Dynamic molecular network analysis of iPSC-Purkinje cells differentiation delineates roles of ISG15 in SCA1 at the earliest stage.

Better understanding of the earliest molecular pathologies of all neurodegenerative diseases is expected to improve human therapeutics. We investigated the earliest molecular pathology of spinocerebellar ataxia type 1 (SCA1), a rare familial neurodegenerative disease that primarily induces death and dysfunction of cerebellum Purkinje cells. Extensive prior studies have identified involvement of transcription or RNA-splicing factors in the molecular pathology of SCA1. However, the regulatory network of SCA1 pathology, especially central regulators of the earliest developmental stages and inflammatory events, remains incompletely understood. Here, we elucidated the earliest developmental pathology of SCA1 using originally developed dynamic molecular network analyses of sequentially acquired RNA-seq data during differentiation of SCA1 patient-derived induced pluripotent stem cells (iPSCs) to Purkinje cells. Dynamic molecular network analysis implicated histone genes and cytokine-relevant immune response genes at the earliest stages of development, and revealed relevance of ISG15 to the following degradation and accumulation of mutant ataxin-1 in Purkinje cells of SCA1 model mice and human patients.

Intracerebral transplantation of MRI-trackable autologous bone marrow stromal cells for patients with subacute ischemic stroke.

BACKGROUND: Ischemic stroke is one of the leading causes of death and neurological disability worldwide, and stem cell therapy is highly expected to reverse the sequelae. This phase 1/2, first-in-human study evaluated the safety, feasibility, and monitoring of an intracerebral-transplanted magnetic resonance imaging (MRI)-trackable autologous bone marrow stromal cell (HUNS001-01) for patients with subacute ischemic stroke. METHODS: The study included adults with severe disability due to ischemic stroke. HUNS001-01 cultured with human platelet lysates and labeled with superparamagnetic iron oxide was stereotactically transplanted into the peri-infarct area 47-64 days after ischemic stroke onset (dose: 2 or 5 × 107 cells). Neurological and radiographic evaluations were performed throughout 1 year after cell transplantation. The trial was registered at UMIN Clinical Trial Registry (number UMIN000026130). FINDINGS: All seven patients who met the inclusion criteria successfully achieved cell expansion, underwent intracerebral transplantation, and completed 1 year of follow-up. No product-related adverse events were observed. The median National Institutes of Health Stroke Scale and modified Rankin scale scores before transplantation were 13 and 4, which showed improvements of 1-8 and 0-2, respectively. Cell tracking proved that the engrafted cells migrated toward the infarction border area 1-6 months after transplantation, and the quantitative susceptibility mapping revealed that cell signals at the migrated area constantly increased throughout the follow-up period up to 34% of that of the initial transplanted site. CONCLUSIONS: Intracerebral transplantation of HUNS001-01 was safe and well tolerated. Cell tracking shed light on the therapeutic mechanisms of intracerebral transplantation. FUNDING: This work was supported by the Japan Agency for Medical Research and Development (AMED; JP17bk0104045 and JP20bk0104011).

The Movement Disorder Society Criteria: Its Clinical Usefulness in Multiple System Atrophy.

Objective In 2022, Wenning et al. proposed the Movement Disorder Society Criteria (MDS Criteria) for the Diagnosis of Multiple System Atrophy (MSA). These criteria were expected to provide useful alternatives to the second consensus statement. We examined trends in these diagnostic criteria. Methods We used patient data registered with the Hokkaido Rare Disease Consortium for Multiple System Atrophy, which has been recruiting patients with MSA through medical facilities in Hokkaido since November 2014. Patients were evaluated according to the MDS criteria based on neurological examinations and imaging findings at three separate times: the first evaluation, the time of enrollment (diagnosis), and the most recent evaluation (final evaluation). Results The MDS criteria were examined in 68 of 244 patients enrolled between November 2014 and July 2022. At the initial evaluation, the classifications were as follows: clinically established (n=27; 39.7%); clinically probable (n=13; 19.1%); possible prodromal (n=12; 17.6%); and negative (did not meet criteria (n=16; 23.5%). At the time of diagnosis, the classifications were as follows: clinically established (n=45; 66.2%); clinically probable (n=12; 17.6%); possible prodromal (n=4; 5.9%); and negative (n=7; 10.3%). At the final evaluation, the classifications were as follows: clinically established (n=52; 76.5%); clinically probable (n=9; 13.2%); possible prodromal (n=2; 2.9%); and negative (n=5; 7.4%). Conclusions We were able to clarify the changes in the criteria values and transition of patients due to the clarification of imaging and supportive findings in the MDS criteria.

Reliability of the unified multiple system atrophy rating scale using the telephone.

OBJECTIVE: The unified multiple system atrophy rating scale (UMSARS) was used to evaluate various symptoms of multiple system atrophy (MSA). And UMSARS part 1 was originally developed for use in interviews, but the need for telemedicine is increasing in COVID-19 pandemic. The purpose of this study is to evaluate the reliability of the UMSARS part 1 telephone survey. METHODS: Thirty-two MSA patients took the UMSARS part 1 face-to-face, followed by two more telephone evaluations. Intraclass correlation coefficients (ICC) and Cronbach's alpha (α) coefficients were calculated, and the inter-rater reliability was determined. At the same time, we asked about the problems in COVID-19 pandemic. RESULTS: The study participants included 15 men and 17 women with mean age of 67.1 years (SD, 8.3). For the total UMSARS part 1 score, the inter-rater ICC and Cronbach's α coefficient were 0.89 to 0.92, and 0.84 to 0.87, respectively. More than half of the items had a relatively high ICC. Cronbach's α coefficients were more than 0.7 for all items. Changes that occurred in COVID-19 pandemic included reduced outings and lack of rehabilitation in about half of the cases. CONCLUSION: The UMSARS part 1 has high inter-rater reliability and internal consistency. Evaluation of subjective symptoms showed that some variability could occur. In addition, there was concern about the influence of lack of rehabilitation due to COVID-19 pandemic.

[Recent clinical advances in hereditary spinocerebellar degeneration].

Spinocerebellar degeneration (SCD) is a neurodegenerative disorder characterized by cerebellar ataxia and other multisystem manifestations, such as Parkinsonism and pyramidal tract symptoms. No effective treatment is available for SCD. Approximately one-third of the cases of SCD are inherited, and the remaining two-third are sporadic, including multiple system atrophy. This article provides an overview of hereditary SCD, its clinical features, recent treatment advances, biomarkers, role of genomic medicine, and future treatment prospects.

Differentiation of speech in Parkinson's disease and spinocerebellar degeneration using deep neural networks.

INTRODUCTION: Assessing dysarthria features in patients with neurodegenerative diseases helps diagnose underlying pathologies. Although deep neural network (DNN) techniques have been widely adopted in various audio processing tasks, few studies have tested whether DNNs can help differentiate neurodegenerative diseases using patients' speech data. This study evaluated whether a DNN model using a transformer architecture could differentiate patients with Parkinson's disease (PD) from patients with spinocerebellar degeneration (SCD) using speech data. METHODS: Speech data were obtained from 251 and 101 patients with PD and SCD, respectively, while they read a passage. We fine-tuned a pre-trained DNN model using log-mel spectrograms generated from speech data. The DNN model was trained to predict whether the input spectrogram was generated from patients with PD or SCD. We used fivefold cross-validation to evaluate the predictive performance using the area under the receiver operating characteristic curve (AUC) and accuracy, sensitivity, and specificity. RESULTS: Average ± standard deviation of the AUC, accuracy, sensitivity, and specificity of the trained model for the fivefold cross-validation were 0.93 ± 0.04, 0.87 ± 0.03, 0.83 ± 0.05, and 0.89 ± 0.05, respectively. CONCLUSION: The DNN model can differentiate speech data of patients with PD from that of patients with SCD with relatively high accuracy and AUC. The proposed method can be used as a non-invasive, easy-to-perform screening method to differentiate PD from SCD using patient speech and is expected to be applied to telemedicine.

Prevalence of repeat expansions causing autosomal dominant spinocerebellar ataxias in Hokkaido, the northernmost island of Japan.

In Japan, approximately 30% of spinocerebellar degeneration (SCD) is hereditary, and more than 90% of hereditary SCD is autosomal dominant SCD (AD-SCD). We have previously reported the types of AD-SCD in Hokkaido, twice. In this study, we investigated the status of AD-SCD mainly due to repeat expansions, covering the period since the last report. We performed genetic analysis for 312 patients with a clinical diagnosis of SCD, except for multiple system atrophy at medical institutions in Hokkaido between January 2007 and December 2020. The median age at the time of analysis was 58 (1-86) years. Pathogenic variants causing AD-SCD due to repeat expansion were found in 61.5% (192 cases). Spinocerebellar ataxia (SCA) 6 was the most common type in 25.3% (79 cases), followed by Machado-Joseph disease (MJD)/SCA3 in 13.8% (43), SCA1 in 6.4% (20), SCA2 in 5.1% (16), SCA31 in 4.8% (15), dentatorubral-pallidoluysian atrophy in 4.8% (15), SCA7 in 0.6% (2), and SCA8 in 0.6% (2). SCA17, 27B, 36, and 37 were not found. Compared to previous reports, this study found a higher prevalence of SCA6 and a lower prevalence of MJD/SCA3. An increasing number of cases identified by genetic testing, including cases with no apparent family history, accurately revealed the distribution of disease types in Hokkaido.

Survey of medications for myelomeningocele patients over their lifetime in Japan.

BACKGROUND: This study aimed to investigate medication prescriptions for patients with myelomeningocele (MMC) across different age groups, particularly in adulthood and after middle age. METHODS: The Japan Medical Data Center (JMDC) database, based on medical claims data, was utilized for this analysis. Patients were divided into 10-year age groups, and prescriptions for analgesics, anticonvulsants, psychotropic drugs, lifestyle disease-related drugs, drugs for urinary incontinence, and laxatives were examined. To compare the differences in the utilization of medications unrelated to lifestyle-related diseases across different age groups, the data was categorized into three age groups: 19 or under, 20-39, and 40 or older. RESULTS: Among the 556 MMC patients, the percentage of those regularly prescribed analgesics increased from 2.8% in patients ≤ 19 to 31.7% in patients 40 or older (p < 0.01). Psychotropic medication use also increased with age, rising significantly from 6.3% in patients ≤ 19 to 34.6% in patients 40 or older (p < 0.01). Patients with MMC showed an increasing trend in prescriptions for lifestyle-related disease medications compared to the normal control group. Notably, the percentage of patients in their 30 s taking hypertension medication was 4.9%, significantly higher than the 0.86% in the control group (p = 0.029). In their 40 s, 22.9% of MMC patients were prescribed hyperlipidemia medication, significantly higher than the 3.9% in the control group (p < 0.01). CONCLUSION: Comprehensive multidisciplinary support and follow-up are crucial to enhance the quality of life for MMC patients, with particular attention to pain management, psychological care, and treatment of lifestyle-related diseases.

A retrospective study of autoimmune cerebellar ataxia over a 20-year period in a single institution.

BACKGROUND: It is important to differentiate autoimmune cerebellar ataxia (ACA) from neurodegenerative CA, but this is sometimes difficult. We performed a retrospective study in a single institution in Japan over a 20-year period to reveal the clinical features of ACA. METHODS: Patients with CA as the primary neurological symptom were enrolled from those admitted to the Department of Neurology, Hokkaido University Hospital between April 2002 and March 2022. ACA was diagnosed retrospectively according to the following criteria: (1) CA being the predominant symptom; (2) identification of cancer within 2 years of onset; (3) improvement in cerebellar symptoms following immunotherapy; and (4) ruling out alternative causes of CA. Patients fulfilling criteria (1), (2), and (4) were classified as paraneoplastic cerebellar degeneration (PCD), while those fulfilling (1), (3), and (4) were classified as non-PCD and enrolled as patients with ACA. Neurodegenerative diseases, e.g., multiple system atrophy (MSA), were confirmed retrospectively based on generally used diagnostic criteria and enrolled. Furthermore, the ACA diagnostic criteria proposed by Dalmau and Graus were applied retrospectively to the ACA patients to examine the validity of the diagnoses. RESULTS: Among the 243 patients with CA, 13 were enrolled as ACA; five were PCD and eight were non-PCD. Eight of these cases met the proposed diagnostic criteria by Dalmau and Graus. MSA was the most prevalent disease among CA patients, with 93 cases. The incidence of cerebellar atrophy was significantly lower in ACA (3/13) than in MSA (92/92). Cerebrospinal fluid (CSF) pleocytosis was significantly more frequent in ACA than in MSA (4/13 vs. 2/55, respectively). However, there was no significant difference in the presence of oligoclonal bands, increased protein in CSF, and laterality differences in ataxia. CONCLUSION: ACA was present in ~ 5% of Japanese CA patients. The absence of cerebellar atrophy, despite the presence of CA, strongly supports ACA over MSA. While CSF pleocytosis was observed more often in ACA, the positivity rate was only ~ 30%. Since ACA is treatable, further studies are needed to identify additional clinical features and accurate diagnostic biomarkers.

Roles of the cerebellum and basal ganglia in temporal integration: Insights from a synchronized tapping task.

OBJECTIVE: The aim of this study was to clarify the roles of the cerebellum and basal ganglia for temporal integration. METHODS: We studied 39 patients with spinocerebellar degeneration (SCD), comprising spinocerebellar atrophy 6 (SCA6), SCA31, Machado-Joseph disease (MJD, also called SCA3), and multiple system atrophy (MSA). Thirteen normal subjects participated as controls. Participants were instructed to tap on a button in synchrony with isochronous tones. We analyzed the inter-tap interval (ITI), synchronizing tapping error (STE), negative asynchrony, and proportion of delayed tapping as indicators of tapping performance. RESULTS: The ITI coefficient of variation was increased only in MSA patients. The standard variation of STE was larger in SCD patients than in normal subjects, especially for MSA. Negative asynchrony, which is a tendency to tap the button before the tones, was prominent in SCA6 and MSA patients, with possible basal ganglia involvement. SCA31 patients exhibited normal to supranormal performance in terms of the variability of STE, which was surprising. CONCLUSIONS: Cerebellar patients generally showed greater STE variability, except for SCA31. The pace of tapping was affected in patients with possible basal ganglia pathology. SIGNIFICANCE: Our results suggest that interaction between the cerebellum and the basal ganglia is essential for temporal processing. The cerebellum and basal ganglia and their interaction regulate synchronized tapping, resulting in distinct tapping pattern abnormalities among different SCD subtypes.

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.

Case series: Downbeat nystagmus in SCA27B.

BACKGROUND: Spinocerebellar ataxia (SCA) 27B, first reported in late 2022, is caused by the abnormal expansion of GAA repeats in the first intron of the FGF14 gene, which encodes the fibroblast growth factor 14. CASE PRESENTATION: We present two late-onset cases, each manifesting mild cerebellar ataxia accompanied by omnidirectional downbeat nystagmus, which was enhanced in a suspended head position. None of the patients exhibited impaired head impulse or caloric tests. Repeat-primed PCR and targeted long-read nanopore sequence analysis of the FGF14 GAA repeat site identified more than 250 repeats, leading to the diagnosis of SCA27B. DISCUSSION: Downbeat nystagmus is reported to be associated with disturbances in the suppression of the vestibulo-ocular reflex (VOR). Our patients with SCA27B demonstrated downbeat nystagmus, likely due to a disruption of the VOR at the level of the cerebellar cortex, a potentially characteristic clinical feature of SCA27B. We have included video footages of eye movements recorded using Frenzel goggles for these cases. CONCLUSIONS: Omnidirectional downbeat nystagmus may be a distinctive clinical feature of SCA27B.

[A case of Seizure-related 6 homolog like 2 (Sez6l2) antibody-associated autoimmune cerebellar ataxia].

A 35-year-old male patient had been repeatedly involved in car accidents since the age of 34 years, had difficulty in tidying his room, and developed speech and gait disorders. At the first examination, he had a hypophonia and poor gait, but he could talk and walk by himself. His Mini-Mental State Examination (MMSE) score was 23 and mild cognitive impairment was observed. Three months later, neurological findings showed subacute progression to loss of speech, and poor right dominant diadochokinesia and finger tapping, poor finger-nose test and heel-knee test, and loss of ability to stand and walk. Cerebellar atrophy was observed on head MRI, and the patient was positive for Seizure-related 6 homolog like 2 (Sez6l2) antibody, leading to a diagnosis of Sez6l2 antibody-associated autoimmune cerebellar ataxia. Immunotherapy halted the progression of symptoms, and the patient showed slight improvement. Sez6l2 antibody measurement and immunotherapy were considered necessary for subacute progressive cerebellar ataxia of unknown cause.

Gait video-based prediction of unified Parkinson's disease rating scale score: a retrospective study.

BACKGROUND: The diagnosis of Parkinson's disease (PD) and evaluation of its symptoms require in-person clinical examination. Remote evaluation of PD symptoms is desirable, especially during a pandemic such as the coronavirus disease 2019 pandemic. One potential method to remotely evaluate PD motor impairments is video-based analysis. In this study, we aimed to assess the feasibility of predicting the Unified Parkinson's Disease Rating Scale (UPDRS) score from gait videos using a convolutional neural network (CNN) model. METHODS: We retrospectively obtained 737 consecutive gait videos of 74 patients with PD and their corresponding neurologist-rated UPDRS scores. We utilized a CNN model for predicting the total UPDRS part III score and four subscores of axial symptoms (items 27, 28, 29, and 30), bradykinesia (items 23, 24, 25, 26, and 31), rigidity (item 22) and tremor (items 20 and 21). We trained the model on 80% of the gait videos and used 10% of the videos as a validation dataset. We evaluated the predictive performance of the trained model by comparing the model-predicted score with the neurologist-rated score for the remaining 10% of videos (test dataset). We calculated the coefficient of determination (R2) between those scores to evaluate the model's goodness of fit. RESULTS: In the test dataset, the R2 values between the model-predicted and neurologist-rated values for the total UPDRS part III score and subscores of axial symptoms, bradykinesia, rigidity, and tremor were 0.59, 0.77, 0.56, 0.46, and 0.0, respectively. The performance was relatively low for videos from patients with severe symptoms. CONCLUSIONS: Despite the low predictive performance of the model for the total UPDRS part III score, it demonstrated relatively high performance in predicting subscores of axial symptoms. The model approximately predicted the total UPDRS part III scores of patients with moderate symptoms, but the performance was low for patients with severe symptoms owing to limited data. A larger dataset is needed to improve the model's performance in clinical settings.

Clinical Characteristics of Patients with Cryptococcal Meningitis in Hokkaido: A Case Series.

We retrospectively reviewed the medical histories, examination results, treatments, and prognoses of nine patients with cryptococcal meningitis who were diagnosed and treated at Hokkaido University Hospital and its affiliated hospitals over the past 10 years. Cryptococcal meningitis can develop even in immunocompetent hosts, and its prognosis is poor owing to diagnostic difficulties and delayed treatment. Although liposomal amphotericin B and oral 5-fluorocytosine are standard therapies, voriconazole or intraventricular administration of amphotericin B may also be considered treatment options for refractory patients. Some patients develop delayed exacerbations owing to immunological mechanisms that require steroid therapy.

Lambert-Eaton Myasthenic Syndrome Complicated by anti-GABAB Receptor Encephalitis.

A 74-year-old man experienced diplopia, generalized muscle weakness, and acute respiratory failure. He was diagnosed with Lambert-Eaton myasthenic syndrome (LEMS) and treated with immunotherapy, but no improvement was observed, and additional symptoms, including central apnea and hallucinations, appeared. Subsequent serum and cerebrospinal fluid (CSF) analyses confirmed the presence of GABAB receptor antibodies, indicating the coexistence of autoimmune encephalitis. Although there were no findings of malignancy, it is highly likely that occult small-cell lung carcinoma was present. When atypical symptoms occur in patients with LEMS, it is important to consider the possibility of concomitant autoimmune encephalitis.

Prediction of amyloid positron emission tomography positivity using multiple regression analysis of quantitative susceptibility mapping.

PURPOSE: To develop a method for predicting amyloid positron emission tomography (PET) positivity based on multiple regression analysis of quantitative susceptibility mapping (QSM). MATERIALS AND METHODS: This prospective study included 39 patients with suspected dementia from four centers. QSM images were obtained through a 3-T, three-dimensional radiofrequency-spoiled gradient-echo sequence with multiple echoes. The cortical standard uptake value ratio (SUVR) was obtained using amyloid PET with 18F-flutemetamol, and susceptibility in the brain regions was obtained using QSM. A multiple regression model to predict cortical SUVR was constructed based on susceptibilities in multiple brain regions, with the constraint that cortical SUVR and susceptibility were positively correlated. The discrimination performance of the Aß-positive and Aß-negative cohorts was evaluated based on the predicted SUVR using the area under the receiver operating characteristic curve (AUC) and Mann-Whitney U test. RESULTS: The correlation coefficients between true and predicted SUVR were increased by incorporating the constraint, and the AUC to discriminate between the Aß-positive and Aß-negative cohorts reached to 0.79 (p < 0.01). CONCLUSION: These preliminary results suggest that a QSM-based multiple regression model can predict amyloid PET positivity with fair accuracy.

Genome-wide association study identifies a new susceptibility locus in PLA2G4C for Multiple System Atrophy.

To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association ( P = 6.5 × 10 -7 ) that was replicated in additional Japanese samples ( P = 2.9 × 10 -6 . OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data ( P = 5.0 × 10 -15 . Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples ( P =0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.