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The Japanese Society of Neurology discusses research, education, and medical care in the field of neurology and makes recommendations to the national government. Dr. Mizusawa, the former representative director of the Japanese Society of Neurology, selected committee members and made - Recommendations for Promotion of Research for Overcoming Neurological Diseases" in 2013. After that, the Future Vision Committee was established in 2014, and these recommendations have been revised once every few years by the committee. This time, the Future Vision Committee made the latest recommendations from 2020 to 2021. In this document, the general part is 1) What is neurological disease? 2) Current status of neurological disease overcoming research, 3) Significance and necessity of neurological disease overcoming research, 4) Research promotion system for overcoming neurological disease, 5) the roadmap for overcoming neuromuscular diseases, 6) a summary version of these recommendations are explained using figures that are easy for the general public to understand.

Purpose of Review: This review aims to summarize migraine attack triggers and understand variance across lifestyles, religions, and regions. Recent Findings: Experts from 11 countries collaborated to suggest a definition of migraine attack triggers. After investigating the geographical distribution of various triggers, referring to an earlier review written by the International Headache Academy (iHEAD) of the International Headache Society, we collected literature and summarized findings on both globally observed triggers and region- or culture-specific triggers. The most common triggers included stress, menstruation, and sleep disturbances. Several triggers were observed only in certain cultural contexts, such as fasting during Ramadan or Yom Kippur, or in specific regions, including barometric pressure in Eastern Asia, Lodos winds in Türkiye, midnight sun in the Arctic region, and watermelon consumption in Brazil. Summary: We summarized migraine attack triggers reported universally and specifically in different settings. In addition to using conventional methodology, future studies should address the mechanisms and causality of these triggers.

INTRODUCTION: Real-world evidence for lecanemab remains limited, particularly among Asian populations. We evaluated the feasibility, safety, biomarker profiles, and short-term clinical outcomes of lecanemab in practice in Japan. METHODS: We screened 321 patients with early Alzheimer's disease (AD) and confirmed amyloid pathology using amyloid positron emission tomography (PET) or cerebrospinal fluid analysis. Plasma amyloid-β42/40 was assessed when available. Among these, 102 initiated lecanemab and underwent structured magnetic resonance imaging (MRI) surveillance with 6 months of follow-up. RESULTS: Most treated patients had a Clinical Dementia Rating–Global (CDR-Global) score of 0.5 (96.1%), and 6-month treatment persistence exceeded 85%. Amyloid-related imaging abnormalities (ARIA), predominantly mild and asymptomatic ARIA-H, occurred in 11.4%, whereas no cases of isolated ARIA with effusion or edema (ARIA-E) were observed. One macrohemorrhagic and two moderate–severe radiographic ARIA with hemorrhage or hemosiderin deposition (ARIA-H) developed, which led to discontinuation of the treatment. Cognitive and functional measures remained generally stable over 6 months, with changes comparable to those reported in the phase 3 CLARITY-AD trial. Plasma–PET discordance highlighted the complementary value of multimodal biomarker interpretation. DISCUSSION: Lecanemab was feasible and generally well tolerated under structured MRI monitoring in routine Japanese practice.

Thymoma-associated myasthenia gravis (TAMG) is frequently refractory, particularly when complicated by myasthenic crisis in advanced invasive disease. Complement C5 inhibitors and neonatal Fc receptor (FcRn) inhibitors have expanded the treatment of acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis; however, their optimal selection, sequencing, and combined use in refractory TAMG remain undefined. We report a case of a 46-year-old man with Masaoka–Koga stage IVa invasive thymoma and pleural dissemination who developed a prolonged ventilator-dependent myasthenic crisis after debulking surgery. Immunoadsorption plasmapheresis, intravenous immunoglobulin, and ravulizumab produced only transient benefit. Serum complement activity became undetectable after ravulizumab was switched to zilucoplan (a peptide C5 inhibitor chosen because it is not affected by FcRn blockade), yet sustained respiratory stability was not achieved. Only after subcutaneous efgartigimod was added to ongoing zilucoplan did the patient attain sustained daytime ventilator independence, with a parallel decline in anti-AChR antibody titer and total immunoglobulin G. He was discharged and remained clinically stable, with no worsening during a subsequent mild infection. Reviewing this case together with previously reported patients who received concurrent or sequentially overlapping C5 and FcRn inhibition, we discuss the biological rationale for dual-pathway targeting, pharmacological considerations relevant to agent selection and sequencing, and infectious-safety implications. This temporal association does not establish efficacy; however, combined C5 and FcRn inhibition may be considered, on an individualized basis, in selected refractory TAMG cases when single-pathway therapy is insufficient.

The acute immune-mediated disorder, Bickerstaff brainstem encephalitis (BBE), is characterized by consciousness disturbance, external ophthalmoplegia, and ataxia. BBE is usually readily diagnosed and patients recover well, but rare features may sometimes obscure the diagnosis, and some patients develop prolonged weakness. We herein describe a Japanese patient with BBE who presented with uncharacteristic features of a decorticate-like posture, involuntary movements, and impaired visual acuity, entered a coma requiring intubation, and later required orthosis-assisted ambulation for 10 months. Despite these uncharacteristic features, the typical triad and other BBE characteristic features can be valuable for making an early diagnosis. BBE with a coma or intubation may therefore occasionally lead to prolonged weakness.

Introduction: Pain significantly impairs quality of life in Parkinson's disease (PD). While the PD Pain Classification System (PD-PCS) categorizes PD-related pain into nociceptive, neuropathic, and nociplastic pain, the clinical and structural correlates of these subtypes, particularly nociplastic pain, remain poorly characterized. The objective of this study was to elucidate the distinct features of each PD-related pain subtype. Methods: This single-center cross-sectional study involved a two-stage PD-PCS-based evaluation. First, 192 PD patients were assessed for the prevalence of pain subtypes and their associations with demographic and clinical variables. Second, 40 PD patients with pain underwent detailed physician-led assessments using validated motor and non-motor scales, including MDS-UPDRS, KPPS, KPPQ, NMSS, HADS, PDSS-2, PDQ-8, WOQ-9, and VAS. Structural and diffusion MRI analyses, including free-water imaging and neurite orientation dispersion and density imaging, were performed in a subset of participants to explore pain-related neural correlates. Results: Among 192 PD patients in the first survey, 107 (55.7%) reported pain, classified as nociceptive (37.4%), neuropathic (18.7%), nociplastic (23.4%), or PD-unrelated pain (20.6%). Compared with nociplastic pain, neuropathic pain showed higher PD-PCS scores (39.8 ± 29.2 vs 14.3 ± 16.9; p = 0.0014) and higher King's Parkinson's Pain Questionnaire scores (5.8 ± 2.7 vs 2.9 ± 1.5; p = 0.00014). Compared with nociceptive pain, neuropathic pain also showed higher questionnaire scores (5.8 ± 2.7 vs 3.8 ± 2.1; p = 0.013). In the second survey, neuropathic pain was associated with greater motor complications than nociplastic pain (MDS-UPDRS Part IV: 10.2 ± 2.9 vs 3.9 ± 3.4; p = 0.029). In the supplementary MRI analysis, neuropathic pain showed distinct microstructural abnormalities in pain-processing neural networks. Conversely, nociplastic pain showed no distinctive motor/non-motor features or detectable MRI abnormalities, despite a comparable negative impact on quality of life. Conclusion: Neuropathic pain in PD represents a severe phenotype linked to both motor fluctuations and structural brain changes, underscoring the need for mechanism-specific management strategies. By contrast, the absence of defining clinical or structural markers in nociplastic pain highlights it diagnostic challenge and suggests that current assessment tools may insufficiently capture this pain mechanism. These findings emphasize the need for multidimensional and mechanism-oriented approaches to PD-related pain in clinical practice.

Patients with neuromyelitis optica spectrum disorder (NMOSD) may experience increased signs and symptoms of their underlying disease when vaccinated against meningococcal disease before receiving complement component 5 inhibitor therapies. This retrospective analysis indicated an overall low relapse incidence (mean [range], 3.3% [0.7%–10.6%]) of physician-reported relapses occurring within 4 weeks of meningococcal vaccination in those screened in CHAMPION-NMOSD (NCT04201262), randomized to eculizumab or placebo in PREVENT (NCT01892345), and from the Japanese postmarketing surveillance of eculizumab in patients with anti-aquaporin-4 antibody-positive NMOSD. Further studies are needed to determine if postvaccination relapses are attributable to vaccination or inherent relapse risk among these patients.

BACKGROUND: – To what extent cerebral small vessel disease (SVD) contributes to functional disability remains unclear. We investigated the longitudinal effect of SVD burden on functional decline. METHODS: – In this investigator-initiated, prospective, multicenter, and observational study, patients receiving oral antithrombotic therapy for cerebrovascular or cardiovascular diseases were enrolled from 52 hospitals across Japan (2016–2019) and followed for 24 months. SVD score (range, 0–4) was calculated on baseline magnetic resonance imaging obtained under prespecified conditions. The outcomes were an increase in modified Rankin Scale (mRS) score from baseline to end of follow-up (ΔmRS score ≥1). Logistic regression evaluated the association between ΔmRS score ≥1 and SVD score, adjusting for age, sex, premorbid mRS, vascular risk factors, antithrombotic therapy, magnetic resonance imaging field strength, and bleeding or ischemic events during follow-up. Bleeding and ischemic events were treated as time-dependent covariates. Causal mediation analyses using a 4-way decomposition separated the effects of SVD score ≥3 on ΔmRS score ≥1 into direct and indirect effects (mediated by major bleeding or ischemic events). RESULTS: – Of 5378 patients enrolled, 613 were excluded mainly due to the lack of clinical or imaging data. Finally, 4765 patients were analyzed (1573 women; median age, 73 years); ΔmRS score ≥1 was observed in 13.2% of patients with SVD score 0, 16.1% with 1, 20.7% with 2, 28.1% with 3, and 28.2% with 4. SVD score of 3 (adjusted odds ratio, 1.65 [95% CI, 1.27–2.15]) and SVD score of 4 (1.62 [95% CI, 1.19–2.19]) were associated with ΔmRS score ≥1 compared with SVD score of 0. Causal mediation analysis indicated that 73.05% of the total effect of SVD score ≥3 on ΔmRS score ≥1 was attributed to the controlled direct effect (coefficient, 0.497 [95% CI, 0.26–0.73]). CONCLUSIONS: – SVD burden was associated with functional decline beyond significant bleeding or ischemic events.

Background: CD36 deficiency is associated with abnormal fatty acid metabolism, which may increase the risk of developing atherosclerosis. However, there are few reports on a possible link between CD36 deficiency and cerebral white matter lesions. Case report: We present the case of a 44-year-old woman with heart failure due to CD36 deficiency and multiple white matter lesions. Her comprehensive examination for heart failure, including a single-photon emission computed tomography (SPECT) with 201thallium and 123I-β-methyl-p-iodophenyl pentadecanoic acid, revealed a fatty acid metabolism disorder in the myocardium. Flow cytometry confirmed CD36 deficiency, and a subsequent head magnetic resonance imaging (MRI) demonstrated multiple T2-hyperintense lesions in the cerebral white matter. Although the patient had hypertriglyceridemia and a history of smoking, the contribution of CD36 deficiency to the formation of white matter lesions remains unclear. Conclusion: This case suggests a potential association between CD36 deficiency and cerebral small-vessel disease. Further studies in patient cohorts with CD36 deficiency are warranted to clarify the impact of this condition on cerebral microcirculation.

Introduction: Chronic sialorrhea is common in Parkinson's disease (PD), but its clinical correlates and patient awareness of treatment options remain unclear. We examined factors associated with drooling, focusing on autonomic dysfunction and dysphagia, and assessed perceptions of botulinum toxin therapy.Methods: We conducted a questionnaire-based study of consecutive PD outpatients at Keio University Hospital from October to December 2025. Drooling was defined using MDS-UPDRS Part II item 2. Autonomic symptoms were assessed with SCOPA-AUT and swallowing with the Swallowing Disturbances Questionnaire (SDQ). Clinical variables and 123I-metaiodobenzylguanidine myocardial scintigraphy indices were extracted from medical records. Multivariable logistic regression identified factors independently associated with drooling. K-means clustering (k = 3) was also performed among droolers using standardized SCOPA-AUT and SDQ scores.Results: Among 208 patients, 116 (55.8%) were classified as droolers. Droolers were more often male and had longer disease and treatment duration, higher Hoehn and Yahr stage, higher levodopa equivalent daily dose, higher SDQ scores, more severe autonomic symptoms, and lower MIBG heart-to-mediastinum ratios. In multivariable analysis, higher SCOPA-AUT and SDQ scores remained independently associated with drooling. Only 34.5% of droolers perceived drooling as problematic, 14.7% were aware of botulinum toxin therapy, and 21.6% were willing to receive injections. Clustering identified three phenotypes: low autonomic/low dysphagia, high autonomic/high dysphagia, and high autonomic/low dysphagia.Conclusion: Chronic sialorrhea in PD is associated with dysphagia burden and broader autonomic dysfunction, suggesting heterogeneous mechanisms. Limited awareness highlights the need for systematic screening and patient education.

Objectives: While smoking is a well-established risk factor for various cardiovascular diseases, its association with intracerebral haemorrhage (ICH) remains controversial. Cerebral microbleeds (CMBs) are markers of haemorrhage-prone small vessel disease, but ICH can also occur without detectable CMBs. Therefore, we investigated the association between smoking and ICH according to CMB status. Design: Single-centre retrospective case-control study. Setting: A tertiary stroke centre in Osaka, Japan (2017–2021). Participants: 487 patients with ICH as their first stroke (female sex 41.5%) and 322 controls with non-stroke neurological conditions (female sex 47.5%) were included. Patients with missing CMB evaluation or smoking status data were excluded. Primary and secondary outcome measures: The primary outcome was ICH status, analysed according to CMB status, with current smoking as the primary exposure. Secondary analyses evaluated the association between smoking cessation duration and the odds of ICH, using current smoking as the reference. Results: Patients with ICH (median age, 70.0 years; presence of CMBs, 53.6%) and controls (median age, 71.0 years; presence of CMBs, 13.4%) were analysed. Among individuals without CMBs, current smoking was more frequently observed in patients with ICH than in controls (25.7% vs 14.0%, p<0.001) and was independently associated with ICH following adjustment for potential confounders (adjusted OR (aOR) 1.84, 95% CI 1.02 to 3.31, p=0.042). Long-term smoking cessation (>10 years) was associated with lower odds of ICH than current smoking (aOR 0.31, 95% CI 0.14 to 0.67, p=0.003), whereas short-term cessation (≤10 years) showed no significant difference. Among individuals with CMBs, no significant association was observed between smoking status and ICH. Conclusions: Current smoking was associated with higher odds of ICH among individuals without CMBs, whereas long-term cessation was associated with lower odds. These findings suggest that the absence of CMBs should not be interpreted as the absence of modifiable ICH risk, highlighting the clinical relevance of smoking history in this population. Trial registration number: NCT02251665.

Background: Microglia remodel neuronal circuits in pathological conditions; however, the molecular requirements for these responses and their consequences for motoneuron survival remain unclear. Methods: Aif1 (Iba1) knockout mice were generated using CRISPR/Cas9-mediated deletion, and baseline phenotypes and responses to unilateral facial nerve axotomy were assessed using immunohistochemistry, transmission electron microscopy, and single-nucleus RNA sequencing of the facial motor nucleus. Motoneuron survival and nuclear γH2AX foci were evaluated 28 days post-axotomy. Findings: Under baseline conditions, Iba1−/− mice had reduced body weights and mild behavioral abnormalities compared to wild-type mice. After axotomy, microglial ensheathment of ChAT-positive facial motoneurons was reduced, with fewer neurons showing extensive perisomatic microglial coverage than in Iba1+/+ mice. Ultrastructurally, somatic synapse loss observed after injury in wild-type mice was not detected in Iba1−/− mice, and fewer injured motoneurons were in contact with microglial processes. Single-nucleus transcriptomics showed an exaggerated expansion of an interferon-responsive microglial state in Iba1−/− mice after axotomy, whereas injured motoneurons displayed altered transcriptional programs related to synapse organization and neurotransmission. At 28 days, Iba1−/− mice showed reduced motoneuron survival, lower ChAT expression, and increased nuclear γH2AX foci. Interpretation: Iba1 supports microglia-neuron cross-talk that enables effective perisomatic remodefling after axonal injury; disruption of this response is accompanied by inflammatory-state shifts and compromised motoneuron survival.

Objective: This study aimed to (1) investigate changes in the quality of life among people with Parkinson's disease (PwPD) over a 1-year group-based telerehabilitation (TR) program and (2) explore the TR program's perceived impacts from the perspectives of the PwPD and their caregivers. Design: Observational and longitudinal study. Setting: Group-based TR program. Participants: PwPD who voluntarily enrolled in a 1-year group-based TR program. Interventions: Group-based TR program that included physical, rhythmic, cognitive, and swallowing exercises plus education about disease management. Main Outcome Measures: The primary outcome was Parkinson's Disease Questionnaire-39 (PDQ-39) total score at baseline, 6 months, and 1 year. Secondary outcomes were PDQ-39 domain scores, responses by the PwPD and their caregivers to the self-reported questionnaire to evaluate perceived emotional, physical, and lifestyle effects, and Client Satisfaction Questionnaire-8 (CSQ-8). Results: A total of 49 PwPD and 43 caregivers participated; 24 (49%) PwPD and 22 (51%) caregivers met the regular participation criterion (≥80% of scheduled sessions). Baseline characteristics were similar between regular and nonregular participants. Mixed models for repeated measures (MMRM) adjusted for baseline PDQ-39, Hoehn & Yahr stage, and disease duration showed better adjusted PDQ-39 total scores in the regular group than in the nonregular group (group effect P=.046). The emotional well-being domain showed a significant time effect (P=.007), and better adjusted scores in the regular than in the nonregular group at 1 year. The social support domain also favored the regular group (P=.017), and the communication domain showed a significant group × time interaction, indicating more favorable trajectories in the regular group. Both the PwPD and caregivers reported greater emotional benefits than physical benefits, and Client Satisfaction Questionnaire-8 scores indicated high satisfaction in both groups. Conclusions: Although causal relationships cannot be inferred, these findings suggest that higher and sustained participation in long-term, group-based TR is associated with maintenance of overall quality of life and improvements in emotional well-being among PwPD.

Cryptogenic new-onset refractory status epilepticus (C-NORSE) is a rare, severe condition characterized by refractory status epilepticus without identifiable causes. It is often unresponsive to first-line immunotherapy. The C-NORSE score is a useful diagnostic tool, but in the early phase, when the score remains low and antibody test results are unavailable, it is difficult to initiate second-line immunotherapy, including cyclophosphamide. We report a 27-year-old man with C-NORSE who achieved early recovery and favorable outcome following administration of intravenous cyclophosphamide, despite a low C-NORSE score on admission, suggesting the importance of repeated assessment using the C-NORSE score and early administration of cyclophosphamide.

INTRODUCTION: Isolated intraventricular hemorrhage (IVH) is a rare phenotype of intracerebral hemorrhage (ICH), and its mechanistic basis is poorly understood. METHODS: This retrospective study used a prospectively collected single-center database of patients treated between December 2010 and December 2022. Patients with ICH were classified into isolated IVH and intraparenchymal hemorrhage (IPH). The clinical profiles of patients with isolated IVH and IPH were compared. RESULTS: Of 2,310 patients with acute ICH, 41 were excluded because of underlying vascular lesions, trauma, and tumor as possible causes. Of the remaining 2,269 patients, there were 23 patients (1%) with isolated IVH (female 44%; mean age, 73 ± 11 years) and 2,246 (99%) with IPH (43%; 71 ± 13 years). Compared with the IPH group, the isolated IVH group had a higher frequency of diabetes mellitus (35% vs. 16%) and prior anticoagulant use (44% vs. 13%). Diabetes mellitus (adjusted odds ratio: 2.50 [95% confidence interval, 1.03-6.07]) and prior anticoagulant use (3.74 [1.05-13.33]) were independently associated with isolated IVH. Compared with the IPH group, the isolated IVH group had a significantly lower NIHSS score at discharge (median 2 [interquartile range 0-12] vs. 8 [2-18], p = 0.011). Unfavorable outcome, defined as mRS 4-6, was marginally less common at 90 days (27% vs. 47%, p = 0.061) for isolated IVH than for IPH. CONCLUSIONS: Compared to IPH, isolated IVH was more frequently associated with prior anticoagulant use and diabetes mellitus and had a tendency for milder neurologic deficits and better functional outcomes.

BACKGROUND AND OBJECTIVES: Enlarged perivascular spaces (ePVSs) are considered to increase the risk of stroke. However, data regarding the benefits and risks of antithrombotic therapy in patients with ePVSs are currently limited. This study assessed the association between ePVSs and the risks of hemorrhagic or ischemic events in patients taking antithrombotic agents. METHODS: This prospective, multicenter observational study enrolled patients with cerebrovascular or cardiovascular diseases who had newly started or were continuing to take oral antithrombotic agents at 52 hospitals across Japan between 2016 and 2019. Baseline multimodal MRI was performed for all of the study participants. The images were then centrally evaluated for cerebral small vessel disease (SVD), including white matter hyperintensities, cerebral microbleeds, lacunes, and basal ganglia-enlarged perivascular spaces (BGPVSs). BGPVSs were categorized as 0, 1-10, 11-20, or ≥21. Outcomes included major bleeding, intracranial hemorrhage, ischemic events, ischemic stroke, and mortality. Multivariable Cox proportional hazards models were used for the BGPVSs (in categorical and ordinal forms), adjusted for patient demographics, vascular risk factors, and other SVD markers. RESULTS: Of the total 5,065 patients (1,663 women; median age 74 [interquartile range 67-81] years), antiplatelets and anticoagulants were administered at the baseline to 3,820 (75.4%) and 1,502 (29.7%) patients, respectively. Their BGPVS distributions were as follows: 0, 475 (9.4%); 1-10, 2,615 (51.6%); 11-20, 1,267 (25.0%); and 21+, 708 patients (14.0%). Over a median follow-up period of 2.0 (interquartile range 1.8-2.0) years, we noted 266 ischemic events, 188 ischemic strokes, 92 major bleeding events, 54 intracranial hemorrhages, and 198 deaths. Higher BGPVS was associated with an increased risk of major bleeding (BGPVS ≥21: adjusted hazard ratio [aHR] 4.04, 95% CI 1.17-13.92; per-unit increase: aHR 1.38, 95% CI 1.07-1.77) and ischemic stroke (BGPVS ≥21: aHR 2.58, 95% CI 1.21-5.50; per-unit increase: aHR 1.28, 95% CI 1.07-1.53) but was not significantly associated with higher risks of ischemic events, intracranial hemorrhage, or mortality. DISCUSSION: Higher BGPVS burdens are associated with higher risks of ischemic stroke and major bleeding in patients receiving antithrombotic therapy. BGPVSs may serve as useful imaging biomarkers for vascular risk assessment and personalized therapy.

Aim Several studies have reported a higher prevalence of migraine in patients with multiple sclerosis (MS) than in healthy controls (HCs). The aim of this study was to elucidate the headache prevalence in patients with MS or other neuroimmunological disorders, as well as to investigate the associations between headache characteristics and disease activity. Methods In this multicenter study in Japan, a headache questionnaire was distributed to patients with MS (n = 338), aquaporin-4 IgG-positive neuromyelitis optica spectrum disorder (NMOSD; n = 106), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD; n = 51) or acetylcholine receptor antibody-positive myasthenia gravis (MG; n = 104), and healthy controls (HCs; n = 407). We included only participants aged 18–65 years in this study. The questionnaire responses were classified according to the International Classification of Headache Disorders, 3rd edition. The questionnaire was designed to systematically capture headache characteristics based on established diagnostic criteria. Results In total, any type of headache was found for 54.1% in MS, 63.2% in NMOSD, 43.1% in MOGAD, 43.3% in MG and 43.5% in HCs. After Holm–Bonferroni correction for comparisons among the five groups, the MS (p = 0.015) and NMOSD (p < 0.001) groups had significantly higher odds of any headache compared to the HC group. No difference was observed for migraine (MS 16.0%, NMOSD 16.0%, MOGAD 9.8%, MG 12.5%, HCs 17.0%). In contrast, patients with MS (24.0%) and NMOSD (37.7%) showed a significantly higher frequency of tension-type headache (TTH) than HCs (16.7%) even after adjusting for age and sex. Neither disease activity nor disease-modifying therapy displayed any association with headache severity in patients with MS, NMOSD, or MOGAD. Conclusions Our study showed no increased prevalence of migraine in MS and other neuroimmunological disorders, whereas TTH comorbidity was higher in MS and NMOSD than in controls.

The intestinal epithelium plays a critical role in immune-microbiota interactions, yet its contribution to systemic autoimmunity remains unclear. Here, we identify intestinal epithelial cells (IECs) as initiators of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). In both EAE mice and patients with MS, IECs up-regulate antigen presentation pathways and are associated with increased intestinal T helper 17 (TH17) cell accumulation. Epithelial major histocompatibility complex class II (MHC II) was highly expressed during EAE, particularly in the ileum, and its conditional deletion reduced pathogenic TH17 cell generation and disease severity. Using parabiosis and photoconversion models, we demonstrate that TH17 cells induced in the intestinal lamina propria migrate to the spinal cord. Functional coculture assays showed that IEC organoids with cognate myelin oligodendrocyte glycoprotein antigen induce RORγt+CD4+ T cell differentiation in an MHC II–dependent manner. These findings uncover a conserved gut–central nervous system axis in autoimmunity and position epithelial antigen presentation as a key initiator of neuroinflammation.

Objective Patients with migraine are at increased risk of developing psychiatric comorbidities, particularly depression and anxiety. Recently, anti-calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) have been suggested to be effective not only for migraine but also for comorbid depression. However, their effectiveness in depression and anxiety remains inconclusive, particularly in Asian populations. This study evaluated the effect of galcanezumab on depressive and anxiety symptoms in patients with migraine. Methods We conducted a single-center, retrospective, real-world study of 27 Japanese patients with migraine who received galcanezumab at Keio University Hospital, using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) scores at two time points (baseline and 3-5 months after initiating galcanezumab) to evaluate depressive and anxiety symptoms. Results During galcanezumab treatment, the mean monthly migraine days (MMD) significantly decreased from 13.6±8.2 to 8.5±9.3 (p<0.001). PHQ-9 scores significantly decreased from 5.8±4.4 to 4.5±4.2 (p=0.010) and GAD-7 scores from 4.0±3.9 to 3.1±3.5 (p=0.030). No significant correlation was observed between changes in PHQ-9/GAD-7 scores and changes in MMD, numerical rating scale scores, or associated symptoms. Furthermore, Fisher’s exact tests showed no significant association between improvements in PHQ-9/ GAD-7 scores and MMD reduction. Conclusion Galcanezumab improved PHQ-9 and GAD-7 scores in Japanese patients with migraine. These improvements may be partly attributable to the direct effects of galcanezumab, independent of its effect on migraine frequency.

Ketone bodies have traditionally been recognized as glucose-sparing energy sources, with hepatic ketogenesis and peripheral ketolysis serving pivotal functions in maintaining energy homeostasis during fasting. Although they are commonly seen as harmful due to their link with ketoacidosis, recent studies emphasize their roles in organ protection. This has sparked interest in their possible use as a treatment for chronic kidney disease (CKD). In this study, we examined both exogenous and endogenous ketone body supplementation in adenine-induced kidney injury in mice. Supplementation with the ketone body precursor 1,3-butanediol significantly improved adenine-induced renal fibrosis, inflammation, and apoptotic cell death. However, genetically deleting 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the key enzyme for ketogenesis, in the liver, kidney, or entire body, and removing Succinyl-CoA:3-ketoacid-CoA Transferase 1 (OXCT1), the enzyme for ketolysis, in the kidney alone, did not affect the severity of adenine-induced kidney damage. In contrast, the protective effects of 1,3-butanediol were partially diminished in mice with kidney-specific OXCT1 deficiency, indicating that OXCT1-mediated ketolysis is at least partly necessary for the renal protection afforded by exogenous ketone body supplementation. These findings suggest that supplementing with exogenous ketone bodies, rather than relying on endogenous hepatic or renal ketone production, protects the kidneys in adenine-induced kidney injury in mice, implying that local ketolysis within the kidney plays a mechanistic role in this protection. Our results highlight the therapeutic potential of exogenous ketone body administration in CKD and offer insights into how renal ketone metabolism helps protect against kidney injury.