With the COVID–19 pandemic starting in 2020, digitization is accelerating worldwide, and the trend is reaching the medical community. Various new technologies have been introduced into methodologies of new medical technology development, which has expanded at a rapid pace. In Japan, while delays in responding to digitalization have become apparent, particularly in the medical and administrative sectors, rapid changes have also begun to take place that incorporate the new trends. Japan's regulatory authority, the Pharmaceuticals and Medical Devices Agency (PMDA), has also been taking various actions in response to the COVID–19 pandemic and the rapid changes that followed. This paper introduces the PMDA's work and recent initiatives, including utilization of real world data, international activities, and promoting patient and public involvement.

Repulsive guidance molecule–a (RGMa), which is a glycosylphosphatidylinositol–linked glycoprotein, is expressed in glial cells and immune cells. RGMa was previously recognized as the protein that regulates axon growth negatively in the adult central nervous system (CNS). Enhanced recovery of skilled forelimb movement as well as neural rewiring was observed after spinal cord injury (SCI) in adult macaque monkey following anti–RGMa antibody treatment. Based on the findings by the preclinical studies, the international clinical trials of humanized anti–RGMa monoclonal antibody (Unasnemab) for SCI is ongoing currently.

Furthermore, RGMa was shown to be involved in immune regulation. RGMa expressed in dendritic cells promotes activation of T cells, leading to deterioration of autoimmune encephalomyelitis. Further, under the condition of neuromyelitis optica (NMO), RGMa was expressed by the spared neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. Aquaporin4–IgG–induced astrocytopathy and clinical exacerbation in NMO rats were ameliorated by anti–RGMa antibody treatment. Anti–RGMa antibody treatment significantly suppressed neutrophil infiltration, and decreased the expression of neutrophil chemoattractants. Neogenin–expressing macrophages accumulated in the lesion expressed CXCL2, a strong neutrophil chemoattractant, and further analysis revealed that RGMa directly regulated CXCL2 expression in macrophages.

In addition to the roles of RGMa in immune regulation, we recently reported that RGMa also regulates blood–brain barrier integrity and cell survival in the CNS. The multiple modes of actions of anti–RGMa antibody may explain the potent effects on the neurodegenerative and neuroimmune diseases as well as the CNS injuries. The clinical trial of Unasnemab for HTLV–1–associated myelopathy is also ongoing.

Facial pain disorders are not as frequently seen as the headache, but these are similarly incapacitating to the patients. Among them, trigeminal neuralgias (TNs) are thought to be one of the worst pain disorders and the cause may be diverse. Although the neurovascular compression of the trigeminal nerve root accounts for the majority of classical TN, one may encounter with TN, secondary to tumor, demyelinating disease or others. It is imperative therefore to understand the pain mechanism of TNs for the diagnosis and appropriate treatment. Diagnostic algorithm proposed by Cruccu is useful in this regard. Ophthalmic herpes zoster and otic herpes zoster (Hunt syndrome) are followed by postherpetic neuralgia often in elderly. Early appropriate antiviral therapy is imperative and in particular, amenamevir, a helicase–primase inhibitor, appears promising for arresting the disease process. Persistent idiopathic facial pain (atypical facial pain) does not have an identifiable cause, but the patient's daily life is distressed with the ill–defined pain. One may need to assess, if there are any organic features to the pain, psychological burden and/or personality trait. If unsuccessful in controlling the pain, psychosomatic approach may be necessary.

Central nervous system (CNS) inflammatory demyelinating diseases include multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), myelin oligodendrocyte glycoprotein antibody–associated disorders (MOGAD). Regarding to treatments for these diseases, a series of drugs have been approved for MS and NMOSD in recent years.

In MS, the increasing number of disease–modifying drugs (DMDs) has led to a change in the treatment algorithm, with high efficacy treatments (HET) now recommended as the first line of treatment. In Japan, natalizumab and ofatumumab are considered to be classified as HETs among DMDs approved in Japan, and treatment initiation from these HETs has been increasing in Japan. In NMOSD, four biologics have been approved successively in the last three years, enabling steroid–free prevention of relapse, whereas previously prednisolone was the mainstay of relapse prevention. On the other hand, the increase in treatment options requires more expertise and experience to implement optimal treatment.

With the enactment of the 21st Century Cures Act in the U.S. and the GCP Renovation proposal of the International Conference on Harmonization of Technical Requirements for the Regulation of Pharmaceuticals (ICH), there has been an active discussion on the utilization of real world data (RWD), which is data obtained in actual medical environments, such as patient registries and medical information by disease, not in experimental environments such as clinical trials (including clinical studies). Real world data (RWD) and Real–world evidence (RWE) generated from the analysis of RWD and RWE are being actively discussed for their utilization under the pharmaceutical affairs system.

In Japan, the Medical Information Database Infrastructure Development Project (MID–NET) and Clinical Innovation Network (CIN) concept, the Conditional Early Approval System for Drugs, and two guidelines by the Ministry of Health, Labor and Welfare and the Pharmaceuticals and Medical Devices Agency (PMDA) regarding the use of registries in regulatory applications are launched.

This symposium will provide an overview of recent trends in the use of RWD/RWE, and will lead to presentations by speakers from industry, government, and academia at this symposium.

The Rare diseases have been slow to make progress in elucidating their pathogenesis and developing new drugs. In the area of rare diseases, it is important to build a platform to promote drug discovery research, and it is important to establish a patient registry for rare diseases. Furthermore, the platform should be used to elucidate pathological conditions through clinical epidemiological analysis and genomic and omics analysis, as well as to promote drug development through the promotion of corporate collaboration.

The Rare Disease Data Registry of Japan (RADDAR–J) is an intractable disease information platform that covers approximately half of the 338 designated intractable diseases. The website provides catalog information on the registries and repositories of rare disease research group and promotes collaboration between rare disease research groups and pharmaceutical companies.

Recently, there has been an increase in the number of cases in which patient registries are utilized in the development of pharmaceuticals and other products, such as post–marketing surveillance, disease control groups, and patient recruitment. This paper outlines the activities of the Rare Disease Platform and introduces trends in the utilization of real–world data in the area of rare diseases.

RWD is mainly used in clinical research and Post Marketing Surveillance (PMS), and recently its use in clinical trials is also being actively discussed in pharmaceutical companies. However, there are still issues regarding the variety and quantity of RWD and the reliability of outcomes, so further development is expected.

On the other hand, in overseas where the development and utilization of RWD has preceded, the evolution is still continuing.

Some trends in RWD development include, for example, “accumulation of outcome validation results” “structuring of unstructured data” “conversion to common data models” and “anonymization of risk-based approaches”

“Accumulation of outcome validation” is to validate the outcome defined in RWD, and to calculate indicators such as positive predictive value and sensitivity compared to the gold standard.

Although it is also required for PMS in Japan, there are still issues in implementing validation and accumulating results.

In “structuring of unstructured data” the text portion of an electronic medical record is structured using Natural Language Processing (NLP) to enable analysis of patient background information and efficacy of drug treatment. This will lead to more efficient recruitment for clinical trials at each hospital in terms of primary use, and will enable the generation of RWD that can be used for research and clinical trials in terms of secondary use.

“Conversion to a common data model” is an effort to integrate and analyze different RWD such as medical claims and electronic medical records, and a representative common data model is OMOP CDM (Observational Medical Outcomes Partnership Common Data Model). OMOP conversion enables coaxial analysis of multiple RWDs using standard programs that have already been accumulated, leading to more efficient research.

“Anonymization of risk-based approaches” is a common approach in the U.S. that addresses the dilemma that the more information in RWD is processed by deleting or masking, the less risk there is of re–identification, while the more useful information for research is lost at the same time. Efforts based on this concept have been started in Japan as well.

Parkinson disease (PD) is a neurodegenerative disease with various motor and non–motor symptoms such as bradykinesia, rigidity, tremor, constipation, sleep disturbance, cognitive dysfunction, and depression. Although multiple risk factors including aging, genetic predisposition, and environmental factors are involved in the pathogenesis of PD, the number of patients with PD has been increasing in recent years in the world. Previous reports have shown that the severity of PD is high in elderly patients from the early stage of the disease and that a particularly high percentage of them have symptoms such as impaired postural instability, freezing of gait, hallucination, and cognitive dysfunction that reduce their quality of life (QOL). In addition, it is necessary to take into account factors that may reduce motor function, such as frailty, cerebrovascular disease, and spinal disease, as well as the effects of multiple medications for comorbid diseases and the environment surrounding the patient, such as elderly caregivers. In this section, we discuss future issues, focusing on the epidemiology of PD.

The average life expectancy of Japanese people in 2021 is 81.47 years for men and 87.57 years for women. Because of recent improvements in nutrition and sanitation, as well as the advances in medical care, it is predicted that the average life expectancy will reach 100 years, so–called the era of 100–year–life. Although the lifespan is getting longer, very few people will be free from disorder throughout their lives, and the majority will live with various diseases, especially chronic diseases.

Parkinson disease (PD) is the second most common, progressive neurodegenerative disorder, and its global incidence is on the rise, due to the aging of the world's population. “Elderly PD patients” are divided into two groups : patients with PD those who have been living with PD for a long time and those who develop PD at an old age. In the clinical practice for the elderly with PD, it is indispensable for clinicians to keep complex physical conditions, such as pharmacokinetics, comorbidities, and polypharmacy in “the elderly” in mind, as well as “PD” itself. In addition, reduced physical activity in the elderly could make it difficult to attend distant medical facilities; therefore, clinicians should provide PD care in their lives locally. In other words, the essence of clinical practice for the elderly with PD is not only to provide specialized “PD” treatment but also to treat and care for “the elderly”.

In general, it is difficult to establish evidence in the medical field for the elderly, because each elderly has a wide variety of background factors, including comorbidities or polypharmacy, which could be biases in the clinical research. Japan is one of the first countries in the world to face a super–aging society, and we are in a position to establish evidence about the clinical practice for “the elderly patients with PD”. We need to discuss what we can and should do for the elderly patients with PD and to provide evidence, preparing for the world's PD pandemic.

One of the clinical characteristics of elderly Parkinson disease (PD) is an increased incidence of postural reflex impairment, falls, and freezing of gait compared to other age groups with PD. Aging is considered a risk factor for PD, in addition to genetic and environmental factors. Abnormal protein accumulation associated with aging has been observed in several proteins, including tau, amyloid beta, argyrophilic grains, and TDP–43, all of which show an increased incidence with age. However, the presence of Lewy pathology, a hallmark of PD, is reported to decrease after the age of 80, and may be absent in cases over 100 years old. Thus, it may be said that the pathological feature of PD in the elderly is characterized by the absence of Lewy pathology in cases over 100 years old.

The number of PD patients in Japan continues to increase, and it is expected that the number of elderly PD patients will continue to increase for the next 20 years. In addition, advances in diagnostic imaging techniques, drug therapy and device aided therapy have improved the life prognosis of elderly PD patients. As a result, the number of aging patients with advanced PD is steadily increasing. The role of a university hospital is to provide advanced medical care as a core medical institution and to conduct clinical research that contributes to the benefit of the public. This lecture outlines the role of university hospital for elderly PD treatment.

Guillain–Barré syndrome (GBS) which is an acute immune–mediated neuropathy is developed after antecedent infections such as Campylobacter jejuni, Mycoplasma pneumoniae, and various virus. In December 2019, coronavirus disease 2019 (COVID–19) occurred by severe acute respiratory coronavirus 2 (SARS–CoV–2) infection in Wuhan, China, and it has rapidly expanded worldwide. A first case with GBS associated with COVID–19 was reported in April 2021. Some systematic reviews and research papers have described the characteristics of GBS following COVID–19 (e.g., facial palsy in 30–40%, acute inflammatory demyelinating polyneuropathy by electrophysiological examination in 80%, and negative for anti–ganglioside antibodies in more than 90%). A meta–analysis has shown that the prevalence of GBS is presumed to be 0.15‰ amongst COVID–19 patients. On the other hand, GBS following SARS–CoV–2 vaccination also has been reported although the incidence was approximately 1 case per 1,000,000 doses. Further investigations regarding epidemiology of GBS after pandemic of COVID–19 are required in future.

It has been recognized that autoantibodies against paranodal cell adhesion proteins, such as neurofascin 155 (NF155) and contactin–1 (CNTN1), are detected in a small subset of patients fulfilling criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). IgG subclass analysis of these antibodies reveals the predominant elevation of the IgG4 subclass. Patients with IgG4 autoantibodies against NF155 or CNTN1 have some distinct clinical features, including poor response to intravenous immunoglobulin and high efficacy of rituximab, leading to the separation of this group from CIDP as autoimmune nodopathy in the revised international guideline on diagnosis and treatment of CIDP. Autoimmune nodopathy patients with IgG4 anti–NF155 and anti–CNTN1 antibodies are also regarded as representatives of IgG4 autoimmune diseases (IgG4–AID), an emerging group of autoimmune diseases that are caused by pathogenic autoantibodies of the IgG4 subclass. Members of IgG4–AID, such as glomerulonephritis, pemphigus vulgaris, myasthenia gravis, and autoimmune encephalitis, share relevant immunobiological and therapeutic aspects even though different antigens, tissues, and organs are affected. Because IgG4 is immunologically inert, patients’ IgG4 subclass autoantibodies hypothetically block protein–protein interactions.

Autoimmune nodopathy patients with either antibody commonly show sensory ataxia, severe demyelination on nerve conduction studies, very high cerebrospinal protein levels, and detachment of terminal loops from the axolemma at the node of Ranvier in biopsied sural nerves. While younger age at onset and higher frequency of tremor are characteristic of anti–NF155 antibody–positive nodopathy, anti–CNTN1 antibody–positive nodopathy is characterized by higher age at onset, early axonal damage, aggressive subacute course, and concurrence of membranous nephropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune peripheral neuropathy characterized by muscle weakness in the extremities. Three immunotherapies (immunoglobulin, corticosteroid, and plasma exchange) have been established as effective, with 70–80% of patients actually responding to treatment. However, there are a certain number of cases with inadequate or resistant response to treatment, and new treatment methods are desired. Potential treatment options include (1) intravenous immunoglobulin therapy combined with intravenous methylprednisolone pulse, (2) fetal Fc receptor (FcRn) inhibitors, (3) anti–CD20 monoclonal antibody (rituximab), and (4) autologous hematopoietic stem cell transplantation (AHSCT).

(1) A pilot study reported that 59% of patients were in remission at 1 year after receiving intravenous immunoglobulin therapy in combination with intravenous methylprednisolone pulse, and a randomized controlled trial (RCT) (OPTIC Study) is currently underway to evaluate the combination therapy. (2) FcRn inhibitors have been shown to reduce blood IgG levels by inhibiting IgG recycling, and two subcutaneous drugs (rozanolixizumab and efgartigimod) are being tested in RCT. (3) Efficacy of rituximab has been reported mainly as case report, and a systematic review and meta–analysis indicated that rituximab is effective or CIDP, although confirmation of its efficacy in RCT remains lacking. The therapeutic efficacy of rituximab is more pronounced in patients with anti–paranode IgG4 antibody–positive CIDP. A RCT has been conducted in Japan for IgG4 antibody–positive CIDP (RECIPE study), and the results are awaited to be announced. (4) AHSCT is expected to restore immune tolerance to self–antigens by “resetting” the immune system, and its efficacy has already been established in multiple sclerosis. In a prospective, open–label study conducted in the U.S., 60 CIDP patients who were resistant or dependent to standard immunotherapies were included. The results showed that 83% of the patients no longer needed immunotherapy and 83% were walking on their own after one year (32% before treatment), indicating that AHSCT is a treatment that can aim for a complete cure of the disease.

Restless legs syndrome (RLS), also known as Willis–Ekbom disease (named after the physicians Thomas Willis and Karl–Axel Ekbom, who established its concept), is a neurological and sleep–related disorder. This sensorimotor disorder is characterized by an urge to move associated with an unpleasant sensation in the lower limbs that is present at rest and is resolved or improved by movement ; these symptoms occur in a circadian pattern, with onset in the evening or at night. Although the complete pathophysiology of RLS remains unresolved, several studies utilizing imaging, genetics, and animal models have made progress in elucidating the underlying mechanisms. Magnetic resonance imaging studies have linked RLS with reduced iron concentrations in specific brain regions, while positron emission tomography and single–photon emission computed tomography studies have demonstrated functional abnormalities in dopaminergic nerves and the mesolimbic system. Additionally, functional magnetic resonance imaging studies have demonstrated abnormalities in brain regions belonging to both the sensorimotor system and the limbic network. Recent studies have suggested that abnormalities of adenosine, dopamine, and glutamatergic innervation in the striatum could be downstream of impaired iron utilization in the brain, leading to brain iron deficiency. RLS has numerous comorbidities and may be classified as secondary. It is a complex condition in which predisposing genetic, environmental, and comorbid factors contribute to the development of the disorder. The current treatment guidelines recommend treatment initiation with low–dose dopamine agonists or gabapentin enacarbil. Although dopamine agonists are very effective during induction, their long–term use can lead to serious worsening of the disease, known as augmentation. Other treatment options include opioids, iron supplements, and other new therapeutic candidates. Nevertheless, some patients still experience poor long–term symptom management. A better understanding of the pathological mechanisms of RLS can aid new therapeutic possibilities with the emergence of new avenues of research in pharmacology.

Restless legs syndrome (RLS) is a sensorimotor disorder characterized by a strong, nearly irresistible urge to move limbs. The symptoms worsen at rest and follow a circadian pattern, i.e., worsen during evening or at night. Furthermore, patients with RLS also frequently have insomnia. RLS is a complex condition in which predisposing genetic factors (e.g., MEIS1 and BTBD9), environmental factors, and comorbidities contribute to disease expression. RLS can occur alone or with comorbidities, for example, iron deficiency, end–stage renal disease requiring hemodialysis, pregnancy, drug or substance use, neurological disorders, such as migraine, Parkinson disease, multiple sclerosis, and polyneuropathy, cardiovascular diseases, diabetes mellitus, rheumatological disorders, and respiratory disorders, such as chronic obstructive pulmonary disease. The primary pathophysiological mechanism of RLS is related to brain iron deficiency, which might induce dopaminergic dysfunction and changes in the adenosinergic and glutamatergic pathways. Such interplay between brain iron concentration and neurotransmitters may affect the arousal systems, leading to insomnia, and alter the functioning of the cortico–striatal–thalamic–cortical circuits, leading to the sensorimotor symptoms of RLS and periodic leg movements. Other factors involved in the pathophysiology of RLS remain to be identified.

To be clarified as trustworthy guidelines, it is desirable to adopt the GRADE approach which recognized the international standard. It includes that a transparent structure of the developing organization, adequate management of conflict of interest of participating members, and strict developing process. The guideline executive committee of Japanese Society of Neurological Therapeutics decided to update the Restless legs syndrome (RLS) clinical practice guidelines along “Minds clinical practice guidelines developing manual 2020 ver.3.0” (Minds manual 2020). A guideline developing group and systematic review teams were organized from July, 2021 and the seminar to learn GRADE approach was held for them.

A chairperson was elected after the COI management by the responsible society. Members were able to share the developing policy of RLS clinical practice guidelines by developing a scope beforehand. Clinical questions from important clinical topics were established, and then systematic reviews were performed using foreground questions. A process of systematic review and developing recommendation were proceeded using Minds templates. When future research questions that no studies were extracted by comprehensive literature retrieval using clinical questions, it should be emphasized that the society organized preferential research themes for the future guidelines’ revision and promoted creation of the evidence. In addition, when there is only indirect evidence in the medical practice, good practice statements (GPSs) could be adopted, however, both systematic review and recommendation were not necessary. This paper draws that the GRADE approach is useful at developing of clinical practice guidelines in the rare disease with few evidences.

Alzheimer disease (AD) is the most common age–related neurodegenerative disorder and is characterized by major pathological hallmarks in the brain, including plaques composed of amyloid β–protein (Aβ) and neurofibrillary tangles of tau protein. Although the present therapy of AD is limited to symptomatic therapy, recently, pathological and biochemical approaches aimed at disease–modifying therapy (DMT), especially the approaches focused on Aβ have been developed remarkably. Aβ molecules aggregate to form oligomers, protofibrils, and mature fibrils. Although it was previously thought that insoluble fibrils of Aβ, which accumulates as amyloid in the brain, exert toxicity, recently attention has been focused on the study of oligomers and protofibrils, which are more toxic aggregates of Aβ (oligomer hypothesis). 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.

Biomarkers for detecting Alzheimer disease (AD) are expected to play many roles in preemptive medicine. In addition to molecular imaging such as amyloid PET and tau PET, cerebrospinal fluid (CSF) Aβ42, phosphorylated tau and total tau have been used as biomarkers that reflect the pathological characteristics of AD, namely Aβ accumulation (A), tau accumulation (T), and neurodegeneration (N). In recent years, plasma biomarkers such as plasma Aβ and p–tau have also been developed. In this article, body fluid biomarkers for preemptive medicine of AD are reviewed.

In the brain, arteries and veins do not run in parallel, and its perfusion system has characteristics not found in other organs. The presence of a tight blood–brain barrier and lack of authentic lymphatic vessels in the parenchyma means clearance of some waste products, such as amyloid β (Aβ), is impeded. Aβ is thus cleared from the brain via at least four clearance pathways including 1) transcytotic delivery, 2) intramural periarterial drainage, 3) glymphatic drainage and 4) enzymatic or glial degradation. Failure in any four such pathways has been implicated in the pathophysiological processes behind Alzheimer disease. In clinical trials of Aβ vaccination therapy, vascular Aβ deposition was paradoxically enhanced, with encephalitis subsequently occurring in a fraction of patients. This serious side effect may be associated with insufficient clearance of solubilized Aβ through clearance systems in response to immunotherapy. Transcytotic delivery, intramural periarterial drainage, and glymphatic drainage clearance pathways depend on vascular integrity and are partly driven by vascular wall motion; therefore arteriosclerosis or perfusion pressure reduction is assumed to increase Aβ accumulation. Strategies activating clearance systems may be helpful in the treatment of intractable disease through reduction of brain Aβ, therefore aiding development of neurovascular prevention strategies for Alzheimer disease.

In neurodegenerative dementias exemplified by Alzheimer disease, various abnormal proteins such as amyloid β and tau accumulate in the brain, which are pathognomonic characteristic. These abnormal protein accumulations in the brain are considered important treatment targets for preemptive medicine for dementia, as they are observed prior to clinical symptoms such as memory loss and are closely associated with neuronal damage. In the United States, monoclonal antibodies against amyloid β in Alzheimer disease have already been approved as disease–modifying drugs for Alzheimer's patients. However, the interpretation of clinical trial data for approved drugs, medical–economic issues, and the effectiveness of such disease–modifying drugs as preemptive medicine for preclinical patients are still under discussion and require further evidence accumulation. Nevertheless, the emergence of the second and third candidate drugs for disease–modifying agents indicates that the future of preemptive medicine for dementia is not far away. In recent years, the development of disease–modifying drugs that lead the way for preemptive medicine for dementia has accelerated, partly due to the fact that brain imaging, such as amyloid PET, has become a fundamental technology in pathophysiology research and drug development processes. Among the aforementioned disease–modifying candidate drugs, some have achieved excellent study designs and cleverly achieved primary endpoints by utilizing tau PET in addition to amyloid PET. Thus, abnormal protein accumulations in the brain are important targets not only for treatment but also for diagnosis and assessment of treatment efficacy, and the development of imaging biomarker technology to visualize them has become a powerful promoter of the drug development process. This paper focuses on neuroimaging in relation to the recent progress in dementia pathophysiology research, and introduces examples of the role of disease–modifying drug development in achieving preemptive medicine for dementia. Additionally, the requirements for achieving preemptive medicine in actual clinical practice, as well as the use of imaging biomarkers and challenges in preemptive care practice are discussed.

A number of disease–modifying therapies (DMT) against Alzheimer disease (AD) are currently being tested in clinical trials, some of which met the clinical endpoints in registration–level trials like Clarity for lecanemab, which recently got accelerated approval in the United States, whereas others, especially those conducted in dementia stages, have failed, underscoring the needs for early intervention and biomarkers. To establish imaging and fluid biomarkers that surrogate the clinical and pathophysiological progression of AD, longitudinal observational studies as represented by AD Neuroimaging Initiative (ADNI) in US, as well as the Japanese ADNI, has been conducted, which contributed greatly towards the goal of very early treatment at the prodromal and preclinical AD stages by delineating the early natural course of AD. It has been demonstrated that the clinical and biomarker profiles of prodromal AD in J–ADNI were remarkably similar to those in North American ADNI, supporting the harmonization of global clinical trials. Furthermore, secondary prevention trials in preclinical AD, i.e., anti–Aβ therapies in asymptomatic, amyloid positive elderly individuals (the A4 study), as well as projects to establish trial ready cohorts (TRC) of preclinical and prodromal AD, are being conducted in US and Japan. J–TRC is comprised of a webstudy and an on–site study, recruiting ∼13000 and ∼528 participants, respectively. These clinical activities, accelerated by the development and implementation of biomarkers, will pave the way toward the development of very early treatment of AD.

Recent technological innovations in nucleic acid medicine have opened the way for personalized gene therapy for rare neurological diseases for which there is no cure. In 2018, at Harvard Medical School Boston Children's Hospital, a personalized nucleic acid medicine was developed and manufactured targeting the unique genetic sequence of a girl with neuronal ceroid lipofuscinosis (Batten disease) ; the fatal neurodegenerative disease, and was administered in a physician–driven N–of–1 clinical trial within one year of development. Since this pioneering effort, “N–of–1+ trials” using nucleic acid medicine for one or a few patients have started in the United States. “N–of–1+ trial” is a new approach for the rapid development of treatment for rare diseases with a severe prognosis that have no treatment, and it can be applied to many inherited rare neurological diseases. However, it requires collaboration and coordination among healthcare professionals, patients and patient groups, pharmaceutical companies, and regulatory agencies.

IRUD has been launched in 2015 according to a worldwide trend of promotion of rare disease medicine. Nationwide surveys by AMED revealed more than 37000 cases were in such situation in Japan, while various measures on rare diseases were available once the diagnosis was made since 1972 and were greatly strengthened by the new Law on rare disease since 2015 in Japan. By the March 2021, causative gene variants were identified in 2677 families (Detection rate : 44.4%) out of 6031 families with whole exome sequence and 7069 families registered. There were 25 new pathogenic genes, 6 new diseases with new variants of known pathogenic genes and 14 new phenotypes of new variants of known pathogenic genes. Among 2247 families caused by 652 genes, 70% of which were responsible for only 1 or 2 families suggesting they were very rare. These rare disease–causing variants detected in IRUD appear good candidates to develop nucleic acid therapies in near future.

Pharmaceutical products are approved through a long and careful process to secure the balance of safety and efficacy, however, there is a risk of unpredictable events in a real world because of limitations of settings of clinical trials. Pharmaceutical companies have a responsibility to monitor the use of approved drugs and then promote their appropriate use based on latest information after approval in parallel with stable supply. It is expected that N–of–One medicine could provide clinical benefit to a very small number of patients by minimum changes in the sequence of approved nucleic acid drugs. On the other hand, it is quite difficult to predict effects of such changes and differences of application on the balance of safety and efficacy under the condition of clinical study with a highly limited number of participants. Additionally, quality control for products of small quantity and wide variety does not seem to be equal to that for a single product of larger quantity, resulting in the difficulty of the use of a common product line. Additionally, quality control for products of small quantity and wide variety does not seem to be always equal to that for a single product of larger quantity, resulting in the difficulty of the use of a common product line. As described above, a framework to secure the balance of safety and efficacy of N–of–One medicine with a controlled quality for the benefit of corresponding patients is more important than financial challenges. Roles and responsibilities of industries in the frame, together with those of the regulatory authority and medical institutes, needs to be clarified and then its social consensus must be made.

Clinical Practice Guideline for Headache Disorders 2021 was published in 2021, in which the GRADE system was adopted in the section of acute migraine therapy. The number of clinical questions was increased to 132. There have been a number of notable changes in headache medicine. The International Headache Society released the International Headache Classification of Headache Disorders, 3^rd Edition (ICHD–3) in 2018, which made some important modifications in classification and diagnostic criteria of headache disorders. Moreover, basic and clinical research has advanced our understanding on the pathophysiology of headache disorders. As a consequence, calcitonin gene–related peptide (CGRP)–targeted therapy was introduced to the treatment of migraine and cluster headache. In particular, this novel therapy has had a great impact on migraine prevention. Furthermore, novel therapeutic approaches, such as non–invasive neuromodulation and cognitive and behavioral therapy, are in clinical use. The new clinical guideline provides clinically relevant information on headache management, thus serving as a new compass for navigating headache management in the new era.

Patients with migraine have been found to have impediments in all areas of their lives, including impacts on work and home, due to headache attacks. On the other hand, it is also known that despite the disruption to their lives, patients do not seek medical care. In recent years, migraine treatment has entered a new stage with the advent of new therapeutic agents such as CGRP–related antibodies and ditan, and patients should seek medical attention (headache specialist) if their lives are impdimented with headache.

Calcitonin gene–related peptide (CGRP) is a 37–amino acid peptide primarily located in C and A delta sensory fibers of sensory nerves. These fibers are widely distributed in both central and peripheral perivascular areas and are believed to play a role in nociception by releasing CGRP from sensory nerves. Additionally, they are involved in the stimulation function of peripheral vascular smooth muscle cells and vascular endothelial cells through the descending transmission of CGRP from sensory nerve endings. The vasodilatory effect of CGRP release from trigeminal nerve endings on dural blood vessels is considered a critical pathway related to the pathogenesis of migraine. Based on these findings, a series of anti–CGRP antibody drugs targeting CGRP were launched in 2021. This overview of the pathophysiology of migraine provides a perspective for understanding the mechanism of action of these anti–CGRP antibody drugs.

Treatment of migraine consists of acute and prophylactic therapy. Acute therapy mainly consists of analgesics such as NSAIDs and triptans, serotonin agonists. Based on the vascular theory of the migraine pathophysiology, serotonin (5–HT) is depleted during a migraine attack. After that, blood vessels are diluted and a migraine attack occurs. Triptans suppress migraine attacks by contracting blood vessels and reducing the release of some substances associated with neuroinflammation such as CGRP. Triptans selectively act on 5–HT_1B and _1D receptors. However, Lasmiditan which selectively acts on 5–HT_1F receptor has developed. 5–HT_1D and _1F receptors are present in the trigeminal nerve peripheral terminal, while 5–HT_1B receptor is present in vascular smooth muscle. Therefore, 5–HT_1B has a vasoconstrictive effect. We cannot describe triptans to migraine patients with cardiovascular and cerebrovascular risks. However, 5–HT_1F receptor is present in the trigeminal nerve (Aδ fibers and C fibers), not in vascular smooth muscle. Then, lasmiditan has no vasoconstrictor effect, and it can be used for migraine patients who are contraindicated for triptans. In addition, unlike triptans, it passes through the blood–brain barrier, so it has the advantage that there is no need to worry about the timing of oral administration during a migraine attack.

The FilmArray Meningitis/Encephalitis (ME) Panel is a diagnostic test used to detect the presence of multiple pathogens that can cause meningitis/encephalitis in cerebrospinal fluid (CSF) samples. The test is a novel molecular multiplex PCR for detecting the 14 most common causative pathogens of central nervous system infections. The pathogens detected by the FilmArray ME Panel include six bacteria (Escherichia coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, and Streptococcus pneumoniae), seven viruses (herpes simplex virus types 1 [HSV–1] and 2 [HSV–2], varicella–zoster virus [VZV], cytomegalovirus, human herpesvirus 6, human parechovirus, and enterovirus), and one yeast group (Cryptococcus neoformans/gattii). The FilmArray ME Panel uses a multiplex polymerase chain reaction (PCR) technology to simultaneously test for the presence of multiple pathogens in a single CSF sample, with results available within a few hours. This contrasts with traditional microbiological testing methods, which can take several days to provide results and may require testing for each pathogen individually. The rapid and accurate detection provided by the FilmArray ME Panel can help clinicians quickly identify the cause of meningitis or encephalitis and choose the most appropriate treatment for their patients. It is worth noting that a negative test result does not necessarily rule out the possibility of an infection, and the clinical findings should always be considered in interpreting the results.

Progressive multifocal leukoencephalopathy (PML) is a neuroinfectious disease caused by the JC virus, and there are no established treatments for PML. Previously, most cases of PML were associated with severe complications such as acquired immunodeficiency syndrome (AIDS) and cancers. Recently, PML has been attracting attention in drug–associated cases without severe complications. One of the most important drugs among drug–associated PML is natalizumab, a disease modifying drug for multiple sclerosis (MS). Recently, cases with drug–associated PML related to other drugs have been reported, and those drugs have been classified according to risk levels for PML. When following up patients receiving PML–risk medications, it is important to suspect and diagnose PML at an early stage, as earlier intervention for drug–associated PML can lead to better patient outcomes. Drug–associated PML often shows abnormal findings on MRI before the onset of symptoms ; therefore, routine and frequent MRI imaging is required in patients receiving PML–risk medications. It is also important to understand the imaging characteristics of PML, as drug–associated PML has been reported to have slightly different MRI findings than PML in patients with AIDS or cancer. As such, careful follow–up in patients receiving PML–risk medications is warranted.