History of Vasospasm Research in Japan: Commemoration of Professor Tomio Ohta.

In the 1960s Professor Setsuro Ebashi, a physiologist from the University of Tokyo, discovered calcium ion plays a pivotal role in muscle contraction for the first time. However, he was confounded by icy neglect of the society of physiologists. The International Conference on Physiology was held in Boston in 1962, and Dr. Ebashi and his coworker Dr. Anne Mary Weber gave a talk about calcium signal which is a key mechanism for regulating muscle contraction. Every single attendant stood against their theory and even laughed at them.

One-stage Stent-assisted Coil Embolization for Rupture-side-unknown Bilateral Vertebral Artery Dissecting Aneurysms in an Acute Stage: A Case Report.

Bilateral vertebral artery dissecting aneurysms (VADAs) with subarachnoid hemorrhage (SAH) are rare and their management is still challenging. In this report, we successfully performed one-stage stent-assisted coil embolization (SAC) for bilateral VADAs with SAH in an acute stage, because the ruptured side could not be diagnosed. A 47-year-old woman presented with a sudden onset of headache without laterality, and left-side dominant SAH with bilateral VADAs was noted on computed tomography (CT) scans. The size of aneurysmal dome and neck was similar between the two VADAs, and a bleb was observed only on the right VADA. In computational fluid dynamics (CFD) simulations, findings of wall shear stress (WSS), normalized WSS, and WSS gradient suggested that the left VADA was ruptured, while the oscillatory shear index and aneurysm formation indicator suggested the opposite-side one to be ruptured. Thus, we could not determine which VADA was ruptured by clinical data and CFD analyses. Therefore, we performed simultaneous treatment for the bilateral VADAs by using SAC technique 8 h after the onset under dual antiplatelet and anticoagulation therapies. There was no evidence of rebleeding and stent thrombosis. Stent thrombosis was monitored by duplex color-coded ultrasonography after the intervention. She was discharged without neurological deficits, and 6-month follow-up cerebral angiography demonstrated no recanalization of VADAs. This is the first report showing bilateral VADAs with SAH treated by one-stage SAC within 24 h of SAH, and the potential risks are discussed.

[Pontine Hemorrhage Suspected due to Dural Arteriovenous Fistula at the Craniocervical Junction:A Case Report].

Dural arteriovenous fistulas occurring at the craniocervical junction(CCJd-AVF)are uncommon; however, they demonstrate a wide range of clinical presentations. We describe the case of a patient with pontine hemorrhage suspected due to CCJd-AVF. A 68-year-old man presented to our hospital with a sudden onset of left hemiparesis. Cranial computed tomography(CT)revealed pontine and subarachnoid hemorrhage. Magnetic resonance imaging, as well as MR, CT, and left vertebral angiograms were performed and showed a CCJd-AVF in addition to a varix coincident with the hematoma cavities. The patient was successfully treated using surgical drainer clipping. A CCJd-AVF presenting concomitantly with a pontine hemorrhage is extremely rare. Careful assessment of the anatomical relationship between the skull base and the surrounding vascular structures is important to plan neurosurgical procedures for direct interruption of the draining vein. Three-dimensional CT angiography is a useful modality that facilitates visualization of complex and anomalous anatomical structures.

Mechanical Recanalization for Acute Embolic Occlusion at the Origin of the Superior Mesenteric Artery.

PURPOSE: We report a combined technique consisting of thrombectomy and thromboaspiration for the treatment of acute embolic occlusion of the superior mesenteric artery (SMA) at the origin. CASE: A 90-year-old female with chronic atrial fibrillation had a sudden onset of abdominal pain and hematochezia due to acute embolic occlusion at the origin of the SMA. Computed tomographic findings showed reversible bowel wall ischemia. We performed mechanical thrombectomy using the Solitaire FR revascularization device, a self-expanding and fully retrievable stent-based thrombectomy system for acute intracranial large artery occlusion, combined with manual aspiration through a 6F guiding sheath placed at the SMA origin via a right brachial approach. Prompt and complete recanalization of the SMA was obtained without distal embolism, and intestinal necrosis was avoided. CONCLUSION: Combined endovascular procedures of mechanical thrombectomy using the Solitaire FR with thromboaspiration may allow prompt recanalization, clot removal, and prevention of distal embolism and therefore would be a new therapy for acute embolic occlusion at the origin of the SMA.

Simultaneous Spinal and Intracranial Chronic Subdural Hematoma Cured by Craniotomy and Laminectomy: A Video Case Report.

Simultaneous spinal and intracranial chronic subdural hematoma (CSDH) is a rare entity. A 67-year-old man visited our hospital due to headache after diving into a river 2 weeks before. Non-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) revealed bilateral intracranial CSDH. The bilateral CSDH was evacuated and his symptoms improved. Three days after craniotomy, he complained of sensory disturbance on his buttocks. Lumbar MRI showed a space-occupying lesion behind the thecal sac at L5. CT with myelography showed a subdural mass lesion; there was no communication with the subarachnoid space. Fourteen days after craniotomy, L5 laminectomy was performed and the dura mater was incised carefully. The video shows that a liquid hematoma similar to the intracranial CSDH flowed out, followed by cerebrospinal fluid. His symptoms improved after the operation and the hematoma did not recur. This is a rare condition of spinal CSDH demonstrated by neuroimaging and intraoperative video.

The Role of Matricellular Proteins in Brain Edema after Subarachnoid Hemorrhage.

Accumulated evidence suggests that blood-brain barrier disruption or brain edema is an important pathologic manifestation for poor outcome after aneurysmal subarachnoid hemorrhage. Many molecules may be involved, acting simultaneously or at different stages during blood-brain barrier disruption via multiple independent or interconnected signaling pathways. Matricellular protein is a class of nonstructural, secreted, and multifunctional extracellular matrix proteins, which potentially mediates brain edema formation. This study reviews the role of osteopontin and tenascin-C, representatives of matricellular proteins, in the context of brain edema formation after subarachnoid hemorrhage in both clinical and experimental settings.

Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage.

Predictors for cerebral infarction, an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH), were examined. This study used data from the Prospective Registry of Subarachnoid Aneurysms Treatment (PRESAT) cohort, which included 579 patients whose ruptured aneurysms were treated with either clipping or coiling within 12 days of onset. Patient, clinical, radiographic, and treatment variables associated with cerebral infarction were determined. Ruptured aneurysms were clipped in 282 patients and coiled in 297 patients. Cerebral infarction occurred in 162 patients (28.0 %): 101 patients by cerebral vasospasm, 34 patients by clipping, and 33 patients by coiling. Univariate analyses showed that significant factors associated with cerebral infarction development were Fisher computed tomography (CT) group 3 on admission, premature aneurysm rupture during clipping procedure, cerebrospinal fluid drainage, symptomatic vasospasm, endovascular treatment for vasospasm, and shunt-dependent hydrocephalus. Multivariable logistic regression analyses showed that cerebral infarction was significantly associated with Fisher CT group 3 on admission, larger aneurysm dome size, ruptured posterior circulation aneurysms, premature aneurysm rupture during clipping procedure, symptomatic vasospasm, and infection, while endovascular treatment for vasospasm significantly decreased the development of cerebral infarction. The most important potentially treatable factor associated with cerebral infarction was symptomatic vasospasm.

Usefulness of arterial spin-labeling images in periictal state diagnosis of epilepsy.

PURPOSE: Arterial spin-labeling (ASL) perfusion MRI, a noninvasive method of assessing cerebral blood flow, is becoming a diagnostic tool of epilepsy. This study was undertaken to evaluate the diagnostic validity of ASL in patients with status epilepticus (SE) in a periictal state. METHOD: Twenty cases with SE were studied. Patients were imaged at a 3T MRI including ASL and diffusion-weighted imaging (DWI), and were also examined using electroencephalography (EEG). The abnormal findings of ASL were compared with those obtained from DWI and EEG. RESULT: Focal hyperperfusion was found in the cortical territory of 13 cases (65%). In 10 of those 13 cases, the ASL hyperperfusion region corresponded to DWI high intensity and EEG abnormality. Two cases showed hyperperfusion corresponding to EEG abnormalities in ASL despite the absence of high intensity in DWI. The remaining single case showed hyperperfusion in ASL despite the absence of high intensity in DWI and EEG abnormalities. Hyperperfusion in the subcortical territory was observed in the ipsilateral thalamus in three cases and in the contralateral cerebellum in one case. CONCLUSION: Our results suggest that ASL is a useful tool to diagnose status epilepticus and localization of the epilepsy focus.

Effects of tenascin-C on early brain injury after subarachnoid hemorrhage in rats.

BACKGROUND AND PURPOSE: We previously reported that tenascin-C (TNC), a matricellular protein, was involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH), but the role of TNC in early brain injury (EBI) is unknown. This study assessed whether inhibition of TNC upregulation in brain by imatinib mesylate (imatinib), an inhibitor of the tyrosine kinases of platelet-derived growth factor receptors, prevents EBI after experimental SAH. METHODS: Rats were assigned to sham, SAH plus vehicle, and SAH plus imatinib groups (n = 4 per group). Imatinib (50 mg/kg body weight) was administered intraperitoneally to rats undergoing SAH by endovascular perforation, and EBI was evaluated using terminal deoxynucleotidyl transferase-mediated uridine 5-triphosphate-biotin nick end-labeling staining at 24 h after SAH. Imatinib-treated SAH rats were also treated by a cisternal injection of recombinant TNC. RESULTS: SAH upregulated TNC and caused EBI. Imatinib treatment suppressed both TNC upregulation and EBI at 24 h. Recombinant TNC reinduced EBI in imatinib-treated SAH rats. CONCLUSIONS: TNC may be involved in the pathogenesis of EBI after SAH.

Vasoconstrictive effect of tenascin-C on cerebral arteries in rats.

BACKGROUND AND PURPOSE: The authors have reported that tenascin-C (TNC), a matricellular protein, is induced after subarachnoid hemorrhage (SAH), associated with cerebral vasospasm. In this study, we examined whether TNC alone causes cerebral vasospasm-like constriction of the intracranial internal carotid arteries (ICAs) in rats, focusing on the p38 mitogen-activated protein kinase (MAPK)-mediated mechanisms. METHODS: First, we injected 10 µg of TNC into the cisterna magna of healthy rats and studied morphologically whether TNC caused constriction of the left ICA at 24-72 h after administration. Second, we examined the effect of SB203580 (a p38 MAPK inhibitor) on the vessel diameter of the left ICA in healthy rats at 24 h. Third, we evaluated the effect of SB203580 on TNC-induced constriction of the left ICA in healthy rats at 24 h. RESULTS: TNC significantly induced cerebral vasospasm-like angiographic constriction of the left ICAs, which continued at least for 72 h. SB203580 itself had no effect on the diameter of normal ICAs, but abolished the TNC-induced vasoconstrictive effect on the left ICA. CONCLUSION: These findings show that TNC causes left ICA constriction via activation of p38 MAPK, resembling post-SAH vasospasm, and suggest the possible involvement of TNC in the pathogenesis of cerebral vasospasm.

Tenascin-C is a possible mediator between initial brain injury and vasospasm-related and -unrelated delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Tenascin-C (TNC), a matricellular protein, exerts diverse functions, including tissue remodeling and apoptosis, and is induced in cerebrospinal fluid (CSF) after aneurysmal subarachnoid hemorrhage (SAH). The purpose of this study was to examine the relationships among CSF TNC levels, initial brain injury, delayed cerebral ischemia (DCI), and vasospasm after SAH. METHODS: CSF TNC levels were measured in 30 patients with aneurysmal SAH of Fisher computed tomography (CT) group III who were treated microsurgically or endovascularly with CSF drainage within 24 h of SAH. Admission World Federation of Neurosurgical Societies (WFNS) grade was supposed to indicate the severity of initial brain injury. Cerebral vasospasm was defined as narrowed (≥ 25 %) cerebral arteries demonstrated by angiography. DCI was defined as any neurological deterioration presumed related to ischemia that persisted for ≥ 1 h. RESULTS: Higher CSF TNC levels were correlated with worse admission WFNS grades. Vasospasm was aggravated with higher TNC levels. DCI occurred regardless of the degree of vasospasm but was associated with TNC induction. Multivariate analyses showed that higher TNC levels and vasospasm were independent predictors of DCI occurrence. CONCLUSIONS: SAH (initial brain injury) that is more severe induces more TNC, which may cause the subsequent development of both vasospasm and vasospasm-unrelated secondary brain injury, leading to DCI.

Risk factors for vasospasm-induced cerebral infarct when both clipping and coiling are equally available.

INTRODUCTION: Vasospasm-induced cerebral infarct is still a significant cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). MATERIALS AND METHODS: In 537 patients of the Prospective Registry of Subarachnoid Aneurysms Treatment cohort, ruptured aneurysms were treated either microsurgically or endovascularly judged by the attending neurosurgeon to be appropriate for the individual patient within 3 days of onset. Factors for vasospasm-induced cerebral infarct were examined. RESULTS: Clipping (273 patients) was preferably performed for middle cerebral artery aneurysms, while coiling (264 patients) was preferred for larger, internal carotid artery and posterior circulation aneurysms. After aneurysmal obliteration, cerebrospinal fluid drainage was performed more in clipped patients, and antithrombotic treatment was performed more in coiled patients. Vasospasm-induced cerebral infarct occurred in 17.7 %, and multivariable logistic regression showed that vasospasm-induced cerebral infarct increased the odds of poor outcome by a factor of 5.2 (adjusted odds ratio, 5.2; 95 % confidence interval, 2.8-9.8; P < 0.001). Multivariate analyses showed that vasospasm-induced cerebral infarct was significantly associated with admission World Federation of Neurosurgical Societies grade IV-V, Fisher computed tomography (CT) group 3-4, and ruptured middle cerebral artery aneurysms. CONCLUSIONS: New treatment strategies for vasospasm-induced cerebral infarct are needed, especially for ruptured middle cerebral artery aneurysm cases associated with massive SAH.

Neuromelanin magnetic resonance imaging in Parkinson's disease and multiple system atrophy.

Pigmented neurons in the substantia nigra pars compacta (SNc) and locus coeruleus (LC) show decreased numbers differentially in Parkinson's disease (PD) and multiple system atrophy (MSA). Recent reports have described that fast spin-echo T1-weighted magnetic resonance imaging (MRI) by a 3-tesla machine can visualize neuromelanin-related contrast of the noradrenergic and dopaminergic neurons respectively in the LC and the SNc. Using neuromelanin MRI at 3 T, we investigated possible alterations of these catecholaminergic neurons in 32 PD and 9 MSA patients, and compared the results with those of 23 normal volunteers. The contrast ratio of the LC and SNc was decreased in MSA and PD patients, most prominently in the LC in MSA patients. The contrast ratio of the SNc was correlated with the Hoehn-Yahr stage of PD and the severity of neuroradiological abnormalities in MSA. These results indicate a potential diagnostic value of neuromelanin MRI to distinguish MSA patients from normal and PD patients.

Tenascin-C induces prolonged constriction of cerebral arteries in rats.

Tenascin-C (TNC), a matricellular protein, is induced in association with cerebral vasospasm after subarachnoid hemorrhage. The aim of this study was to assess the vasoconstrictive effects of TNC and its mechanisms of action on cerebral arteries in vivo. Two dosages (1 and 10µg) of TNC were administered intracisternally to healthy rats, and the effects were evaluated by neurobehavioral tests and India-ink angiography at 24, 48, and 72h after the administration. Western blotting and immunohistochemistry were performed to explore the underlying mechanisms on constricted cerebral arteries after 24h. The effects of toll-like receptor 4 (TLR4) antagonists (LPS-RS), c-Jun N-terminal kinase (JNK), and p38 inhibitors (SP600125 and SB203580) on TNC-induced vasoconstriction were evaluated at 24h. Higher dosages of TNC induced more severe cerebral arterial constriction, which continued for more than 72h. TNC administration also upregulated TLR4, and activated JNK and p38 in the smooth muscle cell layer of the constricted cerebral artery. LPS-RS blocked TNC-induced TLR4 upregulation, JNK and p38 activation, and vasoconstrictive effects. SP600125 and SB203580 abolished TNC-induced TLR4 upregulation and vasoconstrictive effects. TNC may cause prolonged cerebral arterial constriction via TLR4 and activation of JNK and p38, which may upregulate TLR4. These findings suggest that TNC causes cerebral vasospasm and provides a novel therapeutic approach against it.

Matricellular protein: a new player in cerebral vasospasm following subarachnoid hemorrhage.

INTRODUCTION: Matricellular protein (MCP) is a class of nonstructural and secreted extracellular matrix proteins that exert diverse functions, but its role in vascular smooth muscle contraction has not been investigated. MATERIAL AND METHODS: First, rat subarachnoid hemorrhage (SAH) models were produced by endovascular perforation and examined for tenascin-C (TNC) and osteopontin (OPN) induction (representatives of MCPs) in vasospastic cerebral arteries using immunostaining. Second, recombinant TNC (r-TNC), recombinant OPN (r-OPN), or both were injected into a cisterna magna in healthy rats, and the effects on the diameter of basilar arteries were determined using India ink angiography. RESULTS: In SAH rats, TNC immunoreactivity was markedly induced in the smooth muscle cell layers of spastic cerebral arteries on day 1 but not in control animals. The TNC immunoreactivity decreased on day 3 as vasospasm improved: OPN immunoreactivity, on the other hand, was more induced in the arterial wall on day 3. r-TNC injections caused prolonged contractions of rat basilar arteries, which were reversed by r-OPN, although r-OPN itself had no effect on the vessel diameter. CONCLUSIONS: MCPs, including TNC and OPN, may contribute to the pathophysiology of cerebral vasospasm and provide a novel therapeutic approach against it.

Role of platelet-derived growth factor in cerebral vasospasm after subarachnoid hemorrhage in rats.

BACKGROUND AND PURPOSE: The role of platelet-derived growth factor (PDGF) remains unknown in cerebral vasospasm after subarachnoid hemorrhage (SAH). In this study, we examined the effects of PDGF receptor (PDGFR) inactivation on cerebral vasospasm in the endovascular perforation model of SAH in rats. METHODS: Rats were assigned to sham, SAH plus vehicle, and SAH plus imatinib mesylate (imatinib) groups (n = 4 per group). Imatinib (50 mg/kg body weight), an inhibitor of the tyrosine kinases of PDGFR, or vehicle was administered intraperitoneally 30 min post-SAH. Vasospasm was evaluated in the left (perforation-sided) internal carotid artery by means of neurobehavioral tests, India ink angiography, and immunohistochemistry at 24 h after SAH. RESULTS: Imatinib significantly inhibited post-SAH PDGFR activation in the left internal carotid artery, in which vasospasm was significantly prevented. Animal's neurobehavior also showed a tendency to improve by imatinib treatment. CONCLUSIONS: PDGF may play an important role in the pathogenesis of vasospasm after SAH.

Imatinib mesylate prevents cerebral vasospasm after subarachnoid hemorrhage via inhibiting tenascin-C expression in rats.

Platelet-derived growth factor (PDGF) has been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH), but the mechanism remains unknown. The purpose of this study was to assess whether imatinib mesylate (imatinib), an inhibitor of the tyrosine kinases of PDGF receptors (PDGFRs), prevents cerebral vasospasm after SAH in rats, and to elucidate if tenascin-C (TNC), a matricellular protein, is involved in the mechanism. Imatinib (10 or 50 mg/kg body weight) was administered intraperitoneally to rats undergoing SAH by endovascular perforation, and the effects were evaluated by neurobehavioral tests and India-ink angiography at 24-72 h post-SAH. Western blotting and immunohistochemistry were performed to explore the underlying mechanisms in cerebral arteries at 24h post-SAH. Recombinant TNC was administered intracisternally to imatinib-treated SAH rats, and the effects were evaluated by neurobehavioral tests, India-ink angiography and immunohistochemistry at 24 h post-SAH. Both dosages of imatinib significantly prevented post-SAH neurological impairments and vasospasm at 24-72 h. SAH caused PDGFR-ß upregulation, PDGFR activation, mitogen-activated protein kinase activation, and TNC upregulation in the spastic cerebral arteries, all of which were significantly suppressed by imatinib treatment. Recombinant TNC reversed the anti-vasospastic effects and protein expression changes by imatinib. This study suggests that imatinib prevents cerebral vasospasm at least partly via inhibiting the upregulation of TNC, implying that TNC may be a new therapeutic target for post-SAH vasospasm.

Cerebrospinal fluid tenascin-C in cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Tenascin-C (TNC) has been reported to be a useful biomarker for the activity of inflammatory diseases. This study investigated the association between TNC levels in the cerebrospinal fluid (CSF) and symptomatic vasospasm after aneurysmal subarachnoid hemorrhage (SAH), and the prognostic value of TNC levels. METHODS: TNC levels were measured in CSF in 33 consecutive patients diagnosed with aneurysmal SAH of Fisher computed tomography group III and were compared between those with and without subsequent cerebral vasospasm. Factors influencing symptomatic vasospasm were determined using multivariate logistic regression analyses. The receiver-operating characteristic curve technique was used to assess specificity and sensitivity in the prediction of symptomatic vasospasm. RESULTS: The CSF TNC levels peaked immediately after SAH and were significantly higher in patients who subsequently developed symptomatic vasospasm than in those who did not. On multivariate analyses, higher TNC levels in the CSF (odds ratio, 1.059; 95% confidence interval, 1.023-1.096; P<0.001) and World Federation of Neurosurgical Societies grades IV to V on admission (odds ratio, 3.238; 95% confidence interval, 1.033-10.152; P<0.05) significantly predicted symptomatic vasospasm. To predict the onset of symptomatic vasospasm, 16.2 ng/mL was considered as an appropriate cut-off value for CSF TNC on days 1 through 6, giving a sensitivity of 81.0% and a specificity of 79.5% (negative and positive predictive values: 82.3% and 76.7%, respectively). CONCLUSIONS: TNC in the CSF may be a useful biomarker for predicting subsequent development of cerebral vasospasm.

Astrocytic neuroprotection through induction of cytoprotective molecules; a proteomic analysis of mutant P301S tau-transgenic mouse.

Hyperphosphorylated tau protein constitutes a significant portion of intracellular inclusions in some neurodegenerative diseases. In addition, mutations in tau protein cause familial forms of frontotemporal dementia (FTD), indicating that dysfunction of tau protein is responsible for neurodegeneration and dementia. P301S tau-transgenic (Tg) mouse expressing human mutant tau in neurons exhibits similar features of human tauopathies including neuronal degeneration and filament accumulation consisted of hyperphosphorylated tau protein. In the present study, we attempted to characterize protein expression profiles in P301S tau-Tg mouse by using two-dimensional differential in-gel electrophoresis (2D-DIGE) coupled by peptide mass fingerprinting (PMF). As a result, we identified four upregulated proteins; heat shock protein 27 (Hsp27), peroxiredoxin 6 (Prdx6), apolipoprotein E (ApoE), and latexin (LTXN), all of which may function as a neuroprotective mechanism against tau toxicity. In immunohistochemistry, these four proteins were increased invariably in astrocytes, and these astrocytes infiltrated the area in which there are numerous accumulations of hyperphosphorylated tau and neuronal loss. Therefore, these results may indicate that astrocytes provide a neuroprotective mechanism against tau toxicity.

Subarachnoid hemorrhage causes pulmonary endothelial cell apoptosis and neurogenic pulmonary edema in mice.

OBJECTS: Neurogenic pulmonary edema (NPE) is a well-known complication of subarachnoid hemorrhage (SAH), which potentially causes a poor outcome. The aim of this study was to examine if NPE occurs in the endovascular perforation model of SAH in mice and if apoptosis contributes to NPE development after SAH in mice. METHODS: Sham-operated or SAH mice were treated with an intraperitoneal administration of vehicle or an antiapoptotic drug Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK) 1 h post-SAH. Pulmonary edema measurements and evaluation of apoptosis occurrence were performed on the lung at 24 h post-SAH. RESULTS: SAH caused NPE, which was associated with apoptosis of pulmonary endothelial cells. Z-VAD-FMK significantly prevented apoptosis and NPE. CONCLUSIONS: Pulmonary endothelial cell apoptosis contributes to the pathophysiology of NPE after SAH in mice.