The Japanese Society of Neurological Therapeutics has promoted (1) publication of treatment guidelines for rare diseases, (2) industry–government–academia collaboration, (3) globalization, and (4) support of clinical trials. In the future its role will be expanded focusing on clinical trial support and drug recovery/development. In 2021, the committee for promotion of drug discovery has been launched. The committee will activate (1) research and development, advices on the trial protocol and participating institutes, (2) support for collection of participants (patients), matching of industry and academia, (3) development of trial–ready registry, and (4) patient and public involvement. The Japanese Society of Neurological Therapeutics should play an important role in the promotion of drug recovery and clinical trials.

In Japan, a hyper–aged society, do the elderly account for more than one–fourth of the total population and more than one–eighth of the elderly aged 75 years or older. The gap between average and healthy life expectancy may widen as life expectancy increases. There are concerns about the further impact on household finances due to increased medical and nursing care costs.

Since the introduction of intravenous levodopa in 1961, levodopa has remained the gold standard for symptomatic treatment, and this therapy has dramatically improved disease outcomes. Despite developing many adjunctive agents since the discovery of levodopa, disease–modifying cures have been slow. In 1817, James Parkinson reported “shaking palsy,” In 1888, Charcot praised Parkinson by adding myoclonus to the list of PDs. This was followed by the discovery of Lewy bodies in the substantia nigra by Frederic H. Lewy in 1919, the simultaneous discovery of dopamine deficiency in the East and West by Sano, Ehringer, and others in 1960, the introduction of Levodopa, a therapeutic agent based on this deficiency, and the discovery of MPTP–induced parkinsonism in 1983. The discovery of MPTP–induced parkinsonism followed in 1983. The discovery of MPTP–induced parkinsonism, in particular, was a breakthrough from the viewpoint that mitochondrial dysfunction was also linked to mitochondrial dysfunction in solitary PD, followed by the discovery of the PARK1 (alpha–synuclein)–causing gene for familial Parkinson disease in 1997 and the PARK2 (parkin)–causing gene from our group the following year. The discovery of the PARK1 (alpha–synuclein) causative gene in 1997, followed by the discovery of the PARK2 (parkin) causative gene in the following year by our group, has provided an endless list of findings in the study of hereditary PD since 1990.

Furthermore, hereditary PD associated with a single gene abnormality has been identified as far as Park1–24. We have successfully identified three genes in our laboratory, Park2, 22, and 24. The gene products of single genes have revealed some of the mechanisms of nigrostriatal neuronal cell death in the proteolytic system, lysosomal function, neuroinflammation, and hereditary PD. Since there are at least 24 types of hereditary PD, we can say that at least 24 molecules are involved in the degenerative mechanism, and we can speculate that multiple pathways are involved. PD is a highly diverse disease, and we believe that precision medicine is essential for disease–modifying therapies ; the number of patients with PD is expected to reach 30 million worldwide by 2030, and the elucidation of its pathophysiology is an urgent issue.

On the other hand, several new drugs have been launched for symptomatic treatment in the past three years. The increased number of medications has complicated the treatment of this neurological disease. Motor symptoms are still the core of therapy. Still, there are now more options, including Levodopa, Dopamine agonists, MAO–B inhibitors, COMT inhibitors, anticholinergics, adenosine A2a receptor antagonists, and combinations of adjunctive agents and Levodopa. The development of device therapies, in addition to oral medications, has improved the long–term prognosis for motor symptoms. Although there are high expectations for near–future therapies, such as cell transplantation using iPS cells and gene therapy, the ideal treatment is expected to be disease–modifying therapy that can prevent the progression of the disease.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder leading to respiratory muscle paralysis a few years after the onset because of motor neuron death. After the discovery of SOD1 in 1993 as the causative gene, more than 20 genes, such as FUS, the second most frequent in Japan, and C9ORF72, the most frequent in Europe and the United States, have been clarified. Based on the dying back hypothesis, we focused on axonal pathology of ALS. We developed microfluidic device system to elucidate the pathomechanism of axon fraction from patient–derived induced pluripotent stem (iPS) cells and its gene–editing isogenic controls. Key molecules in axonal pathology in the early stages of the disease are becoming clearer.

GNE myopathy is rare muscle disease affecting distal muscles like tibialis anterior. GNE gene, which encodes for a key enzyme in the sialic acid biosynthesis pathway, is mutated in the homozygote or compound heterozygote manner. The lack of sialic acid in skeletal muscle is the critical pathological process in GNE myopathy. GNE myopathy mouse model was established, and supplementation of sialic acid improves the phenotype of these models. Phase 1 clinical trial in Japan was conducted at Tohoku University Hospital using aceneuramic acid, followed by the trials using slow–release product. Phase II/III study, subsequent extended trial and confirmational trial were performed. Regulatory approval is currently under discussion.

I will describe how to make the medical networks and to organize it in the actual disasters and routine clinics based on my personal experience at East Japan Great Earthquake in Fukushima on March 11, 2011. In this paper, I will summarize some tips in organizing the medical networks because I wrote actual matters in making and using the medical networks previously.

As mentioned in my previous papers, neurologists should play a role as one doctor, not specialist, in the acute phase of the disaster, and in the subacute phase, play a role as an organizer for the patients transfer corroborating with nationwide staffs of any kinds including Self–Defense Force members and local doctors or medical staffs. When recovered to usual medical situation, we used the medical networks, such as telemedicine. The COVID pandemic has made us to use the telemedicine more frequently as compared with pre–COVID time because the patients had several difficulties in visiting our clinics often.

The most important tip to prepare the medical networks and make a new network is to communicate with all kinds of staffs frankly and to make a mood to say anything to all members without hesitation. The frank mutual communication between all members within the group or between the groups is also the most critical point for using the prepared networks on site. This point is also stressed in the guideline for the ideal leaders.

My final message is simple as follows.

MAKE A FRIENDLY, JOYFUL MOOD IN YOUR WORKPLACE, AND COMMUNICATE WITH ALL STAFFS OF ANY KINDS FRANKLY.

National Hospital Organization Akita National Hospital has 340 beds, 290 of which are convalescence/nursing care beds. Our hospital employs 28% (9/33) of the neurologists working in Akita Prefecture. Eighty–seven percent (356/403) of inpatient referrals in the past 5 years came from the three secondary medical regions Yuri Honjo/Nikaho, Akita, and Daisen/Senboku, with only 1% (4/403) coming from outside the prefecture.

According to a survey of the number of patients with muscular diseases in Akita Prefecture conducted in 2018, the prevalence per 100,000 people was 9.7 for myotonic dystrophy and that per 100,000 males was 5.3 for Duchenne muscular dystrophy, which represented a substantial increase in patients with myotonic dystrophy as compared with 2008. Recently, we experienced the transition to home care of a patient with Duchenne muscular dystrophy who had been hospitalized for 22 years, but finding a dwelling, training of caregivers, and so forth did not go smoothly due to the Covid–19 pandemic, which we dealt with by temporary accommodation after discharge, holding discharge conferences online, and training caregivers online, etc.

Our hospital was designated a core hospital for intractable disease medical care by the Akita Prefecture Intractable Disease Medical Care Network in October 2019. A questionnaire survey was conducted, in which respondents asked for workshops on the welfare system to be held as there is insufficient understanding of the convalescence/nursing care system.

Under the mission of establishing better treatment for neurological diseases, JSNT aims to investigate the issue and the needs for academic societies and conducted a survey on pharmaceutical companies. As an open–ended questionnaire, we asked about two questions : “current issues in promoting drug discovery and clinical trials in the area of neurological diseases” and “requests and expectations for academic societies in promoting drug discovery in neurological diseases”.

As a result, we obtained opinions from a total of 23 companies. Current issues include opinions on delays in clinical trial enrollment in Japan, especially limits on the number of cases enrolled per facility, high hurdles in pharmaceutical regulations and the need to develop clinical trial evaluation indicators. Regarding needs related to academic societies, we categorized comments into the following 10 items : “Support for clinical trials conducted by a pharm company”, “Building a disease registry and conducting longitudinal research of neurological diseases”, “building a foundation for efficacy evaluation in clinical research”, “building a foundation for industry-government-academia collaboration to revitalize drug discovery research and development in Japan”, “information delivery at academic conferences and lectures”, “development of human resources to lead drug discovery research, “cooperation with overseas academic societies”, support for doctors participating in clinical trials”, “provision of information to citizens and patients and listening to patient voices” and “approaches to regulatory authorities”.

The survey results clearly indicated issues in drug discovery from the perspective of pharmaceutical companies and the expected role of academic societies. Interestingly, well alignment between their expectations and JSNT's vision was confirmed. It is important to initiate implementation promptly depending on the prioritization and to make continuous effort in cooperation with other relevant stakeholders.

The Japanese Society for Neurological Therapeutics aims to promote clinical research for the further enhancement of treatment of neurological diseases and collaborative research activities for the discovery of new treatments. The first difficulty encountered by pharmaceutical companies in conducting clinical trials in Japan is the collection of information on the patient population of the target disease. Pharmaceutical companies have no choice but to find and interview neurologists who are likely to be treating a large number of patients with the target disease. As a feasible solution, pharmaceutical companies may expect the Society to provide consultation services, including assistance in site selection and patient enrollment, in order to improve the efficiency of locating such neurologists. In this paper, I firstly discuss the current status of global drug development and Japan–specific challenges in drug development, which include high cost and low patient aggregation. I then establish the significance of creating a neurological disease registry as a medium– to long–term means of resolving these issues and set forth our expectations for the Society to promote creating of a neurological disease registry.

Clinical trials are planned and conducted to evaluate the efficacy and safety of pharmaceuticals. It is important to refer to guidelines for clinical trial or clinical practice, as well as information of previous clinical trials when considering the target population and efficacy endpoints of clinical trials. The goals of treatment and the concept of efficacy evaluation described in clinical guidelines are useful to conduct clinical trials that are in line with clinical practice. The guidelines and diagnostic criteria developed by academic societies provide important information for the planning of clinical trials in terms of target population. It is expected that the development of new drugs will be promoted through the development and revision of clinical practice guidelines by academic societies.

Unapproved and off–label use of drugs and devices have several problems : insufficient evidence, unstable supplies, serious adverse effects not covered by the official relief system, disadvantage of physicians in the event of a lawsuit, assessment of reimbursements, etc. Moreover, clinical trials for pediatric and rare diseases are often not conducted owing to their poor profitability and the difficulty of developing drugs and devices and recruiting patients.

For these reasons, the Clinical Trial Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery (hereinafter the Society) began a clinical trial promotion project in 2015 and renewed the initiative in 2018. The society receives compensation under contract with a sponsor, and the project team provides support at each stage of a clinical trial : 1) pre–trial (planning, survey of eligible patients and their willingness to participate, and selecting institutions for participation) ; 2) during the trial (holding meetings, publicity and provision of information to members of the Society) ; and 3) post–trial (preparing reports and articles, conducting post–marketing surveillance, etc.).

To date, the Society has facilitated the testing and approval of seven drugs and three surgical materials through this program. Clinical trials have been completed for five subjects, one of which has qualified for insurance coverage and is now available commercially. Experience has shown that clinical trials that progress quickly are characterized by the following : 1) pediatric trials are initiated before approval for insurance coverage is obtained for adult patients ; 2) strategy meetings are held frequently ; and 3) the Society is involved from the planning stage to improve feasibility.

We hope that the Society's system for supporting clinical trials under contract with sponsors will help promote clinical trials in collaboration with industry, government, and academia so that patients can receive effective and safe treatments that qualify for insurance coverage as soon as possible.

The Japanese Society of Neurological Therapeutics (JSNT) was founded in 1983 as the predecessor of the Society for Neurological Therapy, with the aim of disseminating knowledge of neurological treatment and providing the best treatment available at that time in daily practice. The society has developed with the treatment of neurological diseases, and in recent years with the continuous development of innovative treatments for neurological diseases, the society has been working to promote drug discovery efforts through industry–government–academia exchanges, support for clinical trials, and education for practical clinical research and trials. In order to promote these activities, the Drug Discovery and International Committee and the Drug Discovery Promotion Committee, which is an extension of the International Committee, have been organized to promote drug discovery activities.

Past achievements include the development of guidelines for “standard neurotherapy,” visualization of unmet medical needs through a survey of medical needs in neurological diseases, provision of sessions related to drug discovery at annual meetings, and symposium with the Ministry of Health, Labour and Welfare, the Pharmaceuticals and Medical Devices Agency, the pharmaceutical industry, and others. In addition, the committee has contributed to the promotion of clinical trials in Japan by providing information on clinical trials with the support of academic societies and promoting recruitment through the encouragement of professional networks. Currently, the Drug Discovery Promotion Committee is taking the lead in providing further support by conducting a questionnaire for academic society members to support drug discovery and considering the establishment of a consultation service for academic society members and others. The achievement of JSNT efforts to promote drug discovery to date and the prospects for further activities in the future will be presented.

Gliomas, especially, diffuse gliomas are rare but challenging cancers in human beings. We have still many issues to solve in both diagnostics and therapeutics for diffuse gliomas. Recently, however, there have been several advancements that are now available in daily practice in Japan. One of these are progresses in surgery, such as technologies of image guidance of surgery with navigations and intraoperative MRIs. Awake surgery becomes popular for preservation of brain functions, such as language, and other higher brain functions. All these are helpful to achieve the “maximal safe resection”, which is a goal of resection for basically all diffuse glioma subtypes. An intraoperative photodynamic diagnosis with 5–aminolevulinic acid and a photodynamic therapy with talaporfin sodium plus a laser light can be applicable during surgery. Intraoperative chemotherapy with CCNU can be used and its wafers are placed on the postoperative resection cavity wall. In terms of progress in therapeutics, we have now new and unique adjuvant therapies, such as a tumor–treating field therapy and an oncolytic viral therapy for glioblastomas. Here, in this article, current diagnosis and therapies for diffuse gliomas are described and discussed, based on the latest WHO classification of central nervous system tumors, the 5th Edition, released in 2021.

The term “gene therapy” refers to the following activities to treat or prevent disease. Gene therapy is defined as the administration of a gene or transgenic cells into a human body (gene addition), the modification of a human gene by targeting a specific nucleotide sequence (gene correction), or the administration of genetically modified cells into a human body (gene modifications, ex vivo). Although gene therapy for human beings started around the 1980s, mainly in the United States, its practical application has not been easy due to many problems such as safety and efficiency of transfection. However, a gene therapy drug for spinal muscular atrophy, an intractable neurological disease, has finally succeeded and is now available in Japan. This review will introduce the basic concept of gene therapy and recently approved gene therapy drugs focusing on nervous system diseases.

Japanese Association of Rehabilitation Medicine has added a new object of rehabilitation medicine, “Improvements of Activities in Human”. It is expected that such a fundamental revision of rehabilitation medicine will promote rehabilitation treatment especially for patients with neuromuscular diseases. The efficacy of exercise therapy is preventing the harmful effects of bed rest, improving physiological function, and maintaining and improving ADL. Some cytokines are secreted from skeletal muscle during exercise and are beneficial for metabolism and immune function. A typical cytokine IL–6 was considered an inflammatory cytokine, however to exhibit anti–inflammatory effects. Promoting active exercise therapy for patients with neuromuscular disease has been contraindicated. For example, overuse weakness in patients with Charcot–Marie–Tooth disease was a common debate, however, most of physicians agree that exercise therapy increases muscle strength in them. It was expected that regenerative medicine and robot–based rehabilitation treatments are being actively developed, and we have reported the effectiveness in combines of passive movement and functional electrical stimulation. The first step to advance rehabilitation medicine should be education in physicians and therapists. Under and post–graduate education for physicians and therapists should be insufficient for understanding the exercise physiology and acquiring knowledge of pathophysiology for people with disabilities. We hope that rehabilitation medicine and medical care will be advanced to improve the activities of patients with neurological disorders.

Alzheimer disease (AD) is a major dementia. Toxicity of amyloid–β protein (Aβ), especially Aβ42 oligomers, is considered important in the AD pathogenesis. Alternatively, the diabetes mellitus (DM)–like mechanism is suggested in AD brain, and AD is called as ‘type 3 diabetes’. We induced insulin deficiency (type 1 DM) via injection of streptozotocin (STZ) or insulin resistance (type 2 DM) via high fructose diet (HFuD) in 3xTg–AD mice. Both type DM accelerated accumulation of Aβ42 and hyper–phosphorylated tau protein, causing co–aggregation of them in neurons. Two insulin signaling–related molecules, phosphorylated Akt and phosphorylated GSK–3β, decreased in the STZ and HFuD mice brain, indicating impairment of the insulin signaling. In addition, microglia were activated and proliferated in the STZ and HFuD mice, indicating the exacerbation of neuroinflammation. Thus, peripheral DM may enhance the AD pathology.

Previously, we have reported apomorphine (APO) as a novel drug to promote degradation of the intraneuronal Aβ42 improving insulin resistance of neurons in the 3xTg–AD mice brain. In fact, APO treatment counteracted the inhibitory effects of Aβ peptides on insulin signaling of the cultured Neuro2a cells. Thus, APO may activate PI3K–Akt pathway in the AD neurons and microglia, contributing to the cure of AD.

To consider the prevention of AD, it is noted that dementia, DM and sarcopenia may interact with each other. We presume that the advanced glycation end–products (AGEs), which are known as the age– and DM–related biomarker, may be the key factor among those three diseases. We have reported that dermal AGEs may correlate with the prevalence of mild cognitive impairment as well as a useful biomarker for sarcopenia in men. Thus, life style and supplements that may inhibit the AGEs accumulation may be beneficial for the prevention of AD. We are investigating the collagen peptide as a preventive supplement for atherosclerosis and cognitive decline in the elderly people.

Magnetic resonance imaging (MRI) is the most important diagnostic tool in multiple sclerosis (MS). Furthermore, MRI is crucial for providing imaging biomarkers for monitoring disease activity and treatment response. Software for measuring the volume of anatomical structures and MS lesions visualized by MRI has been evolving and has frequently been used in research studies and clinical trials. MRI is also useful for evaluating and/or predicting the therapeutic effects of disease–modifying drugs (DMDs) for MS and plays an important role in the early diagnosis of progressive multifocal leukoencephalopathy, a side effect of DMDs. This review summarizes the latest information on MRI as an imaging biomarker in MS.

Newly identified autoantibodies in relation with autoimmune encephalitis have enabled the reclassification of diseases in neurology and psychiatry and its clinical scope has steadily grown. Many of them present with psychosis, memory disturbances, seizures, and movement disorders. Detection of disease–specific autoantibodies is useful for proper diagnosis and not missing immune therapy. Also, characterizing these antibody–binding antigens offer opportunities to investigate underlying pathogenesis of neurological features and understand general mechanisms of autoimmunity. However, the number of autoantibodies is increasing, which makes it difficult to use them as a diagnostic tool. Commercially available antibody–testing is limited to several autoantibodies. Others need to be sent to certain research laboratories. Additionally, several papers caution about frequently occurring false positive or false negative results and advise testing using several different detection techniques, such as brain tissue immunohistochemistry and live–cell based assays. It is crucial to think about the diagnosis of the patients very carefully not depending on only the results of the autoantibody–test, but rather observing detailed clinical features for proper treatments.

According to estimates by the Ministry of Health, Labor and Welfare, the number of dementia patients in 2012 was 4.62 million, and the number of mild cognitive impairment patients was about 4 million. For the diagnosis of dementia, treatable dementia is first ruled out, and then common dementia such as Alzheimer disease (AD), vascular dementia (VaD), and dementia with Lewy bodies (DLB) are differentiated. The typical symptoms of AD include time disorientation and delayed recall disturbance. Cerebral blood flow single photon emission computed tomography (CBF–SPECT) shows poor blood flow in the posterior cingulate gyrus and/or precuneus in AD patients. In VaD, cognitive impairment is milder than in AD, and there are clinical courses such as stepwise exacerbation of symptoms, and various cerebrovascular lesions are observed on brain MRI. The patients with DLB have clinical symptoms such as visual hallucinations and Parkinsonian symptoms. CBF–SPECT and MIBG myocardial scintigraphy show the decreases of occipital lobe blood flow and cardiac uptake, respectively.

At the present, acetylcholinesterase inhibitors and the NMDA receptor antagonist memantine are currently available for the treatment of AD. Although these drugs are limited to symptomatic therapy in AD patients, recently, approaches aimed at disease–modifying therapy (DMT), especially the approaches focused on amyloid β–protein (Aβ) have been developed remarkably. Anti–Aβ antibody therapy is central to the current development of DMT for AD. Clinical trials of anti–Aβ antibodies have repeatedly reported poor results, but clinical trials of anti–Aβ antibodies that target Aβ aggregates, such as aducanumab and lecanemab, have reported significant effects on the primary endpoint in phase 3 trials.

Therapeutic oligonucleotide is one of most promising modalities for molecular–targeted therapy as well as antibody therapy and gene therapy. This nucleic acid drugs bind to targeted molecules, mainly RNA, directly and include antisense nucleotides and small interfering RNA. Recent progress in basic and clinical research of therapeutic oligonucleotides has been remarkable, especially for treatment of intractable neuromuscular diseases. In 2016, nusinersen was approved by the FDA as the first drug which enables disease–modifying and improving clinical outcome of spinal muscular atrophy. In addition, in 2020, viltolarsen was approved as a first antisense oligonucleotide which has been developed in Japan. Patisiran for TTR–type FAP was approved in 2018 as the first siRNA drug. In 2022, Vutrisiran was newly approved by the FDA and approved to date in Japan. Here, we review molecular mechanism and progress of clinical development of nucleic acid medicines targeting neuromuscular disease which have been accepted in Japan for clinical application.

OBJECTIVES : We have re–evaluated several neurological techniques based on the statistical analysis.

MATERIALS AND METHODS : We have established a corresponding database for the data of detail bedside neurological examination and its final diagnosis using an auxiliary diagnostic procedure. This database was created using FileMaker Pro software containing 5,938 fully neurologically examined cases. (3,438 cases of NHO Omuta hospital and 2,500 cases of Kochi medical hospital) These cases were finally diagnosed into 50 neuro–muscular disorders and each neurological findings were statistically evaluated by Chi–square test for the relationship between findings and disorders.

RESULTS : Statistical analysis reveals,

(1) Palmo–Mental reflex (PMR) was positive in 579 cases in 4,530 patients (12.8%), and 39 cases (0.9%) showed left–right laterality. Abnormal PMR significantly observed in Neuronal intranuclear inclusion disease (NIID) (p＜.01), Parkinson–related diseases (PRD), and multiple cerebral infarction with dementia (DMCI). (p＜.05)

(2) Rossolimo reflex was examined in 1,440 patients, and 152 (10.6%) showed abnormalities, which significantly appeared in patients with PRD, temporal lobe degeneration (FTLD), frontotemporal dementia (FTD) / ALS (FTD / ALS complex), and DMCI (p＜.05)

(3) Abnormal abdominal skin reflex (ASR) (positive with laterality) was observed in 116 cases in 1,134 patients (10.2%). Statistically significant was observed in Cerebro–vascular disease (CVD) and demyelinating disease such as MS or NMO and myelitis or myelopathy. (p＜.05)

(4) To examine cervical and lumbar radiculopathy precisely, checking for left–right difference of pronator teres and supinator muscle, and sartorius muscle in addition to the usual manual muscle testing are useful. Furthermore, checking for difference of vibratory sensation of medial and external condyle is also useful for detecting the lumbar radiculopathy.

CONCLUSIONS : Simple statistical analysis reveals several classical neurological reflexes correlate with some neurological disorders. And detail manual muscle testing is useful for detecting precise cervical and lumbar lesion. These results will improve the accuracy of bed–side neurological diagnosis.

Currently, Japan is in a super–aging society that the world has never experienced before, and although the total population has entered a declining phase, the aging rate is steadily increasing. As the population ages further, it is predicted that Parkinson disease, a major factor of which is aging, will increase in the future. As the number of patients with problems such as multimorbidities and polypharmacy, which are characteristic of the elderly, is increasing, there is a strong need for a comprehensive response from the perspective of geriatric medicine, not just a single disease such as Parkinson disease. For that purpose, it is important that multi–professionals collaborate throughout the region to support the patient's sense of values. However, rural areas in Japan face many problems, such as the shortage and uneven distribution of movement disorder specialists, the shortage of caregivers, and the aging of caregivers. Therefore, it is not always easy for elderly people with Parkinson disease to access specialized medical care. One of the solutions to such problems is the use of ICT. In the Aizu region, where the author conducts medical care, a system is being put in place for collaboration and cooperation among multiple professions using ICT as described above in medical care, nursing care, and welfare. There must be many regions in Japan with medical care problems like Aizu. Therefore, it would be our great pleasure if you could make use of ICT as tool for regional medical and nursing care cooperation, and reconsider multi–professional collaboration for personalized comprehensive support, using this region as a model.

Synucleinopathy is known as an entity of neurodegenerative disorders due to aggregation of alpha–synuclein. The disorders include Parkinson disease, Lewy body dementia, and multiple system atrophy. Synucleinopathy showed movement disorders with several non–motor symptoms, such as dementia, sleep disorders, psychiatric problems, and autonomic nerves system disturbance. These symptoms are usually associated with a low quality of life in patients with synucleinopathy. Therefore, precise diagnosis and disease–modifying therapy for synucleinopathy should be needed. However, the diagnosis of synucleinopathy is challenging because of based on clinical findings. Furthermore, the judgment of the therapeutical effect is based on motor functions, which will be restricted and ambiguous clinical markers for assessment. In this context, precise diagnostic biomarkers, biomarkers associated with disease progression, and biomarkers reflecting neuropathological mechanisms should be needed. Recently, several reports described detecting a small amount of alpha–synuclein oligomers from CSF, blood, skin, salivary gland, and gut. These markers might be useful for diagnostic biomarkers. Furthermore, neuroimaging, including advanced diffusion MRI and synuclein PET, has been developed. These imaging technologies will be useful biomarkers for the management of synucleinopathy. In this review, we introduce the new biomarkers of synucleinopathy.

Progressive supranuclear palsy (PSP) is a disease characterized by the accumulation of tau protein. In general, tau, amyloid, α–synuclein, and TAR DNA binding protein–43, the major pathogenic proteins, coincidently accumulate both intracellularly and extracellularly in the brains of patients with neurodegenerative diseases. However, in PSP, only tau protein is thought to be accumulated. Therefore, two clinical trials using anti–tau antibodies (tilavonemab and gosuranemab) were conducted to target gain of toxic function due to reduced tau protein accumulation, especially extracellular tau protein. However, the antibodies did not demonstrate efficacy. Furthermore, five autopsy cases after treatment showed no suppression of tau protein expression. Since these antibodies recognize the N–terminus of the tau protein, clinical trials are currently underway for anti–tau antibodies that recognize other regions, such as bepranemab. In addition to anti–tau antibodies, antisense oligonucleotides and small–molecule compounds are also being investigated in clinical trials. It is important to select patients early in the disease course for successful clinical trials when developing disease–modifying therapies. We discussed the incorporation of patients in the early stages of disease based on biomarkers and tau positron emission tomography studies to conduct successful clinical trials.

Japan Stroke Society Guideline 2021 for the Treatment of Stroke (GL2021) is the totally revised version from the 2019 update version. The clinical question format was partially introduced, and we employed five grades of recommendation originally developed by the Guideline Committee and three levels of evidence. For the first time as Japan Stroke Society Guideline of the treatment of stroke, GL2021 was published also in English. The part of the main topics in GL 2021 are as follows : left atrial appendage closure, acute dual antiplatelet therapy, dual antiplatelet therapy including cilostazol on the chronic phase, optimal target for antihypertensive therapy in patients with stroke on the chronic stage, antithrombotic therapy for patients with cryptogenic stroke or embolic stroke of undetermined source, and so on. After the publishment of GL 2021, following topics have been introduced : mechanical thrombectomy for patients with large ischemic core, mechanical thrombectomy skipping intravenous thrombolysis, mechanical thrombectomy for basilar artery occlusion, and prasugrel for secondary stroke prevention. The next update 2023 Japanese version will be published in early summer 2023. We are just in the process of creating this update.

Stroke is a disease that requires long–term seamless linkage between medical care, nursing care, and welfare, including rehabilitation, life support, and support for returning to work. Therefore, it is necessary to build a one–stop information provision and consultation support system at stroke center. At the stroke consultation / support desk, a stroke specialist is in charge, and each professional who is familiar with stroke, such as certified nurses, medical social workers, physical therapists, occupational therapists, speech therapists, pharmacists, registered dietitians, and clinical psychologists (certified public psychologists), collaborate as counselors for stroke care and support. Those team provide information and support to stroke patients and their families on medical care, welfare, nursing care, etc., and share information with collaborating medical institutions.

Neuromyelitis optica spectrum disorder (NMOSD) is caused by aquaporin 4 (AQP4) antibodies and results in refractory inflammatory lesions in the central nervous system. Traditionally, oral prednisolone and immunosuppressive drugs have been used to prevent relapses, but in the past three years, four monoclonal antibody drugs, eculizumab, satralizumab, inebilizumab, and rituximab, have been approved in Japan. Among these, eculizumab, which targets complement C5, is highly effective in preventing relapse, even with monotherapy, immediately after induction. Even when used in patients who relapse despite receiving at least 10 mg/day of prednisolone, the dose of prednisolone can be reduced or discontinued relatively quickly. Because it blocks the terminal complement activation pathway, it can affect encapsulated bacterial infections, particularly Neisseria meningitidis infections, and therefore vaccination should be given before eculizumab administration, with a booster vaccination at least 8 weeks apart and a routine vaccination every 5 years. In addition, genetic analysis prior to administration is strongly recommended because the C5 polymorphism, present in 3.5% of Japanese patients, prevents eculizumab from binding to the drug and thus prevents it from being effective. Eculizumab has a 2–week dosing interval and is also available as an intravenous infusion, requiring a clinic visit every 2 weeks. However, ravulizumab, which targets the same C5, is expected to be approved soon because the administration interval can be extended to 8 weeks and the infusion time can be reduced by increasing the concentration.