundation, Chiba, Japan 9 Department of Neurology, Kashiwado Hospital, Chiba, Japan 10 Department of Neurology, Chiba Rosai Hospital, Chiba, Japan 11 Department of Neurology, Chibaken Saiseikai Narashino Hospital, Chiba, Japan 12 Department of Neurosurgery, Higashi Funabashi Hospital, Chiba, Japan 13 Department of Internal Medicine, Chiba Aoba Municipal Hospital, Chiba, Japan 14 Department of Pharmacology, Shiga University of Medical Science, Shiga, Japan 15 Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 16 Clinical Research Center, Chiba University Hospital, Chiba, Japan 17 Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan Correspondence to: Takaki Hiwasa, email: // Keywords : TIA; PDCD11; cerebral infarction; autoantibody; biomarker; Gerotarget Received : August 08, 2017 Accepted : November 16, 2017 Published : December 24, 2017 Abstract Background: Disease specific autoantibodies have been detected in the sera of patients with atherosclerosis-related diseases, such as cerebral infarction, cardiovascular disease. In the present study, we aimed to identify novel autoantibodies responsible for transient ischemic attack (TIA), a prodromal condition for cerebral infarction. Methods: To identify candidate antigens, we screened a human aortic endothelial cell cDNA library using sera from 20 patients with TIA. Serum antibody levels were measured using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) in 2 independent patient/healthy donor (HD) cohorts ( n = 192 and n = 906 in the second screening and validation cohort, respectively). Results: First screening identified 3 candidate antigens. Of these, programmed cell death 11 (PDCD11) was determined to be associated with stroke ( p < 0.0001), as evidenced from the second screening using AlphaLISA. The validation cohort revealed significantly higher antibody levels against PDCD11 (PDCD11-Ab levels) in patients with TIA than in HDs. Multivariate logistic regression analysis indicated that the predictive value of PDCD11-Ab levels for TIA [Odds ratio (OR): 2.44, 95% confidence interval (CI): 1.33-4.57, p = 0.0039] was not inferior to other known risk factors for ischemic stroke, including age (OR: 4.97, 95% CI: 2.67–9.48, p < 0.0001); hypertension (OR: 3.21, 95% CI: 1.76–5.86, p = 0.0001); and diabetes (OR: 4.31, 95% CI: 1.74–11.2, p = 0.0015). Conclusion: Serum PDCD11-Ab level may serve as a potential biomarker for TIA.

Objective Although uncommon, subcortical low-intensity (SCLI) changes on fluid-attenuated inversion recovery images are observed in various diseases, including cerebral ischemia. Here, we aimed to clarify the incidence and clinical implications of SCLI changes after revascularization surgery for moyamoya disease, focusing on the correlation with postoperative transient neurologic events (TNEs). Methods In this retrospective case series analysis, we included 10 hemispheres from 9 adults with moyamoya disease who underwent revascularization surgery. Subcortical signal intensity at the 5 gyri around the anastomosis point was quantitatively measured at 1 week and 3 months postoperatively. Changes in cerebral blood flow (CBF) were assessed using single-photon emission computed tomography. Results Images taken 1 week after surgery showed widespread SCLI changes below the operative fields in all 10 cases, but these changes normalized by 3 months. In addition, the changes in signal intensity at anastomoses negatively correlated with the changes in CBF ( R 2 = 0.36; P = 0.039). Postoperative TNEs occurred in 6 cases (60%) but were resolved within 17 days after surgery. Postoperative CBF increased in 9 of the 10 cases, with a median of 23%; however, these increases were not associated with the development of TNEs. The SCLI changes at the anastomosis points did not differ by the experience of TNEs. Conclusions Early after surgery, SCLI changes are common findings below the operative fields but negatively correlate with increases in CBF. Although no significant association was found between TNEs and the SCLI changes, the synchronized development of these phenomena may suggest a common underlying pathogenesis.

Recent clinical research has revealed a significant correlation between atherosclerosis, one of the primary etiologies of ischemic stroke, and the immune system. Assuming that "disease-specific autoantibodies are produced in the sera of patients with ischemic stroke," we investigated multiple arteriosclerosis-related antibodies using the serological identification of antigens by recombinant cDNA expression cloning (SEREX), an established method for identifying antigenic proteins. We either screened a human aortic endothelial cell cDNA library or conducted protein array screening using the sera from patients with ischemic stroke, such as carotid artery stenosis or transient ischemic attack (TIA). Next, we measured serum antibody levels using amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) in patient/healthy donor (HD) cohorts and identified several antigens, the antibody levels of which were significantly higher in patients with ischemic stroke than in HDs. This review introduced the method of identifying antigens by the SEREX and protein microarray and summarized antigenic proteins. In particular, it focused on anti-replication protein A2 antibody and anti-programmed cell death 11 antibody, which are significantly related to atherosclerotic plaque and ischemic brain tissue, respectively, and proposed the mechanism of elevated autoantibody levels against them. Furthermore, this review suggests a possibility of clinical application as an atherosclerotic disease diagnostic marker for TIA or cerebral infarction.

OBJECTIVEEncephalo-myo-synangiosis (EMS) is an effective revascularization procedure for the treatment of moyamoya disease (MMD). However, the temporalis muscle used for EMS sometimes swells and causes ischemic complications by compressing the underlying brain. This study aimed to elucidate the effect of sagittal splitting (SS) of the muscle for prevention of ischemic complications and its impact on the postoperative development of collateral vessels.METHODSIn this historical case-control study, we analyzed 60 hemispheres in adult patients with MMD who underwent EMS using the temporalis muscle from December 1998 to November 2017. The muscle was divided anteroposteriorly by coronal splitting, and the anterior, posterior, or both parts of the muscle were used for EMS in 17, 4, and 39 hemispheres, respectively. In cases performed after 2006, the muscle was halved by SS, and the medial half was used for EMS to reduce the muscle volume (n = 47). The degree of postoperative muscle swelling was evaluated by measuring the maximum thickness of the muscle on CT scans obtained 3 to 7 days after surgery. The collateral developments of the anterior deep temporal artery (aDTA), posterior deep temporal artery (pDTA), and middle temporal artery (MTA) were assessed using digital subtraction angiography and MR angiography performed 6 months or more after surgery.RESULTSSS significantly reduced the temporalis muscle thickness from 12.1 ± 5.0 mm to 7.1 ± 3.0 mm (p < 0.01). Neurological deterioration due to the swollen temporalis muscle developed in 4 of the 13 hemispheres without SS (cerebral infarction in 1, reversible neurological deficit in 2, and convulsion in 1) but in none with SS. There were no significant differences in the postoperative collateral developments of the aDTA, pDTA, and MTA between hemispheres with and without SS. The MTA more frequently developed in hemispheres with EMS in which the posterior part of the muscle was used (30/37) than those in which this part was not used (4/16) (p < 0.01).CONCLUSIONSSS of the temporalis muscle might prevent neurological deterioration caused by the swollen temporalis muscle by reducing its volume without inhibiting the development of the collateral vessels.

Background Hypotension is a significant risk factor for the development of ischemic complication following revascularization surgery for moyamoya disease (MMD). However, it is currently unknown whether autonomic dysfunction also plays a role. Case Description Here we report a case of MMD in which hypotension due to autonomic dysfunction caused postoperative cerebral ischemia. A 30-year-old female patient with MMD had a history of transient right hemiparesis following laughter. Single-photon emission computed tomography showed impaired cerebral blood flow (CBF) in both cerebral hemispheres, so she underwent revascularization surgery in her left cerebral hemisphere. She awoke from anesthesia uneventfully; however, 1 hour after the surgery her blood pressure suddenly dropped to 90/40 mm Hg and she became comatose. A perfusion computed tomography scan demonstrated a widespread reduction in CBF in the left hemisphere. Bezold-Jarisch reflex was thought to be the cause of the hypotension. Following treatment with a vasopressor agent, her BP increased and her consciousness rapidly recovered. The reduced CBF had almost completely recovered the next day. Head-up tilt test conducted 2 weeks after surgery demonstrated latent vasopressor-type autonomic dysfunction, which was possibly another cause of the hypotension. She was discharged from the hospital, and the laughter-induced hemiparesis gradually resolved. Conclusion Situational neurologic deterioration in patients with MMD suggests latent autonomic dysfunction, which may be a risk factor for postoperative ischemic complications.

Background: Atherosclerosis is leading to mortal diseases such as Cerebral Infarction (CI), and Cardiovascular Disease (CVD), and closely related to Diabetes Mellitus (DM) and Chronic Kidney Disease (CKD). Biomarkers are useful but not sufficient for early detection. In the present study, we aimed to identify novel antibody markers for atherosclerosis-related diseases. Methods: The protein array method was used for the initial screening, and a peptide containing a possible epitope domain was used to evaluate serum antibody levels using the Amplified Luminescent Proximity Homogeneous Assay (AlphaLISA) method. Results: The protein array identified prolylcarboxypeptidase (PRCP) as one of the target antigens recognized by IgG antibodies in the sera of patients with atherosclerosis. We then prepared a possible antigenic peptide of amino acids 214-227 of PRCP. Results of AlphaLISA showed significantly higher serum antibody levels against the PRCP peptide in patients with DM, CVD, acute-phase cerebral infarction, transient ischemic attack or CKD, than in healthy donors. Furthermore, areas under the receiver operating characteristic curves of these antibodies were higher in patients with DM or CKD than in other patients. Spearman correlation analysis revealed that the serum anti-PRCP antibody levels were associated with hypertension, artery stenosis, and smoking habit.. Conclusion: The serum anti-PRCP antibody may be useful for early detection of atherosclerosis-related diseases, and may have a pathogenic role in the development of atherosclerosis.

Background: Growth arrest and DNA-damage-inducible gene 34 (GADD34) has been identified as an antigen by serological identification of antigens by cDNA expression cloning (SEREX) using the sera of patients with atherosclerosis. It is possible that GADD34 is associated with atherosclerosis-related diseases such as diabetes mellitus (DM), acute-phase cerebral infarction (aCI), cardiovascular disease (CVD), and chronic kidney disease (CKD) as well as endoplasmic reticulum stress-related Parkinson disease (PD). Methods: GADD34 protein was bacterially expressed and purified. Amplified luminescent proximity homogeneous assay (AlphaLISA) was used to evaluate serum antibody levels against GADD34 protein in serum samples. Results: AlphaLISA revealed significantly higher serum antibody levels against GADD34 protein in patients with DM, aCI and CVD than those in healthy donors (HDs). The difference in levels between DM and HD was more prominent than that between aCI or CVD and HDs. The anti-GADD34 antibody levels were also elevated in the sera of diabetic CKD patients; thus, the anti-GADD34 antibodies appeared to be the most associated with DM, which is also a risk factor of PD. Anti-GADD34 antibody levels were also higher in patients with PD but not in those with amyotrophic lateral sclerosis as compared with those in HDs. Conclusion: Anti-GADD34 antibody may be a useful diagnostic tool for DM and PD. GADD34 may account for the pathophysiological relationship between DM and PD.

Background: The discovery and development of novel biomarkers that could facilitate early diagnosis and thus prevent the progression of atherosclerosis-related diabetes mellitus (DM), cerebral infarction (CI), and cardiovascular disease (CVD) has garnered much research interest. Notably, recent reports have described a number of highly sensitive antibody markers. In this study, we aimed to identify additional antibody markers that would facilitate screening. Methods: The amplified luminescent proximity homogeneous assay (AlphaLISA) method, which incorporates glutathione- or streptavidin-donor beads and anti-human-IgG-acceptor beads, was used to evaluate serum antibody levels in serum samples. The protein array method was used for the initial screening, and peptide arrays were used to identify epitope sites. Results: The protein array identified SH3 domain-binding protein 5 (SH3BP5) as a target antigen of serum IgG antibodies in the sera of patients with atherosclerosis. We prepared recombinant glutathione S-transferase (GST)- fused SH3BP5 protein. Peptide arrays revealed that the epitope site recognized by serum antibodies is located within amino acids 161–174 of SH3BP5. AlphaLISA revealed significantly higher serum antibody levels against both the SH3BP5 protein and peptide in patients with DM, acute-phase CI, transient ischemic attack, CVD or chronic kidney disease (CKD), than in healthy donors. Furthermore, areas under the receiver operating characteristic curves of these antibodies were higher in patients with CKD and DM than in other patients. Spearman correlation analysis revealed associations between the serum antibody levels against SH3BP5 peptide and artery stenosis, hypertension, and smoking. Conclusions: The serum anti-SH3BP5 antibody marker appears to be useful for estimating the progress of atherosclerosis and may discriminate atherosclerosis associated with hypertension and/or habitual smoking.

Here we report a case of moyamoya disease in which cortical veins reddened after superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis, following postoperative hyperperfusion. A 37-year-old man with moyamoya disease suffered cerebral infarction in his right hemisphere. Single photon emission computed tomography (SPECT) showed impaired cerebral blood flow (CBF) in both cerebral hemispheres. The patient underwent STA-MCA anastomosis in the right cerebral hemisphere. During operation, soon after declamping the STA, cortical veins near the anastomosis site changed its color from blue to red. This change was repeatable by clamping and declamping of the STA. Postoperative SPECT and computed tomography (CT) demonstrated increased CBF and subarachnoid hemorrhage at the anastomosis site, suggesting the occurrence of postoperative hyperperfusion. By strictly controlling the patient's blood pressure, the syndrome resolved 1 week after the operation. We propose that the venous reddening after STA-MCA anastomosis may be a sign of postoperative hyperperfusion.

Background and Purpose— Venous oxygen saturation (SO 2 ) is measured in medical fields to assess tissue circulation insufficiency. This study aimed to elucidate the use of a cortical venous redness measurement to evaluate hemodynamic changes during revascularization surgery for patients with moyamoya disease. Methods— In this retrospective case-series analysis, we first quantitatively measured and correlated SO 2 and R intensity of 24-bit color digital red–green–blue pictures of blood samples from 3 volunteers. Subsequently, based on intraoperative digital pictures of 29 patients with moyamoya disease, we measured the R intensities of a cortical vein near the anastomosis site before and after anastomosis. Cerebral blood flow (CBF) at the site was measured using a single-photon emission computed tomography before and 1 to 3 days after surgery. Venous R intensity and CBF were measured twice by 4 raters, and their correlations were examined using generalized linear mixed effect model and linear regression analysis. Results— A strong linear correlation was found between blood R intensity and its SO 2 (coefficients, 0.522; 95% confidence interval, 0.364–0.680, using generalized linear mixed effect model). Venous R intensity before the anastomosis was not correlated with preoperative CBF (coefficients, 0.000352; 95% confidence interval, −0.000369 to 0.00107, by generalized linear mixed effect); however, the increases in venous R intensity after anastomosis were correlated with postoperative increases in CBF ( R 2 , 0.367; 95% confidence interval, 0.116–0.618 to 0.548; 95% confidence interval, 0.331–0.764, by linear regression analysis). Conclusions— Cortical venous redness represented impaired CBF and could be a useful parameter for assessing hemodynamic changes during revascularization surgery.

The natural history of intracranial arterial dissection (ICAD) is not known precisely, so that treatment strategy is hard to determine in some cases. We examined the clinical features, treatment and long-term outcomes in the ICAD of ischemic onset. Among 214 consecutive patients with ICAD [199 in the vertebrobasilar system (VBs) and 15 in the internal carotid system (ICs)], 76 presented with brain ischemia. Those were classified into 2 groups: 63 in the VBs and 13 in the ICs. We analyzed age, site of dissection, progression or recurrence of ischemia, medical and surgical treatment, and long-term outcomes. The outcomes were evaluated by modified Rankin disability scale (mRS). Good outcome was defined as mRS 0 to 2. Results: 1) The patients were younger in the ICs (mean: 44.8 years) than in the VBs (mean: 53.0 years). 2) The vertebral artery was mostly affected in both arterial systems. 3) The acute stage progression or recurrence of ischemia was observed in 37% of the VBs and 54% of the ICs. The progression or recurrence is more frequent in the patients of the VBs with antithrombotic therapy (p=0.0224). 4) Treatment: Medical treatment was performed in 94% of the VBs and in all of the ICs. In addition, antithrombotic agents were prescribed in 38% of the VBs and in 85% of the ICs. Four patients (6%) of the VBs were surgically treated because of enlargement of the aneurysmal dilatation on follow-up study of MRI/MRA or 3D-CT angiography. 5) Long-term outcomes: In the medical group, good outcomes were achieved in 77% of the VBs and all of the ICs. In the VBs, the patients with antithrombotic therapy had poorer outcomes than those without the therapy (P=0.0399). All the patients in the surgical group had good outcomes in the VBs. These results suggest that antithrombotic therapy might lead to the progression or recurrence of ICAD and a poorer outcome. This therapy should be selected prudently in the ICAD of ischemic onset, especially in the VBs.