Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.

Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC), a rare and complex neurological disorder, is predominantly observed in the Western Pacific islands, including regions of Japan, Guam, and Papua. This enigmatic condition continues to capture medical attention due to affected patients displaying symptoms that parallel those seen in either classical amyotrophic lateral sclerosis (ALS) or Parkinson's disease (PD). Distinctly, postmortem examinations of the brains of affected individuals have shown the presence of α-synuclein aggregates and TDP-43, which are hallmarks of PD and classical ALS, respectively. These observations are further complicated by the detection of phosphorylated tau, accentuating the multifaceted proteinopathic nature of ALS/PDC. The etiological foundations of this disease remain undetermined, and genetic investigations have yet to provide conclusive answers. However, emerging evidence has implicated the contribution of astrocytes, pivotal cells for maintaining brain health, to neurodegenerative onset, and likely to play a significant role in the pathogenesis of ALS/PDC. Leveraging advanced induced pluripotent stem cell technology, our team cultivated multiple astrocyte lines to further investigate the Japanese variant of ALS/PDC (Kii ALS/PDC). CHCHD2 emerged as a significantly dysregulated gene when disease astrocytes were compared to healthy controls. Our analyses also revealed imbalances in the activation of specific pathways: those associated with astrocytic cilium dysfunction, known to be involved in neurodegeneration, and those related to major neurological disorders, including classical ALS and PD. Further in-depth examinations revealed abnormalities in the mitochondrial morphology and metabolic processes of the affected astrocytes. A particularly striking observation was the reduced expression of CHCHD2 in the spinal cord, motor cortex, and oculomotor nuclei of patients with Kii ALS/PDC. In summary, our findings suggest a potential reduction in the support Kii ALS/PDC astrocytes provide to neurons, emphasizing the need to explore the role of CHCHD2 in maintaining mitochondrial health and its implications for the disease.

Degeneration of olivospinal tract in the upper cervical spinal cord of multiple system atrophy patients: Reappraisal of Helweg's triangular tract.

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder that presents with variable combinations of autonomic dysfunction, cerebellar ataxia, parkinsonism, and pyramidal signs. The inferior olivary nucleus is targeted in MSA, with a phenotype of olivopontocerebellar atrophy in particular, and involvement of the olivocerebellar tract is well known. However, degeneration of the olivospinal tract has not been studied in MSA. We examined 97 spinal cords from consecutively autopsied patients with MSA. Myelin staining revealed that 22 cords (22.7%) had small, bilateral, triangular-shaped tract degeneration in the boundary of the anterior and lateral funiculi, which appeared continuously from C1 to C5. The anatomical pathway of the degenerated tract was consistent with the description of the olivospinal tract provided by Helweg in 1888. The MSA patients showing degeneration of this tract were younger at disease onset (average: 56.4 ± 8.7 years, range: 42-74), and had longer disease duration (average: 10.1 ± 4.8 years, range: 2-25) and more severe olivopontocerebellar changes compared to other MSA patients. Quantitative analyses revealed that patients with olivospinal tract degeneration had a lower neuronal density in the inferior olivary nucleus compared to other patients. Microglial density in this tract was negatively correlated with the neuronal density in the inferior olivary nucleus. The densities of glial cytoplasmic inclusions in the inferior olivary nucleus and in the olivospinal tract were strongly correlated with each other. Neurologically healthy controls (n = 22) and disease controls with Lewy body disease (n = 30), amyotrophic lateral sclerosis (n = 30), and progressive supranuclear palsy (n = 30) did not present the olivospinal tract degeneration. Our results indicate an impairment of the neural connection between the inferior olivary nucleus and the spinal cord in MSA patients, which may develop in a descending manner.

Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome.

The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients.

BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

Effect of therapeutic exercise on the balance of patients with progressive supranuclear palsy: A pilot study.

Background: Progressive supranuclear palsy (PSP) is a parkinsonian-like progressive neurodegenerative syndrome. Key clinical features include ocular motor dysfunction, postural instability, and cognitive dysfunction. Maintaining and improving balance function and gait function are very important for patients with PSP with severe postural dysfunction and repeated falls. In addition, patients with PSP have a poor response to pharmacological treatment; hence, rehabilitation is a key approach in dealing with this syndrome. However, no conclusion on the beneficial effects of rehabilitation for patients with PSP have been established in the literature. Objectives: The effectiveness of multiple therapeutic exercise program with probable or possible PSP according to the Movement Disorder Society criteria for the clinical diagnosis of PSP was validated. Methods: Participants underwent multiple therapeutic exercise program customized for each participant, including resistance training, balance training, and walking exercises that were performed for 60-80 minutes a day, 5 days a week for 4 weeks. The outcomes measured were as follows: pull test, Berg Balance Scale (BBS), timed up and go test (TUG), and gait speed test. Results: A total of 117 patients with PSP were enrolled and the analysis was performed on 20 patients with probable PSP. Four-week rehabilitation significantly improved pull test (p = 0.034) and BBS scores (p = 0.001). There were no significant differences both TUG (p = 0.502) and gait speed (p = 0.813). Conclusion: The multiple therapeutic exercise program had beneficial effects on balance performance in patients with PSP in 4 weeks and could be an essential element in their rehabilitation. Although this pilot study was conducted without a control group, it provided valuable information for future prospective randomized controlled trials.

Neuropathology and emerging biomarkers in corticobasal syndrome.

Corticobasal syndrome (CBS) is a clinical syndrome characterised by progressive asymmetric limb rigidity and apraxia with dystonia, myoclonus, cortical sensory loss and alien limb phenomenon. Corticobasal degeneration (CBD) is one of the most common underlying pathologies of CBS, but other disorders, such as progressive supranuclear palsy (PSP), Alzheimer's disease (AD) and frontotemporal lobar degeneration with TDP-43 inclusions, are also associated with this syndrome.In this review, we describe common and rare neuropathological findings in CBS, including tauopathies, synucleinopathies, TDP-43 proteinopathies, fused in sarcoma proteinopathy, prion disease (Creutzfeldt-Jakob disease) and cerebrovascular disease, based on a narrative review of the literature and clinicopathological studies from two brain banks. Genetic mutations associated with CBS, including GRN and MAPT, are also reviewed. Clinicopathological studies on neurodegenerative disorders associated with CBS have shown that regardless of the underlying pathology, frontoparietal, as well as motor and premotor pathology is associated with CBS. Clinical features that can predict the underlying pathology of CBS remain unclear. Using AD-related biomarkers (ie, amyloid and tau positron emission tomography (PET) and fluid biomarkers), CBS caused by AD often can be differentiated from other causes of CBS. Tau PET may help distinguish AD from other tauopathies and non-tauopathies, but it remains challenging to differentiate non-AD tauopathies, especially PSP and CBD. Although the current clinical diagnostic criteria for CBS have suboptimal sensitivity and specificity, emerging biomarkers hold promise for future improvements in the diagnosis of underlying pathology in patients with CBS.

[Autonomic Dysfunction in Tauopathies].

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are tauopathies that clinically present with atypical parkinsonism. Autonomic dysfunction is known to occur in synucleinopathies, particularly in cases of multiple system atrophy; however, the frequency and features of autonomic dysfunction in patients with tauopathies remain unclear. Recent studies have reported that urinary dysfunction and constipation are common and affect the prognosis of patients with PSP. In contrast, neurogenic orthostatic hypotension is rare in PSP, which is useful to distinguish PSP from multiple system atrophy and Lewy body disease. Urinary dysfunction is also commonly observed in patients with CBD and serves as an inclusion criterion for PSP syndrome in patients with CBD. However, this finding is not validated in other cohorts; therefore, further studies are warranted to confirm the usefulness of this criterion.

Analysis of factors contributing to medication errors during self-management of medication in the rehabilitation ward: a case control study.

BACKGROUND: In the rehabilitation ward, many elderly patients require continuous use of medication after a stroke or bone fracture, even after discharge. They are encouraged to self-manage their medications from the time of admission. Medication errors, such as a missed dose or incorrect administered medication can worsen conditions, resulting in recurrent strokes, fractures, or adverse effects. The study was aimed to identify risk factors, such as medication and prescription, contributing to errors in self-management of medication. METHODS: This study was conducted on patients who self-managed their medication in the rehabilitation ward of Higashinagoya National Hospital from April 2018 to March 2020. The patient background including age and sex were investigated. The medication factors examined include the number of medications and administrations per day, dosing frequency on indicated days, prescription and start date are the same, medications from multiple prescriptions, and one package or one tablet at each dosage. The group of medication error cases were defined as the medication error group and that of control cases as the no-medication error group. A logistic regression analysis was performed for factors related to medication errors. RESULTS: A total of 348 patients were included in the study, of which 154 patients made medication errors, with 374 total medication error cases. The median number of medications in the medication error group was six, and that in the no-medication error group was five. Statistically significant factors correlated with errors made during self-management of medication were the number of medications, number of administrations per day, dosing frequency on indicated days, and medication from multiple prescriptions. CONCLUSIONS: When a patient is self-managing their medications, errors are likely to occur due to a high number of medicines they are taking and the complexity of the dosage regimen. Therefore, to prevent medication errors, reviewing the prescribed medications and devise ways to simplify the dosage regimens is crucial.

[Career Path and Leadership in Female Neurologists at a City Hospital].

My own career path at a hospital evolved into multicenter joint research by advancing clinical research on the theme of clinicopathological study, and falls in the clinical field after the period of life events. Even if your work is temporarily delayed during a life event, you do not have to worry as you can fully recover by continuing what you think is important. A variety of approaches, including leadership education, are essential for female physicians to continue their work without burnout.

Mutation screening of the DNAJC7 gene in Japanese patients with sporadic amyotrophic lateral sclerosis.

DNAJC7 has recently been identified as an amyotrophic lateral sclerosis (ALS) gene via large-scale exome analysis, and its involvement in ALS is still unclear in various populations. This study aimed to determine the frequencies and characteristics of the DNAJC7 variants in a Japanese ALS cohort. A total of 807 unrelated Japanese patients with sporadic ALS were screened via exome analysis. In total, we detected six rare missense variants and one splice-site variant of the DNAJC7 gene, which are not reported in the Japanese public database. Furthermore, the missense variants are located around the TPR domain, which is important for the function of DNAJC7. The total frequency of the DNAJC7 variants in Japanese ALS patients was estimated at 0.87%. Collectively, these results suggest that variants of DNAJC7 are rare cause of Japanese patients with sporadic ALS.

Multiple system atrophy variant with severe hippocampal pathology.

The striatonigral and olivopontocerebellar systems are known to be vulnerable in multiple system atrophy (MSA), showing neuronal loss, astrogliosis, and alpha-synuclein-immunoreactive inclusions. MSA patients who displayed abundant neuronal cytoplasmic inclusions (NCIs) in the regions other than the striatonigral or olivopontocerebellar system have occasionally been diagnosed with variants of MSA. In this study, we report clinical and pathologic findings of MSA patients characterized by prominent pathologic involvement of the hippocampus. We assessed 146 consecutively autopsied MSA patients. Semi-quantitative analysis of anti-alpha-synuclein immunohistochemistry revealed that 12 of 146 patients (8.2%) had severe NCIs in two or more of the following areas: the hippocampal granule cells, cornu ammonis areas, parahippocampal gyrus, and amygdala. In contrast, the remaining 134 patients did not show severe NCIs in any of these regions. Patients with severe hippocampal involvement showed a higher representation of women (nine women/three men; Fisher's exact test, p = 0.0324), longer disease duration (13.1 ± 5.9 years; Mann-Whitney U-test, p = 0.000157), higher prevalence of cognitive impairment (four patients; Fisher's exact test, p = 0.0222), and lower brain weight (1070.3 ± 168.6 g; Mann-Whitney U-test, p = 0.00911) than other patients. The hippocampal granule cells and cornu ammonis area 1/subiculum almost always showed severe NCIs. The NCIs appeared to be ring-shaped or neurofibrillary tangle-like, fibrous configurations. Three of 12 patients also had dense, round-shaped NCIs that were morphologically similar to pick bodies. The patients with Pick body-like inclusions showed more severe atrophy of the medial temporal lobes and broader spreading of NCIs than those without. Immunohistochemistry for hyperphosphorylated tau and phosphorylated TDP-43 revealed minimal aggregations in the hippocampus of the hippocampal MSA patients. Our observations suggest a pathological variant of MSA that is characterized by severe involvement of hippocampal neurons. This phenotype may reinforce the importance of neuronal alpha-synucleinopathy in the pathogenesis of MSA.

Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial.

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P < 0.0001). Incidences of adverse events and deaths were similar between groups. This well-powered study suggests that N-terminal tau neutralization does not translate into clinical efficacy.

Urine levels of the polyglutamine ataxin-3 protein are elevated in patients with spinocerebellar ataxia type 3.

INTRODUCTION: Accumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients. METHODS: We analyzed urine samples from 30 SCA3 subjects (including one pre-symptomatic subject), 35 subjects with other forms of ataxia, and 37 healthy controls. To quantify polyQ ATXN3 protein levels, we used our previously developed immunoassay. RESULTS: PolyQ ATXN3 can be detected in the urine of SCA3 patients, but not in urine samples from healthy controls or other forms of ataxia. There was a significant statistical association between polyQ ATXN3 levels in urine samples and those in plasma. Further, the levels of polyQ ATXN3 urine associated with an earlier age of SCA3 disease onset. CONCLUSION: As clinical trials for SCA3 advance, urine polyQ ATXN3 protein has potential to be a useful, non-invasive and inexpensive biomarker for SCA3.

Skeletal muscle loss and body composition in progressive supranuclear palsy: A retrospective cross-sectional study.

INTRODUCTION: Skeletal muscle mass loss has been associated with decreased physical performance; however, the body composition characteristics in progressive supranuclear palsy (PSP) are not well understood. We investigated body composition parameters, focusing on skeletal muscle mass, in patients with PSP and compared them with those of healthy older adults. METHODS: This retrospective cross-sectional study included 39 patients with PSP and 30 healthy older adults (control group). Using a multi-frequency bioelectrical impedance analysis, we measured the skeletal mass index (SMI), basal metabolism, extracellular water/total body water ratio (ECW/TBW), and body fat percentage and examined the relationship between SMI and age, body mass index (BMI) and other body composition parameters. RESULTS: The PSP group had a higher rate of low muscle mass (56.4%) than the control group (10.0%), although the ages and BMIs were similar. The leg SMI was lower for the PSP group, while the ECW/TBW was higher for the PSP group. The basal metabolism was lower for the PSP group than for the controls but only in the women. The basal metabolism and BMI showed a significant correlation with SMI in the PSP group. There was a significant correlation between SMI and age, ECW/TBW, and body fat percentage in the PSP group but only in the women. CONCLUSION: This study is the first to show that a high proportion of patients with PSP have low muscle mass. We showed differences in terms of sex in muscle mass loss in women with PSP, which was associated with inactivity and aging.

[Burnout in Japanese neurologists: comparison of male and female physicians].

A questionnaire survey was conducted on 8,402 members of the Japanese Neurological Society to examine the current status and countermeasures for physician burnout, and 1,261 respondents (15.0%) responded. In this paper, we report the results of a comparison between male and female physicians. There was a significant difference in working and living conditions only for married people. It was confirmed that men work under stricter conditions in terms of working hours, and that the burden on women is heavier in the division of housework. Analysis using the Japanese Burnout Scale revealed no gender differences in overall scores, but as for factors related to burnout, in addition to factors common to both men and women, factors specific to men or women were clarified.

[Current and future strategies for burnout in Japanese neurologists].

To identify factors associated with burnout among Japanese physician and to use them in future measures, the Japanese Society of Neurology conducted a survey of neurologists on burnout using a web-based questionnaire in October 2019. A total of 1,261 respondents, 15.0% of the 8,402 members, responded to the survey. The mean of the subscales of the Japanese Burnout Scale was 2.86/5 points for emotional exhaustion, 2.21/5 points for depersonalization, and 3.17/5 points for lack of personal accomplishment. In addition, the burnout of our country's neurologists is not related to workloads such as working hours and the number of patients in charge, but also to a decreased meaningfulness and professional accomplishment. Therefore, it is necessary to take comprehensive measures to improve these issues at the individual, hospital, academic and national levels.

Genetic and functional analysis of KIF5A variants in Japanese patients with sporadic amyotrophic lateral sclerosis.

Two recent genetic studies reported that loss-of-function mutation of the C-terminal cargo-binding tail domain of the KIF5A gene cause amyotrophic lateral sclerosis (ALS). The aim of this study is to investigate the frequency of KIF5A variants in Japanese patients with sporadic ALS. In total, 807 sporadic ALS patients and 191 normal controls from a multicenter ALS cohort in Japan were included. Whole exome sequencing on an Illumina HiSeq 2000/2500 sequencer was used to identify and select variants within the KIF5A gene. Thirteen patients harbored a nonsynonymous variant in the KIF5A gene; These were considered variants of uncertain significance. One patient harbored a novel splice-site variant (c.2993-3C>A) in the C-terminal cargo-binding tail domain of the KIF5A gene. Functional analysis of this variant revealed that it caused skipping of exon 27. The frequency of KIF5A mutations in Japanese patients with sporadic ALS was 0.12% (1/807). This study reports a novel loss-of-function variant in KIF5A, and indicates that loss-of-function variant in KIF5A is a rare cause of sporadic ALS in Japanese patients.

Video-tutorial for the Movement Disorder Society criteria for progressive supranuclear palsy.

BACKGROUND: The International Parkinson and Movement Disorder Society-endorsed Progressive Supranuclear Palsy Study Group published clinical diagnostic criteria for progressive supranuclear palsy in 2017, aiming to optimize early, sensitive and specific diagnosis. OBJECTIVE: To assist physicians in the application of these criteria, we developed a video-based tutorial in which all core clinical features and clinical clues are depicted and explained. METHODS: Patients provided written informed consent to the publication of their videos. High-quality videos along with essential descriptions were collected by the study group members. Most educational videos were selected in a structured consensus process. RESULTS: We provide 68 videos of all core clinical features and clinical clues defined by the diagnostic criteria, along with instructive descriptions of the depicted patients, examination techniques and clinical findings. CONCLUSIONS: This comprehensive video-based tutorial will support physicians in the application of the diagnostic criteria of progressive supranuclear palsy.

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.