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Interneuronal information transfer occurs at synapses, where AMPA receptors play a key role. With regard to physiological function, synaptic trafficking of AMPA receptors underlies memory, learning and experience. Analysis of animal models of disease and postmortem brains of patients has revealed that abnormal expression and functions of AMPA receptors may trigger various neuropsychiatric disorders. Such findings are currently being used for the development of therapeutic drugs through quantification of AMPA receptors in patients' brains in real-world practice.

Positron emission tomography (PET) refers to a noninvasive imaging modality that enables ultrahigh-sensitivity quantitative evaluation of the spatiotemporal dynamics of targeted molecules within living organisms from outside the body. In this review, we explain the principles of PET imaging technology and the basic properties of ultrahigh sensitivity and quantifiability. Furthermore, we have outlined PET imaging-based integrated approaches to elucidate the fundamental neurobiological mechanisms underlying neuropsychiatric activity, as well as the usefulness of PET imaging in pharmacokinetic analysis and theranostics during drug development.

We have reported on two Catalytides (Catalytic peptides), JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMI). Both peptides belong to the Tob/BTG family proteins and cleave Aβ42. Although Catalytides must be delivered to the brain parenchyma to treat Alzheimer's disease, the blood-brain barrier (BBB) limits their entry into the brain from the systemic circulation. Thus, we evaluated the direct route of ANA-TA9 from the nasal cavity to the brain to bypass the BBB. In this study, we present our findings on JAL-TA9. Animal studies using rats and mice clarified that the plasma clearance of JAL-TA9 was more rapid than its in vitro degradation in plasma, whole blood, and cerebrospinal fluid (CSF). After nasal administration of JAL-TA9, brain concentrations were significantly higher than after intraperitoneal administration, despite much lower plasma concentration. This observation strongly suggests direct delivery of JAL-TA9 to the brain from the nasal cavity. Similar findings were observed for its transport to CSF after nasal and intravenous administration. The concentration of JAL-TA9 in the olfactory bulb peaked at 5 ‍min, while those in the frontal brain peaked at 30 ‍min and in the occipital brain at 60 ‍min. In conclusion, JAL-TA9 was efficiently delivered to the brain by nasal application compared to other routes.

Fibromyalgia (FM) is characterized by chronic generalized pain accompanied by various symptoms, such as extreme fatigue, insomnia and depression. Clinical studies have indicated the presence of psychological stress, sympathetic nervous system hyperexcitation and immune system abnormalities, as a trigger for the onset of the disease, but the contribution to the pathogenesis of the disease remains unclear. Here, we employed the repeated acid saline-induced generalized pain (AcGP) model, as an experimental mouse model of FM. In this model, the unilateral repeated acid injection into gastrocnemius muscle induced transient and long-lasting mechanical hypersensitivity. We focused on the spleen, a secondary lymphoid organ, and found that the intravenous treatments of splenocytes derived from AcGP mice caused mechanical hypersensitivity in naїve mice. Since the spleen is directly innervated by sympathetic nerve, we examined whether adrenergic receptors are necessary for pain development or maintenance. The administration of butoxamine, a selective β 2 -blocker, prevented the development but did not reverse the maintenance of pain-like behavior in AcGP mice. Furthermore, β 2 -blockade in donor AcGP mice eliminated pain reproduction in recipient mice injected with AcGP splenocytes. We currently employed another model of FM, the intermittent psychological stress-induced generalized pain (IPGP) model and found that as in AcGP model, the sympathetic nervous system and the spleen play important roles. These results suggest that sympathetic β 2 signaling is enhanced by physical/psychological stress, and that immune system cells in the spleen activated in response play an important role in the formation and maintenance of chronic pain.

Recently, bottom-up technologies, in particular the utilization of self-assembly of functional polymers to form nanostructures in solutions have been collecting attention. These technologies are being explored for various applications, especially for usage in therapeutics. One of the goals of such studies is to develop a drug delivery system (DDS) that delivers bioactive substances to specific targets within our body, eliciting the desired functionality. The authors have been developing "nanomachines" using biocompatible polymers to safely and efficiently deliver drugs mainly to tumors. The aim of this study is to utilize our expertise in designing a nanomachine to develop a cutting-edge nanomachine that can efficiently penetrate the blood-brain barrier (BBB) and deliver drugs to the brain parenchyma. Furthermore, leveraging this "nanomachine" technology, the authors are advancing the "Hayabusa Nanomachine," which can non-invasively collect and detect brain molecules, correlating them with various biological processes, ultimately leading to a better understanding of brain function and diseases. This paper also introduces the concept and ongoing efforts to the development of "Hayabusa Nanomachines," which have the potential to revolutionize existing approaches in this field.

Because of absence of the objective biomarker for major depressive disorder (MDD) or depressive state, psychiatrists depend on subjective examinations in order to properly diagnose their patients. We recently identified the candidates of the objective biomarker of depressive state of late-onset MDD by profiling gene expressions in white blood cells of patients and model mice. We also investigated whether gene expression profiling of white blood cells was useful to elucidate the biological alterations in the brain. Furthermore, we newly developed transgenic mice which will be useful for elucidating the neurological mechanisms of emotional abnormalities in psychiatric disorder. In this review, I introduce our recent research to help for understanding of translational approaches to develop the biomarker of depression.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury (rmTBI). Clinically, CTE experienced by athletes with rmTBI can lead to long-term neurological impairment, including memory disturbances, Parkinsonism, behavioral changes, speech irregularities, and gait abnormalities, formerly described as punch-drunk syndrome and dementia pugilistica. CTE has gained significant public interest owing to dramatic cases involving retired professional athletes wherein severe behavioral problems and tragic incidents were reported. However, no reliable biomarkers of late-onset neurodegenerative diseases following TBI are available, and a definitive diagnosis can only be made via postmortem neuropathological examination. CTE is characterized by abnormal accumulation of hyperphosphorylated tau proteins. Neuropathological studies have revealed that CTE demonstrates a unique pattern of tau pathology in neurons and astrocytes and accumulation of other misfolded proteins such as TDP-43. Furthermore, gross pathological findings were revealed, especially in severe CTE. Thus, we hypothesized that objective neuroimaging patterns linking the history of rmTBI or CTE might be established using tau positron emission tomography (PET) and magnetic resonance imaging (MRI). In this review, we present the clinical and neuropathological features of CTE and our efforts to develop a prenatal diagnostic method using MRI and tau PET. The unique findings of tau PET images and various signal and morphological abnormalities on conventional MRI in retired athletes with rmTBI may be useful in diagnosing CTE.

Cyclooxygenase-2 (COX-2) has attracted attention as a biomarker for neurodegenerative brain diseases. The aim of this study was to develop a COX-2 imaging agent for positron emission tomography (PET) that binds to and emits radiation from COX-2 in the central nervous system to diagnose brain lesions related to COX-2. To this end, the development of PET imaging probes by derivatizing non-steroidal anti-inflammatory drugs that bind to COX-2 was investigated. Herein, we present the findings of a series of studies on indomethacin and nimesulide derivatives. All five 11 C-labeled indomethacin derivatives showed low brain uptake and were rapidly metabolized in vivo, indicating that they are inadequate COX-2 imaging agents. However, the evaluation of 11 C-labeled indomethacin derivatives revealed an inverse relationship between the amount taken up by the brain and the lipophilicity of the compound, and that P-glycoprotein (P-gp) may be responsible for the low brain uptake of 11 C-labeled indomethacin derivatives. To overcome the problems associated with 11 C-labeled indomethacin derivatives, nimesulide was selected as a novel COX-2 imaging agent. Although the nimesulide derivatives were less lipophilic and unaffected by P-gp, all three 11 C-labeled nimesulide derivatives showed low brain uptake and were rapidly metabolized. However, the 11 C-labeled nimesulide derivatives were partially useful as brain-targeted COX-2 imaging agents because they bound specifically to COX-2 in the brain of mice and successfully imaged the regional brain distribution associated with COX-2. In the development of COX-2 imaging agents, in vivo stability of the compounds is a future objective.

Psychosocial stress is a risk factor for psychiatric disorders, including depression and anxiety, and chronic pain, whereas chronic pain is also closely related to the development of psychiatric disorders. However, the pathological mechanisms of stress-triggered psychiatric disorders and chronic pain are unknown, and their effective treatments have not been established. Recently, the advances in analytical techniques for fatty acids and their metabolites have made it possible to comprehensively measure changes in fatty acid composition in various cells and organs using the lipidomics approach, and to visualize the localization of phospholipids, fatty acids, and other lipid mediators using imaging mass spectrometry. Many researchers have focused on understanding the differences in the distribution of phospholipids, fatty acids, their lipid metabolites in cells and organs, and the changes of fatty acid composition in various diseases. More recently, changes in the fatty acid composition and its distribution during chronic pain and stress have also been reported. We also proposed that modulation of brain fatty acid signaling could be a new therapeutic target for stress-induced chronic pain. In this review, we summarize the latest basic and clinical findings on the role of fatty acid signaling in stress-induced psychiatric disorders and chronic pain.

The production of angiotensin II (Ang II) in the brain plays important roles as neurotransmitter and neuropeptide. Central Ang II is involved in regulating various physiological processes, such as blood pressure and water homeostasis, via Ang II type 1 (AT1) receptors. We have demonstrated that Ang II induces frequent urination via AT1 receptors in the brain even at doses that does not seem to affect the blood pressure in animal experiment. Intracerebroventricular administration of Ang II was also found to reduce the bladder capacity without affecting the maximum voiding pressure, post voiding residual urine volume or voiding efficiency. Additionally, the activation of AT1 receptor downstream signal pathway (phospholipase C/protein kinase C/NADPH oxidase/superoxide anion) and suppression of GABAergic nervous system in the brain are involved in the mechanism underlying the central Ang II-inducted frequent urination. AT1 receptor blockers (ARBs) have been widely used to treat hypertension. We demonstrated that peripherally administered ARBs telmisartan, which can penetrate blood-brain barrier, exerted an inhibitory effect on central Ang II-inducted frequent urination. We present the possible drug therapy targeting AT1 receptors in the brain against frequent urination on the results obtained from our recent research work.

Glial cells are non-neuronal cells that make up the central nervous system, including astrocytes, oligodendrocytes, microglia, and ependymal cells, which play an important role in brain homeostasis. However, activated microglia and reactive astrocytes cause neuroinflammation, which is closely related to neurodegeneration. Neuronal loss, gliosis, and accumulation of misfolded proteins are commonly observed in the brain of many neurodegenerative diseases at autopsy. Therefore, in vivo imaging of glial cell responses by positron emission tomography (PET) would be useful not only for understanding pathological processes, but also for differential diagnosis and evaluation of disease-modifying therapeutics targeting glial cells. The gold standard marker for reactive astrocytes is glial fibrillary acidic protein (GFAP), but no specific ligands are available. To date, there are two targets of reactive astrocytes that are under intense investigation: Monoamine oxidase-B (MAO-B) and imidazoline 2 binding site (I 2 BS). PET radiopharmaceuticals for MAO-B and I 2 BS have been developed and are under clinical investigation. In this chapter, we review the MAO-B and I 2 BS as molecular targets for imaging reactive astrocytes and introduce the PET tracers and their clinical studies.

The free fatty acid receptor 1 (FFAR1) is suggested to function as a G protein-coupled receptor for medium- to long-chain free fatty acids. We have previously shown that FFAR1 signaling pathway plays an important suppressive role in spinal nociceptive processing after peripheral inflammation and nerve injury, and that FFAR1 agonists might serve as a new class of analgesics for treating inflammatory and neuropathic pain. To further pursue the functional significance of central FFAR1 signaling, we investigated the possible involvement of FFAR1 in endogenous pain modulation, depressive-like behavior, and aberrant behavior induced by addictive drugs using FFAR1 agonist (GW9508), FFAR1 antagonist (GW1100), and FFAR1 gene-deficient mice. As a result, FFAR1-deficient mice were found to exhibit stronger inflammatory and peripheral neuropathic pain-like behavior as well as depressive-like behavior. In particular, we noticed that peripheral nerve injury-induced depressive-like behavior was insensitive to imipramine. Next, we employed in vivo microdialysis to investigate whether FFAR1 is actually involved in the regulation of brain monoamines (dopamine and serotonin) releases. Our findings suggest that FFAR1 indirectly regulates dopamine release by promoting serotonin release. Thus, we are currently investigating how FFAR1 is involved in behavioral changes induced by addictive drugs such as cocaine and morphine. In this review, we briefly discuss about the possible involvement of FFAR1 in cocaine-induced locomotor hyperactivity.

Theranostics, a new medical term that combines therapeutics and diagnostics is considered an ideal system for medical care. Ultrasound is considered one of the most reasonable energies for the development of theranostics. Additionally, microbubbles, which are ultrasound contrast agents, have received considerable attention for their effectiveness in diagnosis and therapy. Microbubbles are composed of an inner gas and an outer shell composed of proteins or phospholipids. Under ultrasound exposure, the oscillation or collapse of microbubbles is induced depending on the intensity of the ultrasound. These mechanical effects are important for imaging, drug delivery, and ablation therapies. Therefore, it is essential that microbubbles reach the targeted site and induce mechanical effects to achieve effective and efficient diagnosis and therapy. We have previously developed novel microbubbles with high stability by optimizing the outer shell composition. Recently, microbubbles containing distearoylphosphatidyl glycerol showed high stability and prolonged circulation in the blood. These novel microbubbles may be useful for diagnosis and therapy. The combination of microbubbles and ultrasound has received considerable attention for brain-targeted drug delivery applications. We examined whether microbubbles can be used for brain-targeted drug delivery and evaluated the effect of the encapsulated gas on drug delivery. Thus, novel microbubbles combined with ultrasound can deliver molecules to the brain. Microbubbles containing perfluoropropane or perfluorobutane could efficiently deliver molecules to the brain. The novel microbubbles have long-circulating properties in the blood and could deliver molecules to the brain. The combination of novel microbubbles and ultrasound would contribute to the development of efficient thranostic systems.

In physiotherapy, it is important to attempt to improve skills. The issue of how to perform exercise without fatigue is a factor involved in improvement of skills. However, the mechanism of fatigue is not clear. Therefore, it is a problem when a physiotherapy program is planned. Thus, it is important to clarify the mechanism of fatigue. In this review, the cause of fatigue was clarified from the research of Hill et al. that forms the basis of the peripheral fatigue model, the established theory of the mechanism of fatigue, and the limits of the peripheral fatigue model are suggested by the latest research. We introduce a new mechanism of fatigue derived from brain science, and introduce the application of the new mechanism of fatigue to physiotherapy. [ABSTRACT FROM AUTHOR]

The excitatory glutamate AMPA receptor is the most important molecule for processing information in the brain. We have succeeded in developing the first-in-class PET drug ([ 11 C] K-2) that visualizes AMPA receptors in the living human brain (Nature Medicine 2020). AMPA-PET imaging of patients with psychiatric disorders can disclose the molecular pathology underlying the diseases, contributing to the creation of novel disease animal models based on the phenotype of patients. Our research approach, basic and clinical fusion research, is expected to elucidate the biological basis for multiple neuropsychiatric disorders. AMPA-PET is attributed to the development of therapeutic methods targeting AMPA receptors, which have been delayed worldwide due to the inability of the technology to visualize AMPA receptors in human, leading to the foundation for the development of innovative diagnostic and therapeutic methods based on the molecular evidence of "seeing and treating AMPA receptors."

The living body is composed of diverse organ systems, each of which has its own characteristic control mechanisms and complex in vivo responses. Between the brain and organs such as the heart, kidney, liver, pancreas, gastrointestinal tract, and even muscles, there is a sophisticated and complex regulatory system. Coordinated interactions through communication between organs are essential for maintaining health. In this review, we introduce four research trends in inter-organ networks, with a focus on the digestive system: 1) Inter-organ networks on metabolic systems, 2) Inter-organ networks originating from the gastrointestinal tract, 3) Intestinal bacteria, that is one of the biggest topics in recent years, 4) Research results on the involvement of gut microbiota in the inter-organ network between the kidney and the gastrointestinal tract. An integrated understanding and investigation of the regulatory mechanisms of inter-organ communication networks are expected to extend healthy life span and improve quality of life.

The basal levels of intracellular Zn 2+ and extracellular Zn 2+ are in the range of ～100 pM and ～10 nM, respectively, in the brain. Extracellular Zn 2+ dynamics is involved in both cognitive performance and neurodegeneration. The bidirectional actions are linked with extracellular glutamate and amyloid-β 1-42 (Aβ 1-42 ). Intracellular Zn 2+ signaling via extracellular glutamate is required for learning and memory, while intracellular Zn 2+ dysregulation induces cognitive decline. Furthermore, human Aβ 1-42 , a causative peptide in Alzheimer's disease pathogenesis captures extracellular Zn 2+ and readily taken up into hippocampal neurons followed by intracellular Zn 2+ dysregulation. Aβ 1-42 -mediated intracellular Zn 2+ dysregulation is accelerated with aging, because extracellular Zn 2+ is age-relatedly increased, resulting in Aβ 1-42 -induced cognitive decline and neurodegeneration with aging. On the other hand, metallothioneins, zinc-binding proteins can capture Zn 2+ released from intracellular Zn-Aβ 1-42 complexes and serve for intracellular Zn 2+ -buffering to maintain intracellular Zn 2+ homeostasis. This review summarizes Zn 2+ function and its neurotoxicity in the brain, and also the potential defense strategy via metallothioneins against Aβ 1-42 -induced pathogenesis.

Alzheimer's disease (AD) is one of the most common causes of dementia in the world. Neurodegeneration, gliosis, and misfolded proteins such as amyloid plaques and tau tangles are neuropathological hallmarks in AD. In vivo imaging of these neuropathological lesions would be good biomarkers to understand pathophysiology as well as surrogate markers for clinical trials. We developed THK tau radiotracers including [ 18 F]THK-5351 and tested them in humans. Validations studies identified monoamine oxidase-B (MAO-B) as the off-target binding substrate of [ 18 F]THK-5351. Since the elevation of MAO-B, which is highly expressed in reactive astrocytes, were observed in various neurological conditions, MAO-B would be a promising target for imaging reactive astrogliosis. In fact, [ 18 F]THK-5351 PET studies demonstrated that high tracer uptake in site susceptible regions to occur astrogliosis in various neurological disorders. However, the lack of binding selectivity affects the interpretation of PET images. Therefore, we performed lead optimization from [ 18 F]THK-5351 generating a selective and reversible MAO-B PET tracer, [ 18 F]SMBT-1. These translational and reverse translational studies, from the development of PET tracers to validation of PET images, led to the generation of new biomarkers. In this review, we will introduce the development of [ 18 F]THK-5351, identification of off-target binding substrates, imaging-autopsy validations, new tracer development ([ 18 F]SMBT-1), and finally recent clinical studies of [ 18 F]SMBT-1.

Cerebral edema is a major contributor to the mortality associated with ischemic stroke and traumatic brain injuries; however, limited therapeutic strategies are available for cerebral edema. Aquaporin-4 (AQP4), the main water channel in the brain plays a key role in water homeostasis and edema formation in the central nervous system. Therefore, regulation of AQP4 function or expression is considered a possible target for treatment of edema. Despite extensive research over several decades, AQP4 inhibitors have not been approved for the treatment of edema in humans. Further studies are warranted to gain a deeper understanding of the exact properties and functions of AQP4, to facilitate the development of newer therapeutic approaches for cerebral edema.

Monoamine transporter occupancy of antidepressants in the brain can be measured by positron emission tomography. For antidepressive effects to appear, serotonin transporter (SERT) occupancy should rise to 80% or higher. Despite a recent increase in the number of reports on norepinephrine transporter (NET) occupancy, estimating the threshold level of NET occupancy required for antidepressive effects is difficult based on the analysis of NET alone. Therefore, studies should be conducted on NET occupancy required for a valid treatment, including an ideal balance between SERT and NET occupancy. (Received 24 September 2020; Accepted December 18, 2020; Published June 1, 2021).

Although the involvement of genomic factors in bipolar disorder is clear, its neural basis remains a question. We proposed the mitochondrial dysfunction hypothesis of bipolar disorder in 2000 and have since been testing it. Our results showed that mitochondrial DNA (mtDNA) polymorphisms affected mitochondrial Ca 2+ concentration, and mitochondrial Ca 2+ uptake and intracellular Ca 2+ signaling were altered. Spontaneous repetitive depressive episodes were seen in mice in which mtDNA mutations accumulated in the brain (mutant Polg transgenic mice). We searched for the brain regions with the accumulation of mutant mtDNA in these mice, and found that it was most abundant in the paraventricular nucleus of the thalamus (PVT). Neural circuit manipulation of the PVT caused similar repetitive hypoactive episodes, suggesting that the PVT may be involved in causing bipolar disorder.

Migraine is the sixth most common cause of disability worldwide. Historically, three theories regarding the etiology of headache have been suggested: vascular, neuronal, and trigeminovascular. However, the mechanism of migraine is still unknown. The advantages of studying the premonitory phase are several as it is the earliest clinical change during a migraine attack, and hence, is likely to disclose brain areas involved right at the beginning. Studying this phase may also allow to reveal the generator of migraine. In human neurophysiology, human functional neuroimaging, and preclinical biochemical studies, the relationship between the premonitory phase and hypothalamus has been suggested. On the other hand, calcitonin gene-related peptide (CGRP) has now been firmly established as a key player in migraine. Trigeminal CGRP and its roles in vasodilation, neurogenic inflammation, and peripheral sensitization are likely to be the most relevant peripheral actions causing the condition. CGRP could also be acting as a neuromodulator of light aversion, central sensitization, and cortical spreading depression (CSD).

Cellular transport systems for both essential and toxic trace elements remain elusive. In our studies on the transport systems for cadmium (Cd), we found that the cellular uptake of Cd is mediated by the transporter for manganese (Mn). We identified ZIP8 and ZIP14, members of the ZIP zinc (Zn) transporter family, as transporters having high affinities for both Cd and Mn. Notably, the uptake of Cd into rice root from soil is mediated by a transporter for Mn as well. We found that ZIP8 is highly expressed at the S3 segment of the kidney proximal tubule and can transport glomerulus-filtered Cd and Mn ions in the lumen into epithelial cells of the proximal tubule, suggesting that ZIP8 has an important role in the renal reabsorption of both toxic Cd and essential Mn. Mutations in ZIP8 and ZIP14 genes were found in humans having congenital disorders associated with the disturbed transport of Mn, although ZIP8 mutation causes whole-body Mn deficiency while ZIP14 mutation causes Mn accumulation in the brain. Mutations in ZnT10, a Zn transporter responsible for Mn excretion, also cause hyperaccumulation of Mn in the brain. Results of genome-wide association studies have indicated that ZIP8 SNPs are involved in a variety of common diseases. Thus, ZIP8, ZIP14, and ZnT10 play crucial roles in the transport of Mn and thereby control Mn- and Cd-related biological events in the body.

Development of therapeutics for Alzheimer's disease (AD) is an urgent research task. Amyloid β (Aβ) is one of the causative proteins of AD. Irie et al. identified a toxic conformer among the various structures of 42-mer Aβ (Aβ42). This conformer, which possesses a turn structure at the positions Glu22-Asp23, exhibits rapid oligomerization and potent neurotoxicity. By the generation of conformationally-specific antibodies against this toxic conformer of Aβ, elevation of the toxic conformer in the AD brain was strongly suggested. To investigate the pathogenic role of the toxic conformer in AD, passive immunization experiments against conventional AD model mice were conducted. Specific antibody administration improved the behavioral abnormalities observed in AD model mice without affecting senile plaque pathology. Next, knock-in mice exclusively producing the toxic conformer of Aβ were generated. These mice exhibited cognitive dysfunction and oligomerization of Aβ, which preceded the onset of the plaque deposition. Taken together, the toxic conformer of Aβ is confirmed to be involved in the pathogenesis of AD, and our knock-in mice could be useful in analyzing the Aβ oligomer-related pathology of AD.

Background: 18 F-florbetapir is an amyloid β (Aβ) -targeted 18 F-labeled positron emission tomography (PET) tracer for the clinical diagnosis of Alzheimer's disease. The standardized uptake value ratio (SUVR) serves as a tool with which to differentially diagnose. The present study aimed to cross-validate and compare SUVR derived from Amygo neuro and MIMneuro software., Methods: We injected 40 individuals with 18 F-florbetapir and then acquired PET images from 50 to 60 minutes later. All images were separately normalized to the standard 18 F-florbetapir PET template using Amygo neuro and MIMneuro. Volumes of interest (VOIs) were automatically placed on six target regions each in Amygo neuro and MIMneuro. The composite SUVR (cSUVR) and regional SUVR (rSUVR) were calculated from mean values measured in VOI. A cSUVR of>1.10 was defined as representing Aβ positivity. Correlation coefficients were calculated in the two types of software., Results: A cSUVR>1.10 was determined by Amygo neuro and MIMneuro in 15 of the 40 individuals. The rSUVR in the posterior cingulate, parietal lobe, precuneus, and temporal lobe significantly differed between Amygo neuro and MIMneuro, whereas the cSUVR did not. The SUVR calculated by the two types of software closely correlated to each other (R=0.89-0.96, P<0.05)., Conclusions: The cSUVR was not different between Amygo neuro and MIMneuro. We suggest that Amygo neuro is comparable to MIMneuro in quantitative analysis using SUVR for 18 F-florbetapir imaging, thus facilitating the use of standardized quantitative approaches to amyloid PET imaging.

The blood-brain barrier (BBB) consists of brain capillary endothelial cells linked by tight junctions and serves to regulate the transfer of endogenous compounds and xenobiotics between the circulating blood and brain interstitial fluid. We have developed a methodology to characterize brain-to-blood efflux transport in vivo, using the Brain Efflux Index and an in vitro culture model of the BBB, i.e., a conditionally immortalized cell line of the neurovascular unit. Employing these methods, we showed that the BBB plays an important role in protecting the brain by transporting neurotransmitters, neuromodulators, metabolites, uremic toxins, and xenobiotics together with atrial natriuretic peptide from the brain interstitial fluid to the circulating blood. We also developed a highly selective, sensitive LC-MS/MS method for simultaneous protein quantification. We found significant species differences in the expression amounts of various BBB transporter proteins among mice, rats, marmosets, cynomolgus monkeys, and humans. Among transporter proteins at the BBB, multidrug resistance protein 1 (Mdr1/Abcb1) is known to generate a concentration gradient of unbound substrate drugs between the blood and brain. Based on measurements of the intrinsic efflux transport rate of Mdr1 and the protein expression amounts of Mdr1 in mouse brain capillaries and Mdr1-expressing cell lines, we predicted the unbound drug concentration gradients of 7 drugs in the mouse brain in vivo. This was the first successful prediction of in vivo drug transport activity from in vitro experimental data and transporter protein concentration in tissues. This methodology and findings should greatly advance central nervous system barrier research.

We have been investigating the physiological and pathological roles of stem cells and progenitor cells in the central nervous system using multimodal imaging methods, including positron emission tomography (PET), in vivo optical imaging, and light as well as electron microscopy. Furthermore, we generated transgenic rats for selective ablation of these cells. Imaging studies have demonstrated the proliferation and dynamics of neural stem cells in neurogenic regions and glial progenitor cells expressing a chondroitin sulfate proteoglycan (neuron-glial antigen 2; NG2) in the brain of adult rodents. Glial progenitor cells change their direction of differentiation into mature oligodendrocytes or astrocytes by neural activity following their proliferation. This phenomenon was thought to control the local tissue structure for maintenance of moderate neural activity. Furthermore, selective ablation of glial progenitor cells in the brain induced defects of neurons via neuroinflammation with microglial activation and proinflammatory cytokine production in the region. Thus, we have proposed a novel concept that glial progenitor cells regulate the neuro-immune system in the central nervous system, in addition to their role as germinal cells, giving rise to mature glial cells. Neuroinflammation is associated with the onset and progression of depression, chronic fatigue syndrome, and neurodegenerative diseases, including Alzheimer's disease. Anti-inflammatory effects of glial progenitor cells might bring about the possibility of these cells as the new therapeutic targets for such neurological disorders.

Beta-propeller protein-associated neurodegeneration (BPAN) is categorized in Neurodegeneration with brain iron accumulation. The clinical feature of BPAN is global developmental delay in early childhood, followed rapid progression of cognitive disfunction and parkinsonism in adulthood. This case was pointed out intellectual disability at the age of 9, followed left dominant progressive parkinsonism from the age of 31. Brain MRI showed the T 1 -weighted signal hyperintensity of the substantia nigra with a central band of hypointensity and the T 2 star weighted image hypointensity of substantia nigra and globus pallidus presenting dominant at right side. DAT SPECT also showed specific binding ratio decreased dominant in right side. She was diagnosed BPAN based on her genetic test revealing a novel mutation (c.411dupT) in WDR45. No studies reported detailed parkinsonism like laterality in BPAN. This case indicates the left dominant parkinsonism was caused by right dominant iron deposition to substantia nigra and globus pallidus in view of MRI findings and DAT SPECT.

The central nervous system (CNS) is segregated from the circulating blood and peripheral tissues by endothelial and epithelial barriers. To overcome refractory CNS diseases, it is important to understand the membrane transport systems of drugs and the endogenous compounds that relate to the pathogenesis of CNS diseases at these barriers. The endothelial barrier in the brain is the blood-brain barrier (BBB). Our studies clarified the efflux transport of prostaglandin E 2 (PGE 2 ), a modulator of neural excitation and inflammatory responses, across the BBB via plasma membrane transporters such as organic anion transporter 3 (Oat3) and multidrug resistance-associated protein 4 (Mrp4). This efflux transport was attenuated by peripheral inflammation or cerebral treatment with neuroexcitatory l-glutamate, suggesting that BBB-mediated PGE 2 elimination was altered under several pathological conditions. We also examined excitatory amino acid transporter (EAAT) 1 and 3 as l-glutamate efflux transporters of the inner blood-retinal barrier (BRB) and blood-cerebrospinal barrier. It was considered that these efflux membrane transporters participated in the homeostasis of neuroexcitatory and neuroinflammatory responses in the brain and retina. Moreover, we identified connexin 43 (Cx43) hemichannels as a new membrane transport system that is activated under pathological conditions and recognizes several monocarboxylate drugs, such as valproate. As it is expected that the action of these membrane transporters across the CNS barriers is of great importance in understanding the pathology of various neuroexcitatory diseases, our studies should contribute to the establishment of therapeutic strategies for refractory CNS diseases.

Monoamine neurotransmitters are released by specialized neurons that regulate behavioral and cognitive functions. Although localization of monoaminergic neurons in the brain is well known, the distribution, concentration, and kinetics of monoamines remain unclear. We used mass spectrometry imaging (MSI) for simultaneous and quantitative imaging of endogenous monoamines to generate a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels. We observed several nuclei rich in both 5-HT and a catecholamine (DA or NE). Additionally, we analyzed de novo monoamine synthesis or fluctuations in those nuclei. We propose that MSI is a useful tool to gain deeper understanding of associations among the localization, levels, and turnover of monoamines in different brain areas and their role in inducing behavioral changes.

In an amyloid PET for visualizing amyloid beta plaque accumulated in the brain, an amyloid imaging agent generally tends to adsorb to the inner walls of materials used in routes of administration to the patient. Therefore, we evaluated the adsorption of the amyloid imaging agent 18 F-flutemetamol by measuring the residual radioactivity of the injection route material (intravenous catheter, extension tube, three-way stopcock) and the dispensed material (needle, syringe) in 35 patients during amyloid PET. The average actual radioactivity administered to the patients was 188.5±6.0 MBq (mean±standard deviation). When the radioactive concentration was 66.5±14.5 MBq/ml, the residual radioactivity was 1.4±0.2% for the injection route material, 0.8±0.3% for the dispensed material and 2.2±0.5% for both materials added based on the radioactivity of the amyloid imaging agent 18 F-flutemetamol used for administration to the patient. There was a correlation between radioactive concentration and residual radioactivity. As the radioactive concentration increased, the residual radioactivity of all the materials tended to increase. Validation of adsorption to the tube and other materials used to administer patients can predict the residual radioactivity of the amyloid imaging agent 18 F-flutemetamol prior to administration.

Intracerebral hemorrhage (ICH) results from blood vessels rupture in the brain, forming a blood clot in the brain parenchyma. Leakage of blood constituents causes detrimental tissue damages, ensuing long-lasting neurological deficits; however, effective therapeutic approaches are not yet developed to date. In this study, leukotriene B 4 (LTB 4 ) and its receptor leukotriene B 4 receptor 1 (BLT1) are proposed as novel therapeutic targets for ICH therapy. After the onset of ICH, the LTB 4 content in the brain transiently elevated. Microglia are considered as the source of LTB 4 production. Thrombin, a blood constituent, activated the BV-2 microglia and increased the LTB 4 secretion from the BV-2 cells. Microglia-released LTB 4 promoted its own microglial activation and neutrophil-like differentiated HL-60 cell migration activity. LTB 4 receptors comprised of two types: BLT1 and BLT2, with BLT1 known to be a high-affinity receptor associated with chemotaxis. BLT1 knockout mice showed decreased neutrophil invasion, attenuating sensorimotor dysfunction after ICH. Furthermore, therapeutic administration of ONO-4057, an orally active LTB 4 receptor antagonist, attenuated neutrophil invasion, microglial activation, axonal fragmentation, and sensorimotor deficits induced by ICH. These results suggest that LTB 4 and its receptor BLT1 can be potential promising therapeutic targets that prevent tissue damages following ICH.

α-Synuclein (αS) is the major component of the filamentous inclusions that constitute the defining characteristic of neurodegenerative synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. αS is deposited in a hyperphosphorylated and ubiquitinated form with a β-sheet-rich fibrillar structure in diseased brains. In 2008, some researchers reported that embryonic neurons transplanted into Parkinson's disease brains had Lewy body-like pathologies, suggesting that pathological αS propagates from diseased neurons to young neurons. Subsequently, a growing body of evidence supported the cell-to-cell spread of αS pathologies. Recent studies have revealed that intracerebral injection of insoluble αS into wild-type mice can induce prion-like propagation of phosphorylated αS pathology even 1 month after injection, while injection into αS-knockout mice failed to induce any pathology. We also showed that intracerebral injection of insoluble αS into adult common marmoset brains results in the spreading of abundant αS pathology. These in vivo experiments clearly indicate that insoluble αS has prion-like properties and that it propagates through neural networks. The underlying mechanisms of αS propagation are still poorly understood, but αS propagation model animals could be helpful in elucidating the pathogenetic mechanisms and developing drugs for synucleinopathies.

This review focuses on the anti-dementia and antidepressant-like effects of peptides including glucagon-like peptide (GLP)-1, GLP-2, neuromedin U (NmU), and oxytocin, and the intranasal delivery of these peptides to the brain. Intracerebroventricularly administered GLP-1, NmU, and oxytocin improved impairment of learning and memory in mice treated with lipopolysaccharide or β-amyloid protein. GLP-1 also improved impairment of learning and memory in juvenile diabetes model rats. On the other hand, GLP-2 exhibited antidepressant-like effects in mice during the forced-swim test, which were associated with 5-HT 1A , α 2 , β 1 , and D 2 receptors. GLP-2 also exerted antidepressant-like effects in adrenocorticotropic hormone (ACTH)-treated mice through restoration of the hypothalamic-pituitary-adrenal-axis and neurogenesis in the subgranular zone of the dentate gyrus. Because intracerebroventricular administration is invasive and the peptides are unable to penetrate the blood-brain barrier, we introduced our new method of intranasal administration to deliver the peptides to the brain. We prepared a GLP-2 derivative containing cell-penetrating peptides (CPPs) and a penetration accelerating sequence (PAS). Intranasally administered PAS-CPPs-GLP-2 was distributed throughout the brain, and exhibited antidepressant-like effects in both naive and ACTH-treated mice. The derivatives of GLP-1, NmU, and oxytocin with the PAS and CPPs were also distributed throughout the brain after intranasal administration, and improved impairment of learning and memory. We confirmed that our peptide derivatives were effectively delivered into the brain by intranasal administration. As such, these derivatives may be useful for the clinical treatment of psychiatric and neurological diseases.

Abnormal proteins such as tau or α-synuclein that accumulate in brains with dementia have been shown to propagate like prion proteins. However, the expression patterns of tau in the mouse brain are different from those in humans, and the pathogenesis in the animal model of abnormal tau propagation remains incompletely understood. To overcome this problem, a novel mouse showing tau expression patterns similar to those of humans was developed using genome editing techniques. We inoculated the brain of this mouse with a sarkosyl-insoluble fraction containing abnormal tau derived from tauopathy patients and examined the accumulation of tau pathologies. We also performed a detailed analysis of the relationship between the inoculation site and the sites where tau accumulates abnormally by histochemical and neuronal circuitry and elucidated the propagation mechanism of the abnormally accumulated protein. This research is expected to lead to the development of novel drugs for the treatment of dementia using the innovative approach of "inhibition of abnormal protein propagation".

Pathological α-synuclein (αSyn) has been shown to retain the ability to propagate as prions in humans and animals. However, the molecular basis underlying the prion-like properties of αSyn remains poorly understood. We examined whether brain tissues from cases of dementia with Lewy bodies (DLB), which contain serine 129 (Ser129)-phosphorylated insoluble aggregates of αSyn, exhibit prion-like seeding activity in vitro using the real-time quaking-induced conversion (RT-QuIC) seeding assay. Brain tissues from cases of diffuse neocortical DLB yielded a 50% seeding dose of 10 7.3 -10 9.8 /g brain. The RT-QuIC assay could discriminate between DLB and other neurological and neurodegenerative disorders, suggesting its potential applicability for differential diagnosis. Insoluble aggregates of αSyn>250 kDa detected only in DLB brain tissues by Western blotting analysis were specifically phosphorylated at Ser129. Therefore, we postulated that Ser129-phosphorylated insoluble aggregates of αSyn have prion-like seeding activity. However, insoluble aggregates of recombinant human αSyn (rSyn) with increased β-sheet structures showed little seeding activity in either the phosphorylated or nonphosphorylated state. In contrast, prefibrillar oligomers of rSyn showed seeding activity both with and without phosphorylation. The findings of the present study suggested that soluble oligomeric αSyn, but not the fully fibrillary form, is a seeding species in vitro.

In neurodegenerative diseases, such as Alzheimer's disease (AD) and spinal cord injury (SCI), inhibited axonal regeneration lead to irreversible functional impairment. Although many agents that eliminate axonal growth impediments have been clinically investigated, none induced functional recovery. I hypothesized that the removal of impediments alone was not enough and that promoting axonal growth and neuronal network reconstruction were needed for recovery from neurodegenerative diseases. To promote axonal growth, I have focused on neurons and microglia. In vitro models of AD and SCI were developed by culturing neurons in the presence of amyloid β (Aβ) and chondroitin sulfate proteoglycan, respectively. These were then used to identify several extracts of herbal medicines and their constituents that promoted axonal growth. Oral administration of these extracts and their constituents improved memory and motor function in in vivo mouse models of AD and SCI, respectively. The bioactive compounds in these extracts were identified by analyzing brain and spinal cord samples from the mice. Their protein targets were identified using the drug affinity responsive target stability method. Analysis of early events in the axons after culture with Aβ revealed that the inhibition of endocytosis was sufficient to prevent the axonal atrophy and memory deficits caused by Aβ. The compounds that increased M2 microglia were observed to promote axonal normalization and growth; they were also found to recover memory and motor function in mice models of AD and SCI, respectively. The above results indicate that axonal growth plays important roles in the recovery from AD and SCI.

In general, the blood-brain barrier (BBB) poses a major challenge to drug development efforts targeting brain/central nervous system (CNS) diseases, since it limits the distribution of systemically administered therapeutics to the brain/ CNS. Therefore, the development of effective strategies for enhancing drug delivery to the brain has been a topic of great interest in both the clinical and pharmaceutical fields. Intranasal administration has been noted as a method for noninvasive delivery of a drug to the brain/CNS by bypassing the BBB via the "nose-to-brain" route. This nose-to-brain delivery system has the potential to be highly versatile, and a combination of this system with new drugs and siRNA shows promise in the treatment of CNS diseases. Cell-penetrating Tat peptide-modified block copolymer micelles have the potential for improving mucosal permeability and nose-to-brain transport efficiency. In addition, nano-sized drug carriers can improve nose-to-brain delivery through their ability to increase the stability of encapsulated drugs against biological degradation in the nasal cavity and brain/CNS. In this review, we introduce the assessment of and mechanisms for delivery to the brain after intranasal drug/siRNA administration with our cell-penetrating peptide-modified nano-sized polymer micelles. Our findings show that the use of polymer micelles with surface modification by cell-penetrating peptides for intranasal administration enables the noninvasive delivery of therapeutic agents to the brain/CNS by increasing the nose-to-brain transfer of the drug or siRNA administered from the nasal cavity.

G-protein-coupled receptor 40 (GPR40)/free fatty acid receptor (FFAR) 1 is activated by long-chain fatty acids such as docosahexaenoic acid (DHA). Its receptor is expressed predominantly in the central nervous system (CNS) and in β-cells in the pancreatic Islets. We have already demonstrated that the intracerebroventricular administration of DHA or GW9508, a GPR40/FFAR1 agonist, suppresses formalin-induced pain behavior. It also attenuates complete Freund's adjuvant-induced mechanical allodynia and thermal hyperalgesia, suggesting that these effects occur by increasing β-endorphin release from propiomelanocortin neurons. Furthermore, we found that the brain GPR40/FFAR1 signaling may involve in the regulation of the descending pain control system, whereas the deletion of GPR40/FFAR1 might exacerbate mechanical allodynia in postoperative pain. Therefore, it is possible that the brain n-3 fatty acid-GPR40/FFAR1 signaling may play a key role in the modulation of the endogenous pain control system and emotional function. Here, we discuss the role of brain n-3 fatty acids-GPR40/FFAR1 signaling in a pain, and we review the current status and future prospects of the brain GPR40/FFAR1.

Histamine acts as a neurotransmitter to regulate various physiological functions in CNS. Recent reports showed the involvement of histaminergic dysfunction in neurological disorders. Neurotransmitter clearance is essential to determine brain neurotransmitter concentration. However, molecular mechanism of brain histamine clearance remains largely unknown. First, we examined the molecular mechanism of histamine clearance in primary human astrocytes. We demonstrated that extracellular histamine was transported through organic cation transporter (OCT) 3 and plasma membrane monoamine transporter (PMAT), and subsequently intracellular histamine was inactivated by histamine N-methyltransferase (HNMT) in cytosol. Next, we generated HNMT knockout (HNMT KO) mice to investigate the role of HNMT in vivo. HNMT deficiency dramatically enhanced brain histamine concentration, indicating the important role of HNMT in histamine inactivation. HNMT KO mice showed high aggression via abnormal histamine H2 receptor (H2R) activation and the disrupted sleep-wake cycle via excessive H1R activation. These observations show that HNMT plays a pivotal role in regulating brain histamine concentration, and modulates aggression as well as the sleep-wake cycle. Although importance of OCT3 and PMAT in histaminergic nervous system remains still unknown, our preliminary data show the contribution of PMAT to brain histamine concentration. We also try to find novel inhibitors targeting brain histamine clearance. We hope our study could lead a better understanding of neuropsychiatric disorders and the development of new drugs inhibiting HNMT, OCT3 and PMAT activity.

Cerebral ischemic stress often induces a hyperglycemic condition. This postischemic hyperglycemia exacerbates the development of cerebral ischemic neuronal damage, although the mechanism of this exacerbation remains to be clarified. We previously discovered that the cerebral sodium-glucose transporter (SGLT) was closely involved in the development of cerebral ischemic neuronal damage. SGLT is a member of the glucose transporter family and moves glucose together with sodium ions. SGLT-1, -3, -4, and -6 are distributed in the brain. We conducted further experiments to elucidate the detailed mechanism of the exacerbation of cerebral ischemia by cerebral SGLT. The results clarified: 1) the relationship between cerebral SGLT and postischemic hyperglycemia; 2) the involvement of cerebral SGLT-1 (a cerebral SGLT isoform) in cerebral ischemic neuronal damage; and 3) the effects of sodium influx through cerebral SGLT on the development of cerebral ischemic neuronal damage. This paper presents our data on the involvement of cerebral SGLT in the exacerbation of cerebral ischemic neuronal damage.

There are numerous characteristics of females as a higher organism and maintaining appropriate level of estrogen is possibly the most fundamental and important factor for reproductive aged women. Appropriate secretion of estrogen during the reproductive age is indispensable to keep female in healthy condition. In addition to natural menopause and surgical menopause, aberrant secretion of estrogen in reproductive aged women may predispose to increase risk of osteopenia, dyslipidemia and impaired glucose tolerance, and epidemiological studies and experimental data strongly support that estrogen possesses anti-diabetic properties. The function of estrogen in glucose homeostasis can be explained by direct functions of estrogen and by indirect function through estrogen receptors(ERs), although the latter is believed to be mainstream. ERα is believed to be the key ER in brain, pancreatic, liver, muscle, adipose tissues, and macrophages.

Objective: Cerebral hyperperfusion syndrome(CHS)and cerebral hyperperfusion phenomenon(CHP)induce intracranial hemorrhage and can become critical complications after carotid artery stenting(CAS). The purpose of the present study was to predict and avoid CHS after CAS using bilateral rSO 2 intraoperative monitoring., Methods: We retrospectively analyzed 100 consecutive patients who underwent CAS between January 2012 and May 2014 in our institution. We performed continuous bilateral rSO 2 monitoring from anesthetic induction to the day following CAS. CHS was defined as the deterioration of neurological conditions post-CAS, no ischemic changes on post-CAS head CT or brain MRI, an increase in cerebral blood flow(CBF)and cerebral blood volume(CBV), and shortening of the mean transit time(MTT)or time to peak(TTP)on CT perfusion. To compare the CHS/CHP group and non-CHS/CHP group, we defined four parameters:rSO 2 difference(rSO 2 at the endpoint of the procedure-baseline rSO 2 ), ΔrSO 2 difference(affected side rSO 2 difference-unaffected side rSO 2 difference), rSO 2 ratio(rSO 2 at the endpoint of the procedure/baseline rSO 2 ), and ΔrSO 2 ratio(affected side rSO 2 ratio/unaffected side rSO 2 ratio)., Results: There were 2 CHS cases(2.2%)and 3 CHP cases(3.3%). In the CHS/CHP group, the ΔrSO 2 difference and ΔrSO 2 ratio were significantly higher than those in the non-CHS/CHP group(p value<0.05);however, no significant differences were found in the affected side rSO 2 difference(p value=0.063)and affected side rSO 2 ratio(p value=0.054)between the groups., Conclusion: We could promptly detect CHS and CHP in all cases by using continuous bilateral rSO 2 monitoring and analysis of the ΔrSO 2 difference and ΔrSO 2 ratio.

In clinical diagnostic imaging of Alzheimer's disease (AD), MRI and nuclear medicine studies such as cerebral blood flow SPECT are positioned as biomarkers expressing pathological conditions. With understanding its usefulness and limitations, it is important to conduct appropriate application and to utilize the correct evaluation of the result in clinical practice. Although FDG-PET and amyloid PET are still not covered for dementia by health insurance, they are extremely useful for differential diagnosis as well as early diagnosis of AD. As image biomarkers, they may have complementary implications. In addition, tau PET under development not only realizes more accurate evaluation of AD but also is expected to be applied in dementia other than AD. In the future, image biomarkers are indispensable for patient selection (early diagnosis) in mild cognitive impairment (MCI) or earlier stages and for judging the therapeutic effect of interventions in cases when early intervention for AD.

Microglia, traditionally known as resident immune cells in the brain, have been recently identified as one of the important cell types engaging in the formation and maintenance of neural circuitry, especially during the development. In this review, I describe the diversity of microglial functions revealed in different phases of development, ranging from neurogenesis to circuit formation. In particular, microglia possess dual functions in supporting the survival of neuronal structures or neural cells themselves, and removing excess neural components. Understanding these processes and underlying molecular mechanisms will provide important insights into the regulation of neural circuitry development. It further implicates the involvement of microglial dysfunction in neurodevelopmental disorders.

Recent advancement in magnetic resonance spectroscopy (MRS) has elucidated the pathophysiology of mental illness, including schizophrenia. MRS is a neuroimaging technique that non-invasively measures chemicals, using nuclear magnetic resonance. This narrative review explains proton MRS ( 1 H-MRS) and introduces pivotal studies to examine a glutamate hypothesis for schizophrenia, employing 1 H-MRS.

It is well-known that the blood-brain barrier (BBB) plays significant roles in transporting intravascular substances into the brain. The BBB in cerebral capillaries essentially impedes the influx of intravascular compounds from the blood to the brain, while nutritive substances, such as glucose, can be selectively transported through several types of influx transporters in endothelial cells. In the choroid plexus, intravascular substances can invade the parenchyma as fenestrations exist in endothelial cells of capillaries. However, the substances cannot invade the ventricles easily as there are tight junctions between epithelial cells in the choroid plexus. This restricted movement of the substances across the cytoplasm of the epithelial cells constitutes a blood-cerebrospinal fluid barrier (BCSFB). In the brain, there are circumventricular organs, in which the barrier function is imperfect in capillaries. Accordingly, it is reasonable to consider that intravascular substances can move in and around the parenchyma of the organs. Actually, it was reported in mice that intravascular substances moved in the corpus callosum, medial portions of the hippocampus, and periventricular areas via the subfornical organs or the choroid plexus. Regarding pathways of intracerebral interstitial and cerebrospinal fluids to the outside of the brain, two representative drainage pathways, or perivascular drainage and glymphatic pathways, are being established. The first is the pathway in a retrograde direction to the blood flow through the basement membrane in walls of cerebral capillaries, the tunica media of arteries, and the vessels walls of the internal carotid artery. The second is in an anterograde direction to blood flow through the para-arterial routes, aquaporin 4-dependent transport through the astroglial cytoplasm, and para-venous routes, and then the fluids drain into the subarachnoid CSF. These fluids are finally considered to drain into the cervical lymph nodes or veins. These clearance pathways may play a role in maintenance of the barrier in the entire brain. Obstruction of the passage of fluids through the perivascular drainage and glymphatic pathways as well as damage of the BBB and BCSFB may induce several kinds of brain disorders, such as vascular dementia. In this review, we focus on the relationship between damage of the barriers and the pathogenesis of vascular dementia and introduce recent findings including our experimental data using animal models.