Objective: The aim of this study was to show that 2-min inhalation xenon CT (Xe-CT) can create cerebral blood flow (CBF) images comparable with those by conventional 4-min inhalation Xe-CT. Methods: 2-min inhalation Xe-CT was conducted on consecutive 8 patients aged 75 or older who visited the department of neuropsychiatry. Basal ganglia and lateral ventricle levels were selected for Xe-CT. 30% xenon was inhaled for 2 minutes, then air was inhaled for 3 minutes (2-min wash-in/3-min washout protocol). Contiguous 20 and 18 circular regions of interest (ROIs) were placed around the cortex at the basal ganglia and lateral ventricle levels respectively, and CBF was calculated for each ROI. Utilizing AD patients’ CBF range (AD range) and healthy volunteers’ CBF range (normal range) for each ROI obtained by the 4-min wash-in/4-min washout protocol, the ROI distribution (number of ROIs in AD ranges minus number of ROIs in normal ranges) was obtained. Results: Using the optimal cutoff value of the ROI distribution obtained by the 4-min wash-in/4-min washout protocol, one patient diagnosed as normal was identified as “normal”, and 4 of the 5 patients diagnosed as AD were identified as “AD”. Since the conventional optimal cutoff value was effective, CBF values by the 2-min wash-in/3-min washout protocol were close to those by the 4-min wash-in/4-min washout protocol. Conclusions: We demonstrated that CBF images by 2-min inhalation Xe-CT would be close to those by conventional 4-min inhalation Xe-CT and could be effectively used for clinical evaluation.

Cerebral salt wasting syndrome (CSWS) is a group of diseases that causes hyponatremia and dehydration following conditions including head trauma and subarachnoid hemorrhage. We experienced three cases with different chief complaints and consultation processes. An 86-year-old woman (Case 1) and an 83-year-old man (Case 2) were consulted for consciousness disturbance and hydrocephalus. Both cases had hyponatremia, hypouricemia, and obstructive hydrocephalus after trauma. A 51-year-old woman (Case 3) visited with dizziness and nausea. She had hyponatremia and hypouricemia after trauma. We diagnosed them with CSWS because of trauma history and examination findings. Although the mechanism of CSWS is unknown, it is pointed out to be related to suppression of reabsorption of sodium, uric acid and water in the proximal renal tubule by the natriuretic peptide. In cases with hyponatremia which progresses after head injury, we need to verify if hypouricemia is present so that CSWS is to be diagnosed, and if so, hyponatremia and dehydration should be corrected.

Evolution of reperfusion therapy in acute stroke has been accelerated after the encouraging evidence of endovascular therapy after/without iv rt-PA. Reperfusion therapy has moved from time window selection to tissue window selection, although certain imaging criteria has not yet been established. Penumbral imaging has the potential to solve this tissue selection issue both by CT and MRI scanning. Optimal mismatch ratio between MRI DWI/CT perfusion and PWI Tmax may predict the favorable outcome. These criteria must be discussed to improve the reperfusion therapy strategy in further perspectives using multimodality imaging along with expanding the treatment time window.

4-dimensional computed tomography (4D-CTA) has been developed in recent years as a technique that combines the rapid noninvasive nature of CTA with the dynamic acquisition of DSA. In clinical settings, 4D-CTA has been used for the evaluation of intracranial shunt diseases and hemorrhagic stroke, but now it is expected to play an important role for the image analysis of emergent large vessel occlusions (ELVO). At Ise Red Cross hospital, we have applied 4D-CTA to the patients suspected of ELVO using 64 row-detector scanner and shuttle mode and obtained the following critically important information on the application of mechanical thrombectomy: 1) vessel occlusion site, 2) collateral status, 3) penumbra and core, 4) clot position, length, and characteristics. Based on our experience with 432 cases subjected to emergent 4D-CTA from February 2015 to May 2017, this article shows the usefulness and feasibilities of this technique in the era of mechanical thrombectomy.

Development of vasoprotective drugs that attenuate hemorrhagic transformation (HT) after tissue plasminogen activator (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) as a therapeutic target molecule for HT after tPA treatment. We demonstrated that HT was inhibited by administration of anti-VEGF neutralizing antibody/VEGF receptor antagonist in a rat thromboembolic model. After the animal studies, we acquired intellectual property rights in Japan and United States, established an academic-industrial alliance, and examined the role of VEGF in HT using human samples. Our goal is to conduct a clinical trial to assess the effect of VEGF-inhibiting drugs on HT. In addition, we found that a growth factor progranulin could protect against acute focal cerebral ischemia by variety of mechanisms, which we call “brain protection”, including neuroprotection in part by inhibition of cytoplasmic redistribution of TDP-43, suppression of neuroinflammation via anti-inflammatory interleukin-10 in microglia, and attenuation of blood-brain barrier disruption via VEGF. We’d like to accelerate further researches towards the development of novel combination treatments with “brain protective” drugs and tPA or thrombectomy.

Cerebral amyloid angiopathy (CAA) induces various forms of cerebrovascular diseases from vascular amyloid-β accumulation, resulting in acceleration of cognitive impairment in patients with Alzheimer’s disease, although Alzheimer’s disease and CAA is currently untreatable. Insufficient amyloid-β clearance is more crucial than amyloid-β overproduction in sporadic Alzheimer’s disease and CAA patients. Amyloid-β is mainly eliminated by four mechanisms: (1) enzymatic/glial degradation, (2) transcytosis, (3) glymphatic system, and (4) intramural periarterial drainage (IPAD). IPAD route closely corresponds with the distribution of amyloid-β in CAA patients, suggesting that amyloid-β congestion in the IPAD is closely associated with the pathogenesis of CAA. Cilostazol, a PDE-3 inhibitor, promoted the IPAD clearance system, and rescued cognitive deficits in rodent models. Favorable effects of cilostazol were described in several observational clinical studies. The randomized placebo-controlled clinical trial, COMCID study is ongoing for patients with mild cognitive impairment. Taxifolin, a flavonol with strong anti-oxidative and anti-glycation activities, suppressed amyloid-β assembly by inhibiting oligomer formation, which increased amyloid-β₄₀ clearance into the systemic circulation. Combinational treatment of cilostazol and taxifolin would be a good candidate for the treatment of Alzheimer’s disease and CAA.

Brain vascular pericytes (PCs) which localized in association with the endothelial cells via basal membrane play an important role in maintaining blood-brain barrier (BBB) function and may have multipotent stem cell activity to differentiate into a variety types of cells. Brain PCs are suggested to be neural crest derivatives but in another aspect they derive from the mesodermal cells through hemangioblast of the embryonal stage. Although the precise role of PCs on central nervous system (CNS) injury has not been elucidated, we have demonstrated that PCs can be reprogrammed into multipotent stem cells in response to ischemia/hypoxia, suggesting that the PCs under ischemic condition such as cerebral infarction (ischemic PCs: iPCs) contribute to CNS repair as ischemic injury-induced multipotent stem cells (iSCs) to differentiate into both neural and vascular lineage cells. Because iPC/iSCs express predominantly Nestin and Sox2, neural stem cell markers, they can play an essential role in the reparative process of neurovascular unit in CNS. Our findings may indicate a new concept that the PCs may function as latent multipotent stem cells under diseased, but not normal, condition of CNS.

We introduce our basic and clinical researches to improve the prognosis of the patients suffering from acute ischemic stroke and discuss their future. 1) A nationwide project to promote endovascular therapy for acute stroke (RESCUE-Japan Project): Although clinical evidence was established, mechanical thrombectomy is not widespread in our country. We started promotion of this treatment over the country based on our nationwide surveillance. 2) Development of a new computer application to predict stroke subtypes at prehospital: In acute cerebral large vessel occlusion, the affected vessels should be recanalized as soon as possible for better patient’s outcome. We developed a new computer application to predict stroke subtypes, and would be useful for patient transferring system. 3) A clinical trial regarding lipid lowering therapy for acute stroke and carotid/intracranial artery stenosis: Based on our previous clinical studies, we will start a new study to elucidate the efficacy and safety of PCSK-9 inhibitor. 4) Basic and clinical studies of cell therapy for acute ischemic stroke: We will start clinical trial of cell therapies using bone-marrow mononuclear cells, and ischemia-induced multipotent stem cells (iSCs) to improve clinical outcome of acute stroke patients.

Inflammatory process has been reported to play a significant role in the pathogenesis of cerebral aneurysmal development, growth and rupture, and new possible treatment modalities has been investigated. Clinical cohort studies have produced a new scoring system to estimate risk of aneurysmal rupture, and recent development in vascular wall imaging for cerebral aneurysms also has a possibility to evaluate aneurysmal rupture risk. Preventive pharmacological intervention with anti-inflammatory agents might inhibit aneurysmal growth and rupture, and further precise risk estimation for cerebral aneurysmal rupture is warranted.

Cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO₂) and cerebral oxygen extraction fraction (OEF) are some of the most fundamental parameters to characterize the pathophysiologic status of cerebral tissue, especially. after the onset of cerebral infarction. Positron emission tomographic imaging (PET) using [¹⁵O]O₂ gas is a useful tool for measuring these parameters, but there is no time to perform PET studies in clinical practice. Therefore, animal examination is effective to explore cerebral circulatory metabolic condition in the acute phase. We developed an injectable [¹⁵O]O₂ imaging agent for the purpose of measuring OEF and CMRO₂ in an animal model using a small animal PET system. Furthermore, we developed a quantitative CBF evaluation method without arterial blood sampling using [^99mTc]HMPAO with a small animal SPECT system.

Moyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease of unknown etiology characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain. The disease can cause ischemic and hemorrhage injuries. A hyperperfusion phenomenon complicated with transient neurologic deterioration may be recognized in the acute stage after direct revascularization surgery for MMD, but its pathology is unclear. We evaluated cerebral blood flow and metabolism during hyperperfusion using 15 O-gas PET in the acute stage after surgery to clarify the pathological cause of hyperperfusion. During the hyperperfusion state, cerebral blood flow (CBF) increases markedly, and there was an increase in cerebral blood volume (CBV) as well as a decrease in oxygen extraction fraction (OEF). However, other factors that could not be evaluated by analysis of cerebral hemodynamics may be involved in symptomatic hyperperfusion, and we hope to accumulate more knowledge in the future.

Positron emission tomography (PET) with the use of ¹⁵O-labeled compounds allows estimates of cerebral blood flow (CBF) and oxygen metabolism in a quantitative fashion. In addition to well-known clinical utility for understanding of the pathophysiology of cerebrovascular diseases, a role as a tool for validating newly-developed methods is extremely important. In clinical practice, other imaging modality, i. e. the bolus tracking technique with computed tomography (CT) or magnetic resonance (MR) imaging and the completely non-invasive arterial spin labeling (ASL) MR imaging, is frequently used; however, its reliability for the quantitative CBF measurement is still in debate. Direct comparisons with ¹⁵O PET in clinical research are quite useful for validating the methods. Future studies dedicated for shortening the examination time and non-invasive techniques are required to promote the use of ¹⁵O PET.

Acute thrombectomy has significantly altered cerebral infarction treatment. In a national survey of cases treated with acute thrombectomy (RESCUE-Japan Project), researchers found that 7,702 (6.06/100,000 people/year) procedures were performed in Japan in 2016, thereby accounting for approximately 6% of cases of whole-brain infarction. Accordingly, expanding the application of acute thrombectomy in Japan is urgently needed. Despite its efficacy, half of cerebral infarction patients are unable to recover functional independence after undergoing acute thrombectomy. For these patients with neurological deficits due to cerebral infarction, injury-induced multipotent stem cells (iSCs) are expected to aid in the recovery or regeneration of neurons. In humans, iSCs are endogenous stem cells that develop from pericytes in response to cerebral infarction. Such cells have characteristics of the neural crest, thereby indicating that they are able to differentiate into neurons. Accordingly, iSCs are believed to have a potential role in repairing and regenerating neuronal systems within living organisms. For this reason, the clinical application of iSCs is expected in the near future.

Axonal remodeling is critical to reorganization of damaged brain tissue and associated with functional outgrowth after stroke. We analyzed the mechanisms of axonal outgrowth after stroke. In the peri-infarct area of rat brains, axonal outgrowth and myelination were induced from 7 to 56 days after middle cerebral artery occlusion. In primary cortical neurons, phosphatase tensin homolog deleted on chromosome 10/Akt/Glycogen synthase kinase 3β signaling was related to axonal outgrowth after ischemia. In rat cerebral hypoperfusion, L-carnitine regulated the phosphatase tensin homolog deleted on chromosome 10/Akt/ mammalian target of rapamycin signaling pathway, and enhanced axonal plasticity while concurrently ameliorating oxidative stress and increasing oligodendrocyte myelination of axons, thereby improving white matter lesions and cognitive impairment in rats. Thus, the diverse mechanisms that axons regrow after stroke, potential candidates for a novel therapeutic agent to enhance axonal outgrowth and improve functional outcome human stroke survivors are warranted.

The post-ischemic sterile inflammation will be a hopeful therapeutic target for ischemic stroke. Damage-associated molecular patterns (DAMPs) which are released from dying brain cells activate infiltrating immune cells through pattern recognition receptors. Inflammatory cytokines produced from activated macrophages/neutrophils induce T-cell-mediated secondary ischemic damages in the delayed phase of ischemic stroke. DAMPs are removed from ischemic brain through scavenger receptors, MSR1 which is highly expressed by repairing macrophages, for the resolution of cerebral post-ischemic inflammation. Thus, DAMPs are important regulators of sterile inflammation after ischemic stroke.