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Background: Amyotrophic lateral sclerosis (ALS)-related white-matter microstructural abnormalities have received considerable attention; however, gray-matter structural abnormalities have not been fully elucidated. This study aimed to evaluate cortical microstructural abnormalities in ALS and determine their association with disease severity. Methods: This study included 34 patients with ALS and 30 healthy controls. Diffusion-weighted data were used to estimate neurite orientation dispersion and density imaging (NODDI) parameters, including neurite density index (NDI) and orientation dispersion index (ODI). We performed gray matter-based spatial statistics (GBSS) in a voxel-wise manner to determine the cortical microstructure difference. We used the revised ALS Functional Rating Scale (ALSFRS-R) to assess disease severity and conducted a correlation analysis between NODDI parameters and ALSFRS-R. Results: In patients with ALS, the NDI reduction involved several cortical regions [primarily the precentral gyrus, postcentral gyrus, temporal cortex, prefrontal cortex, occipital cortex, and posterior parietal cortex; family-wise error (FWE)-corrected P<0.05]. ODI decreased in relatively few cortical regions (including the precentral gyrus, postcentral gyrus, prefrontal cortex, and inferior parietal lobule; FWE-corrected P<0.05). The NDI value in the left precentral and postcentral gyrus was positively correlated with the ALS disease severity (FWE-corrected P<0.05). Conclusions: The decreases in NDI and ODI involved both motor-related and extra-motor regions and indicated the presence of gray-matter microstructural impairment in ALS. NODDI parameters are potential imaging biomarkers for evaluating disease severity in vivo. Our results showed that GBSS is a feasible method for identifying abnormalities in the cortical microstructure of patients with ALS.
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Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder, characterized by progressive limb weakness, dysphagia, dysphonia, and respiratory failure due to degeneration of upper and lower motor neurons. The pathogenesis of ALS is still unclear. Neuroinflammation has been found to be involved in its development and progression. Cytokines play a significant role in the inflammatory process. This study aims to identify novel biomarkers that may assist in the diagnosis of ALS. Methods: In Fujian Medical University Union Hospital and Huashan Hospital Fudan University, two independent centers, we prospectively recruited 50 ALS patients, and 41 healthy controls (25 ALS and 26 controls in the first stage and 25 ALS and 15 controls in the validation stage). An 18-plex Luminex kit was used to screen the serum cytokines levels in the first stage. Commercial ELISA kits were used to measure the levels of target cytokines in the validation stage. A single-molecule array HD-X platform was applied to assess the levels of serum neurofilament light chain (NFL). Results: The levels of serum IL-18 were markedly increased in patients with ALS in the first stage (p = 0.016). The ROC curve showed an area under the curve at 0.695 (95% CI 0.50-0.84) in distinguishing ALS patients from healthy controls. The IL-21 was decreased in elderly patients when grouped by 55 years old (the medium age). Furthermore, the IL-5, IL-13, IL-18, and NFL had a positive relationship with the disease progression of ALS. We also found that serum IL-18 was markedly increased in ALS patients in the validation stage (167.67 [148.25-175.59] vs 116.44 [102.43-122.19]pg/ml, p < 0.0015). Conclusion: In this study, we identified systemic cytokine profile changes in the serum of ALS patients, especially the elevated IL-18, as well as the decreased IL-21 in elder patients. These changes in serum cytokine profiles may shed new light on an in-depth understanding of the immunopathogenic characteristics of ALS.
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AIMS: To evaluate microstructural impairment in the thalamus and thalamocortical connectivity using neurite orientation dispersion and density imaging (NODDI) in amyotrophic lateral sclerosis (ALS). METHODS: This study included 47 healthy controls and 43 ALS patients, whose structural and diffusion-weighted data were collected. We used state-of-the-art parallel transport tractography to identify thalamocortical pathways in individual spaces. Thalamus was then parcellated into six subregions based on its connectivity pattern with the priori defined cortical (i.e., prefrontal/motor/somatosensory/temporal/posterior-parietal/occipital) regions. For each of the thalamic and cortical subregions and thalamo-cortical tracts, we compared the following NODDI metrics between groups: orientation dispersion index (ODI), neurite density index (NDI), and isotropic volume fraction (ISO). We also used these metrics to conduct receiver operating characteristic curve (ROC) analyses and Spearman correlation. RESULTS: In ALS patients, we found decreased ODI and increased ISO in the thalamic subregion connecting the left motor cortex and other extramotor (e.g., somatosensory and occipital) cortex (Bonferroni-corrected p < 0.05). NDI decreased in the bilateral thalamo-motor and thalamo-somatosensory tracts and in the right thalamo-posterior-parietal and thalamo-occipital tracts (Bonferroni-corrected p < 0.05). NDI reduction in the bilateral thalamo-motor tract (p = 0.017 and 0.009) and left thalamo-somatosensory tract (p = 0.029) was correlated with disease severity. In thalamo-cortical tracts, NDI yielded a higher effect size during between-group comparisons and a greater area under ROC (p < 0.05) compared with conventional diffusion tensor imaging metrics. CONCLUSIONS: Microstructural impairment in the thalamus and thalamocortical connectivity is the hallmark of ALS. NODDI improved the detection of disrupted thalamo-cortical connectivity in ALS.
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Esclerose Lateral Amiotrófica , Neuritos , Humanos , Imagem de Tensor de Difusão/métodos , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Vias Neurais/diagnóstico por imagemRESUMO
AIM: To clarify the role of Eomesodermin (EOMES) to serve as a disease-relevant biomarker and the intracellular molecules underlying the immunophenotype shifting of CD4+T subsets in amyotrophic lateral sclerosis (ALS). METHODS: The derivation and validation cohorts included a total of 148 ALS patients and 101 healthy controls (HCs). Clinical data and peripheral blood were collected. T-cell subsets and the EOMES expression were quantified using multicolor flow cytometry. Serum neurofilament light chain (NFL) was measured. In 1-year longitudinal follow-ups, the ALSFRS-R scores and primary endpoint events were further recorded in the ALS patients of the validation cohort. RESULTS: In the derivation cohort, the CD4+EOMES+T-cell subsets were significantly increased (p < 0.001). EOMES+ subset was positively correlated with increased serum NFL levels in patients with onset longer than 12 months. In the validation cohort, the elevated CD4+EOMES+T-cell proportions and their association with NFL levels were also identified. The longitudinal study revealed that ALS patients with higher EOMES expression were associated with higher progression rates (p = .010) and worse prognosis (p = .003). CONCLUSIONS: We demonstrated that increased CD4+EOMES+T-cell subsets in ALS were associated with disease progression and poor prognosis. Identifying these associations may contribute to a better understanding of the immunopathological mechanism of ALS.
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Esclerose Lateral Amiotrófica , Humanos , Estudos Longitudinais , Esclerose Lateral Amiotrófica/diagnóstico , Linfócitos T , Prognóstico , Progressão da Doença , BiomarcadoresRESUMO
Spinocerebellar ataxia type 11 (SCA11) is a rare disease and the tau tubulin kinase 2 (TTBK2) gene was the causative gene. To date, only six SCA11 families have been reported. Here, we reported a Chinese SCA11 pedigree with cerebellar ataxia. Both patients in the family demonstrated typical clinical features of cerebellar ataxia and cerebellar atrophy on brain MRI. A novel heterozygous duplication mutation (c.1211_1217dupAGGAGAA) of the TTBK2 gene was identified in the proband using whole-exome sequencing (WES), which resulted in a frameshift mutation and formed a premature stop codon (p. N406Kfs*47). The mutation was detected in the proband's affected brother, and his unaffected mother, who with a lower percentage of the mutation and considered as an asymptomatic mutation carrier. Our study delineated the genotypic spectrum of SCA11.
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Background and Aims: Current knowledge on the temporal dynamics of the brain functional organization in amyotrophic lateral sclerosis (ALS) is limited. This is the first study on alterations in the patterns of dynamic functional connection density (dFCD) involving ALS. Methods: We obtained resting-state functional magnetic resonance imaging (fMRI) data from 50 individuals diagnosed with ALS and 55 healthy controls (HCs). We calculated the functional connectivity (FC) between a given voxel and all other voxels within the entire brain and yield the functional connection density (FCD) value per voxel. dFCD was assessed by sliding window correlation method. In addition, the standard deviation (SD) of dFCD across the windows was computed voxel-wisely to measure dFCD variability. The difference in dFCD variability between the two groups was compared using a two-sample t-test following a voxel-wise manner. The receiver operating characteristic (ROC) curve was used to assess the between-group recognition performance of the dFCD variability index. Results: The dFCD variability was significantly reduced in the bilateral precentral and postcentral gyrus compared with the HC group, whereas a marked increase was observed in the left middle frontal gyrus of ALS patients. dFCD variability exhibited moderate potential (areas under ROC curve = 0.753-0.837, all P < 0.001) in distinguishing two groups. Conclusion: ALS patients exhibit aberrant dynamic property in brain functional architecture. The dFCD evaluation improves our understanding of the pathological mechanisms underlying ALS and may assist in its diagnosis.
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TANK-binding kinase 1 (TBK1) has been identified as a causative gene of amyotrophic lateral sclerosis (ALS) in the Caucasian population in 2015. Here, we sequenced for TBK1 variants in a cohort of 15 familial ALS (fALS) and 275 sporadic ALS (sALS) of Chinese origin by targeted next-generation sequencing. We identified one likely benign missense variant (p. Ser398Pro), two missense variants of uncertain significance (p. Ile37Leu and p. Tyr677Asn), and two novel heterozygous variants in introns of TBK1, c.1522-3T > G and c.2066 + 4A > G. We performed splicing assays through minigene plasmids and RNA pull-down assay to determine that the two substitutions of nucleotides disrupted the binding of the important splicing regulator hnRNPA1 and promoted aberrant pre-mRNA splicing modes. The c.1522-3T > G variant promoted nearly 50.0% of abnormal transcripts (3 different types of insertions and deletions (indels) in junction of intron 13-exon 14) and the c.2066 + 4A > G variant inhibited about 75.0% inclusion of exon 19, both causing premature stop codon and producing TBK1 protein without CCD2. Immunofluorescence analysis showed that the expression of TBK1 with intronic variants was lower since less TBK1 distribution was observed in HEK293T cells. Both patients carrying TBK1 c.1522-3T > G and c.2066 + 4A > G variants developed a rapidly progressive ALS, with a survival of 31 and 10 months, respectively. The frequency of loss of function (LoF) variants in TBK1 was 0.73% in sALS in our cohort. We emphasize that intronic sequencing and pre-mRNA splicing analysis cannot be ignored to demonstrate the complex mutational spectrum and pathogenesis of ALS.
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Mutations in the valosin-containing protein (VCP) gene have been linked to amyotrophic lateral sclerosis (ALS) in the Caucasian populations. However, the phenotype of VCP mutations in Chinese patients with (ALS) remains unclear. Targeted next-generation sequencing covered 28 ALS-related genes including the VCP gene was undertaken to screen in a Chinese cohort of 275 sporadic ALS cases and 15 familial ALS pedigrees. An extensive literature review was performed to identify all patients with ALS carrying VCP mutations previously reported. The clinical characteristics and genetic features of ALS patients with VCP mutations were reviewed. One known p.R155C mutation in the VCP gene was detected in two siblings from a familial ALS pedigree and two sporadic individuals. In addition, the same VCP p.R155C mutation was detected in an additional patient with ALS referred in 2021. Three patients with VCP p.R155C mutation presented with muscular weakness starting from proximal extremities to distal extremities. The other patient developed a phenotype of Paget's disease of bone in addition to the progressive muscular atrophy. We reported the first VCP mutation carrier manifesting ALS with Paget's disease of bone in the Chinese population. Our findings expand the phenotypic spectrum of the VCP mutations in Chinese patients with ALS and suggest that ALS patients with VCP p.R155C mutations tend to present with relatively young onset, symmetrical involvement of proximal muscles weakness of arms or legs, and then progressed to distal muscles of limbs.
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BACKGROUND AND PURPOSE: Mutations in the FIG4 gene have been linked to amyotrophic lateral sclerosis (ALS) type 11 in Caucasian populations. The purpose of this study was to identify FIG4 variants in a cohort of 15 familial ALS (FALS) indexes and 275 sporadic ALS (SALS) patients of Han Chinese origin. METHODS: All 23 exons of FIG4 were sequenced using targeted next-generation sequencing. An extensive literature review was performed to detect genotype-phenotype associations of FIG4 mutations. RESULTS: No FIG4 variants were identified in the FALS patients. One novel heterozygous missense variant (c.352G>T [p.D118Y]) and one novel heterozygous nonsense variant (c.2158G>T [p.E720X]) in FIG4 were identified in two SALS patients. The p.E720X variant is interpreted as likely pathogenic while the p.D118Y variant is a variant of uncertain significance. The patient carrying the p.E720X mutation developed lower-limb-onset slowly progressive ALS, and survived for 11.5 years. The patient harboring the FIG4 p.D118Y variant also presented with progressive ALS, with the score on the ALS Functional Rating Scale-Revised (ALSFRS-R) decreasing by 0.4 per month. The rate of decrease in the ALSFRS-R scores from symptom onset to diagnosis seemed to be lower in the patients carrying FIG4 variants than the no-FIG4-mutation ALS patients in this study. CONCLUSIONS: Our findings suggest that ALS patients carrying FIG4 mutations are not common in the Chinese population and are more likely to exhibit slow progression.
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RATIONALE AND OBJECTIVES: To investigate the microperfusion and water molecule diffusion alterations in sensorimotor-related areas in amyotrophic lateral sclerosis (ALS) using intravoxel incoherent motion (IVIM) magnetic resonance imaging. MATERIALS AND METHODS: IVIM data were obtained from 43 ALS patients and 31 controls. This study employed the revised ALS Functional Rating Scale (ALSFRS-R) in evaluating disease severity. IVIM-derived metrics were calculated, including diffusion coefficient (D), pseudo-diffusion coefficient, and perfusion fraction. Conventional apparent diffusion coefficient was also computed. Atlas-based analysis was conducted to detect between-group difference in these metrics in sensorimotor-related gray/white matter areas. Spearman correlation analysis was employed to establish correlation between various metrics and ALSFRS-R. RESULTS: ALS patients had perfusion fraction (× 10-3) reduction in the left presupplementary motor area (60.72 ± 16.15 vs. 71.15 ± 12.98, p = 0.016), right presupplementary motor area (61.35 ± 17.02 vs. 72.18 ± 14.22, p = 0.016), left supplementary motor area (55.73 ± 12.29 vs. 64.12 ± 9.17, p = 0.015), and right supplementary motor area (56.53 ± 11.93 vs. 63.67 ± 10.03, p = 0.020). Patients showed D (× 10-6 mm2/s) increase in a white matter tract projecting to the right ventral premotor cortex (714.20 ± 39.75 vs. 691.01 ± 24.53, p = 0.034). A negative correlation between D of right ventral premotor cortex tract and ALSFRS-R score was observed (r = -0.316, p = 0.039). CONCLUSION: These findings suggest aberrant microperfusion and water molecule diffusion in the sensorimotor-related areas in ALS patients, which are associated with motor impairment in ALS.
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Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Humanos , Imageamento por Ressonância Magnética , Movimento (Física) , ÁguaRESUMO
Purpose: Static and dynamic analyses for identifying functional connectivity (FC) have demonstrated brain dysfunctions in amyotrophic lateral sclerosis (ALS). However, few studies on the stability of dynamic FC have been conducted among ALS patients. This study explored the change of functional stability in ALS and how it correlates with disease severity. Methods: We gathered resting-state functional magnetic resonance data from 20 patients with ALS and 22 healthy controls (HCs). The disease severity was assessed with the Revised ALS Functional Rating Scale (ALSFRS-R). We used a sliding window correlation approach to identify dynamic FC and measured the concordance of dynamic FC over time to obtain the functional stability of each voxel. We assessed the between-group difference in functional stability by voxel-wise two-sample t-test. The correlation between the functional stability index and ALSFRS-R in ALS patients was evaluated using Spearman's correlation analysis. Results: Compared with the HC group, the ALS group had significantly increased functional stability in the left pre-central and post-central gyrus and right temporal pole while decreased functional stability in the right middle and inferior frontal gyrus. The results revealed a significant correlation between ALSFRS-R and the mean functional stability in the right temporal pole (r = -0.452 and P = 0.046) in the ALS patients. Conclusions: ALS patients have abnormal stability of brain functional architecture, which is associated with the severity of the disease.
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BACKGROUND: White matter (WM) impairment is a hallmark of amyotrophic lateral sclerosis (ALS). This study evaluated the capacity of mean apparent propagator magnetic resonance imaging (MAP-MRI) for detecting ALS-related WM alterations. METHODS: Diffusion images were obtained from 52 ALS patients and 51 controls. MAP-derived indices [return-to-origin/-axis/-plane probability (RTOP/RTAP/RTPP) and non-Gaussianity (NG)/perpendicular/parallel NG (NGâ¥/NG||)] were computed. Measures from diffusion tensor/kurtosis imaging (DTI/DKI) and neurite orientation dispersion and density imaging (NODDI) were also obtained. Voxel-wise analysis (VBA) was performed to determine differences in these parameters. Relationship between MAP parameters and disease severity (assessed by the revised ALS Functional Rating Scale (ALSFRS-R)) was evaluated by Pearson's correlation analysis in a voxel-wise way. ALS patients were further divided into two subgroups: 29 with limb-only involvement and 23 with both bulbar and limb involvement. Subgroup analysis was then conducted to investigate diffusion parameter differences related to bulbar impairment. RESULTS: The VBA (with threshold of P < 0.05 after family-wise error correction (FWE)) showed that ALS patients had significantly decreased RTOP/RTAP/RTPP and NG/ NGâ¥/NG|| in a set of WM areas, including the bilateral precentral gyrus, corona radiata, posterior limb of internal capsule, midbrain, middle corpus callosum, anterior corpus callosum, parahippocampal gyrus, and medulla. MAP-MRI had the capacity to capture WM damage in ALS, which was higher than DTI and similar to DKI/NODDI. RTOP/RTAP/NG/NGâ¥/NG|| parameters, especially in the bilateral posterior limb of internal capsule and middle corpus callosum, were significantly correlated with ALSFRS-R (with threshold of FWE-corrected P < 0.05). The VBA (with FWE-corrected P < 0.05) revealed the significant RTAP reduction in subgroup with both bulbar and limb involvement, compared with those with limb-only involvement. CONCLUSIONS: Microstructural impairments in corticospinal tract and corpus callosum represent the consistent characteristic of ALS. MAP-MRI could provide alternative measures depicting ALS-related WM alterations, complementary to the common diffusion imaging methods.
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Esclerose Lateral Amiotrófica , Substância Branca , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Imagem de Tensor de Difusão , Humanos , Imageamento por Ressonância Magnética , Tratos Piramidais , Substância Branca/diagnóstico por imagemRESUMO
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that predominately involves the motor neurons in the brain and spinal cord. The TARDBP gene, encoding TAR DNA-binding protein 43 (TDP-43) protein, has been identified as a major causative gene in ALS. In this study, we screened 275 SALS patients and 20 unrelated FALS probands for TARDBP mutations. We identified three TARDBP mutations in three SALS patients and two TARDBP mutations in two FALS probands, including a previously unreported mutation, p.K176I, in FALS patients consistent with frontotemporal dementia (FTD) and parkinsonism. The p.K176I mutation is the first mutation outside exon 6 of the TARDBP gene manifesting parkinsonism and the first TARDBP mutation manifesting parkinsonism identified in the Chinese population. Our results support that TARDBP mutations are one of the most common changes in both FALS and SALS in China. Patients with TARDBP mutations may have a broad phenotype spectrum of ALS, FTD, and parkinsonism. The TARDBP gene should be included in genetic screening for ALS with FTD, and/or parkinsonism.
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Esclerose Lateral Amiotrófica/genética , Proteínas de Ligação a DNA/genética , Demência Frontotemporal/genética , Mutação de Sentido Incorreto/genética , Transtornos Parkinsonianos/genética , Adulto , Idoso , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/diagnóstico , Povo Asiático/genética , China , Feminino , Demência Frontotemporal/complicações , Demência Frontotemporal/diagnóstico , Estudos de Associação Genética , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/diagnósticoRESUMO
BACKGROUND: Aberrant static functional connectivity (FC) has been well demonstrated in amyotrophic lateral sclerosis (ALS); however, ALS-related alterations in FC dynamic properties remain unclear, although dynamic FC analyses contribute to uncover mechanisms underlying neurodegenerative disorders. PURPOSE: To explore dynamic functional network connectivity (dFNC) in ALS and its correlation with disease severity. STUDY TYPE: Prospective. SUBJECTS: Thirty-two ALS patients and 45 healthy controls. FIELD STRENGTH/SEQUENCE: Multiband resting-state functional images using gradient echo echo-planar imaging and T1-weighted images were acquired at 3.0 T. ASSESSMENT: Disease severity was evaluated with the revised ALS Functional Rating Scale (ALSFRS-R) and patients were stratified according to diagnostic category. Independent component analysis was conducted to identify the components of seven intrinsic brain networks (ie, visual/sensorimotor (SMN)/auditory/cognitive-control (CCN)/default-mode (DMN)/subcortical/cerebellar networks). A sliding-window correlation approach was used to compute dFNC. FNC states were determined by k-mean clustering, and state-specific FNC and dynamic indices (fraction time/mean dwell time/transition number) were calculated. STATISTICAL TESTS: Two-sample t test used for comparisons on dynamic measures and Spearman's correlation analysis. RESULTS: ALS patients showed increased FNC between DMN-SMN in state 1 and between CCN-SMN in state 4. Patients remained in state 2 (showing the weakest FNC) for a significantly longer time (mean dwell time: 49.8 ± 40.1 vs. 93.6 ± 126.3; P < 0.05) and remained in state 1 (showing a relatively strong FNC) for a shorter time (fraction time: 0.27 ± 0.25 vs. 0.13 ± 0.20; P < 0.05). ALS patients exhibited less temporal variability in their FNC (transition number: 10.2 ± 4.4 vs. 7.8 ± 3.8; P < 0.05). A significant correlation was observed between ALSFRS-R and mean dwell time in state 2 (r = -0.414, P < 0.05) and transition number (r = 0.452, P < 0.05). No significant between-subgroup difference in dFNC properties was found (all P > 0.05). DATA CONCLUSION: Our findings suggest aberrant dFNC properties in ALS, which is associated with disease severity. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.
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Esclerose Lateral Amiotrófica , Mapeamento Encefálico , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
FUS gene is one of the most common mutated genes in amyotrophic lateral sclerosis (ALS). We sequenced for FUS mutations in a cohort of 15 familial ALS and 275 sporadic ALS of Chinese origin. All 15 exons of the FUS gene were sequenced by targeted next-generation sequencing in a cohort of 15 familial ALS indexes and 275 sporadic ALS patients of Chinese origin. One novel p.Y526F mutation in FUS was detected in one familial ALS proband. Another novel FUS p.Q140R variant and two known FUS mutations (p.R495Efs*33 and p.R521C) were identified in four sporadic ALS cases. The frequency of FUS mutation in our cohort is 6.7% in familial ALS and 1.5% in sporadic ALS. The familial ALS proband carrying the FUS p.Y526F mutation presented with juvenile-onset lower limbs weakness and demonstrated an aggressive course, with respiratory muscles involvement 6 months after onset. The other patients in the family all had limbs weakness and died 1-2 years after disease onset. Our results strengthen that FUS mutations are the most frequent genetic causes of young-onset aggressive ALS. Genetic testing of the FUS gene should be performed in early-onset ALS patients especially those with a rapid progression.
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Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/genética , Éxons , Testes Genéticos , Humanos , Mutação/genética , Proteína FUS de Ligação a RNA/genéticaRESUMO
BACKGROUND: Hereditary diffuse leukoencephalopathy with spheroid (HDLS) is an autosomal dominant white matter disease characterized by adult-onset cognitive impairment, behavioral or emotional changes, paresis, Parkinsonism, and seizures. Mutations in the gene encoding colony-stimulating factor 1 receptor (CSF1R) have been identified as the cause of HDLS. METHODS: Detail medical history, clinical features and brain imaging of a patient with adult-onset leukoencephalopathy, cognitive impairment and motor dysfunction was reviewed and next generation sequencing was performed. An extensive literature research was then performed to identify all patients with HDLS previously reported. The clinical characteristics, brain imaging and genetic features of patients with HDLS were reviewed. RESULTS: A novel CSF1R mutation, c.1952G>A p.G651E was identified in the patient. Extensive review showed that HDLS typically presents with broad phenotypic variability. The most common symptoms of HDLS were cognitive impairment, followed by psychiatric symptoms, Parkinsonism, gait disorder, and dysphagia. The most common brain imaging findings of HDLS were bilateral white matter lesion, mostly around the ventricles, frontal lobe, and parietal lobe. Calcifications in white matter on CT, cerebral atrophy and thinning of corpus callosum were also common features. Although HDLS demonstrates an autosomal dominant pattern, sporadic cases are not uncommon. CONCLUSIONS: Early recognition of clinical and neuroradiographical characteristics of HDLS is key for the correct diagnosis of the disease.
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Esclerose Lateral Amiotrófica/genética , Perna (Membro)/fisiopatologia , Profilinas/genética , Esclerose Lateral Amiotrófica/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/genética , Debilidade Muscular/fisiopatologia , Mutação de Sentido Incorreto/genética , Linhagem , Sequenciamento do ExomaRESUMO
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which cerebral structural impairment is a consistent feature. PURPOSE: To investigate cerebral microstructural changes in ALS using diffusion kurtosis imaging (DKI) for the first time. STUDY TYPE: Prospective. SUBJECTS: Eighteen ALS patients and 20 healthy controls. FIELD STRENGTH/SEQUENCE: DKI images were obtained by a spin-echo echo-planar imaging sequence on a 3T MRI scanner, with three b-values (0, 1000, and 2000 s/mm2 ) and 64 diffusion encoding directions. ASSESSMENT: The revised ALS Functional Rating Scale (ALSFRS-R) was administered to assess disease severity, and the symptom duration and disease progression rate were also recorded. Voxel-based analysis was applied to examine the alteration of DKI metrics (ie, mean kurtosis metrics [MK], axial kurtosis [AK], and radial kurtosis [RK]) and the conventional diffusion metrics (ie, fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity). STATISTICAL TESTS: Student's t-test, chi-square test, and Pearson correlation analysis. RESULTS: ALS patients showed MK reductions in gray matter areas, including the bilateral precentral gyrus, bilateral paracentral lobule, and left anterior cingulate gyrus; they also showed decreased MK values in white matter (WM) in the bilateral precentral gyrus, bilateral corona radiata, bilateral middle corpus callosum, left occipital lobe, and right superior parietal lobule. The spatial distribution of the regions with reduced RK was similar to those with decreased MK. No significant AK difference was found between groups. The correlation analysis revealed significant associations between DKI metrics and clinical assessments such as ALSFRS-R score and disease duration. Additionally, several WM regions showed between-group differences in conventional diffusion metrics; but the spatial extent was smaller than that with reduced DKI metrics. DATA CONCLUSION: The reduction in DKI metrics indicates decreased microstructural complexity in ALS, involving both motor-related areas and extramotor regions. DKI metrics can serve as potential biomarkers for assessing disease severity. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:554-562.
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Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Substância Branca , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Imagem de Tensor de Difusão , Humanos , Estudos ProspectivosRESUMO
OBJECTIVE: Mutations in optineurin (OPTN) have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). We screened a cohort of Chinese patients for mutations in optineurin. We also performed an extensive literatures review of all mutations in optineurin identified previously to detect genotype-phenotype associations. METHODS: All 16 exons of the OPTN gene in a cohort of 15 familial ALS indexes and 275 sporadic ALS patients of Chinese origin were sequenced by targeted next generation sequencing. RESULTS: Two known heterozygous missense mutations in the OPTN, c.1481T> G (p.L494W), and c.1546G> C (p.E516Q), as well as one novel heterozygous missense mutation c.1690G> C (p.D564H) were each detected in one sporadic ALS patient. The patient carrying the p.E516Q mutation developed clinical features of ALS-frontotemporal dementia (FTD) and the patient carrying the p.D564H mutation showed a phenotype of ALS. They both had an aggressive course, with a survival of 18 and 14 months respectively. Literature review showed that the clinical phenotypes in OPTN mutated ALS were not homogeneous, although some individuals showed a relatively slow progression and a long duration, some mutations carriers developed an aggressive progression and a short survival. INTERPRETATION: OPTN mutations contribute to ALS in Chinese population and account for 0.8% of sporadic ALS patients and 1.5% of familial ALS in the pooled Chinese ALS cohorts. Mutations in optineurin can cause aggressive ALS+/-FTD.