The purpose of this study was to validate the usefulness of digital subtraction angiography (DSA) using the fluoroscopic mode of a small-animal PET/CT in detecting recanalization of occluded middle cerebral artery (MCA), and to evaluate reperfusion by ¹⁵O-water positron emission tomography (PET) in rats with transient unilateral occlusion of MCA. Methods: Rats with (n=6) and without transient unilateral MCA occlusion (n=6) were examined. DSA was performed in the X-ray fluoroscopic mode with small-animal PET/CT. An iodine contrast medium (0.3 mL) was administered by bolus injection via the catheter in the internal carotid artery under isoflurane anesthesia. A 10-min dynamic PET scanning was started simultaneously with an intravenous bolus injection of ¹⁵O-water during MCA occlusion (occlusion duration: 45 min) and approximately 30 min after recanalization in ischemic rats. Cerebral blood flow (CBF) was evaluated semi-quantitatively as CBF index determined from the ¹⁵O-water PET images, which is normalized to the injected dose per body weight. Results: DSA revealed recanalization of the ipsilateral MCA in the ischemic rat models. The ¹⁵O-water PET images showed decreased CBF during MCA occlusion and recovery of the CBF after recanalization in the ipsilateral MCA territory. The CBF index of the ipsilateral and contralateral MCA territories during MCA occlusion were 0.84±0.12 and 1.66±0.13, respectively, and those after recanalization were 1.24±0.17 and 1.67±0.10, respectively. The CBF index of the ipsilateral MCA territory increased significantly after recanalization (p=0.04), although it remained significantly lower than the CBF index of the contralateral MCA territory (p=0.04). Conclusions: This study demonstrated the feasibility of DSA using the X-ray fluoroscopic mode of a small-animal PET/CT. Recovery of the CBF was not sufficient at 30 min after recanalization in rats with transient MCA occlusion.

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Purpose: To quantitatively evaluate fibrillar β-amyloid burden in patients with probable Alzheimer’s disease (AD), mild cognitive impairment (MCI), and frontotemporal lobar degeneration (FTLD), as well as in healthy control (HC), using 18F-AV-45 (florbetapir) positron emission tomography (PET). Methods: We performed ¹⁸F-AV-45 PET on 28 patients with probable AD (16 men; mean Mini-Mental State Examination (MMSE) score, 22±5.0; mean age, 69.8±10.4 years), 14 patients with MCI (7 men; mean MMSE score, 26±3.4; mean age, 67.1±6.1 years), 11 patients with FTLD (8 men; mean MMSE score, 25.6±2.5; mean age, 65.5±11.8 years), and 8 HCs (3 men; mean age, 70.8±6.1 years). Dynamic PET was performed from 0 to 80 min after tracer injection (370 MBq), and time-activity curves were constructed. Standardized uptake value (SUV) and cortex-to-cerebellum SUV ratio (SUVR) were calculated for cortical (frontal, temporal, parietal, and occipital lobes) and non-cortical (hippocampus, caudate, putamen, thalamus, and pons) regions of interest. We made an examination of MMSE and WMS-R for all patients and HC. Results: In the 10-min period from 50 to 60 min after tracer injection, cortex-to-cerebellum SUVR were 1.39–1.52 for patients with AD, 1.27–1.34 for patients with MCI, 1.02–1.18 for patients with FTLD, and 1.12–1.33 for HC. In HC, SUVR was higher for white matter than for gray matter. However, for patients with AD, SUVR was higher for gray matter than for white matter. In the frontal, parietal, and temporal regions, SUVR was greater in patients with AD than in patients with FTLD or HC. In the frontal and parietal regions, SUVR was greater in patients with MCI than in FTLD. No significant difference was evident between SUVR in patients with AD and in patients with MCI. In the occipital regions, SUVR was similar in patients with all diseases and in HC. No significant difference was observed in the cortical retention of amyloid of all cortical regions for all subjects. Among patients with AD and MCI, the SUVR of all cortical regions was similar in apolipoprotein E ε4 (APOE-ε4) carriers and ε4 non-carriers. Among patients with AD and MCI, no significant correlation was observed between SUVR and scores of MMSE and WMS Delayed Recall. Conclusion: These results suggest that ¹⁸F-AV-45 PET may be valuable for discriminating between AD dementia and non-AD dementia.

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Ibudilast, phosphodiesterase-4 inhibitor, is widely used in Japan for treating dizziness in the chronic stage of cerebral infarction. We investigated that neuroprotective effects of ibudilast on ischemic injury following permanent focal cerebral ischemia in the rat. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO). An oral suspension of ibudilast (30 mg/kg/day) or vehicle was given for 7 days before ischemia. Magnetic resonance imaging of cerebral blood flow (CBF) was measured 30 minutes and 24 hours after ischemia. Infarct volume, brain edema, neurological outcome, and immunohistological assessments were performed 24 hours after ischemia. Although, there were no differences in the area of decreased CBF 30 minutes after ischemia between vehicle-treated and ibudilast-treated groups, ibudilast treatment significantly reduced the area of decreased CBF, infarct volume, and brain edema 24 hours after ischemia. Ibudilast treatment significantly improved neurological deficit scores accompanied by decreasing lipid peroxidation, oxidative DNA damage, microglial activation, expression of tumor necrosis factor-alpha in the cortical ischemic boundary area compared with the vehicle. Our findings suggest that pre-ischemic oral administration of ibudilast may ameliorate the extent of post-ischemic brain damage and neurological deficits by increasing the CBF and inhibiting oxidative stress and inflammation. Since ibudilast is a well-established drug for a long-term clinical therapy, it may be promising as a candidate therapy for human stroke.

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Background: We perform carotid artery stenting (CAS) under selective general anesthesia for high-risk patients, e.g., those with hemodynamic compromise or contralateral carotid artery obstruction, in order to stabilize the hemodynamics and control body movement. Objective: To conduct a retrospective analysis of the safety of CAS under selective general anesthesia. Methods: CAS for carotid artery stenosis was performed in 22 patients (20 men, 2 women; mean age 70±7 years, 24 procedures) between July 2010 and October 2014 at our institute. These patients were assigned to local and general anesthesia groups primarily on the basis of intracranial hemodynamic considerations or systemic complications. Local anesthesia was used for 11 procedures and general anesthesia for 13. In the general anesthesia group, patients were administered propofol and those with hemodynamic compromise were preoperatively given a free radical scavenger (Edaravone); general anesthesia was continued for a few days after CAS in an intensive care unit. Patients: In the local anesthesia group, 6 patients had ischemic heart disease, 2 patients had no appreciable risk factor, and the others had contralateral carotid artery obstruction, radiation-induced carotid artery stenosis, or hemodynamic compromise. In the general anesthesia group, 5 patients had hemodynamic compromise, 2 patients had contralateral carotid artery obstruction, 3 patients had radiation-induced carotid artery stenosis, one patient had carotid artery stenosis with vulnerable plaque and one had intracranial cerebral aneurysm. Results: Technical and periprocedural angiographic success was achieved in 100% of the patients. Five cases (38%) showed new lesions in MRI-DWI after CAS in the general anesthesia group, compared with three cases (27.7%) in the local anesthesia group; however, the difference is not statistically significant. In the local anesthesia group, one patient with hemodynamic compromise suffered severe disability due to intracranial hemorrhage immediately after CAS, and another had retinal artery occlusion. In the general anesthesia group, there was no neurological disability and no procedure-related complication, even though these were high-risk patients. Conclusion: Carotid artery stenting under selective general anesthesia for CAS in high-risk patients appears to be safe.

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There have been few reports of the stroke related with cerebral venous thrombosis (CVT). We experienced two cases of acute stroke associated with CVT. Case 1: A 79-year-old woman have sudden loss of consciousness due to the CVT of left sigmoid sinus occlusion. Her symptom went well with the anti-coagulant therapy for CVT. Case 2: A 48-year-old man have sudden left hemiplegia due to the CVT of the superior sagittal sinus occlusion. His symptom went well with the anti-coagulant therapy for CVT. We reported previously penumbra-like lesion is found around the ischemic core lesion in the rat venous occlusion model, so early diagnosis is very important for the care for the penumbra-like lesion. In our two cases, the finding of hypo-intense of the occluded sinus in the T2* weighted image is effective for the early diagnosis of CVT.

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Up to 23% of strokes are caused by transient ischemic attack (TIA). Oxidative stress aggravates brain injury following cerebral ischemia. The treatment of anti-oxidant, edaravone is now the standard clinical therapy for only the acute phase of TIA, particularly in Japan. However, edaravone has side effects including acute renal failure and its therapeutic time window is narrow. Thus, safe and prolonged anti-oxidative therapy in the sub-acute phase is required to prevent progressive brain damage after TIA. The glutathione (GSH) system plays a pivotal role in combating oxidative stress. Here, we introduce therapeutic candidates, GSH which elucidates an elevation anti-oxidative system in the brain and inhibits the post-ischemia neuronal damages.

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Preservation of the microcirculation and inhibition of hemorrhagic transformation are the promising strategy of brain protection in the acute cerebral ischemia. It is well established that the pre-ischemic endothelial nitric oxide synthase (eNOS) condition is closely related to cerebral ischemia severity. However, there were few reports about postischemic alterations in the eNOS regulatory system. We evaluated the eNOS phosphorylation and monomerization, and found functional deterioration of eNOS after cerebral ischemia. It is serious issue of the brain protection in the acute phase of ischemia. The endothelial dysfunction after cerebral ischemia may be one of main therapeutic target in acute cerebral ischemia.

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A secreted isoform of receptor for advanced glycation end products (sRAGE) involves sRAGE and endogenous sRAGE (esRAGE). Pentosidine is one of an advanced glycation end product (AGE). Few studies addressed the pivotal roles of the AGEs-RAGE system in acute stroke patients. We measured plasma sRAGE, esRAGE, and pentosidine levels associated with clinical features in acute stroke. The low level of sRAGE was associated with severe leukoaraiosis, high NIHH scores on admission, and cigarette smoking. Significant correlation was observed between the levels of serum sRAGE and esRAGE (R=0.85). Both of which had significant reverse association with estimated glomerular filtration rate. Higher levels of serum pentosidine compared with normal controls were demonstrated in patients with acute stroke. Decreased levels of sRAGE as well as esRAGE in patients with brain hemorrhage were examined 3 days after the onset, however, they increased 14 days after. These findings suggested that sRAGE as well as esRAGE would contribute to the pathogenesis of the onset of brain hemorrhage, and that the serum levels of pentosidine could be a marker of future stroke.

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The clinical profiles was compared between the patients admitted to our hospital with cardioembolic stroke (CE) due to non-valvular atrial fibrillation (NVAF) during the period of 2005 to 2010 (Group A) and those after the introduction of NOAC into Japan until 2014 August (Group B). In Group A, 32% and 23% of the patients were treated with warfarin and anti-platelets at the onset of CE, respectively. In Group B, 35%, 9% and 18% of the patients were treated with warfarin, anti-platelets and NOAC at the onset of CE, respectively, suggesting that the use of antiplatelets in patients with NVAF may have been decreased after the introduction of NOAC. In Group B, NIHSS (NIH stroke scale) and the values of peripheral blood D-dimer at the admission were significantly lower in patients already treated with NOAC than those with warfarin or no anticoagulants. In Goup A, the anticoagulants prescribed at the discharge were warfarin in 76% of the patients and no anticoagulants in 24%. In Group B, the anticoagulants prescribed at the discharge were warfarin in 44% of the patients, NOAC in 43% and no anticoagulants in 13%, indicating that NOAC had already been used in a large portion of CE patients. Long-term safety and efficiency of NOAC should be carefully monitored in future,.

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Observational studies of novel oral anticoagulants (NOACs) have been conducted in Europe and the United States; the results of these studies slightly differed from those of the phase III global study. This difference could probably be attributed to the inclusion and exclusion criteria of the phase III study, which are not reflective of the real-world scenario, as well as problems in NOAC dose setting in the real world. In the large-scale observational study, the efficacy and safety evaluation of NOACs against warfarin was different by the background factors (e.g., CHADS₂ score) of the target population. Dabigatran had superior safety in patients with a low CHADS₂ score. NOACs were consistently superior to warfarin in studies of medication non-adherence rates. A large-scale observational study needs to be conducted in Japan in the future to better reflect the real-world scenario.

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Astroglia play a pivotal role in the brain metabolism as well as in the regulation of cerebral blood flow. In particular, the astroglial metabolic compartment exerts supportive roles in making neurons dedicated to generating action potentials and protects them against oxidative stress associated with high energy consumption. Under ischemia, numerous metabolic derangements occur, resulting in irreversible neuronal damage. The neurovascular unit (NVU) is a conceptual framework used to better understand the pathophysiology of cerebral ischemia. The major components of the NVU are neurons, microvessels and the astroglia that are interposed between the neuronal synapses and the microvasculature. Thus, the metabolic responses of the astroglia in the early stage of ischemia could be either protective or deleterious. In this review, we focus on three major metabolic compartments: the 1) glucose, 2) fatty acid and 3) amino acid, especially D-/L-serine, compartments. Both the beneficial and detrimental roles of the metabolic responses induced in the astroglia will be discussed. A better understanding of the astroglial metabolic response may be expected to lead to the development of a novel strategy in stroke therapy.

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The central nervous system (CNS) white matter (WM) ischemia is an important clinical problem and may produce injury, in part, by reactive oxygen species (ROS)-induced mitochondrial dysfunction. Using the mouse optic nerve (MON) WM model, we tested whether hydrogen (H₂) in drinking water reduced functional WM ischemic injury. Functional integrity of MON was determined by quantitatively monitoring the area of MON compound action potential (CAP) in vitro. A 60 min period of oxygen and glucose deprivation (OGD) caused prompt loss of the CAP followed by an average 20% recovery. After 10–14 days of H₂-water, the CAP area did not disappear during ischemia and recovered to a significantly great extent during reperfusion. Immunostaining of axonal neurofilament also showed significant protection by previous drinking of H₂-water. Accumulation of nuclear 8-oxoguanine (8-oxoG), a marker of oxidative DNA damage, was observed mainly in oligodendrocytes after OGD. The level of 8-oxoG and lipid peroxidation after OGD were significantly reduced in optic nerves from H₂-water drinking mice. The importance of these observations is that ischemic protection of myelinated CNS WM by drinking H₂-water provided partial protection in a novel manner, suggesting oxidative stress-resistance and intriguing therapeutic options.

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Many experimental data from animal stroke have showed strong neuroprotective effects, nevertheless clinical trials of neuroprotective agents was failed to clinical useful therapeutic strategy. A free radical scavenger, edaravone is the first clinical drug for neuroprotection in the world which has been used in almost many ischemic stroke patients in Japan from 2001. Although it is especially useful in neuroprotective therapy with edaravone, we still need the newly more effective neuroprotective drugs which can be applied to many ischemic stroke patients. Although immunosuppressant, FK506, suppressant of astrocyte activation, ONO-2506, and rho-kinase Inhibitor, fasudil has strong neuroprotective agents for stroke, the results of the clinical trial with FK506, ONO-2506, or fasudil has been announced for failure. Now, we review and describe the future neuroprotective strategies in the combination therapy with extra-mild hypothermia.

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Tissue plasminogen activator (tPA) treatment is beneficial for patients with ischemic stroke when started within 4.5 h of stroke onset. However, the risk of intracerebral hemorrhagic transformation (HT) increases with the delay in treatment initiation. Development of vasoprotective drugs that attenuate HT after tPA treatment might improve the prognosis of stroke patients and extend the therapeutic time window of tPA. We identified vascular remodeling factors such as vascular endothelial growth factor (VEGF) and angiopoietin 1 as therapeutic target molecules for HT after tPA treatment. We demonstrated that HT was inhibited by intravenous administration of anti-VEGF neutralizing antibody/VEGF receptor antagonist or recombinant angiopoietin 1 in a rat thromboembolic model. After the animal studies, we acquired intellectual property rights and established an academic–industrial alliance. Presently, we aim to conduct a clinical trial to assess the effect of VEGF-inhibiting drugs on HT. From our experiences, to overcome “the valley of death”, which is the difficult period of transition from laboratory success to human clinical trials, in drug development, academic researchers need to focus on (i) improving the quality of animal studies, (ii) acquiring intellectual property rights, and (iii) promoting academic–industrial alliances.

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A precise understanding of the cellular interplay in the neurovascular unit is fundamental to develop a way of preventing neurodegenerative disorders resulting from cerebrovascular disturbance. A new imaging technique using in vivo two-photon microscopy with a variety of animal models that genetically express fluorescence proteins in the cells enables us to explore the structural and functional plastic changes in the neurovascular unit. Here we report the optical imaging and analytical techniques to visualize and quantify the neurovascular structures and functions. For imaging of brain microvasculature, a capillary length and diameter was automatically measured and their three-dimensional images were reconstructed by using custom-written matlab software. For brain cell imaging, either neurons or glias were fluorescently labeled, and their morphological parameters were determined along with a location of the measured cells. In addition to the static imaging, a dynamic scanning method allows for acquiring a functional property of the cerebral blood flow and/or intracellular calcium concentrations. Finally, a future work should focus on a development of the imaging and quantification methods for cellular environment and genetic and/or protein expressions. Further technical improvements with in vivo two-photon microscopy with a variety of fluorescent proteins will provide a powerful tool for understanding the long-term neurovascular plasticity in health and disease.

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In order to elucidate the mechanisms of cerebral aneurysmal development, growth and rupture, animal models are requisite. The models include 1) direct injury models against arterial walls by direct surgical procedures, and 2) indirect induced models by burdening aneurysm-induction factors. The latter model can induce characteristic histological features similar to human cerebral aneurysms such as disappearance of internal elastic lamina and destruction of smooth muscle layer, and is useful for analyzing pathogenesis of the lesion. We have introduced rat and monkey models by performing unilateral common carotid occlusion and renal artery occlusion with bilateral oophorectomy and fed by high salt diet with a collagen synthesis inhibitor. Possible medical treatments against cerebral aneurysm development are discussed.

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Establishment of human induced pluripotent cells (iPS) promises the possibility of regenerative therapy against stroke. We describe the history of neural stem cell research in brain ischemia. Effective cell transplantation against stroke needs to re-organize cortico-spinal tract including regeneration of motor neurons. Adult neurogenesis in human cannot improve functional recovery after stroke now. We are using rehabilitation using hybrid assistive limbs (HAL) to encourage neurogenesis. It is important for us to establish neurophysiological and neuroradiological assessment system based of scientific evidence.

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Currently more than 600 brain check-up systems are conducted in Japan. They have contributed to early detection of unruptured cerebral aneurysms and silent brain lesions. There are increasing number of participants who expect to have examinations for dementia in addition to stroke. The Japan Brain Doc Society newly obligated brain doc institutes to include T2* images in MRI examination to detect cerebral microbleeds (CMB), because CMBs are known to be a strong risk factor for future cerebral hemorrhage and infarction. Amyloid angiopathy should also be considered when multiple CMBs distribute in the cerebral cortex or subcortex. The Brain Doc Society also obliged to carry out cognitive function tests, which are performed only in 30% of the whole brain doc institutes. Because extra resources are required for implementing these tests as routine, the guideline recommends a simple test using a computer (e.g. CADi: Cognitive Assessment for Dementia, iPad version). In addition to silent brain lesions a quantitative assessment of hippocampal volume is also recommended for MRI examination. In future resting-state functional MRI would provide useful information regarding functional connectivity for early detection of dementia.

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Periodontitis increases the risk of atherosclerotic cardiovascular disease and ischemic stroke. In this study, we evaluated whether serum antibody levels against individual periodontal pathogens are significantly associated with ischemic stroke subtypes and their risk factors. Serum hs-CRP levels were significantly associated with acute ischemic stroke even after controlling for acute ischemic stroke, hypertension, diabetes mellitus, and bulb/ICA atherosclerosis that were statistically selected. The serum-antibody level of Pi was significantly higher in atherothrombotic-stroke patients than in patients with no previous stroke. Detectable serum anti-Pg antibody was significantly associated with atrial fibrillation, and detectable serum anti-Pi antibody was significantly associated with bulb/internal carotid artery atherosclerosis after controlling for the statistically selected associated factors. The levels of serum anti-Pi antibody were significantly associated with atherothrombotic stroke with the statistically selected associated factors excluding bulb/ICA atherosclerosis. However, when we included bulb/ICA atherosclerosis into this model, the levels of serum anti-Pi antibody were no longer significantly associated with atherothrombotic stroke. Our results suggest that anti-Pg antibody is associated with atrial fibrillation and anti-Pi antibody is associated with carotid artery atherosclerosis. Additionally, anti-Pi antibody may be associated with atherothrombotic stroke through its association with carotid artery atherosclerosis. Thus, periodontitis may lead to serious systemic diseases.

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Diabetes, a risk factor for cerebral infarction, increases the risk of vascular dementia by 2.0–4.2 times and that of Alzheimer disease by 1.1–2.4 times. Mechanisms include cerebral ischemia induced by atherosclerosis, white matter lesion caused by small vessel disease, impaired amyloid clearance, glucose toxicity generated with advanced glycation endproducts, and hyperinsulinemia. Amyloid PET, developed recently, was used to assess amyloid loading even before the damage of the neurons. In healthy volunteers without subjective and objective higher cortical dysfunction, age-dependent accumulation of amyloid was observed, showing high amyloid loading in the elderly. The diabetic patients with Alzheimer-type dementia showed no specific accumulation pattern in amyloid. Diabetes may just facilitate amyloid toxicity without diabetes-specific process. Recently amyloid clearance was reported to decrease in Alzheimer disease, especially in cases with white matter lesions. Impaired blood-brain barrier in these cases may reduce amyloid clearance from brain parenchyma. Specific treatments targeting these mechanisms may help decrease the risk for Alzheimer disease in the near future.

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The development of next generation therapy for ischemic stroke is important for the aging society. To control post-ischemic inflammation could be a hopeful therapeutic approach. In this review, we focus on the triggers of inflammation after ischemic stroke. Various danger associated molecular patterns (DAMPs) activate pattern recognition receptors (PRRs) in immune cells and trigger the acute sterile inflammation in brain. The activation of inflammasome is also important for IL-1β production in ischemic brain. Ibrutinib can be a therapeutic agent for ischemic stroke by inhibiting the activity of Bruton’s tyrosine kinase (BTK) which promotes the inf lammasome activation. Thus, further investigation of inflammatory mechanisms will develop a novel therapeutic strategy for ischemic stroke.

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We investigated cerebral hemorrhage 24 hours after MT8148 (MT), the standard strain of S. mutans or TM295 (TW) isolated from a subject with cerebral hemorrhage administered, using cerebral hemorrhage model in mice. Bacteria-induced aggravation of cerebral hemorrhage was observed in mice infected with TW, but not MT. The most important factor for highly virulent strains is the presence of the CBP expression. The reduction of cerebral hemorrhage was observed with TW295CND, a defect of CBP expression. TW caused the activation of MMP-9 in the ipsilateral hemisphere of injured mouse brain and reduced the platelet aggregation induced by collagen. S. mutans strains with collagen-binding protein possess high affinity to the exposed collagen fibers, resulting in the accumulation of highly virulent bacteria in collagen-denuded blood vessels. The accumulation of bacteria consequently leads to the activation of MMP-9 and the inhibition of platelet aggregation in injured blood vessels, resulting in an acceleration of bleeding and hemorrhagic infarction.

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Vascular pericytes (PCs) are a component of the blood-brain barrier (BBB)/neurovascular unit together with astrocytes and endothelial cells. Besides their crucial role in maintaining the BBB, increasing evidence shows that PCs have a potential to be a multipotent stem cell activity. However, their multipotency has not been considered in the pathological brain, such as after an ischemic stroke. Here, we examined whether brain vascular PCs undergoing ischemia (iPCs) have multipotential stem cell activity and differentiate into neural and vascular lineage cells to reconstruct the BBB/neurovascular unit. Using PCs extracted from ischemic regions (iPCs) from mouse brains and human brain PCs cultured under oxygen/glucose deprivation, we show that PCs developed stemness presumably through reprogramming. The iPCs revealed a complex phenotype of angioblasts, in addition to their original mesenchymal properties, and multidifferentiated into cells from both a neural and vascular lineage. These data indicate that under ischemic/hypoxic conditions, PCs can acquire multipotential stem cell activity and can differentiate into major components of the BBB/neurovascular unit. Thus, these findings support the novel concept that iPCs can contribute to both neurogenesis and vasculogenesis (neurovasculogenesis) at the site of brain injuries.

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Stem cell transplantation has emerged as a promising new experimental treatment for stroke; understanding its mechanism of action will facilitate the translation of stem cell therapy to the clinic. The ultimate change in brain plasticity is manifested at the synaptic level, however, the synaptic remodeling after stem cell therapy remains unknown. Vehicle or human neural progenitor cells (hNPCs) derived from fetal cortex were transplanted into the ischemic cortex of Nude rats at 7 days after distal middle cerebral artery occlusion. Transplantation of hNPCs significantly improved behavioral recovery after stroke compared to vehicle-treated rats at 3–4 weeks post-transplantation. We found that transplanted stem cells enhanced endogenous brain repair processes including structural brain plasticity. hNPC-treated rats had a higher density of glutamatergic synapses in layer 5 at 4 weeks posttransplantation, compared to vehicle-treated rats. These results provide novel new information about the organization of synaptic circuitry and its plasticity after stem cell therapy. These data suggest that stem cells alter the synaptic remodeling of glutamatergic synapses after stroke and this is coincident with stem cell-induced functional recovery.

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How can we reduce the cerebrospinal damage subsequent to postcardiac arrest syndrome (PCAS) is depending on whether we could inhibit the progress of the negative spiral cascade to induce cerebral damage and improve the functional recovery. On behalf of the improvement of the BLS (Basic Life Support) and ACLS (Advanced Life Support) at the cardiopulmonary resuscitation and the progress of the blood flow interventinal therapy at cerebral infarction and combination of the brain-oriented intensive care came to be able to find the light, however brain has few reserve forces for ischmeic events and brain does not have enough defense mechanisms for ischemic events. Also, therapeutic window for the treatment is still very narrow because of its complicate mechanisms and difficult all patients to come back to normal life. To progress the brain protection and discover new treatment and drugs, it is important to investigate the mechanisms of ischemic brain damage and its pathophysiology. Especially, to analyze the mechanisms of ischemic brain damage and innovate new drugs focusing on the mitochondrial dyfunction may open new avenue. In this review, we referred to PCAS and referred a mechanism of the ischemic brain damage based on the mitochondria dysfunction and the importance of calcineurin-immunophilin signal transduction pathway to be associated with cell death.

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In epileptic encephalopathy, epileptic activity itself may contribute to severe cognitive and behavioral impairments, and it is a case in severe epilepsies in infancy and early childhood. Epilepsies caused by cortical dysplasia are intractable and hence surgical treatment is recommended for them during early childhood when brain functional plasticity is still expected. MRI is generally difficult to interpret because of poor contrast in infancy. Therefore positron emission tomography (PET) and single photon emission computed tomography (SPECT) are useful to identify seizure focus, and SISCOM (Subtraction Ictal SPECT CO-registered to MRI) is particularly important. Eight patients with severe epilepsies underwent a hemispherectomy during infancy and early childhood at the Epilepsy Center of Okayama University Hospital. In two patients, MRI showed uncertain abnormalities, and SISCOM and PET disclosed pathological cortical regions, demonstrating the validity of functional neuroimaging techniques related to brain circulation and metabolism in the evaluation of very young candidate patients for epilepsy surgery.

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4,620,000 people with dementia and 4,000,000 people with mild cognitive impairment were reported by Japanese government, and dementia prevention measure is regarded as urgent problem. The Japanese Society of Dementia Prevention was started in 2011 to take measure of dementia prevention. The aims of this society are to promote dementia prevention, to cultivate human resources who participate in dementia prevention, to cooperate many job category and community cooperation, and to create scientific evidence of dementia prevention. Initiative of dementia prevention started from Kotoura-cho, Tottori-prefecture and is spreading over the whole country. We made specialized person for dementia prevention and authorized medical technologist for dementia territory as human resources who participate in dementia prevention. We also made the committee for evidence creation and is now in preparation of scientific evidence. It seems to have many joint ownership between the Japanese society of cerebral blood flow and metabolism and the Japanese society of dementia prevention.

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Objective: The purpose of our retrospective study was to find predictors of hyperperfusion syndrome (HPS) before and immediately after carotid artery stenting (CAS). Methods: Included for analysis were patients 1) who underwent elective CAS, 2) who underwent single-photon emission computed tomography (SPECT) and transcranial color-coded real-time sonography before and immediately after CAS. The ratio of cerebral blood flow (CBF) by comparing the CBF in the affected cerebral hemisphere area to the CBF in the ipsilateral cerebellar hemisphere (middle cerebral artery (MCA)-to-cerebellar activity ratio), cerebral vasoreactivity (CVR), MCA mean blood flow velocity in the affected hemisphere and MCA mean blood flow velocity ratio (preoperative to postoperative) were assessed. Results: Sixty-four patients who underwent elective CAS were analyzed retrospectively. Nine patients presented HPS. Logistic regression analysis showed that CVR (p<0.01) and MCA mean blood flow velocity (p<0.05) were the significant predictors among the pre-CAS variables, and that MCA mean blood flow velocity ratio (p<0.05) and MCA-to-cerebellar activity ratio change (p<0.05) were significant predictors among the post-CAS variables. Conclusions: SPECT and transcranial color-coded real-time sonography studies are useful in predicting HPS.

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American Food and Drug Administration(FDA) approved recombinant tissue plasminogen activator(rt-PA) based on the result of the NINDS study in 1996. After that, rt-PA IV therapy came to be performed widely all over the world. In Japan, use of rt-PA was approved in October, 2005. Effective possibility until onset 4.5 hours for time-window is shown in many studies and time-window was extended by 4.5 hours from September, 2012 in Japan as well as other countries. We have performed the IV-rt-PA studies based on MRI after approve of use of rt-PA. In this paper, herein, we mentioned our studies as follows, 1) DWI before the t-PA treatment and patient outcome, 2) t-PA treatment and presence of right left shunt, 3) M1 susceptibility vessel sign (M1 SVS) on T2* and early recanalization after rt-PA therapy, and 4) t-PA treatment and microbleeds on T2*.

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We have come to the time to reconsider the bulk theory that have been hitherto upheld in explaining the cerebrospinal fluid as the third circulatory system next to the blood and lymph. There are possibilities that the cerebral capillaries serve as the site of generation and absorption of tissue and cerebrospinal fluids and as the drainage pathway for metabolic and waste products. If we assume that these functions of cerebrospinal fluid are disturbed when individuals enter pathological states or become aged, there are possibilities that the behaviors of the cerebrospinal fluid involve the neurovascular unit (NVU). Thus it is necessary to examine the correlation of these possibilities with the results of past experiments and clinical findings. If we are to believe that astrocytes, a component constituting NVU, are related to the water channel such as aquaporine, it becomes necessary to re-examine the cerebral blood circulation, which has hitherto been defined by the accepted theories and knowledge, in line with the added concept of cerebrovascular circulation. In the past, the studies on metabolism related to cerebrovascular circulation tended to lean heavily on blood circulation. For the future studies of neuroprotection, complex and comprehensive approaches, such as the concept of the NVFU (NeuroVascular cerebrospinal Fluid Unit) with spacial and functional expansion encompassing not only cerebrovascular but also cerebrospinal fluid circulations may be necessary.

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Recently, impaired cerebral blood flow autoregulation has been reported to be associated with poor outcomes for patients with severe subarachnoid hemorrhage (SAH) and traumatic brain injury (TBI). The Pressure Reactivity Index (PRx) derived from the Pearson correlation coefficient between intracranial pressure (ICP) and mean arterial blood pressure (MABP) has been reported as a useful indicator of impaired cerebrovascular autoregulation at the acute stage of severe SAH and TBI. We investigated whether the indicator monitored during the acute stage strongly correlated with the outcomes for patients with poor-grade SAH and severe TBI. The results of our study revealed that values of the PRx at the acute stage increased in the groups of patients with the development of cerebral vasospasm after SAH. In the group of patients who developed delayed cerebral infarction following cerebral vasospasm, the increase in the mean values of the PRx were significant compared to those for the group of patients without cerebral vasospasm. The PRx values of patients with poor outcomes after severe TBI were significantly higher than those of patients with favorable outcomes. We report the usefulness of PRx monitoring at the acute stage of severe brain damage.

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Neuroendovascular therapy has been widely induced in the treatment of the cerebrovascular disease for the last several decades. Cerebral vessels, targets of the neuroendovascular therapy, have two aspects; the one is a pipe supplying the blood flow to the brain, and the other is a tissue growing, remodeling, and regressing itself. Thus, the assessment of neuroendovascular therapy should not only be done with an angiographic point of view, but also with changes of the blood flow and metabolism in cerebral or targeting tissue. Here, the author discusses the present and the future research of the cerebral blood flow and metabolism in the field of the neuroendovascular management.

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Ischemic tolerance is endogenous neuroprotective phenomenon induced by sublethal ischemia. Ischemic preconditioning (IPC) is the first discovered phenomenon of ischemic tolerance. The phenomenon induced by non-lethal ischemia before the lethal ischemic event is widely seen in many species and various organs. IPC shows strong neuroprotective effect in animal models of ischemia, however it is difficult to perform IPC before the ischemic event occur. After that, some other neuroprotective procedures called ischemic postconditioning, remote ischemic preconditioning and remote ischemic postconditioning were discovered. Because these methods can overcome the problem of IPC, these discoveries had great impact on clinical approach of stroke treatment. Ischemic tolerance is safe and promising technique for treating stroke, and understanding the mechanism of neuroprotection and finding the potential biomarker for classifying the responder is essential.

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It is an established concept that damaged brains undergo irreversible change after cerebral infarction and that only necrotic and inflammatory cells are observed within post-ischemic areas. However, using a mouse model of cortical infarction, we have shown that endogenous neural stem/progenitor cells (NSPCs) are activated within post-ischemic areas following cerebral infarction. We named these cells injury/ischemia-induced NSPCs (iNSPCs) because they can differentiate into neural lineages. However, we recently found that iNSPCs exhibit multipotent stem cell activity and that they can differentiate into not only neural but also non-neural lineage cells. In this article, we introduce the origin and characterization of these brain-derived ischemia-induced multipotent stem cells (BiSCs) based on our reports and recent viewpoints. We also refer to possible regeneration by BiSCs following cerebral infarction.

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In this article, I introduced my career in the research of cerebral blood flow and metabolism. My works of cerebral blood flow and metabolism were divided into three subjects: the basic research of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH), carotid plaque imaging, and the clinical research for moyamoya disease. I investigated the influence of hypoxia-inducible factor-1 on cerebral vasospasm using a rat SAH model. As a part of the research of plaque imaging, I performed the comparison study between the images by magnetic resonance imaging and histological sections of carotid plaques. I evaluated the difference of significance of posterior circulation involvement between pediatric and adult patients with moyamoya disease. Some investigations in which I have recently engaged as graduate mentoring were also shown in this manuscript. I think that neurosurgeons should have an emphasis on clinical practice and research work evenly. I hope I will grow as a neurosurgeon on this principled grounds.

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It is necessary to obtain neurovascular imaging to make treatment decision of revascularization therapy for acute ischemic stroke. Within 4.5 hours of onset, thrombolytic therapy using recombinant tissue-plasminogen activator (rt-PA) is considered if patients with large core are excluded. For this purpose, early ischemic changes on CT or diffusion weighted imaging (DWI) described as low ASPECTS or ASPECTS+W, respectively, is the key finding. DWI has high sensitivity to ischemia than CT, however, difference in detection characteristics needs to be considered and display method should be standardized. Simultaneously, vessel imaging should be performed to explore candidates for endovascular therapy. Recent randomized controlled trials, such as ESCAPE, EXTEND-IA and SWIFT PRIME, confirmed the presence of target vessel occlusion for stent retrievers, small core, and good collateral or tissue at risk. They are the key for successful outcomes. To improve our current rapid MRI first diagnostic system, or to change our strategy to CT first (CTA/multiphase CTA/CT perfusion) style that is common internationally, we need to consider.

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In patients with ischemic stroke, biomarker may be useful to support its early diagnosis and personalize their therapy. Although many biomarkers have been reported as a candidate marker for ischemic stroke, few are currently used in clinical practice. To identify useful markers for ischemic stroke, we have performed REBIOS study and have found that plasma VEGF is associated with clinical outcomes depending on stroke subtypes. Therefore, the clinical importance of biomarkers may be different according to stroke etiology. Heterogeneity in ischemic stroke hampers the clinical usefulness of blood biomarkers. Common study flaws in biomarker studies reported so far are small study sizes, unclear diagnostic cut-points, and lack of clinical validation of the proposed biomarkers. Further study regarding biomarkers for ischemic stroke is needed to validate in large-scaled study size. Efforts toward discovery of stroke biomarkers have the possibility to improve patient outcome.

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The signal transducers and activators of transcription (STAT) were found to be essential for the regulation of apoptosis and cell death initiated by a pro-survival signaling cascade. In focal cerebral ischemia, STAT3 tyrosine 705 phosphorylation has been demonstrated in neurons and activation of STAT3 is correlated with neuronal survival. However, the precise role of STAT3 serine phosphorylation remains unclear. In this study, we examined the phosphorylation status of ser727-STAT3 in the hippocampal CA1 region by using a rat transient global ischemia model. Western blot analysis showed that ser727-STAT3 phosphorylation was induced in hippocampal CA1 neurons after ischemia. Ser727-STAT3 phosphorylation transiently increased in the early stage of reperfusion after lethal ischemia, in contrast, it gradually increased in a time-dependent manner and peaked at 2 day after nonlethal ischemia. In the preconditioned brains, it also increased in the early stage of reperfusion, however, decrease of its levels delayed compared to the nonconditioned brains. Furthermore, inhibition of STAT3 phosphorylation abolished preconditioning-induced neuroprotection. Our results suggest that activation of ser727-STAT3 after nonlethal ischemia is closely associated with acquisition of ischemic tolerance. Although further investigation is necessary to clarify the exact role of STAT3 serine phosphorylation in neuroprotection, STAT3 can be an important target for stroke therapy.

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Previous studies have shown that intraparenchymal transplantation of neural stem cells (NSCs) ameliorates neurological deficits in animals with intracerebral hemorrhage (ICH). However, massive grafted cell death following transplantation, possibly caused by a hostile host brain environment, lessens the effectiveness of this approach. We focused on the effect of oxidative stress induced by hemoglobin against grafted NSCs and showed genetic manipulation to overexpress copper/zinc-superoxide dismutase (SOD1), which is a specific antioxidant enzyme that counteract superoxide anions, enhances survival of grafted NSCs and accelerates amelioration of ICH. Our results suggest that enhanced antioxidative activity in NSCs improves efficacy of stem cell therapy for ICH.

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¹⁵O-labeled gas PET has been performed in clinical settings for over 20 years, the stage classification by Powers has been widely used as a basic theory. However, some cases were unable to classified into any category by Powers in clinical practices. Especially, there has been no comprehensive report about paradoxical reduction after acetazolamide loading. We evaluated the brain regions with paradoxical reduction and demonstrated that high blood f low regions were included in them. Furthermore, we have established the method of quantitative evaluation of cerebral blood flow and oxygen metabolism in small animals by ¹⁵O-labeled gas PET and successfully performed the PET imaging of increased OEF in the ischemia model. ¹⁵O-labeled gas PET and glial PET imaging are expected to bridge between disease models and clinical pathology with the evaluation of cerebral circulation and metabolism.

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