Amyloid β (Aβ) is produced in the neurons and transported into the vessel walls and perivascular space through the extracellular space. These pathways are designated as intramural periarterial drainage (IPAD) pathway or glymphatic system in the brain. Overproduction of Aβ or alternatively, stagnation of Aβ transportation may lead to accumulation of amyloid fibrils in the vessel, thereby causing cerebral amyloid angiopathy (CAA). Spontaneous antibody production against Aβ occurs in patients with CAA, and induce CAA–related inflammation (CAA–ri). In terms of cellular mechanism and symptomatology, this entity is very close to amyloid–related imaging abnormalities (ARIA) which is often encountered in the patients during the course of amyloid vaccination treatment. This review overviews mechanisms of Aβ clearance in the brain and discuss on the Aβ antibody–related pathological conditions, including CAA–ri and ARIA.

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. Separately, the idea for novel treatments is more likely to be arising from young neurologists. The Japanese Society of Neurological Therapeutics should play an important role in the promotion of drug recovery and clinical trials.

How long have ninjas existed and what did they do? Although the ninja originated in Japan and is now known as NINJA around the world, few people know for sure. However, recent empirical research has revealed a different image of the ninja from that of the past. The ninja may have an image of wearing black, throwing shurikens and disappearing with a droning sound, but these are false images that were created later.

The most important duty of the ninja was to gather information and convey it to the lord. And the ninjutsu used by the ninja were not techniques for disappearing or fighting, but for survival, which were condensed with the most advanced technology of the time. If we apply modern classification to it, it can be categorized as medicine, pharmacology, biology, agriculture, meteorology, astronomy, mathematics, psychology, etc. However, it was the ninja who synthesized various knowledge and put it into practice, not as separate and decentralized things. It is from the books on ninjutsu, which were considered secrets, that we can collectively learn what “science” was like in those days, and I think this is extremely valuable.

It can be confirmed that ninja existed in various regions from the period of the Northern and Southern Dynasties in the early 14th century to the end of the Edo period in the late 19th century. Among them, the Iga and Koka ninja were excellent and were hired by the feudal lords and various domains. During the Warring States period, the ninja invaded enemy territory and castles to gather information, and sometimes disturbed or set fires. When the peaceful Edo period came, the ninja lived in castle towns as samurai and were involved in maintaining public order, and sometimes were ordered by the feudal lords to go to remote areas to explore.

The ninjutsu used by the ninja was not an outlandish or mysterious art, but rather a way of judging the weather and direction by sharpening the five senses without the use of equipment, searching for the presence of enemies based on the flight of birds, and learning how to use the body by imitating the movements of animals. I think it can be said that this way of life is a wisdom born from Shugendo, military books, and rules of experience. Although such ninjutsu was passed down from parent to child, it was often the case that important information was passed on orally, and not shared with others.

The aim of this report was to reconstruct the author's presentation at a symposium on community care and therapeutic issues for patients with intractable neurological diseases at the 39th Annual Meeting of Japanese Society of Neurological Therapeutics, held in Tsu, Mie, in October 2021. Two topics were discussed : longitudinal trends of the number of patients with amyotrophic lateral sclerosis (ALS) in a single prefecture, and communication between people with ALS and healthcare professionals, including through non–motor symptoms of ALS. Regarding the former, our observation showed a decrease in domiciliary ALS patients with tracheostomy and ventilation (TIV), although the total number of ALS patients with TIV did not decline. Some possible issues around the decrease were discussed. Regarding the latter : some proposals for better communication between people with ALS and healthcare professionals were discussed, based on the results of short–term educational practice sessions about augmentative alternative communication (AAC) for patients with ALS attended by undergraduates in multiple healthcare disciplines at 4 universities. We found that the participants' knowledge of AAC was retained 6 months after completing a single short training program and that hands–on AAC experience helped them develop their skills and reduce the perceived subjective burden. As a next step, e–learning based AAC practice sessions were experimentally introduced amid the COVID–19 pandemic.

Neurological disorders are chronic progressive conditions and are difficult to cure. Therefore, patients with these conditions are forced to live with disabilities. What is important for the medical treatment of neurological disorders is to maintain the patient's quality of life. Therefore, medical care based on individual values (value–based practice) is required. Home medical care aims to support the patient's life. For future neurological medical practice, we can learn many things from home medical care.

This report discusses a home–visit medical care given by a pediatric neurologist from a viewpoint of pediatric to adult transitional care, which is regarded to be rare. I had worked for 33 years as a pediatric neurologist for children with neuromuscular diseases in Aichi Prefectural Colony Central Hospital, and they have become older and diseases have progressed. After retiring from the hospital, I opened “Kuma home– medical care clinic”． Patients with intractable nervous diseases are our main targets ; including neuromuscular diseases. 68% of them suffer from muscular dystrophy being cared at home with an artificial respirator. Care is given at their home within the fixed time period with an appointment, and prescription and examination are outsourced. We have a doctor, a part–time manager, 2 nurses, and 2 counselors. We have regular and irregular patients, 50 in total. 23 of them live within the range and use the equipment we lend. Others are from far away and receive regular visits by a general practitioner or rent the equipment from other clinics. 28 of them use NPPV at night or all day, while 13 patients use TPPV. We pay attention to prevent worsening or sudden change of symptoms. Anticipated night or emergency calls are rare. For emergency cases, we recommend going to a nearby emergency hospital which we introduce them to in advance, and had their records registered with. This mechanism has worked out so far. However, the local general hospital is not fully ready for accepting such patients. Necessity to provide the home–visit medical care is heightened to improve the QOL of the patients with intractable nervous diseases. It is critical to form a support system based on the cooperation with the local general practitioners involved with home healthcare. To continuously provide a stable home medical care, securing and preparing the institutes/facilities where hospitalization therapy is available are essential. Furthermore, with the recent development of new treatments for example gene therapy, it can be said that medical methods that can participate in home medical care are becoming widespread.

The Medical Association is a professional association that all doctors can join. In Nagoya City, 95.3% of medical institutions listed neurology are enrolled in the Nagoya Medical Association (NMA), but the enrollment rate of board–certified neurologist is as low as 29.2%. The NMA has a hospital and clinic cooperation system, and a network that can share medical records and examination data. Treatment of neurological diseases requires not only the acute phase but also home medical care / long–term care cooperation. For clinics working on home medical care, we enhance the backup system and share patient information using the ICT system called “Hachimaru Network”. About dementia, we conduct forgetfulness screening, and training to improve the ability to respond to dementia. In formulating the regional medical plan, a forum for discussion is provided in each concept area. In the Nagoya–Owarichubu concept area, the president of NMA has been the chairman to discuss and promote the differentiation and cooperation of bed functions. In response to the spread of the new coronavirus infection, “medical care at the time of the spread of emerging infectious diseases” will be added to the medical plan, and discussions will be promoted in each prefecture toward the formulation of the 8th medical plan. The goal of community–based medical training is to understand the characteristics of community–based medical care and the concept and framework of community–based comprehensive care. The role of medical associations in community medicine is great, and it is expected that neurologists will play an important role.

Pharmaceutical companies, healthcare professionals, and regulatory authorities have played a central role in drug development. In recent years, however, since patients are the ultimate users of drugs, it has been recognized that it is important for pharmaceutical companies to directly obtain patients' opinions and requests and to make use of patients' real–life experiences for drug development. In addition, contributing to the realization of a common wish for patients and pharmaceutical companies to “deliver drugs with value to patients faster” is considered to be the most important significance of engaging in drug development that makes use of patients' voices.

One of the visions for 2025 is to “advance drug development with patients” set by the Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (The following is the JPMA). In order to cultivate a culture of drug development that makes use of patients' voices, we consider that medium– to long–term activities are necessary, and have been examining and making proposals since 2016.

In this section, I would like to present the current status, challenges, and future prospects of drug development that takes advantage of patients' voices from pharmaceutical companies, together with the activities that the JPMA has been carrying out since fiscal 2016.

Recently, it has become essential for scientists themselves to understand “the expectations that society has for science” and to make efforts to promote such understanding.

In other words, scientists should not conduct research alone but should cooperate and collaborate in various ways with “non-scientists,” including the general public. The discussion of patient participation in a study is also in line with this trend.

Discussions on patient involvement in research are also in line with this trend.

The “participation and contribution of patient groups (or individual patients and their families) to academic research in a broad sense, in some form of “cooperation or collaboration,” has the potential to discover new values in research through the input of the experiences of patients and their families. For this reason, many people involved are looking forward to this.

However, there are still only a few cases of collaboration with patients from the start to the research goal.

In particular, the number of patients per disease is minimal in rare and intractable diseases, which is the subject of this presentation. Therefore, issues unique to this field include a lack of previous research on the condition and difficulty securing the necessary number of subjects.

It has been pointed out that this is why patients, and their families are sometimes more “experts” on their symptoms, progress, and care than are medical professionals and researchers.

The authors are conducting a patient–driven research study. Specifically, the patient side determines the direction of the research, and the researcher side is responsible for providing the methodology and analysis of the study.

In this presentation, the authors introduce a case of collaboration between the authors and an association of patients with rare neurological diseases as an example of patient research participation.

“Patient–Centered Medicine” is based on the idea that “it is ultimately the patient who decides the treatment method for the patient”, and the medical staff gives sufficient explanation and education to the patient. Furthermore, it is important to be close to the patient. As a neurologist at a general hospital and a clinic, I have long been involved in the medical care of patients with neurodegenerative diseases. Diagnosis and treatment of patients with neurodegenerative diseases may not always be easy, and treatment of comorbidities such as pneumonia and urinary tract infections etc that may occur during the course, as well as the mental distress of patients as the disease progresses. Since the problems of the burden of caring for the family will arise, we will make accurate diagnoses and treatments based on basic science research, and at the same time, listen carefully to the stories of patients and their families and value the heart to be close to them. Recently, I started home visits for patients who cannot come to our clinic because of physical disabilities. I reaffirmed the importance of being close to them. I think these are just “Patient–Centered Medicine”.

The Japanese Society for Neurological Therapeutics holds “Clinical Research Design Workshop” every year. Although this workshop was cancelled last year due to COVID–19, we have conducted a total of five workshops through 2019. This workshop is providing only for beginning researchers. In order to further progress of clinical research, the education program for intermediate and advanced level should be designed. Drug Discovery Promotion WG needs to discuss the contents of education on clinical research and drug development the society should aim for, referring to educational programs conducted by other societies.

Looking at the current trends in the drug discovery and development, the central nervous system is positioned as the next disease area target after cancer. As modality of drug discovery, new fields such as cell therapy, gene therapy and nucleic acid medicine have emerged, and drug development is diversifying. Biotechnology companies are the mainstream of such drug discovery, unlike the conventional methods for screening candidate compounds where major pharmaceutical companies can demonstrate their superiority. Pharmaceutical companies encourage open innovation and have tendency to put biotechnology ventures and academia at the center of drug creation. In recent years, drug discovery is expected to be examined from various viewpoints such as social value including the viewpoint of cost effectiveness and patient's perspective. In addition, digital devices such as treatment apps have also entered the horizons of drug discovery.

Such recent trends have made drug discovery more complex than ever. In order to succeed in drug discovery, the conventional method of drug development, which is carried out by pharmaceutical companies, is no longer the limit. In addition to collaboration with the government, pharmaceutical companies have entered an era in which drug discovery cannot be achieved without building various partnerships with biotechnology companies, external researchers, clinicians, patients, sociologists, medical economists, etc. and there is a limit for pharmaceutical companies to take the lead in facilitating such partnerships. We believe that academia should be at the center of future drug discovery activities and JSNT is expected to take a position there and become a driving force for drug discovery in the field of neurological diseases.

Drug–induced Parkinsonism (DIP) and tardive dyskinesia (TD) are stigmatizing movement disorders associated with exposure to dopamine receptor blocking agents such as antipsychotics. DIP and TD prevalence estimates range from approximately 20 to 35% among antipsychotic users. The majority of DIP cases appear within weeks of initiation of an antipsychotic. TD onset is delayed, typically appearing after at least 3 months, and patients commonly present with involuntary facial movements. Broadly, proposed mechanisms underlying these adverse events include decreased dopamine binding on dopamine D2 receptors of the striatal neurons and resultant dopamine hypersensitivity, for DIP and TD, respectively. DIP often resolves with discontinuation of the causative agent, but DIP patients with preclinical Parkinson's disease often need levodopa treatment. In TD, treatment options include the new reversible vesicular monoamine 2 transporter inhibitors, valbenazine. It is important for clinicians to be able to recognize DIP and TD in patients using antipsychotics so that they can minimize the impact of these adverse events on their patients' quality of life. Collaboration between neurologists and psychiatrists is absolutely necessary to made early accurate diagnosis that will drive the selection of the correct treatment.

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms, such as akinesia, rigidity, and tremor, as well as non–motor symptoms. On initiation of treatment for PD, the medication response for motor symptoms is high, which is known as the “honeymoon period.” However, as the disease progresses, motor complications such as wearing–off and dyskinesia appear, and modulation of oral medications and control of medication timing are required. Thereafter, these symptoms may become unstable and difficult to manage despite intensive drug adjustments. Device–assisted therapy, such as deep brain stimulation (DBS) and levodopa–carbidopa intestinal gel therapy (LCIG), is available to manage these drug–resistant motor complications. DBS improves motor symptoms by regulating the functional neural networks and modulating hyperactive neurotransmission. Therefore, the suitable cases for its indication are limited to those with sufficient dopa–responsiveness and minimal impairment of the non–dopaminergic system, such as absence of dementia or psychiatric symptoms. A commonly targeted nucleus in DBS implantation for PD is the subthalamic nucleus (STN). STN–DBS has a drug–reducing effect in addition to the effects on motor symptoms. DBS targeted at the globus pallidus internus has a strong inhibitory effect on dyskinesia, and the ventral intermediate nucleus of the thalamus–targeted DBS has a strong therapeutic effect on medication–refractory intractable tremor. These DBS targets are chosen based on the patients' condition. LCIG delivers drugs continuously to the gastrointestinal tract so that the absorption profile and therapeutic effect could be kept constant without fluctuations. Different from DBS, LCIG requires daily management and careful attention to drug storage. The benefits obtained from these device–assisted therapies depend also on each patient's condition. It is important to fully understand the details of each treatment including benefits, adverse effects, and applications. Furthermore, the treatment goals should be defined along with the appropriate treatment selection.

MOG–IgG associated disorders (MOGAD) is a central nervous system disorder caused by anti–MOG antibodies and is diagnosed by cell–based assays to detect anti–MOG antibodies. The diagnosis of MOGAD is important to differentiate it from MS and NMOSD. The age of onset of MOGAD has two peaks, in childhood and in the 30s, and there is no sex difference in the number of patients. Symptoms include frequent optic neuritis, often accompanied by ocular pain. Treatment is successful with pulsed steroid therapy, but about half of patients relapse without treatment.

Sporadic cerebral amyloid angiopathy (CAA) is cerebral small vessel disease characterized by deposition of amyloid β (Aβ) in the walls of small arteries and capillaries in the cerebral cortex and leptomeninges. CAA is the most important cause of lobar intracerebral hemorrhage (ICH) in the elderly. It is also frequently detected in patients with Alzheimer disease (AD). Disturbance of intramural periarterial drainage (IPAD) and glymphatic system are thought to contribute to the development and progression of CAA. In particular, the localization of Aβ deposition is consistent with the IPAD pathway, suggesting that disruption of IPAD is directly involved in the development of CAA.

Recent advances in magnetic resonance imaging (MRI) have made it possible to detect CAA–related brain lesions noninvasively. These CAA–related MRI markers include lobar cerebral microbleed (CMB), convexity subarachnoid hemorrhage (cSAH)/cortical superficial siderosis (cSS), enlarged perivascular space in the centrum semiovale, white matter hyperintensity in posterior predominance or multiple subcortical spot pattern, and cortical microinfarcts. Currently, the modified Boston criteria is widely used, which includes lobar, cortical or cortical–subcortical hemorrhage (ICH, CMB) and cSS as CAA–related hemorrhagic marker.

The clinical aspects of CAA include symptomatic lobar ICH, cognitive dysfunction, transient focal neurological episodes (TFNE), and CAA–related inflammation (CAA–ri). CAA–related lobar ICH is more common in women, increases with age, and is characterized by a high recurrence rate. cSS / cSAH is attracting attention as a risk of CAA–related ICH. CAA affects cognitive function independently of AD pathology. It has been suggested that cognitive dysfunction is related to the neurodegeneration associated with CAA caused by chronic cerebral hypoperfusion, decreased vascular reactivity, microbleeds, microinfarcts, and white matter lesions. TFNE is a transient focal neurological symptom associated with CAA, including paresthesia, limb weakness and aphasia. Cortical spreading deporalization triggered by cSAH/cSS is considered to be the pathogenic mechanisms. CAA–ri is an acute to subacute clinical form that presents headache, disturbance of consciousness, cognitive dysfunction or seizures with asymmetric white matter lesions reflecting vasogenic edema on brain MRI. The transient appearance of anti–Aβ antibodies in the cerebrospinal fluid suggests an autoimmune mechanism, and immunotheraphy can be effectively. Similarities with amyloid–related imaging abnormalities (ARIA) in immunotherapy for AD have also been noted.

There is no effective treatment for CAA at this time. A phase II trial of ponezumab, an Aβ40–selective monoclonal antibody, was conducted as a disease–modifying therapy, but showed no efficacy. Animal studies have shown the efficacy of some drugs such as cilostazol, dabigatran, taxifolin, memantine, metformin as potential therapeutic agents. Anti–ApoE antibody, which selectively binds to human apolipoprotein E, is also expected as drug candidates.

Central nervous system demyelinating diseases include multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), MOG–IgG related disorders (MOGAD). The diagnosis of MS is based on the exclusion of other diseases and the findings of MRI and cerebrospinal fluid examination. The diagnosis of NMOSD and MOGAD requires the identification of anti–aquaporin 4 antibodies and anti–myelin oligodendrocyte glycoprotein antibodies, respectively, using a cell–based assay. In addition, it is important to know the characteristic clinical and imaging features of each disease.

The involvement of immunological mechanisms in cerebellar ataxia has long been emphasized from the viewpoint of paraneoplastic syndromes, but with the expansion of the concept of immune–mediated neurological diseases and the identification of many new autoantibodies, immune–mediated cerebellar ataxia has recently attracted attention. Immune–mediated cerebellar ataxia is also an important differential disease in the diagnosis of idiopathic cerebellar ataxia (IDCA). Although immune–mediated cerebellar ataxia is a disease that requires early therapeutic intervention, the diagnosis of immune–mediated cerebellar ataxia is often difficult and depends largely on the clinical course and neurological examinations. There have been reports of cases in which intravenous methylprednisolone therapy and intravenous immunoglobulin therapy were effective and also cases in which biologic products were successful even though the response to those therapies was poor. In the future, there are many important points for the development of treatment for immune–mediated cerebellar ataxia in Japan including the establishment of a system that enables comprehensive and rapid measurement of anti–neuronal antibodies, the development of diagnostic criteria for immune–mediated cerebellar ataxia, and the establishment of a system that enables administration of medications that have been reported to be effective overseas. In this article, we summarize recent findings regarding immune–mediated cerebellar ataxia from the perspective of anti–neuronal antibodies, which play an important role in its diagnosis.

The trigeminovascular theory is currently widely accepted as a pathological hypothesis for migraine. Cortical spreading depression (CSD) evoked by unidentified cause may stimulate the trigeminal nerves distributed in the dural and cerebral pial arteries. Inflammatory neurotransmitters such as calcitonin gene–related protein (CGRP) and substance P are released from the trigeminal nerve endings, causing local aseptic inflammation. This local condition propagates to the periphery via axons and further spreads aseptic inflammation, and is transmitted from the trigeminal nerve to the cerebral cortical sensory area via the brain stem, causing pain and various symptoms. Furthermore, it has been suggested that the sensitization phenomenon and the descending pain modulatory pathways are involved in the headache attacks, and that the hypothalamus is involved in the prodrome stage of headache.

In addition to triptans and analgesics, empirical medication for the prophylaxis have been used to treat migraine. CGRP has been shown to play a major role in the pathophysiology of migraine in recent years. Studies have suggested that blocking CGRP signaling is an effective preventive and therapeutic strategy in patients with migraine. In Japan, two anti–CGRP antibody drugs and one anti–CGRP receptor antibody drug were launched in 2021, and their usefulness has been shown in clinical practice.

Diagnostic measures for spinal cord or root disorders include imaging studies, typically spine MRI, electrodiagnostic studies, and clinical evaluations. MRI may be thought to be the most useful measure, although it is not at all perfect regarding specificity as well as sensitivity. In fact, neurological examinations, especially the manual muscle testing (MMT), are the most reliable measure. Electrodiagnostic measures such as nerve conduction studies and needle EMG evaluate function of the nervous system and can complement neurological signs.

Myotome is the basis for the localization of spinal and neuromuscular disorders. Existing myotomal charts often lack mention to the source of their identifications. Only few studies have provided raw data for myotomal localization. Their methods include pursuit of the nerve course during the systematic dissection, intraoperative root stimulation, and clinical and electromyographical investigations of the single–root radiculopathy. We also published two studies regarding myotome, one for C8/T1 myotomes of forearm flexors, and the other for C5/6/7 myotomes.

Cervical spondylotic amyotrophy (CSA) is a disorder characterized by atrophy and weakness of upper–limb muscles with no or minimal sensory symptoms/signs or long–tract signs. Important differential diagnoses of CSA are neuralgic amyotrophy (NA) and amyotrophic lateral sclerosis (ALS). Among these 3 disorders, only CSA presents with an accurate myotomal distribution of the weakness. Distal type of CSA often presents with drop finger, and its differentiation from NA presenting with posterior interosseous nerve palsy would be achieved by documenting involvements of ulnar–innervated forearm and intrinsic hand muscles. CSA is an important ALS mimic in Japan. Selective involvements in ALS, not only split hand but split finger, arm sparing and weak shoulder signs, would contribute to their differentiation.

Examination of the dizziy patient should include a search for neurological signs and symptpms and a careful observation of nystagmus. Most of neurological signs and symptoms detected are the marker of dizziness of central origin. However, some of them represent the vestibular or other neurological imbalance that causes dizziness. Nystagmus also represents the central or peripheral vestibular imbalance that causes dizziness. Careful examinaiton can also help differentiation of psychogenic (functional) dizziness.

Persistent postural–perceptual dizziness (PPPD) is a newly defined diagnostic syndrome characterized by chronic subjective dizziness that exacerbated by three factors : upright posture, active or passive motion, and exposure to moving visual stimuli or complex visual patterns. The main mechanism of PPPD is thought to be a long–term maladaptation to a neuro–otologic event.

Treatment of Charcot–Marie–Tooth disease (CMT) has been challenging. However, appropriate diagnosis between CMT and other treatable conditions such as inflammatory neuropathies is important. Before pursuing genetic studies, workup should include electrophysiological and imaging studies.

Traditionally, CMT has been divided into demyelinating and axonal subtypes, that are electrophysiologically distinguished by conduction velocities (CV) of the upper limb (i.e., demyelinating if CV is slower, and axonal if CV is faster than 38m/s in the forearm segment). Of note, axonal neuropathy could demonstrate slow conduction velocity due to loss of fast–conducting fibers, such that careful evaluation is necessary in case of a low amplitude of compound muscle action potential (CMAP). If axonal degeneration is too severe to record CMAP, one should consider to record from proximal muscles, such as tibialis anterior and biceps brachii, and even blink reflex to find any demyelinating feature.

On the other hand, imaging studies has been utilized to visualize peripheral nerves. In demyelinating neuropathies, peripheral nerves are thickened and can be visualized by MRI and ultrasound. Among demyelinating neuropathies, CMT1A shows by far the largest nerve size. Nerve enlargement in CMT1A can be visualized in infancy, even before 6 months of age and become larger with age. This information is important in pre–symptomatic detection of demyelinating neuropathy and sonography could be used as a biomarker for therapeutic intervention.

Idiopathic inflammatory myopathies (IIMs) are a group of disorders complicated by inflammation and resultant damage of skeletal muscles without known causes. Major advances have been recently made in the field of IIMs, including new classification criteria to better identify the patients with IIMs, and discovery of detailed muscle pathologic features and myositis–specific and myositis–associated autoantibodies that facilitates subgrouping of patients into more specific clinical phenotypes. IIMs are now classified into four major subgroups, i.e., dermatomyositis (DM), anti–synthetase syndrome (ASSD), immune–mediated necrotizing myopathy (IMNM), and inclusion body myositis (IBM). Patients with concomitant features of other connective tissue diseases are considered overlap syndrome. Almost all patients who used to be diagnosed as having ‘polymyositis’ are now re–classified as IBM, IMNM, or ASSD. IIMs are originally characterized by the presence of myositis, but it has been recently recognized that patients with typical DM rashes or myositis–specific autoantibodies plus interstitial lung disease without apparent skeletal muscle involvement are also included in this spectrum. Recent studies evaluating immunophenotypes of individual IIM subgroups have shown distinct pathophysiologies : type I interferonopathy and activation of the complement system in DM, type II interferon activation in ASSD, autoantibody–mediated complement activation in IMNM, and a primary role of CD8⁺ T cells in IBM. This information is useful in developing unique therapeutic approaches to individual IIM subgroups. Although corticosteroids are still the first–line therapeutic agents, their long–term use is known to increase serious side effects that affect patients' quality of life and survival. Attempts to minimize the accumulated dosage and duration of corticosteroids has been made in patients with systemic lupus erythematosus, and are now applied to patients with IIMs. For this purpose, initial combination of immunosuppressive drugs and molecular–targeting drugs is being actively introduced in the field of IIMs. Over the next few years, management of IIMs will undergo major advances and will be able to provide better medical care to the patients.

We reviewed the current status of neuromuscular diseases in the COVID–19 epidemic and the nursing system for patients with cognitive decline and delirium who are hospitalized with COVID–19. COVID–19–related neurological diseases range from non–specific symptoms such as headache and fatigue to specific symptoms such as olfactory and gustatory disorders, autoimmune diseases, and stroke. The frequency of neurological complications of COVID–19 is higher than that of other viral diseases such as influenza, and the severity is particularly high in severe cases and patients with dementia. In patients with dementia, infection and serious illnesses are more frequent due to lack of understanding of infection prevention measures, and cognitive function may deteriorate due to isolation in nursing care. We believe that it will be important to take a new perspective in response to social structural changes, such as the use of IT equipment and the telemedicine.

Neurologist consider three things of the patient ; 1) where is the lesion?, 2) what is the lesion?, 3) What can I do for the patient? Neurological examination is important for localization of the lesion. If the localization of the lesion is decided, the quality of a pathological change which occurs there will be limited considerably.

A reflex hammer is a symbol of neurological examination. Neurologist needs to be skillful in tendon reflexes. Reliable methods of tendon reflexes depend on adequate reflex hammers, complete relaxation of the muscle, positioning of extremities, and an adequate stretch stimulus. The presence of hyporeflexia or hyperreflexia may indicate an underlying disease. Proper technique and interpretation of results are crucial to localize the lesion. The clinical significance of deviations in the activity of tendon reflexes from the normal depends on comparison with other tendon reflexes and particularly with the reflex of the corresponding muscle of the opposite side. Tendon reflexes are especially important in diagnosis of spinal diseases or peripheral nerve diseases.

Medications such as dopamine replacement therapy and device–aided therapies (DAT) have made it possible to maintain long–term physical function in Parkinson disease (PD) patients, but the role of nurses for caring PD patients with long–term course is increasing. It is necessary PD nurses to accurately understand the patient's symptoms and take care to provide the necessary care and information to the needs of the patients and their family according to the stage of the disease. In the advanced stage of PD, various decision–making support such as introduction of DAT is required in addition to support for daily life of patients and their family. PD nurses accurately assess the care of the patient and their families' needs and act as a spokesperson for the patient and caregiver. PD nurses can also play an important role in planning, acting, assessing, with interdisciplinary cooperation in patient–centered plan. Therefore, it is an urgent task to train PD nurses, who have a good understanding of the patient's condition and treatment and can provide appropriate support that is close to the patient and their family.

Parkinson disease (PD) is a neurodegenerative disorder manifesting not only motor symptoms but also variety of non–motor symptoms. Patients with PD suffer from side effects of anti–PD drugs and from complications such as falls and aspiration pneumonia during the disease course. We also need to take care of the environment surrounding the patients, such as nursing care condition, rehabilitation, and financial status. Recently, the importance of PD nurses has been recognized especially since the introduction of levodopa/carbidopa intestinal gel therapy, which requires comprehensive care involving multiple professions and various professions involved in nursing care. According to the guidelines for PD nurses, the role of the PD nurse is to perform a basic assessment of the patient and caregivers in terms of medical, physical, mental, and social aspects, to develop a patient–centered treatment plan based on the results of the assessment, to implement care based on the developed treatment plan, and to provide support to the patient and caregivers. The first PD nurse started working in 1989 in the UK, and in 1997 in Netherlands. In Japan, the Japanese Society for Parkinson's Disease and Movement Disorders has been leading a nationwide training program to train PD nurses on a regular basis since 2016 ; however, the PD nurse system has yet to be widely adopted. In this article, I will describe the role that physicians expect PD nurses to play and the desirable PD nurse system, focusing on the experience at my own facility.

Neuropsychological assessment methods for the general clinician are described. The following five points are important : (1) the term ‘higher brain dysfunction’ is used in two ways, (2) it is possible to recognize neuropsychological symptoms during the medical examination, (3) what is described as ‘forgetting’ could be a disorder other than memory, (4) note the location of the lesion (left vs. right, anterior vs. posterior, cortex vs. white matter, corpus callosum) on MRI images, (5) check the general cognitive function using the HDS–R and MMSE first, paying attention not only to the total score but also to the incorrectly answered items and error patterns, then add other tests (e.g. tests for apraxia, agnosia, and disconnection syndrome) if necessary.

Oligodendrocyte precursor cells (OPCs) serve as progenitor cells of terminally differentiated oligodendrocytes. Mature oligodendrocytes form myelin sheaths around axons in the central nervous system, and the myelin sheath is essential in the fast impulse propagation along with the myelinated fiber. Because oligodendrocytes do not proliferate, OPCs play a critical role in increasing the number of oligodendrocytes during development or after oligodendrocyte/myelin damage. Although mechanisms of OPC proliferation and differentiation have been examined and some extrinsic signaling molecules were identified as regulators of OPC function, precise mechanisms of OPC proliferation and differentiation still need to be elucidated, especially under the conditions of cerebrovascular diseases. As highlighted by the concept of the neurovascular unit, cell–cell interactions should be critical in supporting/maintaining OPC function, including oligodendrocyte generation. In this symposium session, we presented some key data from our laboratory regarding the roles of endothelial cells, astrocytes, and pericytes in OPC proliferation and differentiation. Because OPC is one of the major cell types in adult white matter, understanding and dissecting OPC–related non–cell–autonomous mechanisms of oligodendrocyte regeneration may lead to novel opportunities for white matter recovery in cerebrovascular diseases.

Neuromyelitis optica (NMO) is a disease characterized by severe optic neuritis and transverse myelitis with autoantibody against aquaporin 4 (AQP4), mainly localized at astrocyte foot processes. Loss of AQP4 and glial fibrillary acidic protein with relatively preserved myelin is the pathological hallmark of active NMO lesions. Several experimental studies suggested the crucial role of AQP4 antibody with diverse mechanisms of tissue injury in NMOSD including antibody– and complement–induced cytotoxicity against astrocytes. This diversity includes several conditions including astrocyte lysis, sub–lysis, clasmatodendrosis, reactive gliosis, and altered expression of other gap junction proteins such as connexin. The damage of glia–neuron networks related to astrocytes could induce the secondary tissue injury such as demyelination and axonal loss.

Alzheimer disease (AD) research began with the neuropathology of autopsy brains and progressed dramatically from biochemical studies to genetics and molecular biology studies of familial AD. Amyloid–β (Aβ) and tau proteins, which are major components of senile plaques and neurofibrillary tangles, respectively, play an important role in the pathogenic process. Pathologically, the activation of glial cells has been thought to be a result of the appearance of these abnormal protein accumulations or neurodegeneration. However, several genetic analyses of sporadic AD have revealed that glial cells, especially microglia, play an important role in the pathogenesis of AD. The development of antibody drugs such as Aducanumab has also highlighted the therapeutic potential of microglia in the treatment of AD. In this article, we discuss recent findings on microglia in AD.

Since 1996, various responsible genes for familial Parkinson's including SNCA disease have been identified. Gene manipulation models for Parkinson disease (PD) have been developed, and a genotype–phenotype correlation has been explored with those PD models. Also, those models contributed to develop various promising therapies modulating alpha–synuclein expression levels, and some of them are in clinical trial phases.

Based on data of genetically manipulated models of neurodegenerative diseases, non–autonomous cell death associated with inflammation is recognized as an important pathogenesis of the diseases. In autopsied PD brains, increase of activated microglia as well as increased levels of inflammatory cytokines have been reported. Also, PET studies showed evidences of microglial activation in the brainstem. Also, the association of microglial function with alpha–synuclein has been proposed by PD models. We reviewed recent advances in molecular research on PD inflammation focusing on glial cells.

Neuroinflammation, consisted of both neuroprotective and neurotoxic reactions by activated glial cells and the infiltrated immune cells, is involved in the pathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). Microglia are resident innate immune cells in central nervous system, and the activation phenotypes in healthy and diseased brain have been extensively examined through RNA–Seq. As an activation phenotype of microglia, M1/M2 hypothesis of microglia has recently been reconsidered by the new concept, disease–associated microglia (DAM). DAM is defined by a small set of deregulated genes, and commonly observed in neurodegenerative diseases including AD, ALS, and aging. We revisited the gene expression profiling of microglia isolated from App^NL–G–F knock–in (Amyloid β) mice, rTg4510 (Tau) mice, and SOD1^G93A (ALS) mice. Comparison of microglia transcriptome revealed that a loss of homeostatic microglia is correlated with a severity of neurodegeneration, suggesting that a loss of homeostatic microglia seems to be more important than DAM phenotype. Moreover, the systemic environment affects and alters the microglial phenotype and disease outcome, revealed by the study using SOD1^G93A mice with distinct genetic backgrounds (C57Bl/6 and Balb/c).

In summary, microglia and immune communication actively contributes to neurodegeneration in ALS and AD through research using rodent models, and accumulating research results indicate glial cells and neuroinflammation as viable therapeutic targets for neurodegenerative diseases.