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Ring finger protein (RNF) 213 is known as a susceptibility gene for moyamoya disease (MMD), which is characterized by bilateral carotid folk stenosis. Cerebral angiopathy after viral infection has been known to present angiographical appearance resembling MMD, however its pathogenesis and genetic background are not well known. We report a case of reversible cerebral angiopathy after viral infection in a pediatric patient with genetic variant of RNF213 mutation. The patient had developed a severe headache after hand, foot, and mouth disease. Magnetic resonance imaging and magnetic resonance angiography (MRA) performed 2-3 weeks after disease onset revealed bilateral carotid folk stenosis and an old cerebral infarction in the left putamen. The patient's headache spontaneously resolved and the follow-up MRA showed a complete spontaneous resolution of the arterial stenosis after 9 months. We were able to determine genetic predisposition to angiopathy by identifying the RNF213 c.14576G>A (rs112735431, p.R4859K) mutation. Based on the present case, we hypothesize that an RNF213 variant might play an important role for the onset of postviral cerebral angiopathy.

BACKGROUND Recent clinical trials demonstrated the efficacy of thrombectomy for ischemic stroke against acute large vessel occlusion (LVO). To overcome the problem with excessive examination time for diagnosis of cerebral perfusion and/or the use of contrast agent to determine penumbra, we adopted a new magnetic resonance imaging technique named Acute Stroke Assessment using rapid Pseudo-continuous arterial spin labeling (ASAP-ASL) method. METHODS The study included healthy volunteers and clinical patients. The signal to noise ratio (SNR) and acquisition time were compared with various numbers of signal average (NSA) of rapid pseudo-continuous arterial spin labeling (pCASL) using the 10-mm thick slice width and narrow scan range focusing the level of basal ganglia by healthy volunteers. After applying clinically acceptable protocol for ASAP-ASL, we then checked image qualities and an accuracy of the method by comparing with the angiographical imaging obtained from the clinical patients regarding the degree of consistency. RESULTS NSA were compared between two and fourteen, and 10 NSA was decided to be introduced for clinical use (1 minutes and 17 second) for obtaining clinically acceptable image, which was shorter than the time required for ordinary whole brain pCASL (approximately 5 minutes). In the clinical study, the occlusion site estimated by ASAP-ASL showed high correlation with that of digital subtraction angiography (κ=0.63-0.79). CONCLUSIONS ASAP-ASL method requires approximately one minutes to obtain clinically relevant brain perfusion imaging which can successfully identify ischemic region in LVO patients.

The spinal trigeminal nucleus is a cranial nerve which extends caudally from the medulla to the upper cervical segment of the spinal cord. An upper cervical lesion can cause pain or dysesthesia of the face sparing the central area, which is called onion-skin pattern.We present a rare case of a 73-year-old man with cervical ossification of the posterior longitudinal ligament(OPLL)causing onion-skin pattern dysesthesia. No other brain lesion was detected by MRI. He had received adequate medication for six months, but his dysesthesia persisted. Cervical radiographic studies showed OPLL with slight instability at the C2-3 level and mild spinal cord compression at the C3 vertebral level. The lesion was considered solely responsible for the onion-skin pattern dysesthesia, and it resulted in posterior cervical decompression. Immediately after the surgery, his dysesthesia disappeared.The onion-skin pattern dysesthesia could have been caused by the C2-3 lesion.

Background The potential application of bone marrow stromal cell (BMSC) therapy in stroke has been anticipated due to its immunomodulatory effects. Recently, positron emission tomography (PET) with [18F]DPA-714, a translocator protein (TSPO) ligand, has become available for use as a neural inflammatory indicator. We aimed to evaluate the effects of BMSC administration after transient middle cerebral artery occlusion (MCAO) using [18F]DPA-714 PET. The BMSCs or vehicle were administered intravenously to rat MCAO models at 3 h after the insult. Neurological deficits, body weight, infarct volume, and histology were analyzed. [18F]DPA-714 PET was performed 3 and 10 days after MCAO. Results Rats had severe neurological deficits and body weight loss after MCAO. Cell administration ameliorated these effects as well as the infarct volume. Although weight loss occurred in the spleen and thymus, cell administration suppressed it. In both vehicle and BMSC groups, [18F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 3 days after MCAO. Although SUV was increased further 10 days after MCAO in both groups, the increase was inhibited in the BMSC group, significantly. Histological analysis showed that an inflammatory reaction occurred in the lymphoid organs and brain after MCAO, which was suppressed in the BMSC group. Conclusions The present results suggest that BMSC therapy could be effective in ischemic stroke due to modulation of systemic inflammatory responses. The [18F]DPA-714 PET/CT system can accurately demonstrate brain inflammation and evaluate the BMSC therapeutic effect in an imaging context. It has great potential for clinical application.

Background Cerebral hyperperfusion complicates the postoperative course of patients with moyamoya disease after direct revascularization surgery. There is no clear distinction between cerebral hyperperfusion syndrome and benign postoperative increase in regional cerebral blood flow (rCBF). Objective The present study aimed to determine clinically relevant changes in rCBF, anatomical correlations, and factors associated with transient neurologic symptoms after revascularization surgery in moyamoya disease. Methods Whole-brain voxel-based perfusion mapping was used to identify regions involved in cerebral hyperperfusion and quantify the changes in 105 hemispheric surgeries with the use of single-photon computed tomography acquired on postoperative day 7. The changes in rCBF were quantitatively analyzed, and associations with cerebral hyperperfusion syndrome were determined. Results Transient neurologic symptoms appeared with rCBF increase in 37.9% of adults. Speech impairments were associated with an increase in rCBF in the operculo-insula region. Cheiro-oral syndrome was associated with the posterior insula as well as the prefrontal region. A receiver operating curve analysis yielded transient neurologic symptoms with maximum accuracy at >15.5% increase from baseline. Age and preoperative rCBF were independently associated with transient neurologic symptoms (P Conclusions Areas showing rCBF increase during the experience of transient neurologic symptoms were spatially compatible with the known functional anatomy of the brain. An increase of approximately 15% from baseline was found to be critical, which is a far lower threshold than what has been reported previously. Increasing age was significantly associated with the occurrence of symptomatic hyperperfusion. Furthermore, patients with preserved rCBF also showed symptomatic hyperperfusion.

A rare case of Mollaret meningitis characterized by four recurrent episodes of aseptic meningitis during the 3-year periods were reported. The patient showed high fever and severe headache accompanied by high level of cerebrospinal fluid (CSF) cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alfa (TNF-a). The symptoms and high CSF cytokines were dramatically resolved immediately after inducing indomethacin treatment. Reactivation of the latent virus is considered to be the cause of this rare disease and indomethacin is estimated to inhibit periodic abnormal generation of eicosanoid in the brain resulting in reducing fever and subsequent inflammation.

© 2014, Springer Science+Business Media New York (outside the USA). Microglia are considered the brain’s resident immune cell involved in immune defense, immunocompetence, and phagocytosis. They maintain tissue homeostasis within the brain and spinal cord under normal condition and serves as its initial host defense system. However, when the central nervous system (CNS) faces injury, microglia respond through signaling molecules expressed or released by neighboring cells. Microglial responses are dual in nature. They induce a nonspecific immune response that may exacerbate CNS injury, especially in the acute stages, but are also essential to CNS recovery and repair. The full range of microglial mechanisms have yet to be clarified, but there is accumulating knowledge about microglial activation in acute CNS injury. Microglial responses require hours to days to fully develop, and may present a therapeutic target for intervention with a much longer window of opportunity compare to other neurological treatments. The challenge will be to find ways to selectively suppress the deleterious effects of microglial activation without compromising its beneficial functions. This review aims to provide an overview of the recent progress relating on the deleterious and beneficial effect of microglia in the setting of acute CNS injury and the potential therapeutic intervention against microglial activation to CNS injury.

Background Stroke is a leading cause of death and disability, and despite intensive research, few treatment options exist. However, a recent breakthrough in cell therapy is expected to reverse the neurological sequelae of stroke. Although some pioneer studies on the use of cell therapy for treating stroke have been reported, certain problems remain unsolved. Recent studies have demonstrated that bone marrow stromal cells (BMSCs) have therapeutic potential against stroke. We investigated the use of autologous BMSC transplantation as a next-generation cell therapy for treating stroke. In this article, we introduce the protocol of a new clinical trial, the Research on Advanced Intervention using Novel Bone marrOW stem cell (RAINBOW). Methods/design RAINBOW is a phase 1, open-label, uncontrolled, dose-response study, with the primary aim to determine the safety of the autologous BMSC product HUNS001–01 when administered to patients with acute ischemic stroke. Estimated enrollment is 6–10 patients suffering from moderate to severe neurological deficits. Approximately 50 mL of the bone marrow is extracted from the iliac bone of each patient 15 days or later from the onset. BMSCs are cultured with allogeneic human platelet lysate (PL) as a substitute for fetal calf serum and are labeled with superparamagnetic iron oxide for cell tracking using magnetic resonance imaging (MRI). HUNS001–01 is stereotactically administered around the area of infarction in the subacute phase. Each patient will be administered a dose of 20 or 50 million cells. Neurological scoring, MRI for cell tracking, 18F–fuorodeoxyglucose positron emission tomography, and 123I–Iomazenil single­photon emission computed tomography will be performed for 1 year after the administration. Discussion This is a first-in-human trial for HUNS001–01 to the patients with acute ischemic stroke. We expect that intraparenchymal injection can be a more favorable method for cell delivery to the lesion and improvement of the motor function than intravenous infusion. Moreover, it is expected that the bio-imaging techniques can clarify the therapeutic mechanisms. Trial registration The trial was registered at The University Hospital Medical Information Network on February 22, 2017 (UNIN ID: UMIN000026130 ). The findings of this trial will be disseminated to patients and through peer-reviewed publications and international presentations.

Bone marrow stromal cell (BMSC) transplantation has the therapeutic potential for ischemic stroke. However, it is unclear which delivery routes would yield both safety and maximal therapeutic benefits. We assessed whether a novel recombinant peptide (RCP) sponge, that resembles human collagen, could act as a less invasive and beneficial scaffold in cell therapy for ischemic stroke. BMSCs from green fluorescent protein-transgenic rats were cultured and Sprague–Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAo). A BMSC-RCP sponge construct was transplanted onto the ipsilateral intact neocortex 7 days after MCAo. A BMSC suspension or vehicle was transplanted into the ipsilateral striatum. Rat motor function was serially evaluated and histological analysis was performed 5 weeks after transplantation. The results showed that BMSCs could proliferate well in the RCP sponge and the BMSC-RCP sponge significantly promoted functional recovery, compared with the vehicle group. Histological analysis revealed that the RCP sponge provoked few inflammatory reactions in the host brain. Moreover, some BMSCs migrated to the peri-infarct area and differentiated into neurons in the BMSC-RCP sponge group. These findings suggest that the RCP sponge may be a promising candidate for animal protein-free scaffolds in cell therapy for ischemic stroke in humans.

Recently, bone marrow stromal cell (BMSC) therapy for stroke is expected due to the immunomodulation effect. Here, we use PET and other detecting method to investigate the inflammatory changes of brain and lymphoid organs in rat stroke model. In this study, F344 rats were used as transient MCAO models. One part of rats were serially monitored by small-animal PET/CT system with new neuroinflammatory ligand [ 18 F]DPA-714. The brains were removed and sliced subsequently for autoradiograph (ARG) and TTC staining. The rest of rats were sacrificed, their brains and lymphoid organs were taken out, weighed, stained, etc. In histology, cytotoxic T cell (CD8α), macrophage (Iba1 and CD68), apoptosis (TUNEL) and proliferation (ki67) antibodies were chosen and analyzed. PET and ARG represented high concentration in the ischemic area which had been confirmed by TTC. In body imaging, no significant change was found. With the increase of ischemic severity, the size of lymphoid organs have a significantly decrease as well as the body weight. Histological assay showed cd8α + and ki67 + cells decreased in the lymphoid organs and increased in brain. Besides macrophages and apoptosis cells increased all the time in liver, in other organs, the rate of cells reached peak and gradually decreased more or less. In summary, [ 18 F]DPA-714 PET has a great potential for evaluating brain damage. Inflammatory responses in brain and lymphoid organs are distinct after stroke. Based on these results, we will continue the study for evaluating immunomodulation effect of BMSC transplantation therapy.

Cell transplantation therapy has been expected as one of the novel therapeutic strategies. However, there still exist several fundamental problems to be solved prior to clinical application of stem cell transplantation, such as optimal cell types, transplantation routes, cell dose, and transplantation timing. It is quite important to determine the most desirable and the maximal therapeutic effects of transplantation methods prior to clinical application of cell-based therapy, but there are not so many studies that scientifically determine the most favorable protocol even in animal experiments. Here, we will review and summarize the current experimental results focusing on the unsolved questions, optimal transplantation route, transplantation cell dose, and transplantation timings.

Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome.Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke. © 2014 Bentham Science Publishers.

Hypothermia is neuroprotective against many acute neurological insults including ischemic stroke. We and others have previously shown that protection by hypothermia is partially associated with the suppression of the inflammatory. Phagocytes are thought to play an important role in the clearance of necrotic debris, paving the way for endogenous repair mechanisms to commence, but the effect of cooling and phagocytosis has not been extensively studied. Triggering receptor expressed on myeloid cells-2 (TREM2) is a newly identified surface receptor shown to be involved in phagocytosis. In this study, we examined the effect of therapeutic hypothermia on TREM2 expression. Mice underwent permanent middle cerebral artery occlusion (MCAO) and were treated with one of 2 cooling paradigms: one where cooling (30 C) began at the onset of MCAO (early hypothermia) and another where cooling began 1h later (delayed hypothermia). In both groups, cooling was maintained for 2h. A 3rd group was maintained at normothermia as a control (37C). Mice from the normothermia and delayed hypothermia groups had similar ischemic lesions sizes and neurological performance, but early hypothermia group showed marked protection as evidenced by smaller lesion size and less neurological deficits up to 30 days after the insult. Microglia and macrophages increased after MCAO as early as 3 days, peaked at 7 days, and decreased by 14 days. Both hypothermia paradigms were associated with decreased numbers of microglia and macrophages at 3 and 7 days, with greater decreases in the early paradigm. However, the proportion of the TREM2 positive microglia/macrophages was actually increased among the early hypothermia group at day 7. Early hypothermia showed long term neurological benefit, but neuroprotection did not correlate to immune suppression. However, hypothermic neuroprotection was associated with relative increased in TREM2 expression, and suggests that TREM2 may serve a beneficial role in brain ischemia.

Background Headache is one of the major clinical presentations in pediatric Moyamoya disease. However, the clinical features and underlying mechanisms are not fully understood. This study aimed to clarify the clinical feature of headache in pediatric Moyamoya disease and the effect of surgical revascularization. Methods This study included 29 pediatric patients who underwent superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis and indirect bypass for Moyamoya disease. Their medical records were precisely evaluated to identify the clinical features of their headache. The findings on magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography also were analyzed. Results Preoperative headache was documented in 11 (38%) of 29 patients. The majority of them complained of severe headache in the frontal or temporal region in the morning. Headache was significantly related to more advanced disease stage and to the decreases in cerebral blood flow and its reactivity to acetazolamide. Surgical revascularization completely resolved headache in all 11 patients. Conclusions These findings strongly suggest that disturbed cerebral hemodynamics may play key roles in developing severe headache in pediatric Moyamoya disease. STA-MCA anastomosis and encephalo-duro-myo-arterio-pericranial synangiosis may be effective procedures to rapidly resolve headache by widely supplying collateral blood flow to the operated hemispheres.

An 86-year-old female presented with rare bilateral chronic subdural hematomas (CSHs) of the posterior fossae which were successfully treated by surgical intervention. She had experienced mild head trauma one month before admission. She was transferred to our hospital because of consciousness disturbance and tetraparesis. Magnetic resonance (MR) imaging showed simultaneous occurrence of supratentorial and infratentorial CSHs. We tried to evacuate the CSHs of the bilateral posterior fossae because brainstem compression was markedly severe. Through bilateral burr-hole trepanations, chocolate-colored fluid, not containing clotted components, gushed out under great pressure. Postoperative course was uneventful. MR imaging revealed that the CSHs of the posterior fossae had completely disappeared and brainstem compression had also improved. The patient's neurological deficits were immediately improved after the operation. The patient was discharged one month after the operation for further rehabilitation. Trepanation and evacuation of the hematoma through the posterior fossa might be one of the therapeutic options for posterior fossa CSH, which is similar to supratentorial CSH. However, we considered that the emergency of this rare entity and the method of anesthesia were quite different from supratentorial CSH.

Stereotactic transplantation of bone marrow stromal cells (BMSCs) enables efficient delivery to the infarct brain. This study was aimed to assess its optimal timing and cell dose for ischemic stroke. The BMSCs were harvested from the green fluorescent protein-transgenic rats and were labeled with quantum dots. The BMSCs (1 × 10(5) or 1 × 10(6) ) were stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion at 1 or 4 weeks post-ischemia. Motor function was serially assessed. Using in vivo near infrared (NIR) fluorescence imaging, the engrafted BMSCs were visualized at 3 weeks post-transplantation. Immunohistochemistry was performed to evaluate their fate. Functional recovery was significantly enhanced when both low and high doses of BMSCs were transplanted at 1 week post-ischemia, but such therapeutic effects were observed only when the high-dose BMSCs were transplanted at 4 weeks post-ischemia. Both optical imaging and immunohistochemistry revealed their better engraftment in the peri-infarct area when the high-dose BMSCs were transplanted at 1 or 4 weeks post-ischemia. These findings strongly suggest the importance of timing and cell dose to yield therapeutic effects of BMSC transplantation for ischemic stroke. Earlier transplantation requires a smaller number of donor cells for beneficial effects.

BACKGROUND: A noninvasive and effective route of cell delivery should be established to yield maximal therapeutic effects for central nervous system (CNS) disorders. OBJECTIVE: To elucidate whether intra-arterial delivery of bone marrow stromal cells (BMSCs) significantly promotes functional recovery in traumatic brain injury (TBI) in rats. METHODS: Rat BMSCs were transplanted through the ipsilateral internal carotid artery 7 days after the onset of cortical freezing injury. The BMSCs were labeled with fluorescent dye, and in vivo optical imaging was employed to monitor the behaviors of cells for 4 weeks after transplantation. Motor function was assessed for 4 weeks, and the transplanted BMSCs were examined using immunohistochemistry. RESULTS: In vivo optical imaging and histologic analysis clearly demonstrated that the intra-arterially injected BMSCs were engrafted during the first pass without systemic circulation, and the transplanted BMSCs started to migrate from the cerebral capillary bed to the injured CNS tissue within 3 hours. Intra-arterial BMSC transplantation significantly promoted functional recovery after cortical freezing injury. A subgroup of BMSCs expressed the phenotypes of neurons, astrocytes, and endothelial cells around the injured neocortex 4 weeks after transplantation. CONCLUSION: Intra-arterial transplantation may be a valuable option for prompt, noninvasive delivery of BMSCs to the injured CNS tissue, enhancing functional recovery after TBI. In vivo optical imaging may provide important information on the intracerebral behaviors of donor cells by noninvasive, serial visualization.

A 68-year-old man presented with severe conscious disturbance caused by pituitary apoplexy resulting in massive intracerebral hemorrhage (ICH). He had been periodically followed up for asymptomatic pituitary adenoma at another hospital for 8 years. Neuroimaging examination revealed pituitary apoplexy and massive ICH located in the left frontal lobe, and the ICH was directly connected to the intratumoral hemorrhage. The diagnosis was massive ICH from pituitary apoplexy. The patient underwent emergent evacuation of hematoma and removal of the pituitary adenoma via bi-frontal craniotomy. Postoperatively, he continued to exhibit deep consciousness disturbance and died 1 month after the operation. Pituitary apoplexy is usually characterized by intra-tumoral hemorrhage. The treatment strategy for asymptomatic pituitary adenoma is still controversial. This case shows that we should always consider the risk of pituitary apoplexy manifesting as ICH which may cause a fatal outcome.

Spontaneous echo contrast (SEC) consists of numerous microechoes swirling in the cardiovascular lumen and is usually seen during blood stasis in dysfunctional left atrium. However, SEC and consecutive local thrombus formation at the carotid artery early after carotid endarterectomy (CEA) have not been reported. This study retrospectively investigated the clinical importance and therapeutic strategy of postoperative SEC and thrombus formation in 113 consecutive patients who underwent CEA between 2001 and 2009. Ultrasonography was routinely performed preoperatively, intraoperatively, and 1 day and 1 week after the operation. If SEC and/or thrombus was detected at any time after the operation, follow-up ultrasonography was performed at short intervals, once a week for inpatients and once every 1-2 months for outpatients. Eight of the 113 patients (7%) had SEC after the operation from Day 1 to 12 (mean 7.2 days), and 6 of these 8 patients developed local de novo thrombus formation at the site of SEC from Day 6 to 33 (mean 14.7 days). The maximum luminal narrowing by the thrombi were 26-62% (mean 37%). After administering anticoagulant therapy, all thrombi disappeared from Day 13 to 190 (mean 57 days) from CEA. SEC seen after CEA is highly associated with consecutive local thrombus formation. Postoperative geometric blood stasis with the absence of intima may be the causative factor for its development.

Recent studies have indicated that bone marrow stromal cells (BMSC) may improve neurological function when transplanted into an animal model of CNS disorders, including cerebral infarct. However, there are few studies that evaluate the therapeutic benefits of intracerebral and intravenous BMSC transplantation for cerebral infarct. This study was aimed to clarify the favorable route of cell delivery for cerebral infarct in rats. The rats were subjected to permanent middle cerebral artery occlusion. The BMSC were labeled with near infrared (NIR)-emitting quantum dots and were transplanted stereotactically (1 × 10⁶ cells) or intravenously (3 × 10⁶ cells) at 7 days after the insult. Using in vivo NIR fluorescence imaging technique, the behaviors of BMSC were serially visualized during 4 weeks after transplantation. Motor function was also assessed. Immunohistochemistry was performed to evaluate the fate of the engrafted BMSC. Intracerebral, but not intravenous, transplantation of BMSC significantly enhanced functional recovery. In vivo NIR fluorescence imaging could clearly visualize their migration toward the cerebral infarct during 4 weeks after transplantation in the intracerebral group, but not in the intravenous, group. The BMSC were widely distributed in the ischemic brain and some of them expressed neural cell markers in the intracerebral group, but not in the intravenous group. These findings strongly suggest that intravenous administration of BMSC has limited effectiveness at clinically relevant timing and intracerebral administration should be chosen for patients with ischemic stroke, although further studies would be warranted to establish the treatment protocol.

Isolated oculomotor nerve palsy occasionally occurs in patients with cavernous sinus invasion with or without pituitary apoplexy. We describe two cases of pituitary apoplexy without cavernous sinus invasion presenting with isolated oculomotor palsy. In both cases, computed tomography (CT) showed erosion of the right posterior clinoid process. Magnetic resonance imaging (MRI) depicted pituitary adenoma with apoplexy protruding latero-posteriorly to the right cavernous sinus. The medio-posterior wall of the cavernous sinus was markedly displaced latero-posteriorly by the tumor, and there was no evidence of cavernous sinus invasion. Oculomotor palsy may be caused first by unilateral erosion of the posterior clinoid process, resulting in latero-posterior protrusion of the adenoma. Hemorrhage may result in sudden kinking of the oculomotor nerve at the entrance of the oculomotor trigone.

We report an unusual case of neurohypophyseal germinoma with abundant fibrous tissue and clival invasion that was initially misdiagnosed as lymphocytic hypophysitis. A 40-year-old woman presented with diabetes insipidus and panhypopituitarism after delivering her second son and which lasted for 4 years. Magnetic resonance imaging showed the intrasellar mass extending to the suprasellar region with enlarged pituitary stalk. The mass was heterogeneously enhanced and invaded the clivus. Biopsy of the intrasellar mass was performed via the trans-sphenoidal route, and histological examination revealed marked fibrous tissue and infiltration of lymphocytes, with no evidence of tumor cells. Lymphocytic hypophysitis was the initial diagnosis, and corticosteroid therapy was begun. Despite intensive treatment, the lesion enlarged and clinical symptoms worsened 2 weeks after surgery. Subtotal removal of the mass was performed, and a second histological examination revealed typical findings of the germinoma. Subsequently, the patient underwent chemoradiotherapy, and complete remission was achieved. Histological diagnosis is sometimes incorrect in fibrous tumors at the sellar region, and biopsy from several points is strongly recommended for this entity.

Background/Objectives Ischemic stroke is one of major complications of cardiac surgery. Although a current American Heart Association (AHA) guideline states that carotid endarterectomy is probably recommended before or concomitant to coronary artery bypass grafting (CABG) for the carotid stenosis, there is no report that analyzed optimal strategies in cardiac surgery for patients with total occlusion of the internal carotid artery (ICA) or the middle cerebral artery (MCA). Therefore, this preliminary study was aimed to clarify whether preoperative blood flow measurements and prophylactic superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis could reduce the incidence of perioperative ischemic stroke during cardiac surgery in patients with total occlusion of the ICA or MCA. Methods This prospective study included eight patients who were admitted to undergo cardiac surgery including CABG. All of them had total ICA or MCA occlusion on preoperative magnetic resonance (MR) examinations. Preoperative cerebral blood flow and its reactivity to acetazolamide were quantitatively determined in all eight patients using single photon emission computed tomography or positron emission tomography. Results Preoperative blood flow measurements revealed that two (25%) of eight patients had normal cerebral hemodynamics because of well-developed collaterals. They safely underwent cardiac surgery. However, a marked impairment of cerebral perfusion reserve was identified in six (75%) of eight patients in the ipsilateral hemispheres. Of these, four patients underwent prophylactic STA-MCA anastomosis prior to CABG. Subsequently, they safely underwent CABG without perioperative ischemic stroke. Conclusion This is the first report suggesting that preoperative identification of hemodynamic compromise and prophylactic STA-MCA anastomosis may reduce perioperative ischemic stroke during cardiac surgery in patients with ICA or MCA occlusion, although further studies are needed to assess the validity.

INTRODUCTION: A persistent primitive hypoglossal artery (PPHA) is a rare vascular anomaly and is usually asymptomatic. However, the PPHA may cause multi-territorial infarction when complicated by internal carotid artery (ICA) stenosis. CASE REPORT: We describe a 73-year-old male who simultaneously developed cerebral infarction in both carotid and vertebrobasilar territories due to ICA stenosis associated with an ipsilateral PPHA. The PPHA mainly provided blood flow to the vertebrobasilar territory in this case, because the bilateral vertebral arteries were markedly hypoplastic. He underwent carotid endarterectomy under internal shunting. Intraoperative multi-modality monitoring including angiography, motor evoked potential, and near infrared spectroscopy was very useful to avoid ischemic complications during surgery. The postoperative course was uneventful. CONCLUSION: It should be reminded that a persistent carotid-basilar anastomosis can cause multi-territorial cerebral infarction mimicking cardiogenic embolism and may be a candidate for aggressive prophylactic intervention, when occlusive lesions develop in the carotid artery. It is very important to monitor hemodynamic and/or electrophysiological status in both carotid and verebrobasilar territories in order to perform carotid endarterectomy safely in such cases.

An 11-year-old female receiving treatment for acute lymphoblastic leukemia presented with superior sagittal sinus (SSS) thrombosis. T(1)-weighted, T(2)-weighted, and fluid-attenuated inversion recovery magnetic resonance (MR) imaging, and MR venography showed that the SSS was totally occluded by thrombus. Susceptibility-weighted MR imaging showed hypointense thrombus in the SSS and markedly dilated cortical veins over the bilateral cerebral hemispheres. Two days later, her symptoms had slightly resolved. Iodine-123 N-isopropyl-p-iodoamphetamine single photon emission computed tomography showed marked decrease of cerebral blood flow in the bilateral frontal lobes, indicating that venous congestion had disturbed the cerebral hemodynamics. MR venography showed that the SSS was still mostly occluded, but susceptibility-weighted imaging showed that the dilation of the cortical veins was less marked, suggesting that collateral venous routes had gradually developed. The finding of dilated cortical veins had almost disappeared at 28 days after the onset. Susceptibility-weighted imaging can be used as a non-invasive method to monitor the severity of venous congestion caused by cerebral venous sinus thrombosis.

A 65-year-old woman presented with a rare case of cervical epidural arteriovenous fistula (AVF) manifesting as radiculopathy of the right upper extremity that mimicked cervical spondylosis. She had a 2-month history of gradually progressive right-hand motor weakness and sensory disturbance. The initial diagnosis was cervical disk herniation. However, computed tomography with contrast medium showed abnormal enhancement at the right C5-6 and C6-7 intervertebral foramina. Magnetic resonance (MR) imaging with gadolinium disclosed an enhanced abnormal epidural mass at the dorsal surface of the dural tube between the C5 and C6 vertebrae. T(2)-weighted MR imaging showed a slight flow void on the dorsal and ventral surfaces of the spinal cord between C3 and T4. Digital subtraction angiography disclosed cervical epidural and dural AVFs fed by the C5 and C6 radicular arteries. The diagnosis was concomitant epidural and dural AVFs. The dilated internal vertebral venous plexus attributable to epidural AVF was considered to be responsible for the radiculopathy. Transarterial embolization using n-butylcyanoacrylate achieved complete occlusion of the lesions. Her symptoms improved immediately and MR imaging and angiography performed 10 days postembolization showed reduction of both the epidural and dural AVFs.

遺残舌下動脈（persistent hypoglossal artery，PHA）を分岐する内頸動脈の狭窄病変により内頸動脈系および椎骨動脈系の塞栓症を同時に発症した1例を報告する．症例は73歳男性．右頸部内頸動脈狭窄とPHAを指摘されていた．突然の意識障害などをきたして搬送された．意識障害（JCS II-10），眼球運動障害，皮質盲，左不全片麻痺が存在し，MRIにて右前頭葉，両側後頭葉，脳幹，両側小脳に急性期の梗塞巣を認めた．保存的治療およびリハビリを行ったが，両側皮質盲を後遺した．諸検査にて心原性塞栓は否定され，右頸部内頸動脈狭窄症に起因するartery-to-artery embolismが内頸動脈，PHAを介して多発性脳梗塞をきたしたと考えられた．PHAを合併した内頸動脈狭窄症による脳梗塞はわずかに報告されているのみであり，その診断や治療については注意が必要である．

A 78-year-old woman presented with preauricular superficial temporal artery (STA) aneurysm and scalp porocarcinoma, which had both increased in size over 2 years. She had no previous history of head trauma. Three-dimensional (3D) computed tomography (CT) angiography revealed a 4-cm diameter STA aneurysm arising from the main trunk of the left STA and located just lateral to the zygomatic arch. The scalp porocarcinoma was excised by dermatologists. The STA aneurysm was carefully dissected from the surrounding tissues, and was resected after ligation of the proximal STA. Histological examination showed the aneurysm consisted of intima, media, and adventitia, and the diagnosis was atherosclerotic fusiform aneurysm. 3D CT angiography is quite useful to plan surgical strategy for such an unusually large STA aneurysm.

Clearing cellular debris after brain injury represents an important mechanism in regaining tissue homeostasis and promoting functional recovery. Triggering receptor expressed on myeloid cells-2 (TREM2) is a newly identified receptor expressed on microglia and is thought to phagocytose damaged brain cells. The precise role of TREM2 during ischemic stroke has not been fully understood. We explore TREM2 in bothin vitroandin vivostroke models and identify a potential endogenous TREM2 ligand. TREM2 knockdown in microglia reduced microglial activation to an amoeboid phenotype and decreased the phagocytosis of injured neurons. Phagocytosis and infarcted brain tissue resorption was reduced in TREM2 knock-out (KO) mice compared with wild-type (WT) mice. TREM2 KO mice also had worsened neurological recovery and decreased viable brain tissue in the ipsilateral hemisphere. The numbers of activated microglia and phagocytes in TREM2 KO mice were decreased compared with WT mice, and foamy macrophages were nearly absent in the TREM2 KO mice. Postischemia, TREM2 was highly expressed on microglia and TREM2-Fc fusion protein (used as a probe to identify potential TREM2 binding partners) bound to an unknown TREM2 ligand that colocalized to neurons. Oxygen glucose deprivation-exposed neuronal media, or cellular fractions containing nuclei or purified DNA, but not cytosolic fractions, stimulated signaling through TREM2. TREM2-Fc fusion protein pulled down nucleic acids from ischemic brain lysate. These findings establish the relevance of TREM2 in the phagocytosis of the infarcted brain and emphasize its role in influencing neurological outcomes following stroke. Further, nucleic acids may be one potential ligand of TREM2 in brain ischemia.

Crossed cerebellar diaschisis (CCD) is defined as functional mpairment due to decreased metabolism or blood flow in the cereellar hemisphere that is remote from, and contralateral to, the ausative supratentorial lesion. This widely known phenomenon is hought to be due to a transneuronal depression that is mediated y the corticopontocerebellar pathway. Crossed cerebellocerebral iaschisis (CCCD) is defined as the reverse of CCD, and has been uch less frequently described [1,2]. In fact, there are no reports n neuronal viability in CCCD. Here we report two cases in which e examined CCCD using 123I iomazenil single-photon emission omputed tomography (SPECT) in order to determine the neuronal iability.

Clearing cellular debris after brain injury represents an important mechanism to re-attain tissue homeostasis and promote functional recovery. Triggering receptor expressed by myeloid cells-2 (TREM2) is involved in the innate immune system, and carries out surveillance functions by binding and phagocytosing pathogens. TREM2 is expressed on macrophages and microglia, and promotes the phagocytosis of apoptotic brain cells. Deficiency of functional TREM2 leads to accelerated dementia, and mutations in the TREM2 gene have been linked to Alzheimer’s. Here we explore the significance of TREM2 in a in-vitro and in-vivo stroke model. Cultures of neurons and microglia were subjected to OGD. TREM2-knockout (KO) and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion ischemic model. TREM2 knockdown in microglia by siRNA led to decreased transformation to an amoeboid morphology following co-culture and OGD exposure, but no effect on overall neuron death. OGD-exposed and nuclear lysates from neurons led to TREM2 signaling. In vivo, phagocytosis and infarcted brain tissue resorption was observed in wild-type mice by 14d, but no phagocytosis and little infarcted brain resorption was seen in TREM2 KO mice (p < 0.01)(Fig). TREM2 KO mice also had worsened neurological recovery (p < 0.05), and decreased viable brain tissue in the ipsilateral hemisphere. Numbers of activated microglia and macrophages in KO mice were decreased compared to WT, and oil red staining to identify foamy macrophages was nearly absent in the KO brains. These findings establish the relevance of TREM2 in phagocytosis of the infarcted brain and emphasize the importance of phagocytosis in neurological outcome following experimental stroke.

A 77-year-old female presented with a very rare case of intracerebral hemorrhage (ICH) from a ruptured aneurysm at the site of the anastomosis 27 years after superficial temporal artery-middle cerebral artery (STA-MCA) bypass manifesting as sudden onset of unconsciousness and right hemiparesis. Computed tomography (CT) on admission demonstrated massive ICH in the left frontoparietal region. Magnetic resonance angiography showed good patency of the anastomosis and no obvious aneurysm, but three-dimensional CT (3D-CT) angiography revealed a small aneurysm at the site of the left STA-MCA anastomosis. Emergency evacuation of the hematoma was performed, and the aneurysm was trapped and resected after ligation. After the operation, she continued to exhibit deep consciousness disturbance. Unfortunately, her general condition grew steadily worse and she died 3 months later. Patients who undergo STA-MCA anastomosis should be carefully followed up by periodical imaging examinations. 3D-CT angiography is very useful to detect aneurysm formation at the anastomosis site.

Case report. To report a patient with superficial siderosis as a complication after posterior fixation surgery for odontoid fracture. Department of Neurosurgery, Hokkaido University, Japan. A 36-year-old man had undergone C1–C2 posterior fixation using lamina hooks for an odontoid fracture in 1997. In 2003, he presented with hearing loss and ataxia; and in 2006, a diagnosis of superficial siderosis was made and spinal instrument malpositioning was detected. The malpositioned instrument, suspected as the cause of superficial siderosis, was removed. Superficial siderosis of the central nervous system is rare; it results in progressive hearing loss, cerebellar ataxia and pyramidal sign. Chronic hemorrhage in the subarachnoid space precipitates hemosiderin around the cerebellum and brainstem resulting in neurological symptoms. Recurrent hemorrhage and cervical root pathology, for example, root avulsion, are factors; the symptoms worsen gradually and result in hemostasis. Superficial siderosis because of complications from spinal instrumentation surgery is extremely rare. If the instrument is malpositioned in the subarachnoid space, we suggest its removal.

Even after the recent randomized clinical trials JET and COSS, it is still unclear that impaired cerebrovascular reactivity (CVR) to acetazolamide and oxygen extraction fraction (OEF) can identify the candidates for superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis. This prospective study was aimed to evaluate the benefits of STA-MCA “double” anastomosis on long-term outcome in patients with reduced cerebral blood flow (CBF) and CVR (Type 3 ischemia) and elevated OEF attributable to occlusive carotid diseases. This study included 49 patients with reduced CBF and CVR on SPECT in the ipsilateral MCA area. Using 15O-gas PET, OEF was also measured in all patients. STA-MCA double anastomosis was recommended to the patients with Type 3 and elevated OEF. Those with Type 3 but normal OEF were medically treated. Of 36 patients with Type 3 and elevated OEF, 25 consented to surgery. No perioperative morbidity or mortality were noted. The other 11 patients with Type 3 and elevated OEF were medically treated. Annual incidence of ipsilateral stroke was 0.7 % and 6.5 % in surgically and medically treated patients with Type 3 and elevated OEF, respectively (P = 0.0188). None of patients with Type 3 but normal OEF developed ipsilateral stroke during follow-up periods. STA-MCA “double” anastomosis significantly decreased OEF. STA-MCA “double” anastomosis may still have the potential to reduce the risk of recurrent ipsilateral stroke in hemodynamically compromised patients. Further studies would be essential to advance diagnosis, surgical procedures, and perioperative managements to bring out maximal effects of bypass surgery.

The sphingolipid metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P) and its enzyme sphingosine kinase (SphK) play an important role in the regulation of cell proliferation, survival, inflammation, and cell death. Ceramide and sphingosine usually inhibit proliferation and promote apoptosis, while its metabolite S1P phosphorylated by SphK stimulates growth and suppresses apoptosis. Because these metabolites are interconvertible, it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determine cell fate. The relevance of this “sphingolipid rheostat” and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations. A central finding of these studies is that SphK is a critical regulator of the sphingolipid rheostat, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro-apoptotic ceramide and sphingosine. Activation of bioactive sphingolipid S1P signaling has emerged as a critical protective pathway in response to acute ischemic injury in both cardiac and cerebrovascular disease, and these observations have considerable relevance for future potential therapeutic targets.

Purpose— Stroke is a complex disorder with a poorly understood multifactorial and polygenic etiology. However, little is known about the underlying pathogenic biomarkers. This study was aimed to reveal the antecedent events in the brain of stroke-prone spontaneously hypertensive rats (SHR-SP), by extensive microarray analysis prior to the occurrence of stroke. Method— Blood pressure was measured every week. 0.5% NaCl was loaded everyday from 9 wks of age to promote hypertension additionally. Male SHR-SPs were sacrificed at 6 and 12 wks of age (n=3 and 3, respectively). Wistar-Kyoto rats (WKY; male, 6-wk-old, n=3) utilized as the control sacrificed at 12 wks. Subsequently, total RNA was extracted from cerebral cortices immediately and gene expression profiles were studied using 27k rat cDNA microarray. Differentially expressed probes were determined by one-factor ANOVA (P Result— All animals did not develop any evidence of stroke symptom. Mean blood pressure was lower than 110 mmHg in all 6-wk-old animals, but gradually elevated up to higher than 180 mmHg only in 12-wk-old SHR-SPs. Extensive microarray analysis identified 414 differentially expressed probes. Of these, k-means cluster analysis revealed 84 probes with significant variance of expression in 12-wk-old SHR-SPs. Of these 84 probes, 39 upregulated and 18 downregulated genes were categorized as recognized genes at NCBI EntrezGene. Gene Ontology analysis of these genes showed no specific patterns. However, this study identified 4 differentially upregulated genes that play an important role in cell growth, cell adhesion, transcription regulation and unknown role, including HtrA serine peptidase 4, periostin, zinc finger protein 189, and oxidation resistance 1. Conclusion— Although further studies are essential to determine the specific roles of these 57 genes in the development of stroke, the present data may provide the first large scale description of alteration in gene expression profiles in SHR-SP and suggest several cues to investigate some biomarkers for cerebral stroke.

Hypothermia is neuroprotective against many acute neurological insults. We and others have previously shown that protection by hypothermia is associated with the suppression of the inflammatory response that accompanies stroke. However, comparative mechanisms of the anti-inflammatory process through different hypothermic paradigms have surprisingly not been studied. In this study, we treated mice to early (protective) and delayed (not protective) hypothermia in a stroke model and compared the effect of cooling on the inflammatory response. We also explored the influence of a novel protein, triggering receptor expressed on myeloid cells-2 (TREM2), which is thought to be an important receptor involved in the innate immune response. TREM2 has previously been shown to promote phagocytosis of apoptotic neurons. We subjected male C57/BL6 mice to permanent middle cerebral artery occlusion (MCAO). We identified 2 cooling paradigms, one where cooling (rectal temp=30C) began at the onset of MCAO (early) and a second where cooling began 1h later (delayed). In both cases, cooling was maintained for 2h. A 3rd group was maintained at normothermia as a control (36C). Mice were survived 1, 3, 7, 14 & 30d (n=6/group/time point). Mice from the normothermic and delayed cooling groups had similar ischemic lesions sizes and neurological performance, but mice cooled early showed marked protection as evidenced by smaller lesion size and few neurological deficits at all time points (p < 0.05, 40% reduction). Microglia/macrophages and TREM2 were decreased only in the early cooling group (P < 0.05). Immune cells were reduced only where hypothermia was protective and we conclude that inflammation is probably related to the amount of injury present, and not whether cooling occurred.

An 86-year-old female presented with rare bilateral chronic subdural hematomas (CSHs) of the posterior fossae which were successfully treated by surgical intervention. She had experienced mild head trauma one month before admission. She was transferred to our hospital because of consciousness disturbance and tetraparesis. Magnetic resonance (MR) imaging showed simultaneous occurrence of supratentorial and infratentorial CSHs. We tried to evacuate the CSHs of the bilateral posterior fossae because brainstem compression was markedly severe. Through bilateral burr-hole trepanations, chocolate-colored fluid, not containing clotted components, gushed out under great pressure. Postoperative course was uneventful. MR imaging revealed that the CSHs of the posterior fossae had completely disappeared and brainstem compression had also improved. The patient's neurological deficits were immediately improved after the operation. The patient was discharged one month after the operation for further rehabilitation. Trepanation and evacuation of the hematoma through the posterior fossa might be one of the therapeutic options for posterior fossa CSH, which is similar to supratentorial CSH. However, we considered that the emergency of this rare entity and the method of anesthesia were quite different from supratentorial CSH.

Cerebrospinal fluid (CSF) shunts are commonly employed to treat patients with hydrocephalus. A large number of papers have been published focusing on complications and failures of CSF shunts. However, there appears to be a paucity of knowledge comprehensively covering both common complications and rare ones. In this systematic review, we surveyed articles about surgical complications of CSF shunts as comprehensively as possible. Quantitative analysis was performed to determine the frequency of well-known complications, mortality and revision rates of CSF shunts. Furthermore, rare complications of CSF shunts have also been reviewed.

Objective To determine whether severe cerebral perfusion defects measured by SPECT prior to rt-PA therapy attribute to severe intracerebral hemorrhage (SICH). Methods We measured baseline cerebral blood flow (CBF) using technetium-99m-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT qualitatively prior to rt-PA therapy, in 52 consecutive patients (range 38–93 years). The degree and extent of the asymmetry of local CBF were analyzed semi-quantitatively. We did not administrate rt-PA in patients with severe perfusion defects. Clinical outcome and the incidence of SICH were studied. Results Three (5.8%) patients had severe perfusion defects that were undetected by CT and/or DWI. The other 49 (94.2%) patients had mild perfusion defects. The asymmetry of local CBF was 0.08±0.08 ( n =3) and 0.3±0.15 ( n =49) in the two groups, respectively. The percentages of the ipsilateral hemisphere in which perfusion was impaired severely were 17.5±9.5% ( n =3) and 0.43±0.87% ( n =49). Two patients were found petechial hemorrhage, but there was no patient who developed SICH in the former group following conventional antithrombotic therapy. In the latter group, SICH occurred in 1/49 (2.0%) patient following rt-PA therapy. Conclusion These results suggest that rt-PA therapy for patients with severe cerebral perfusion defects may cause SICH and baseline CBF may contribute to identify patients at high risk for SICH after intravenous rt-PA therapy.

Although a large number of patients with unruptured middle cerebral artery (MCA) aneurysms (AN) have been treated by surgical clipping in Japan, there has yet been no comprehensive study investigating the surgical risks based on a quantitative evaluation of the extensive existing body of patient records. This systematic review was conducted to determine morbidity of the procedure by performing a meta-analysis of the literature. The authors used a PubMed and J-stage search from 2000 to 2011 for studies containing the surgical clipping of the unruptured MCA AN. There were 21 articles, containing a total 1,323 cases of unruptured AN with morbidity specifically located in the MCA. 54 cases indicated significant neurological deficits for a morbidity rate of 4.1% (95% CI; 3.0-5.1). A limited number of studies disclosed an incremental increase in morbidity with the size of the aneurysm. Smaller MCA AN (7±3 mm) presented a lower morbidity of 1.48%, whereas giant MCA AN (25 mm) corresponded with a higher morbidity of 27.8%. Factors consistently associated with high morbidity included incorporated MCA branches, plaque at the neck of the AN, an unclippable configuration, and M1 superior wall AN. Complex aneurysms required a wide array of intracranial bypass procedures, yielding morbidity of 23.4% (95% CI; 20.9-25.9). This is the first systematic review and quantitative meta-analysis of the surgical complications related to unruptured MCA AN.

Stereotactic transplantation of bone marrow stromal cells (BMSCs) enables efficient delivery to the infarct brain. This study was aimed to assess its optimal timing and cell dose for ischemic stroke. The BMSCs were harvested from the green fluorescent protein-transgenic rats and were labeled with quantum dots. The BMSCs (1 × 10(5) or 1 × 10(6) ) were stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion at 1 or 4 weeks post-ischemia. Motor function was serially assessed. Using in vivo near infrared (NIR) fluorescence imaging, the engrafted BMSCs were visualized at 3 weeks post-transplantation. Immunohistochemistry was performed to evaluate their fate. Functional recovery was significantly enhanced when both low and high doses of BMSCs were transplanted at 1 week post-ischemia, but such therapeutic effects were observed only when the high-dose BMSCs were transplanted at 4 weeks post-ischemia. Both optical imaging and immunohistochemistry revealed their better engraftment in the peri-infarct area when the high-dose BMSCs were transplanted at 1 or 4 weeks post-ischemia. These findings strongly suggest the importance of timing and cell dose to yield therapeutic effects of BMSC transplantation for ischemic stroke. Earlier transplantation requires a smaller number of donor cells for beneficial effects.

Background and Purpose - Less-invasive and efficient donor cell delivery is quite important for the clinical application of cell transplantation therapy. Recently, cell sheet technology has gained a great interest as a novel tissue engineering technology, but there are no studies that evaluate the validity of the bone marrow stromal cell (BMSC) sheets as the donor for cerebral infarct. The aim of this study is to assess whether the BMSC sheet can be an alternative transplantation technique to promote functional recovery after cerebral infarct. Methods - The BMSC were harvested from green fluorescence protein (GFP)-transgenic rat and were cultured on a temperature-responsive culture dishes. The mono-layered BMSC sheet was detached by changing the temperature of culture dishes, and was histologically analyzed. Next, the SD rats were subjected to permanent middle cerebral artery occlusion and were divided into 3 experimental groups. Thus, the vehicle or BMSC suspension was stereotactically transplanted into the ipsilateral striatum, or the BMSC sheet was directly transplanted onto the ipsilateral intact neocortex at 7 days after the insult (n=9, 9, 7, respectively). Motor function was assessed for 28 days after transplantation. Finally, histological analysis was performed. Results - BMSC sheet was composed of 9.8 ± 2.4 x10 5 cells (n=10). Stereotactic injection of BMSC significantly enhanced the recovery of motor function after cerebral infarct. Likewise, non-invasive cell sheet transplantation also significantly promoted functional recovery. The therapeutic effect was comparable to stereotactic cell transplantation. Fluorescence immunohistochemistry revealed that the GFP-positive cells were densely distributed in the dorsal neocortex adjacent to cerebral infarct in both groups. Double fluorescence immunohistochemistry demonstrated that the majority of engrafted GFP-positive cells were positive for NeuN and morphologically simulated the neurons in both groups. The density of reactive astrocytes in the ipsilateral striatum was less pronounced in cell sheet transplantation group than in stereotactic transplantation group. Conclusion - These findings strongly suggest that cell sheet technology would make it possible to non-invasively deliver the BMSC into the infarct brain and to yield significant therapeutic effects, when compared with stereotactic injection of cell suspension. The technology may be a clinically valuable and less-invasive construct for non-invasive and efficient cell delivery to regenerate the infarct brain.

Background: Recent studies have indicated that bone marrow stromal cells (BMSC) have the potential to improve neurologic function when transplanted into animal models of central nervous system disorders. However, no methods have been established to objectively evaluate the beneficial effect of BMSC transplantation on the host brain in clinical situation. Therefore, this study was aimed to assess whether the BMSC significantly improve local glucose metabolism in the peri-infarct area on 18 F-fluorodeoxyglucose (FDG) PET, when transplanted into the infarct brain of rats. Methods: The BMSC were harvested from green fluorescent protein (GFP)-transgenic rats and were cultured. The rats were subjected to permanent middle cerebral artery (MCA) occlusion. The BMSC or vehicle was transplanted into the ipsilateral striatum at 7 days after the onset of MCA occlusion. Using 18 F-FDG PET, local glucose metabolism was semi-quantitatively and serially measured at 6 days post-ischemia and at 4 weeks after BMSC transplantation. Motor function was serially evaluated throughout the experiments. The distribution and fate of engrafted cells were examined, using fluorescence immunohistochemistry at 4 weeks after BMSC transplantation. Simultaneously, the expression of brain-type glucose transporter (GLUT1 and GLUT3) was also evaluated. Results: Local glucose metabolism was significantly lower in the dorsal peri-infarct neocortex at 6 days post-ischemia. However, BMSC transplantation significantly accelerated the recovery of local glucose metabolism in that area at 4 weeks after transplantation. Thus, the ratio of glucose metabolism in the ipsilateral to contralateral dorsal neocortex significantly increased from 72.5 ± 4.2% to 78.7 ± 4.0% in the vehicle group (P Conclusion: These findings strongly suggest that BMSC may enhance the recovery of local glucose metabolism in the peri-infarct area when directly transplanted into the infarct brain at clinically relevant timing. The recovery of local glucose metabolism may inhibit pathological upregulation of GLUT1 and GLUT3. 18 F-FDG PET may be the candidate of valuable modalities to scientifically prove the beneficial effects of BMSC transplantation on the host brain in clinical situation.

This study was aimed to assess whether bone marrow stromal cells (BMSC) could ameliorate brain damage when transplanted into the brain of stroke-prone spontaneously hypertensive rats (SHR-SP). The BMSC or vehicle was stereotactically engrafted into the striatum of male SHR-SP at 8 weeks of age. Daily loading with 0.5% NaCl-containing water was started from 9 weeks. MRIs and histological analysis were performed at 11 and 12 weeks, respectively. Wistar-Kyoto rats were employed as the control. As a result, T2-weighted images demonstrated neither cerebral infarct nor intracerebral hemorrhage, but identified abnormal dilatation of the lateral ventricles in SHR-SP. HE staining demonstrated selective neuronal injury in their neocortices. Double fluorescence immunohistochemistry revealed that they had a decreased density of the collagen IV-positive microvessels and a decreased number of the microvessels with normal integrity between basement membrane and astrocyte end-feet. BMSC transplantation significantly ameliorated the ventricular dilatation and the breakdown of neurovascular integrity. These findings strongly suggest that long-lasting hypertension may primarily damage neurovascular integrity and neurons, leading to tissue atrophy and ventricular dilatation prior to the occurrence of cerebral stroke. The BMSC may ameliorate these damaging processes when directly transplanted into the brain, opening the possibility of prophylactic medicine to prevent microvascular and parenchymal-damaging processes in hypertensive patients at higher risk for cerebral stroke.

Recent studies have indicated that bone marrow stromal cells (BMSC) may improve neurological function when transplanted into an animal model of CNS disorders, including cerebral infarct. However, there are few studies that evaluate the therapeutic benefits of intracerebral and intravenous BMSC transplantation for cerebral infarct. This study was aimed to clarify the favorable route of cell delivery for cerebral infarct in rats. The rats were subjected to permanent middle cerebral artery occlusion. The BMSC were labeled with near infrared (NIR)-emitting quantum dots and were transplanted stereotactically (1 × 10⁶ cells) or intravenously (3 × 10⁶ cells) at 7 days after the insult. Using in vivo NIR fluorescence imaging technique, the behaviors of BMSC were serially visualized during 4 weeks after transplantation. Motor function was also assessed. Immunohistochemistry was performed to evaluate the fate of the engrafted BMSC. Intracerebral, but not intravenous, transplantation of BMSC significantly enhanced functional recovery. In vivo NIR fluorescence imaging could clearly visualize their migration toward the cerebral infarct during 4 weeks after transplantation in the intracerebral group, but not in the intravenous, group. The BMSC were widely distributed in the ischemic brain and some of them expressed neural cell markers in the intracerebral group, but not in the intravenous group. These findings strongly suggest that intravenous administration of BMSC has limited effectiveness at clinically relevant timing and intracerebral administration should be chosen for patients with ischemic stroke, although further studies would be warranted to establish the treatment protocol.

Recent studies have elucidated that transplantation of the bone marrow stromal cells (BMSC) has therapeutic potential for the central nervous system (CNS) disorders. However, no imaging modalities have been established to track the engrafted cells in the CNS in clinical situation. This study aimed to investigate the ability of magnetic resonance imaging (MRI) to visualize the BMSC labeled with superparamagnetic iron oxide (SPIO). The BMSC of mice were labeled with SPIO. Various numbers of the cells were injected into the agar phantom and were visualized using a 3.0-T MR apparatus. The SPIO-labeled cells were injected into the temperature-sensitive gelation polymer (TGP) hydrogel and were cultured for 7 days. They were also visualized just after the injection and at 7 days postinjection. After a 7-day culture, they were stained with Turnbull blue technique. T2-, T2*-, and susceptibility-weighted imaging could identify minimally 1,000 cells in the agar or TGP hydrogel, although it was difficult to quantify their number on MRI. All of these sequences could track the SPIO-labeled BMSC for at least 7 days when injected into the TGP. Turnbull blue staining revealed the survival and proliferation of the SPIO-labeled BMSC in the TGP for 7 days. The findings strongly suggest that the SPIO labeling may enable to track minimally 1,000 cells engrafted in the CNS on clinical MR apparatus. These data would be valuable to consider the application of imaging technique into cell transplantation therapy for CNS disorders.