Treatment for neurological disorders has made remarkable progress over the past two decades, a transformation that can be deeply understood through the traditional Japanese concept of “Shu–Ha–Ri”―a dynamic cycle of inheriting, breaking, and creating clinical paradigms. In the Shu (Tradition) phase, the establishment of the J–ACT trial defined a unique Japanese standard for low–dose alteplase (0.6 mg/kg), which became the foundational “form” of domestic stroke care, ensuring high safety and reproducibility through nationwide education. The Ha (Innovation) phase represents the breaking of existing frameworks through technological advancement, evidenced by the expansion of treatment windows via the ECASS III trial and the paradigm shift from “time–based” to “tissue–based” strategies. This era also witnessed the dramatic progress of mechanical thrombectomy and the optimization of regional emergency transport systems, such as the “Mothership” strategy. Currently, the field has entered the Ri (Creation) phase, pursuing optimal solutions beyond standard treatments tailored to patients' values. Key innovations include the introduction of tenecteplase as a next–generation thrombolytic, the emergence of “Stroke Oncology” guided by a three–axis evaluation model, and the creation of the “FAST–DAN” system for in–hospital strokes. Ultimately, this evolutionary cycle ensures that preserving tradition, embracing innovation, and creating new therapeutic systems fulfills the mission of stroke neurologist to pass on a lasting legacy to the next generation.

I have been appointed as the new president, succeeding Dr. Satoshi Kuwahara, from the 42nd Annual Meeting of the Japanese Society of Neurological Therapeutics (Makuhari Messe) in November 2024. The Society's predecessor, the Neurological Therapeutics Research Group, was established in 1983, when there were still few treatments for neurological disorders, with the aim of spreading knowledge about treatment and providing the best treatment available at the time in daily clinical practice. The Society was established in 1992 with the aim of promoting the development of therapeutics, education and awareness, and the development of new treatments, with a focus on the treatment of neurological disorders.

Here, I will introduce the activities of two representative committees. The Internationalization Committee aims to promote the Society's international collaboration and to share the latest knowledge with the Japanese community. As mentioned above, since 2010, we have been sending members to the ASENT Annual Meeting in the United States, and we planned a special lecture at the Society's academic conference in 2011. Since then, we have held a JSNT–ASENT joint symposium at ASENT, further deepening our relationship.

The Drug Discovery Promotion Committee aims to accelerate innovative drug discovery in the field of neurology through collaboration between industry, government, and academia, and to act as a bridge from seeds to practical application through clinical trial support and clinical development advice. In addition to posting information on clinical trials supported by the society on its website, the committee also works on providing clinical trial facility surveys at the request of companies for clinical trials where it is difficult to enroll subjects due to rare diseases, etc. (clinical trial support project).

Clinical trials targeting hyperacute conditions such as stroke require the initiation of treatment and research interventions within extremely limited time windows, often summarized by the phrase “Time is Brain.” Under these circumstances, obtaining appropriate informed consent (IC) poses significant practical and ethical challenges, particularly when patients are unable to provide consent themselves. Clinical trials in emergency situations, therefore, involve complex interactions among clinical urgency, research ethics, and regulatory requirements.

Alternative approaches to informed consent, including exception from informed consent (EFIC) and deferred consent, have been developed in the United States and Europe to address these challenges in acute stroke trials. In Japan, however, several issues persist, including legal and regulatory constraints, ethics review processes, operational challenges in clinical practice, and a limited public understanding of emergency clinical research.

In response to these challenges, the REFINED–IC research group (“Research on ELSI of Deferred INformed consent in clinical trials for stroke and Emergency Medicine : International Comparison”) engages diverse stakeholders―researchers, clinical trial professionals, ethics and legal experts, and members of the public―to investigate regulatory frameworks and implementation practices in Japan and beyond, assess public attitudes, and delineate practical challenges related to informed consent in emergency clinical trials.

Stroke therapy in the hyperacute stage must be initiated within a limited time window after symptom onset, and clinical practice is often conducted under severe time constraints. When enrolling patients into clinical trials, investigators must also obtain informed consent within this restricted time frame. The authors have conducted clinical trials in this manner for many years. However, stroke patients frequently have consciousness disturbance or aphasia, making communication difficult, and in many cases no legally authorized representative is present, such as when patients live alone. Excluding such patients from clinical trials not only delays trial progress but may also introduce selection bias, resulting in study populations that do not adequately reflect the full spectrum of the disease. Therefore, simplification of informed consent procedures or the use of consent waivers in clinical trials involving acute stroke patients should be actively considered to ensure appropriate trial conduct.

Clinical trials of pharmaceutical products conducted in Japan are subject to stringent regulatory requirements including the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices, the Ministerial Ordinance on Good Clinical Practice for Drugs (J–GCP), and the associated guidance documents (such as the J–GCP Guidance). This regulatory framework is designed to ensure that the protection of participants' rights, safety, and wellbeing are accorded the highest priority, while ensuring scientific quality and the reliability of clinical trial results. These regulations require that investigators shall explain trial–related information appropriately to prospective participants (or their legally acceptable representatives) and obtain written informed consent prior to their trial participation.

However, in life saving clinical trials conducted in emergency situations ―where time is critically limited and the prospective participant is at life–threatening risk ―it may be impracticable to obtain prior informed consent from the participant, and the participant's legally acceptable representative may not be immediately available. Article 55 of the J–GCP sets forth specific provisions the conduct of clinical trials in such cases.

This paper discusses, with reference to the J–GCP and the J–GCP Guidance, the fundamental principles of providing trial–related information and obtaining informed consent before participating in clinical trials, as well as the regulatory considerations applicable to life saving clinical trials conducted in emergency situations when the enrollment proceeds without prior consent from the participant or the participant's legally acceptable representative. To ensure that life–saving clinical trials in emergency settings are implemented in Japan without an undue delay, it is essential to establish a shared understanding among all stakeholders involved in such trials. It is anticipated that this paper will contribute to enhanced understanding among stakeholders engaged in the planning, review, and conduct of such trials.

As part of its internationalization efforts, the Japanese Society of Neurotherapeutics has renewed its English–language website to enhance global visibility and collaboration. Previously, limited English content made it difficult for overseas stakeholders to grasp the Society's structure and activities. The updated website now presents detailed information on governance, committee roles, and organizational structure, improving transparency and credibility. To support international clinical development, the Society clearly outlines its “Clinical Trial Support Project,” providing practical information for pharmaceutical companies and researchers considering clinical trials in Japan. Academic accessibility has also been strengthened through links to the English pages of the Society's journal and resources on standard neurotherapeutic practices. In addition, collaboration with the American Society for Experimental NeuroTherapeutics (ASENT) is highlighted in a dedicated section, underscoring sustained international partnerships. To balance resource constraints with timely information sharing, machine translation has been introduced for selected Japanese content. Through these web–based initiatives, the Society aims to lower barriers to international engagement and contribute to global neurotherapeutic research and drug development.

Japan must strengthen both outbound and inbound clinical development, as domestic patient availability declines while more than half of global cancer patients live in Asia. However, Japan–led investigator–initiated multi–regional clinical trials (MRCTs) have historically been uncommon, and many programs have remained Euro–American led, leaving Asia–relevant questions underexplored. A turning point was the PATHWAY trial, a Japan–led, registration–directed, randomized, double–blind, placebo–controlled phase III study of palbociclib plus tamoxifen conducted across Japan, Korea, Taiwan, and Singapore. The trial demonstrated that a Japanese academic group can operationalize a high–complexity MRCT and translate results into a regulatory outcome in Japan.

Building on this experience, the Asian clinical Trials network for cAncerS (ATLAS) project was launched in 2020 with three integrated pillars : strengthening trial infrastructure, providing international capacity building programs, and continuously implementing multiple international studies. ATLAS has involved 40 participating institutions from 10 Asian countries by early 2025. Governance is ensured through an ATLAS Board representing participating countries, organ–specific working groups, and regular meetings that enable continuous study generation, protocol development, and industry negotiation. ATLAS has implemented collaborative programs including Project CAD, a randomized phase III trial evaluating an AI–assisted colonoscopy detection tool, and MASTER KEY Asia, a rare cancer registry that also functions as an entry point for less–experienced sites.

In parallel, Japan faces increasing “drug loss,” particularly for products developed by emerging biopharma without a Japanese base. The one–stop consultation service (ENSEMBLExJ) was initiated to attract inbound trials by delivering English–based end–to–end support, including expert–board screening, a written evaluation report, and stakeholder matching with clinical experts, sites, partners, and contract research organizations. Together, ATLAS and ENSEMBLExJ provide complementary pillars to reduce lag and loss and deliver needed innovations to patients in Asia.

In recent years, the challenges surrounding access to medicines in Japan have undergone a qualitative shift. With the acceleration of regulatory review by the Pharmaceuticals and Medical Devices Agency (PMDA) and the promotion of multinational clinical trials, the long–standing issue of “drug lag”―the delay in the availability of new medicines in Japan compared with other countries―has been substantially alleviated. In contrast, a new societal challenge known as “drug loss,” in which medicines approved overseas are neither developed nor approved in Japan, has emerged. This issue is particularly pronounced in the fields of neurology and psychiatry, where a high proportion of innovative therapies that are considered standard of care abroad remain unavailable in Japan, resulting in growing concerns about patients being unable to access necessary treatments. This paper outlines the current status and underlying factors of drug lag and drug loss in Japan, introduces the initiatives of Aculys Pharma Inc., a company dedicated to bridging overseas pharmaceutical innovation into the Japanese market, and discusses future institutional challenges and perspectives for improving equitable access to innovative medicines.

In clinical practice, stroke physicians and cancer physicians increasingly work closely together. However, many unresolved issues remain, and clinicians often struggle with how to manage their patients. At the 2020 Annual Meeting of the Japan Stroke Society, the term “Stroke Oncology” was proposed to describe the relationship between the fields of stroke and oncology. Stroke Oncology refers not only to clinical research―such as discussions on the pathophysiology and treatment strategies of patients with both cancer and stroke―but also to the development of a multidisciplinary consensus covering a wide range of issues, including the establishment of care systems and treatment after the coexistence of both diseases. Currently, “Project Team on Stroke Oncology” has been established within the Japan Stroke Society, and a “Stroke Oncology Working Group” has been created within the Japanese Association of Supportive Care in Cancer, and collaborative activities have begun.

Cancer patients have an increased risk of ischemic stroke compared to the general population, presenting unique clinical features related to cancer–induced coagulation activation. Since 2015, we have been working to elucidate the mechanisms behind cancer–associated stroke using various databases (DBs) ranging from a single hospital–based stroke registry to large–scale epidemiological DBs.

We found that coagulation activation in advanced cancer patients is a key determinant of both ischemic stroke onset and long–term prognosis. The AHANDS score–consisting of six parameters at cancer diagnosis : Age, Hypertension, Atrial fibrillation, Neutrophil–to–lymphocyte ratio, D–dimer levels, and advanced cancer Stage– is useful for identifying patients at high risk for cancer–associated stroke. Furthermore, analyses of large–scale epidemiological DBs revealed that the mortality rate in patients with cancer–associated stroke varies significantly by cancer site.

Conventionally, cancer and ischemic stroke have been managed as an independent clinical entity. However, it is now understood that there is a bidirectional interaction between cancer and ischemic stroke. At present, standardized prevention and treatment strategies for cancer–associated stroke have yet to be established, and numerous unresolved issues persist. Therefore, further elucidation of the pathogenesis is warranted.

The mechanism of cancer–related stroke is thought to be due to hypercoagulation caused by mucins produced by cancer cells, and tissue factors expressed on the surface of cancer cells, which can lead to thrombosis. However, the mechanisms of cancer–related stroke are diverse. In addition to direct tumor cell invasion, cardiogenic cerebral embolism due to nonbacterial thrombotic endocarditis (NBTE), and paradoxical cerebral embolism via a patent foramen ovale following deep vein thrombosis are not uncommon. Meanwhile, patients with atrial fibrillation and arteriosclerotic lesions are thought to be at even higher risk of ischemic stroke in the presence of cancer. Recently, we conducted a multicenter registry (CHALLENGE ESUS/CS) of patients undergoing transesophageal echocardiography for cryptogenic stroke. In sub–analysis of CHALLENGE ESUS/CS registry, compared with the non–cancer group, the active cancer group was related to multiple infarctions and high CRP levels, while the inactive cancer group showed significant associations with age, contralateral carotid artery stenosis, aortic arch plaque, and aortic valve calcification. Thus, cryptogenic stroke patients with a history of cancer still have high–risk of stroke.

Cancer–related stroke has a high recurrence rate and a poor prognosis. So far, little evidences have been available on the therapeutic strategy of cancer–related stroke. Sub–analysis of NAVIGATE ESUS and ARCADIA studies show no efficacy of DOACs for stroke prevention. Several retrospective studies indicated that heparin was effective for stroke prevention and reducing D–dimer levels. In the pilot study comparing low–molecular weighted heparin with aspirin, subcutaneous injection of low–molecular weighted heparin was shown as intolerable and cross–overed to aspirin. In the meta–analysis of such studies heparin and antiplatelet agents were shown as effective for stroke recurrence in cancer–related stroke.

Mechanical thrombectomy has become the standard of care for acute ischemic stroke caused by large vessel occlusion, with indications expanding based on evidence from randomized controlled trials. Patients with active or advanced cancer are at increased risk of ischemic stroke ; however, they are excluded from randomized controlled trials because of limited life expectancy, and the benefit of endovascular reperfusion therapy in this population remains unclear. This review summarizes the pathophysiology of cancer–associated stroke, indications for endovascular therapy, and considerations for procedural strategy.

Cancer–associated stroke includes heterogeneous mechanisms, among which arterial thrombosis caused by cancer–related hypercoagulability―referred to here as “cancer-related stroke”―is characterized by platelet–rich, erythrocyte–poor thrombi. Histopathological studies of retrieved thrombi have demonstrated a predominance of platelet and fibrin components, particularly in nonbacterial thrombotic endocarditis and cancer–related cryptogenic stroke. Imaging findings such as the absence of hyperdense vessel sign or susceptibility vessel sign, the presence of a three–territory sign, and elevated D–dimer levels may suggest this thrombus phenotype.

Observational studies indicate that although patients with active cancer have poorer functional outcomes and higher mortality after thrombectomy, successful recanalization rates are comparable to those in patients without cancer ; thus, active cancer alone should not preclude endovascular therapy. Considering thrombus characteristics, contact aspiration with large–bore catheters may be an appropriate first–line strategy. Treatment decisions should be individualized through shared decision–making based on prognosis, risks, and patient preferences. Ongoing registry studies, including the ESPOIR registry, are expected to provide further evidence to optimize patient selection and therapeutic strategies for cancer–associated stroke.

Rehabilitation is an important treatment that could determine quality of daily living in stroke survivors. Rehabilitation in patients with cancer–associated stroke is much more challenging than that in the other stroke patients, both for patients themselves and for attending physicians. One of the main challenges for these patients in post–stroke rehabilitation include general fatigue, pain, risk for stroke recurrence, or medical treatment fee. In addition, not a few patients experience difficulty in finding suitable beds for such rehabilitation. Even if they recover after rehabilitation, cancer treatment such as chemotherapy is often discontinued based on performance status. Stroke physicians play a pivotal role to navigate both rehabilitation treatment and cancer treatment between patients and medical staffs, or between rehabilitation physicians and cancer physicians. It is expected that medical treatment fee system is revised to endorse rehabilitation for cancer–associated stroke, given the prospect for increasing the number of both cancer and stroke survivors.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which disability progressively accumulates. While current disease modifying therapies effectively suppress relapses, progression independent of relapse activity (PIRA) remains a major therapeutic challenge, particularly during transition to progressive MS. Increasing evidence suggests that the gut microbiome influences neuroinflammation through the gut–brain–immune axis.

Animal studies show that germ–free mice rarely develop experimental autoimmune encephalomyelitis (EAE), and antibiotic treatment attenuates disease severity. Human studies further demonstrate that transplantation of fecal microbiota from MS patients exacerbates EAE in recipient mice, indicating a causal contribution of intestinal microbes. Metagenomic analyses of MS fecal samples reveal functional alterations in progressive MS, including enrichment of bacterial DNA repair pathways consistent with adaptation to intestinal oxidative stress.

Strain–level analysis identified a disease–associated pathobiont, Tyzzerella nexilis. Within this species, only a specific lineage was enriched in progressive MS. This lineage contained a large number of mobile genetic elements with abundant sulfur and flagellar genes, induced intestinal Th17 responses, and exacerbated central nervous system inflammation and demyelination in EAE after monocolonization. These findings indicate that MS progression is associated not with microbial species per se but with functionally distinct bacterial strains.

These results support a therapeutic shift from broad microbiome modulation to selective targeting of pathogenic strains. Potential approaches include bacteriophage therapy, endolysin–based antibacterial strategies, and induction of antigen–specific mucosal IgA responses. Strain–level microbiome analysis therefore provides mechanistic insight into MS progression and suggests a framework for precision microbiome therapy aimed at preventing disability progression in MS.

Neuromyelitis optica spectrum disorder (NMOSD) is characterized by ‘autoimmune aquaporin–4 (AQP4)–opathy’. Damages of AQP4–expressing glial cells (e.g., astrocytes) would be caused by (a) complement–dependent cytotoxicity (CDC), (b) antibody–dependent cytotoxicity (ADCC), and (c) internalization of AQP4 water channels in NMOSD. Recent research advances reveal that stage–dependent immune dynamics, composed of neutrophils, T_H17 cells, T_reg cells, and T_RM cells, can modify the pathogenesis of NMOSD in situ. Therefore, modification of these immune dynamics could yield future drug candidates for NMOSD, in addition to complement–depleting antibodies, anti–interleukin–6 receptor antibodies, and B–cell–depleting antibodies. We would provide suggestions for establishing predictive biomarkers of disease activities and treatment responses, and for developing treatment strategies for NMOSD, to advance precision medicine for NMOSD.

Therapeutic strategies for central nervous system (CNS) diseases have traditionally focused on immune modulation, removal of pathogenic proteins, or direct neuroprotection. However, these approaches are often insufficient to halt disease progression in inflammatory and neurodegenerative disorders. Accumulating evidence suggests that disease pathology cannot be fully explained by dysfunction of a single cell type. Recent studies have revealed that astroglia, oligodendroglia, and microglia form a functional network through connexin–mediated intercellular communication, acting as a dynamic cellular assembly that regulates CNS homeostasis and neuroinflammation. In this review, we define this functional network as the “glial assembly” and summarize evidence indicating that its disruption represents a common pathological basis across inflammatory demyelinating and neurodegenerative diseases. Human neuropathological studies, as well as experimental models of multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease, and multiple system atrophy, demonstrate that alterations in connexin–dependent glial interactions critically influence inflammatory amplification, neuronal vulnerability, and pathological protein handling. Importantly, the glia assembly exhibits disease– and stage–specific reorganization rather than uniform failure. Targeting the glia assembly offers a novel therapeutic concept that complements existing immune– and neuron–directed therapies. Modulation or reconstruction of pathological glia assemblies may provide new opportunities for disease modification in currently treatment–resistant CNS disorders.

The Hisayama Study, an ongoing community–based epidemiological study in Hisayama Town, Fukuoka Prefecture since 1961, has begun epidemiological research on dementia in 1985. We conducted seven prevalence survey of dementia covering almost all residents aged ≥65 years in 1985, 1992, 1998, 2005, 2012–2013, 2017–2018, and 2022–2023, achieving consistently high participation rates (≥92%). The crude prevalence of all–cause dementia substantially increased from 6.7% in 1985 to 17.9% in 2012. However, prevalence of dementia subsequently declined, reaching 15.6% in 2017 and 11.9% in 2022. A similar trend was seen even after adjustment for age.

Since prevalence of dementia is determined by both incidence and prognosis of dementia, we also established three cohorts in the residents aged ≥ 65 years without dementia in 1988 (n = 803), 2002 (n = 1,231), and 2012 (n = 1,519), each of which was followed for 10 years.

The age– and sex–adjusted incidence of dementia increased significantly from the 1988 to the 2002 cohort (adjusted hazard ratio [aHR] 1.68, 95% confidence intervals [CI] = 1.38–2.06), but decreased significantly from the 2002 to the 2012 cohort (aHR = 0.60, 95% CI = 0.51–0.70). The age– and sex–adjusted 5–year survival rate after dementia onset increased significantly from the 1988 to the 2002 cohort (47.3% to 65.2% ; p < 0.01), while no significant change was observed from the 2002 to the 2012 cohort (65.2% to 58.9% ; p = 0.42).

In conclusion, the decline in the prevalence and incidence of dementia in Hisayama town in recent years may be due to the prevention and improved management of lifestyle–related diseases, such as hypertension and diabetes, as well as increased awareness and promotion of healthy lifestyle behaviors.

We examined the cross–sectional and longitudinal associations of objectively measured lifestyle factors, such as physical activity, conversation, and sleep using wearable sensors, with cognitive function or positron emission tomography images. The cross–sectional analysis showed that number of walking steps, total sleep time, conversation time, and heart rate were associated with Mini–Mental State Examination (MMSE) scores. Moreover, MMSE scores increased with step count, plateauing at 7,791 steps, and sleep duration showed increasing MMSE scores within the range of 353 to 434 minutes, but decreased beyond 434 minutes. Conversation duration showed increasing MMSE scores within the range of 80 to 321 minutes, but decreased beyond 321 minutes. Shorter sleep duration was associated with greater brain amyloid burden, whereas longer sleep duration was associated with decreased cortical glucose metabolism. The longitudinal analysis showed that lower physical activity and poor sleep quality were associated with subsequent cognitive decline and lower sleep efficiency was associated with greater brain amyloid burden. Moreover, the number of daily walking steps showed a positive correlation with sleep efficiency and an inverse correlation with WASO, awakening time count, and naptime. Our results can help promote walking as an intervention for preventing sleep disturbances in community–dwelling older adults. Our cohort study suggests the importance of lifestyle improvements to delay cognitive decline.

In recent years, the effectiveness of multidomain interventions for dementia prevention has been reported in many countries. In Japan, the J–MINT study was launched in 2019 to examine whether a multidomain intervention program tailored to the Japanese lifestyle could prevent cognitive decline. In this trial, the efficacy of a multidomain intervention was evaluated in individuals with mild cognitive impairment (MCI). Although no significant improvement was observed in the primary outcome of overall cognitive function, participants who attended ≥70% of the exercise sessions showed significant cognitive improvement. In addition to cognitive outcomes, improvements were observed in nutritional status, physical function, social participation, and reductions in blood pressure. Responder analyses further revealed that the intervention produced beneficial effects, particularly in APOE ε4 carriers, individuals with elevated baseline glial fibrillary acidic protein levels, and those with lifestyle–related diseases. Moreover, an economic evaluation of the J–MINT study demonstrated that, compared with usual care, J–MINT was both cost–saving and more effective. Research is currently underway to implement the evidence generated by the J–MINT study into real–world practice.

In May 2024, a decline in the prevalence of dementia in Japan was reported, which has become a hot topic. This decline is thought to be attributable to factors such as improved educational levels and better management of cardiovascular risk factors. The Lancet Standing Committee has provided 14 evidence–based recommendations regarding lifestyle behaviors and interventions. Our study also showed that diabetes prevention and treatment, as well as exercise and nutritional guidance, may be effective for prevention of dementia. Furthermore, brain imaging studies revealed that abnormal glucose metabolism is associated with hippocampal atrophy, which plays a key role in memory and learning. As more people engage in dementia prevention measures, the prevalence of dementia in Japan is expected to continue decreasing.

Nucleic acid therapeutics represent a rapidly advancing class of middle–molecule drugs characterized by high sequence specificity and accelerated drug development timelines. Alongside antibody therapeutics and gene therapy, they have emerged as a major therapeutic modality, particularly in neuromuscular and neurological disorders. The clinical success of nusinersen for spinal muscular atrophy, approved globally since 2016, demonstrated for the first time that intrathecally delivered antisense oligonucleotides (ASOs) can act as disease–modifying therapies for central nervous system (CNS) disorders. More recently, tofersen for SOD1–associated amyotrophic lateral sclerosis (ALS) further expanded the clinical application of nucleic acid therapeutics in neurodegenerative diseases.

Despite these successes, CNS–targeted nucleic acid drug development faces significant challenges. Several ASOs targeting C9orf72–associated ALS and Huntington's disease failed to demonstrate clinical efficacy, highlighting a critical trade–off between efficacy and dose–limiting neurotoxicity. Accumulating evidence indicates that CNS neurotoxicity associated with intrathecal nucleic acid therapeutics comprises two mechanistically distinct entities : acute–onset and late–onset neurotoxicity. Acute neurotoxicity appears shortly after administration and resolves rapidly, whereas delayed neurotoxicity emerges days to weeks later and progresses gradually.

Recent mechanistic studies revealed that acute neurotoxicity is mediated by extracellular effects of nucleic acids, particularly guanine–dependent inhibition of AMPA receptor function leading to reductions in intracellular calcium levels. In contrast, late–onset neurotoxicity arises from intracellular mechanisms, including aberrant interactions with nuclear paraspeckle proteins, resulting in their abnormal localization and subsequent neuronal cell death.

Based on these molecular insights, novel nucleic acid chemical modifications have been developed to mitigate neurotoxicity while maintaining therapeutic efficacy. Modifications such as 2′,4′–BNA/LNA with 9–(aminoethoxy)phenoxazine (BNAP–AEO) and 5′–cyclopropyrene (5′–CP) have demonstrated significant reductions in acute and late–onset neurotoxicity, respectively, in both in vitro and in vivo models.

These findings suggest that neurotoxicity of CNS–targeted nucleic acid therapeutics is not an unavoidable adverse effect but a controllable drug–design parameter. A deeper understanding of structure–toxicity relationships and mechanism–based chemical modifications will be essential for expanding the therapeutic potential of nucleic acid drugs in neurological diseases.

With the advent of tofersen, the landscape of clinical practice is poised to change dramatically not only for familial amyotrophic lateral sclerosis (ALS) but also for sporadic ALS. Mutations in the SOD1 gene are found in approximately 30% of familial ALS and 1.5% of sporadic ALS cases. This has raised the critical issue of how early a diagnosis can be made and treatment initiated. Therefore, it is essential to pursue the diagnostic process with the clinical characteristics of SOD1–ALS clearly in mind.

Typical features of SOD1–ALS include a younger age at onset compared with sporadic ALS, most commonly a lower–limb phenotype with asymmetric involvement, and a relatively slow disease course. Upper motor neuron signs are often absent. Some patients with SOD1–ALS may exhibit a phenotype resembling hereditary peripheral neuropathy. However, depending on the specific gene mutation, some patients develop a rapidly progressive course, and in such cases the disease may be indistinguishable from sporadic ALS. Some patients complain of numbness or sensory disturbances, and abnormalities of sensory nerves may be detected on nerve conduction studies. In addition, although rare, autonomic failure may be observed in advanced stages.

Even in advanced cases, establishing a diagnosis of SOD1–ALS is important, as it has implications for the early diagnosis and early treatment of affected family members. Needless to say, when diagnosing SOD1–ALS, adequate systems of genetic counselling should be in place.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by degeneration of upper and lower motor neurons. Mutations in the superoxide dismutase 1 (SOD1) gene were the first genetic cause identified for familial ALS and remain one of the most extensively studied. In Japan, SOD1 variants account for approximately 30% of familial ALS and a small proportion of sporadic cases. The disease mechanism is thought to involve toxic gain–of–function of structurally unstable mutant SOD1 proteins, leading to intracellular aggregation, oxidative stress, and motor neuron degeneration.

Clinically, SOD1–associated ALS (SOD1–ALS) shares many features with sporadic ALS but often shows variant–dependent characteristics, including differences in age at onset, progression rate, and predominance of lower motor neuron signs. Limb onset, particularly distal lower limb weakness, is common.

Tofersen, an antisense oligonucleotide targeting SOD1 mRNA, has been developed to reduce SOD1 protein expression in the central nervous system. Clinical studies demonstrated reductions in cerebrospinal fluid SOD1 and neurofilament biomarkers, and early treatment may provide clinical benefit. SOD1–ALS thus represents an important model for gene–targeted therapy and precision medicine in neurodegenerative diseases.

Amyotrophic lateral sclerosis (ALS) is a refractory neurological disease that predominantly affects individuals in middle age or later, causing progressive motor neuron degeneration. Currently, riluzole, edaravone, and intramuscular injection of mecobalamin are the only disease–modifying treatments. Approximately 5–10% of ALS cases are familial, and over 30 related genes have been identified. In 2023, tofersen, an antisense oligonucleotide (ASO) therapy for SOD1–ALS, received accelerated approval in the US and obtained Japanese approval in December 2024. Gene therapy is now a practical option, marking a major shift in treatment approaches. ASO targets include SOD1 (around 30% of Japanese familial cases) ; the RNA–binding proteins FUS and TARDBP ; and the C9orf72 gene with hexanucleotide repeat expansion, which is common in Europe and the US. To actively facilitate gene therapy research and clinical trials in Japan, we have collaborated with five domestic institutions to establish and launch the Japan Familial ALS Trial–ready registry (J–FAST). The registry's purpose is to systematically identify and characterize patients eligible for gene therapy trials, and to provide a platform for evaluating new interventions. Targeting familial ALS and sporadic cases with onset under age 40, we screen for SOD1, FUS, TARDBP, and C9orf72, adding exome or whole–genome sequencing when needed. We also record the natural history of each case to confirm their clinical details. Ongoing registry enrollment will identify clinical trial candidates and gather data to assess the efficacy of new treatments. We will validate biological samples to explore surrogate pathogenic markers. This will enable earlier intervention and help turn the registry into a key resource for ALS clinical practice and new therapies.

Post–stroke epilepsy (PSE) is a major cause of epilepsy in older adults and poses multifaceted clinical challenges beyond seizure control, including functional decline, psychiatric comorbidity, driving issues, diagnostic uncertainty, and long–term medication safety. Recent advances in risk stratification, such as the SeLECT and CAVE scores, and refinement of predictors including cortical superficial siderosis have improved the clinical framework for identifying patients at high risk for PSE.

This review summarizes practical strategies for optimizing interventions for PSE from three perspectives : (1) risk stratification and diagnosis, (2) treatment intervention and prevention in acute symptomatic seizures (ASS) after stroke, and (3) long–term pharmacotherapy and regional care coordination. Distinguishing ASS, typically occurring within 7 days after stroke, from late unprovoked seizures is essential because this distinction directly affects diagnosis, patient counseling, driving advice, and long–term antiseizure medication (ASM) decisions. When ASS occurs, treatment is often justified to prevent neurologic deterioration and recurrent seizures ; however, routine prophylactic ASM use in all acute stroke patients is generally not recommended. Instead, intensified monitoring and early specialist involvement should be considered in high–risk cases.

In long–term management, ASM selection should be based not only on antiseizure efficacy but also on tolerability, retention, drug–drug interactions, psychiatric effects, vascular risk, and adherence, particularly in older adults with multimorbidity. Reevaluation of apparent drug–resistant cases, including possible misdiagnosis or psychogenic nonepileptic seizures, is also important. Finally, a cyclical regional care pathway linking acute hospitals, rehabilitation facilities, primary care physicians, and epilepsy/stroke specialists is crucial for sustained optimization of PSE care.

Recent advances in acute stroke therapies have shifted clinical focus toward the long–term outcomes of stroke survivors. Nonmotor complications, such as constipation, are increasingly recognized as key determinants of post–stroke recovery. This review explores the bidirectional relationship between constipation and stroke, positioning constipation as both a risk factor for stroke and common post–stroke sequela. A nationwide epidemiological study in Japan recently identified constipation as an independent risk factor for cardiovascular diseases, including stroke. We suggest the growing evidence that Valsalva straining during defecation can acutely elevate blood pressure, potentially triggering stroke in the elderly. Conversely, meta–analysis of post–stroke complications report that more than half of stroke survivors experience constipation. In these individuals, gut dysbiosis, decreased physical activity, reduced water consumption collectively prolong gastrointestinal transit time, while damage to cortical regions such as the insular and anterior cingulate areas disrupts central defecation control. These findings emphasize the significance of constipation as a mechanistic link within the “brain-gut axis”. Despite these findings, constipation diagnosis remains largely subjective, relying on patient–reported symptoms rather than objective physiological markers. Future strategies should therefore aim to establish quantitative assessment methods. Promising directions include microbiome–based profiling to identify intestinal aging patterns and application of digital biomarkers using smart–sensing technologies within daily toilet use to monitor stool characteristics and circulatory dynamics during defecation. Moreover, interventions will integrate individualized prebiotics–based nutritional therapy tailored to gut microbiome patterns and utilize novel pharmacotherapies. Together, these approaches may provide a framework for personalized management of constipation in stroke survivors and deepen our understanding of brain–gut interactions in cerebrovascular disease.

In 2024, two new drugs for amyotrophic lateral sclerosis (ALS)―mecobalamin and tofersen―were approved in Japan, increasing the total number of available ALS therapies to four, the highest worldwide. Despite these advances no curative treatment has been established, and clinical trials remain essential. However, Japan's participation in global phase III trials remain limited, raising concerns about future drug lag.

The emergence of new therapies has important implications for clinical trial design. When planning trials in the presence of existing treatments, clear criteria for concomitant medication use are required. While allowing concomitant use of approved drugs may reflect real–world practice, it can complicate efficacy evaluation. Conversely, restricting concomitant medications may negatively affect patient recruitment. In addition, as the efficacy of mecobalamin has been demonstrated in patients within one year of disease onset, some patients may prioritize its use over trial participation depending on disease stage.

Tofersen, an antisense oligonucleotide targeting superoxide dismutase 1 (SOD1), is indicated only for SOD1–ALS. Therefore, it is unlikely to affect trials targeting sporadic ALS or other genetic forms. However, in trials focusing on SOD1–ALS, concomitant use of tofersen in likely to be restricted, particularly in studies involving nucleic acid–based therapeutics.

To facilitate timely approval of promising therapies, both drug development and clinical trial infrastructure must be strengthened. Since 2024, we have been conducting an AMED–funded project to develop clinical evaluation guidelines for ALS therapeutics. In parallel, a nationwide questionnaire survey conducted in 2025 assessed the readiness of Japanese institutions to participate in ALS clinical trials. These efforts aim to promote efficient trial implementation and enhance Japan's contribution to global ALS drug development.

Current treatments for Alzheimer disease (AD) approved in Japan consist of three cholinesterase inhibitors and one NMDA receptor antagonist. These agents do not suppress neurodegeneration itself and remain symptomatic therapies that provide only temporary relief. Disease–modifying therapies (DMTs), which target the underlying disease process and slow disease progression, have therefore been expected as a major breakthrough. Drug development based on the amyloid hypothesis initially shifted from unsuccessful vaccine approaches to antibody therapies ; however, solanezumab and aducanumab failed to demonstrate sufficient clinical efficacy. Lecanemab represented a turning point by reducing clinical deterioration by approximately 27% over 18 months in patients with mild cognitive impairment and mild AD, leading to its approval in Japan in 2023. Subsequently, donanemab was also approved, demonstrating an association between amyloid clearance and clinical efficacy. Nevertheless, neither agent halts disease progression or induces clinical improvement, and careful safety management for adverse events such as amyloid–related imaging abnormalities (ARIA) remains essential to ensure optimal use. In addition, AD clinical trials are inherently challenging because of the disease's unknown etiology, slow progression, and difficulties in participant recruitment. To address these issues, the CLIC–D platform was established to accelerate subject recruitment. This platform manages participant contact information and provides end–to–end support for trial participation, thereby facilitating more efficient drug development, including at the preclinical stage.

In 2025, an updated “Clinical Practice Guideline for Polymyositis and Dermatomyositis 2025” was published, reflecting major advances in the understanding and management of inflammatory myopathies. Since the original definition of polymyositis (PM) and dermatomyositis (DM) in 1975, substantial progress in muscle pathology and the identification of myositis–specific autoantibodies have led to a refined disease classification. Currently, inflammatory myopathies are subdivided into PM, DM, immune–mediated necrotizing myopathy, and antisynthetase syndrome. Accurate diagnosis requires an integrated assessment of muscle weakness, cutaneous manifestations, and associated systemic complications, together with detailed laboratory and instrumental evaluations, including serum creatine kinase levels, skeletal muscle imaging, electromyography, and muscle histopathology.

Glucocorticoids remain the first–line therapy for PM/DM, while immunosuppressive agents, intravenous immunoglobulin, and plasma exchange are employed as adjunctive treatments according to disease severity and treatment response. Although optimal therapeutic strategies for refractory cases have not yet been fully established, multiple biologic agents targeting key immunopathogenic pathways are currently under active development.

Given the multidisciplinary nature of PM/DM management, clinical perspectives may vary among specialties. Widespread implementation of this guideline is expected to facilitate the establishment of a shared disease concept and to promote phenotype–driven therapeutic strategies. Standardization of clinical subtypes will enable the design of high–quality clinical trials and accelerate the development of novel targeted therapies for inflammatory myopathies.

Background : Myositis–specific autoantibodies (MSAs) are essential for the diagnosis and classification of idiopathic inflammatory myopathies (IIM). However, comprehensive autoantibody testing is not always available, and serological findings may be discordant with clinical phenotypes. Diagnostic strategies beyond serology therefore remain necessary.

Methods : We retrospectively analyzed three diagnostically challenging IIM cases in which clinical features, muscle magnetic resonance imaging (MRI), and muscle pathology were integrated to establish final diagnoses.

Results : Case 1 involved a man with long–standing asymptomatic hypercreatine kinaseemia initially suggestive of a hereditary myopathy ; muscle MRI and biopsy revealed inflammatory changes, and anti–signal recognition particle antibody confirmed immune–mediated necrotizing myopathy. Case 2 was an elderly woman with typical dermatomyositis skin manifestations in whom muscle pathology, particularly sarcoplasmic myxovirus resistance protein A expression, was decisive and later supported by anti–TIF1–γ and anti–Mi–2 antibody positivity. Case 3 presented with interstitial lung disease and myositis despite negative standard anti–aminoacyl–tRNA synthetase antibody screening ; extended testing identified anti–OJ antibody, confirming antisynthetase syndrome.

Conclusions : Muscle pathology and imaging remain indispensable for accurate IIM diagnosis, particularly in seronegative or diagnostically discordant cases, enabling precise disease classification and timely treatment.