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BACKGROUND AND PURPOSE: Colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is an adult-onset leukoencephalopathy caused by mutations in CSF1R. The present study aimed to explore the broader genetic spectrum of CSF1R-related leukoencephalopathy in association with clinical and imaging features. METHODS: Mutational analysis of CSF1R was performed for 100 consecutive patients with adult-onset leukoencephalopathy. Sequence and copy number variation (CNV) analyses of CSF1R were performed. The genomic ranges of the deletions were determined by long-read sequencing. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing the CSF1R mutants identified in this study. RESULTS: CSF1R mutations were identified in 15 patients, accounting for 15% of the adult-onset leukoencephalopathy cases. Seven novel and five previously reported CSF1R mutations were identified. The novel mutations, including three missense and one in-frame 3 bp deletion, were located in the tyrosine kinase domain (TKD) of CSF1R. Functional assays revealed that none of the novel mutations in the TKD showed autophosphorylation of CSF1R. Two partial deletions of CSF1R were identified that resulted in lack of the C-terminal region, including the distal TKD, in two patients. Various clinical features including cognitive impairment, psychiatric symptoms and gait disturbance were observed. Various degrees of the white matter lesions and corpus callosum abnormalities on magnetic resonance imaging and characteristic calcifications on computed tomography were observed as imaging features. CONCLUSIONS: Our results highlight the importance of examining the CNV of CSF1R even when Sanger or exome sequencing reveals no CSF1R mutations. Genetic examination of sequences and CNV analyses of CSF1R are recommended for an accurate diagnosis of CSF1R-related leukoencephalopathy.
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Leucoencefalopatías , Mutación Missense , Receptores del Factor Estimulante de Colonias , Adulto , Humanos , Variaciones en el Número de Copia de ADN , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Leucoencefalopatías/patología , Mutación , Receptores del Factor Estimulante de Colonias/genéticaRESUMEN
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.
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COVID-19 , Enfermedad de Parkinson , Humanos , Temblor/diagnóstico , Estudios Retrospectivos , Hipocinesia , Enfermedad de Parkinson/diagnóstico , Examen Neurológico/métodos , Pruebas de Estado Mental y Demencia , MarchaRESUMEN
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system with a poor prognosis and is primarily caused by JC virus (JCV) with a mutation called prototype. We encountered a case of PML with moderate progression and analyzed the mutational patterns of JCV in the cerebrospinal fluid (CSF). A 19-year-old Japanese woman with mild neurological symptoms was diagnosed with combined immunodeficiency following pneumocystis pneumonia. Brain magnetic resonance imaging scan showed multiple brain lesions, and real-time polymerase chain reaction testing detected JCV in the CSF, leading to the diagnosis of PML. The disease course of PML was stable after administration of mefloquine and mirtazapine with immunoglobulin replacement therapy. In the JCV genome cloned from the patient CSF, DNA sequences of the gene encoding the capsid protein (VP1) and the non-coding control region exhibited small mutations. However, they were quite similar to those of the archetype JCV, which persists asymptomatically in healthy individuals. These findings provide insight into the mutational characteristics of JCV in PML with mild symptoms and progression.
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Virus JC , Leucoencefalopatía Multifocal Progresiva , Adulto , Encéfalo , Sistema Nervioso Central/patología , ADN Viral/líquido cefalorraquídeo , Femenino , Humanos , Virus JC/genética , Leucoencefalopatía Multifocal Progresiva/diagnóstico por imagen , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Adulto JovenRESUMEN
We reported previously that the average medial-lateral gait amplitude while walking on a straight path determined using triaxial accelerometers fixed on the middle of the upper back may be a quantitative and concise indicator for the severity of cerebellar ataxia. Considering that gait ataxia is a typical initial symptom in a variety of spinocerebellar degeneration (SCD), we aimed to develop quantitative biomarkers for cerebellar ataxia as metric variables. We used triaxial accelerometers to analyze gait parameters in 14 patients with SCD at 3 points over 3 years (at baseline, 1.5 years and 3 years). Analysis of covariance (ANCOVA) models adjusted for the baseline scores were used to estimate sample sizes. The mean medial-lateral amplitude (ML) gained by a triaxial accelerometer fixed on upper back could detect the each 1.5-year change. In the 14 patients, the mean ML(m) was 0.032 ± 0.007(SD) at entry, 0.037 ± 0.008 after 1.5-year follow, and 0.042 ± 0.020 after 3-year follow. In contrast, SARA gait scores were 2.9, 2.9, and 3.0, respectively. The responsiveness of the quantitative evaluation of gait ataxia by triaxial accelerometers is higher than that of the SARA within a 1.5-year follow-up period. Gait analysis by triaxial accelerometers will be complementary to the evaluation of scales like SARA in the assessment of clinical severity of SCD patients in early stage.
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Acelerometría/métodos , Ataxia de la Marcha/diagnóstico , Ataxia de la Marcha/etiología , Degeneraciones Espinocerebelosas/complicaciones , Degeneraciones Espinocerebelosas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The N-terminus of the PRNP gene normally contains a 5-octapeptide repeat (R1-R2-R2-R3-R4), and insertions at this locus can cause hereditary prion diseases. In the present study, we found a 5-octapeptide repeat insertion (5-OPRI) in a sibling case of frontotemporal dementia. Consistent with previous literature, 5-OPRI rarely met the diagnostic criteria for CreutzfeldtâJakob disease (CJD). We propose 5-OPRI as a suspected causative mutation for early-onset dementia, especially the frontotemporal type.
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Tick-borne encephalitis (TBE) is an infection of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is endemic in parts of Europe and Asia. TBEV is transmitted to humans primarily by Ixodes ticks. There have been 5 TBE cases identified in Japan, all on the northern island of Hokkaido. Rodents with TBEV antibodies and Ixodes ticks have been identified throughout Japan, indicating that TBEV infection might be undiagnosed in Japan. Residual serum and cerebrospinal fluid (CSF) collected in 2010-2021 from 520 patients ≥1 year-of-age previously hospitalized with encephalitis or meningitis of unknown etiology at 15 hospitals (including 13 hospitals outside of Hokkaido) were screened by ELISA for TBEV IgG and IgM antibodies; TBEV infection was confirmed by the gold standard neutralization test. Residual serum was available from 331 (63.6%) patients and CSF from 430 (82.6%) patients; both serum and CSF were available from 189 (36.3%). Two patients were TBE cases: a female aged 61 years hospitalized for 104 days in Oita (2000â km south of Hokkaido) and a male aged 24 years hospitalized for 11 days in Tokyo (1200â km south of Hokkaido). Retrospective testing also identified a previous TBEV infection in a female aged 45 years hospitalized for 12 days in Okayama (1700â km south of Hokkaido). TBEV infection should be considered as a potential cause of encephalitis or meningitis in Japan. TBE cases are likely undiagnosed in Japan, including outside of Hokkaido, due to limited clinical awareness and lack of availability of TBE diagnostic tests.
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Virus de la Encefalitis Transmitidos por Garrapatas , Encefalitis Transmitida por Garrapatas , Ixodes , Meningitis , Animales , Humanos , Masculino , Femenino , Encefalitis Transmitida por Garrapatas/diagnóstico , Encefalitis Transmitida por Garrapatas/epidemiología , Japón/epidemiología , Estudios RetrospectivosRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). METHODS: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. RESULTS: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Método Doble Ciego , Humanos , Nitrilos , Piridonas/efectos adversos , Resultado del TratamientoRESUMEN
Tick-borne encephalitis (TBE) is a zoonotic disease that usually presents as a moderate febrile illness followed by severe encephalitis, and various neurological symptoms are observed depending on the distinct central nervous system (CNS) regions affected by the TBE virus (TBEV) infection. In Japan, TBE incidence is increasing and TBEV distributions are reported in wide areas, specifically in Hokkaido. However, an extensive epidemiological survey regarding TBEV has not been conducted yet. In this study, we conducted a retrospective study of the prevalence of antibodies against TBEV in patients with neurological disorders and healthy populations in a TBEV-endemic area in Hokkaido. Among 2000 patients, three patients with inflammatory diseases in the CNS had TBEV-specific IgM antibodies and neutralizing antibodies. The other four patients diagnosed clinically with other neurological diseases were positive for TBEV-specific IgG and neutralizing antibodies, indicating previous TBEV infection. In a total of 246 healthy residents in a TBEV-endemic region, one resident had TBEV-specific antibodies. These results demonstrated undiagnosed TBEV infections in Japan. Further surveys are required to reveal the actual epidemiological risk of TBE and to consider preventive measures, such as a vaccine program, for the control of TBE in Japan.
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Studies on evoked responses in Parkinson's disease (PD) may be useful for elucidating the etiology and quantitative evaluation of PD. However, in previous studies, the association between evoked responses and detailed motor symptoms or cognitive functions has not been clear. This study investigated the characteristics of the visual (VEF), auditory (AEF), and somatosensory (SEF) evoked magnetic fields in patients with Parkinson's disease (PD), and the correlations between evoked fields and the patient's clinical characteristics, motor symptoms, and cognitive functions. Twenty patients with PD and 10 healthy controls (HCs) were recruited as participants. We recorded VEF, AEF, and SEF, collected clinical characteristics, performed physical examinations, and administered 10 cognitive tests. We investigated differences in the latencies of the evoked fields between patients with PD and HCs. We also evaluated the correlation of the latencies with motor symptoms and cognitive functioning. There were significant differences between the two groups in 6 of the cognitive tests, all of which suggested mild cognitive impairment in patients with PD. The latencies of the VEF N75m, P100m, N145m, AEF P50m, P100m, and SEF P60m components were greater in the patients with PD than in the HCs. The latencies mainly correlated with medication and motor symptoms, less so with cognitive tests, with some elements of the correlations remaining significant after Bonferroni correction. In conclusion, the latencies of the VEF, AEF, and SEF were greater in PD patients than in HCs and were mainly correlated with medication and motor symptoms rather than cognitive functioning. Findings from this study suggest that evoked fields may reflect basal ganglia functioning and are candidates for assessing motor symptoms or the therapeutic effects of medication in patients with PD.