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The kinetics of type I interferon (IFN) induction versus the virus replication compete, and the result of the competition determines the outcome of the infection. Chaperone proteins that involved in promoting the activation kinetics of PRRs rapidly trigger antiviral innate immunity. We have previously shown that prior to the interaction with MAVS to induce type I IFN, 14-3-3η facilitates the oligomerization and intracellular redistribution of activated MDA5. Here we report that the cleavage of 14-3-3η upon MDA5 activation, and we identified Caspase-3 activated by MDA5-dependent signaling was essential to produce sub-14-3-3η lacking the C-terminal helix (αI) and tail. The cleaved form of 14-3-3η (sub-14-3-3η) could strongly interact with MDA5 but could not support MDA5-dependent type I IFN induction, indicating the opposite functions between the full-length 14-3-3η and sub-14-3-3η. During human coronavirus or enterovirus infections, the accumulation of sub-14-3-3η was observed along with the activation of Caspase-3, suggesting that RNA viruses may antagonize 14-3-3η by promoting the formation of sub-14-3-3η to impair antiviral innate immunity. In conclusion, sub-14-3-3η, which could not promote MDA5 activation, may serve as a negative feedback to return to homeostasis to prevent excessive type I IFN production and unnecessary inflammation.
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Proteínas 14-3-3 , Caspase 3 , Helicase IFIH1 Induzida por Interferon , Proteínas 14-3-3/metabolismo , Humanos , Helicase IFIH1 Induzida por Interferon/metabolismo , Helicase IFIH1 Induzida por Interferon/genética , Caspase 3/metabolismo , Imunidade Inata , Células HEK293 , Animais , Transdução de Sinais , Interferon Tipo I/metabolismoRESUMO
INTRODUCTION: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of autosomal dominantly inherited Parkinson's disease (PD). Recently, a novel pathogenic variant (N1437D; c.4309A > G; NM_98578) in the LRRK2 gene has been identified in three Chinese families with PD. In this study, we describe a Chinese family with autosomal dominant PD that segregated with the N1437D mutation. A detailed clinical and neuroimaging characterization of the affected family members is reported. We also sought to investigate the functional mechanisms by which the detected mutation could cause PD. METHODS: We characterized the clinical and imaging phenotype of a Chinese pedigree with autosomal dominant PD. We searched for a disease-causing mutation by targeted sequencing and multiple ligation-dependent probe amplification. The functional impact of the mutation was investigated in terms of LRRK2 kinase activity, guanosine triphosphate (GTP) binding, and guanosine triphosphatase (GTPase) activity. RESULTS: The disease was found to co-segregate with the LRRK2 N1437D mutation. Patients in the pedigree exhibited typical parkinsonism (age at onset: 54.0 ± 5.9 years). One affected family member - who had evidence of abnormal tau accumulation in the occipital lobe on tau PET imaging - developed PD dementia at follow-up. The mutation markedly increased LRRK2 kinase activity and promoted GTP binding, without affecting GTPase activity. CONCLUSIONS: This study describes the functional impact of a recently identified LRRK2 mutation, N1437D, that causes autosomal dominant PD in the Chinese population. Further research is necessary to investigate the contribution of this mutation to PD in multiple Asian populations.
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Doença de Parkinson , Humanos , População do Leste Asiático , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Guanosina Trifosfato/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Mutação/genética , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/genética , Doença de Parkinson/patologiaRESUMO
While early-onset Parkinson's disease (EOPD) caused by mutations in the parkin gene (PRKN) tends to have a relatively benign course compared to genetically undetermined (GU)-EOPD, the exact underlying mechanisms remain elusive. We aimed to search for the differences between PRKN-EOPD and GU-EOPD by dopamine transporter (DAT) and glucose metabolism positron-emission-tomography (PET) imaging. Twelve patients with PRKN-EOPD and 16 with GU-EOPD who accepted both 11C-2b-carbomethoxy-3b-(4-trimethylstannylphenyl) tropane (11C-CFT) and 18F-fluorodeoxyglucose PET were enrolled. The 11C-CFT uptake was analyzed on both regional and voxel levels, whereas glucose metabolism was assessed in a voxel-wise fashion. Correlations between DAT and glucose metabolism imaging, DAT imaging and clinical severity, as well as glucose metabolism imaging and clinical severity were explored. Both clinical symptoms and DAT-binding patterns in the posterior putamen were highly symmetrical in patients with PRKN-EOPD, and dopaminergic dysfunction in the ipsilateral putamen was severer in patients with PRKN-EOPD than GU-EOPD. Meanwhile, the DAT binding was associated with the severity of motor dysfunction in patients with GU-EOPD only. Patients with PRKN-EOPD showed increased glucose metabolism in the contralateral medial frontal gyrus (supplementary motor area (SMA)), contralateral substantia nigra, contralateral thalamus, and contralateral cerebellum. Notably, glucose metabolic activity in the contralateral medial frontal gyrus was inversely associated with regional DAT binding in the bilateral putamen. Patients with PRKN-EOPD showed enhanced metabolic connectivity within the bilateral putamen, ipsilateral paracentral and precentral lobules, and the ipsilateral SMA. Collectively, compared to GU-EOPD, PRKN-EOPD is characterized by symmetrical, more severe dopaminergic dysfunction and relative increased glucose metabolism. Meanwhile, SMA with elevated glucose metabolism and enhanced connectivity may act as compensatory mechanisms in PRKN-EOPD. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00077-8.
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BACKGROUND: Recent development in tau-sensitive tracers has sparkled significant interest in tracking tauopathies using positron emission tomography (PET) biomarkers. However, the ability of 18 F-florzolotau PET imaging to topographically characterize tau pathology in corticobasal syndrome (CBS) remains unclear. Further, the question as to whether disease-level differences exist with other neurodegenerative tauopathies is still unanswered. OBJECTIVE: To analyze the topographical patterns of tau pathology in the living brains of patients with CBS using 18 F-florzolotau PET imaging and to examine whether differences with other tauopathies exist. METHODS: 18 F-florzolotau PET imaging was performed in 20 consecutive patients with CBS, 20 cognitively healthy controls (HCs), 20 patients with Alzheimer's disease (AD), and 16 patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). Cerebrospinal fluid (CSF) levels of ß-amyloid biomarkers were quantified in all patients with CBS. 18 F-florzolotau uptake was quantitatively assessed using standardized uptake value ratios. RESULTS: Of the 20 patients with CBS, 19 (95%) were negative for CSF biomarkers of amyloid pathology; of them, three had negative 18 F-florzolotau PET findings. Compared with HCs, patients with CBS showed increased 18 F-florzolotau signals in both cortical and subcortical regions. In addition, patients with CBS were characterized by higher tracer retentions in subcortical regions compared with those with AD and showed a trend toward higher signals in cortical areas compared with PSP-RS. An asymmetric pattern of 18 F-florzolotau uptake was associated with an asymmetry of motor severity in patients with CBS. CONCLUSIONS: In vivo 18 F-florzolotau PET imaging holds promise for distinguishing CBS in the spectrum of neurodegenerative tauopathies. © 2023 International Parkinson and Movement Disorder Society.
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Degeneração Corticobasal , Tomografia por Emissão de Pósitrons , Tauopatias , Humanos , Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Degeneração Corticobasal/diagnóstico por imagem , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons/métodos , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologia , Proteínas tau/metabolismo , Tauopatias/diagnóstico por imagemAssuntos
Selegilina , Paralisia Supranuclear Progressiva , Humanos , Selegilina/farmacologia , Selegilina/uso terapêutico , Paralisia Supranuclear Progressiva/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Proteínas tau , Monoaminoxidase , Tomografia por Emissão de PósitronsRESUMO
PURPOSE: Human post mortem studies have described the topographical patterns of tau pathology in progressive supranuclear palsy (PSP). Recent advances in tau PET tracers are expected to herald the next era of PSP investigation for early detection of tau pathology in living brains. This study aimed to investigate whether 18F-Florzolotau PET imaging may capture the distribution patterns and regional vulnerability of tau pathology in PSP, and to devise a novel image-based staging system. METHODS: The study cohort consisted of 148 consecutive patients with PSP who had undergone 18F-Florzolotau PET imaging. The PSP rating scale (PSPrs) was used to measure disease severity. Similarities and differences of tau deposition among different clinical phenotypes were examined at the regional and voxel levels. An 18F-Florzolotau pathological staging system was devised according to the scheme originally developed for post mortem data. In light of conditional probabilities for the sequence of events, an 18F-Florzolotau modified staging system by integrating clusters at the regional level was further developed. The ability of 18F-Florzolotau staging systems to reflect disease severity in terms of PSPrs score was assessed by analysis of variance. RESULTS: The distribution patterns of 18F-Florzolotau accumulation in living brains of PSP showed a remarkable similarity to those reported in post mortem studies, with the binding intensity being markedly higher in Richardson's syndrome. Moreover, 18F-Florzolotau PET imaging allowed detecting regional vulnerability and tracking tau accumulation in an earlier fashion compared with post mortem immunostaining. The 18F-Florzolotau staging systems were positively correlated with clinical severity as reflected by PSPrs scores. CONCLUSIONS: 18F-Florzolotau PET imaging can effectively capture the distribution patterns and regional vulnerability of tau pathology in PSP. The 18F-Florzolotau modified staging system holds promise for early tracking of tau deposition in living brains.
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Paralisia Supranuclear Progressiva , Humanos , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Proteínas tau/metabolismoRESUMO
Background: Reduced dopamine transporter (DAT) binding in the striatum has been reported in patients with progressive supranuclear palsy (PSP). However, the relationship between striatal dopaminergic lesions and the disease severity of PSP remains to be explored. Objective: To investigate the contributions of striatal dopaminergic lesions to the disease severity of PSP. Methods: One hundred patients with clinically diagnosed PSP were consecutively enrolled in this study. The disease severity was systemically assessed using the PSP rating scale (PSPrs), and the dopaminergic lesions were assessed using the 11C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane positron emission tomography (11C-CFT PET) imaging. To explore the correlations between striatal DAT bindings and the disease severity, both the region-wise and voxel-wise analysis were adopted. Partial correlations and multiple linear regressions were performed to investigate the contribution of striatal dopaminergic lesions to the disease severity in PSP. Results: Sixty-three patients of PSP with Richardson's syndrome (PSP-RS) and 37 patients with PSP-non-RS were finally included. The disease severity in PSP-RS was much heavier than that in the PSP-non-RS. The DAT bindings in the caudate and anterior putamen correlated significantly with the PSPrs total scores, mainly in the domains of history, mentation, bulbar, and ocular motor symptoms. The striatal DAT bindings (caudate) contributed significantly to the disease severity of PSP, independent of the motor, cognition, emotion and behavioral dysfunctions. Conclusion: Our study highlighted the independent contribution of striatal dopaminergic lesions to the disease severity in PSP.
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BACKGROUND: Anecdotal evidence suggests that patients diagnosed with the parkinsonian subtype of multiple system atrophy (MSA-P) may show uptake of the second-generation tau positron emission tomography (PET) tracer 18 F-Florzolotau (previously known as 18 F-APN-1607) in the putamen. OBJECTIVES: This study systematically investigated the localization and magnitude of 18 F-Florzolotau uptake in a relatively large cohort of patients with MSA-P. METHODS: 18 F-Florzolotau PET imaging was performed in 31 patients with MSA-P, 24 patients with Parkinson's disease (PD), and 20 age-matched healthy controls. 18 F-Florzolotau signal in the striatum was analyzed by visual inspection and classified as either positive or negative. Regional 18 F-Florzolotau binding was also expressed as standardized uptake value ratio (SUVR) to assess whether it was associated with core symptoms of MSA-P after adjustment for potential confounders. RESULTS: By visual inspection and semiquantitative SUVR comparisons, patients with MSA-P showed elevated 18 F-Florzolotau uptake in the putamen, globus pallidus, and dentate-a finding that was not observed in PD. This increased signal was significantly associated with the core symptoms of MSA-P. In addition, patients with MSA-P with cerebellar ataxia showed an elevated 18 F-Florzolotau uptake in the cerebellar dentate. CONCLUSIONS: 18 F-Florzolotau tau PET imaging findings may reflect the clinical severity of MSA-P and can potentially discriminate between this condition and PD. © 2022 International Parkinson and Movement Disorder Society.
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Atrofia de Múltiplos Sistemas , Doença de Parkinson , Fluordesoxiglucose F18/metabolismo , Humanos , Atrofia de Múltiplos Sistemas/diagnóstico , Doença de Parkinson/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Putamen/metabolismo , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Previous studies with a limited sample size suggested more severe dopaminergic transporter (DAT) lesions in the striatum of progressive supranuclear palsy (PSP) than those in Parkinson's disease (PD) and multiple system atrophy-parkinsonism (MSA-P). However, few studies had taken various subtypes of PSP into consideration, making the reanalysis of DAT imaging in larger PSP cohort with various subtypes in need. OBJECTIVES: To compare the dopaminergic lesion patterns of PSP with MSA-P and PD, and to explore the specific striatal subregional patterns of different PSP subtypes. METHODS: 11 C-CFT positron emission tomography (PET) imaging was conducted in 83 PSP patients consisting of different subtypes, 61 patients with PD, 41 patients with MSA-P, and 43 healthy volunteers. Demographic and clinical data were compared by the chi-squared test or one-way analysis of variance. A generalized linear model was used to examine intergroup differences in tracer uptake values after adjusting for age, disease duration, and disease severity. Areas under the receiver operating characteristic curve were calculated to assess the diagnostic accuracy of subregional DAT binding patterns. RESULTS: The patients with PSP presented more severe DAT loss in the striatum than in PD and MSA-P, especially in caudate. In PSP, the subregional lesion was still more severe in putamen than in caudate, similar to that in PD and MSA-P. Among detailed subtypes, no significant difference was detected. CONCLUSION: The dopaminergic lesions were more severe in PSP, and no difference was detected among subtypes.
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Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Atrofia de Múltiplos Sistemas/metabolismo , Doença de Parkinson/patologia , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologia , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
BACKGROUND: Frontotemporal lobar degeneration with tauopathy caused by MAPT (microtubule-associated protein tau) mutations is a highly heterogenous disorder. The ability to visualize and longitudinally monitor tau deposits may be beneficial to understand disease pathophysiology and predict clinical trajectories. OBJECTIVE: The aim of this study was to investigate the cross-sectional and longitudinal 18 F-APN-1607 positron emission tomography/computed tomography (PET/CT) imaging findings in MAPT mutation carriers. METHODS: Seven carriers of MAPT mutations (six within exon 10 and one outside of exon 10) and 15 healthy control subjects were included. All participants underwent 18 F-APN-1607 PET/CT at baseline. Three carriers of exon 10 mutations received follow-up 18 F-APN-1607 PET/CT scans. Standardized uptake value ratio (SUVR) maps were obtained using the cerebellar gray matter as the reference region. SUVR values observed in MAPT mutation carriers were normalized to data from healthy control subjects. A regional SUVR z score ≥ 2 was used as the criterion to define positive 18 F-APN-1607 PET/CT findings. RESULTS: Although the seven study patients had heterogenous clinical phenotypes, all showed a significant 18 F-APN-1607 uptake characterized by high-contrast signals. However, the anatomical localization of tau deposits differed in patients with distinct clinical symptoms. Follow-up imaging data, which were available for three patients, demonstrated worsening trends in patterns of tau accumulation over time, which were paralleled by a significant clinical deterioration. CONCLUSIONS: Our data represent a promising step in understanding the usefulness of 18 F-APN-1607 PET/CT imaging for detecting tau accumulation in MAPT mutation carriers. Our preliminary follow-up data also suggest the potential value of 18 F-APN-1607 PET/CT for monitoring the longitudinal trajectories of frontotemporal lobar degeneration caused by MAPT mutations. © 2021 International Parkinson and Movement Disorder Society.
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Doença de Alzheimer , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Estudos Transversais , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Humanos , Mutação/genética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
A biological research framework to define Alzheimer' disease with dichotomized biomarker measurement was proposed by National Institute on Aging-Alzheimer's Association (NIA-AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal ß-amyloid in neocortical regions but prompt cognitive decline by interacting with ß-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer's disease could be illustrated with biomarker measurement under NIA-AA framework. Clinical-neuroimaging-neuropathological studies in other cohorts are needed to validate these findings.
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Doença de Alzheimer , Disfunção Cognitiva , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides , Biomarcadores , Feminino , Humanos , Estudos Longitudinais , Masculino , Tomografia por Emissão de Pósitrons , Proteínas tauRESUMO
Picornaviruses are a diverse and major cause of human disease, and their genomes replicate with intracellular membranes. The functionality of these replication organelles depends on the activities of both viral nonstructural proteins and co-opted host proteins. The mechanism by which viral-host interactions generate viral replication organelles and regulate viral RNA synthesis is unclear. To elucidate this mechanism, enterovirus A71 (EV-A71) was used here as a virus model to investigate how these replication organelles are formed and to identify the cellular components that are critical in this process. An immunoprecipitation assay was combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to identify 172 cellular proteins and four viral proteins associating with viral 3A protein. Secretory carrier membrane protein 3 (SCAMP3) was one of the host proteins we selected for further investigation. Here, we demonstrate by immunoprecipitation assay that SCAMP3 associates with 3A protein and colocalizes with 3A protein during virus infection. SCAMP3 knockdown or knockout in infected cells decreases synthesis of EV-A71 viral RNA, viral proteins, and viral growth. Furthermore, the viral 3A protein associates with SCAMP3 and phosphatidylinositol-4-kinase type III ß (PI4KIIIß) as shown by immunoprecipitation assay and colocalizes to the replication complex. Upon infection of cells with a SCAMP3 knockout construct, PI4KIIIß and phosphatidylinositol-4-phosphate (PI4P) colocalization with EV-A71 3A protein decreases; viral RNA synthesis also decreases. SCAMP3 is also involved in the extracellular signal-regulated kinase (ERK) signaling pathway to regulate viral replication. The 3A and SCAMP3 interaction is also important for the replication of coxsackievirus B3 (CVB3). SCAMP3 also associates with 3A protein of CVB3 and enhances viral replication but does not regulate dengue virus 2 (DENV2) replication. Taken together, the results suggest that enterovirus 3A protein, SCAMP3, PI4KIIIß, and PI4P form a replication complex and positively regulate enterovirus replication. IMPORTANCE Virus-host interaction plays an important role in viral replication. 3A protein of enterovirus A71 (EV-A71) recruits other viral and host factors to form a replication complex, which is important for viral replication. In this investigation, we utilized immunoprecipitation combined with proteomics approaches to identify 3A-interacting factors. Our results demonstrate that secretory carrier membrane protein 3 (SCAMP3) is a novel host factor that associates with enterovirus 3A protein, phosphatidylinositol-4-kinase type III ß (PI4KIIIß), and phosphatidylinositol-4-phosphate (PI4P) to form a replication complex and positively regulates viral replication. SCAMP3 is also involved in the extracellular signal-regulated kinase (ERK) signaling pathway to regulate viral replication.
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Proteínas de Transporte/metabolismo , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/metabolismo , Proteínas de Membrana/metabolismo , Proteínas não Estruturais Virais/metabolismo , Replicação Viral , Proteínas de Transporte/genética , Enterovirus Humano A/genética , Infecções por Enterovirus/genética , Infecções por Enterovirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Proteínas de Membrana/genética , Ligação Proteica , Proteínas não Estruturais Virais/genéticaRESUMO
Enterovirus A71 (EV-A71) and many members of the Picornaviridae family are neurotropic pathogens of global concern. These viruses are primarily transmitted through the fecal-oral route, and thus suitable animal models of oral infection are needed to investigate viral pathogenesis. An animal model of oral infection was developed using transgenic mice expressing human SCARB2 (hSCARB2 Tg), murine-adapted EV-A71/MP4 virus, and EV-A71/MP4 virus with an engineered nanoluciferase gene that allows imaging of viral replication and spread in infected mice. Next-generation sequencing of EV-A71 genomes in the tissues and organs of infected mice was also performed. Oral inoculation of EV-A71/MP4 or nanoluciferase-carrying MP4 virus stably induced neurological symptoms and death in infected 21-day-old weaned mice. In vivo bioluminescence imaging of infected mice and tissue immunostaining of viral antigens indicated that orally inoculated virus can spread to the central nervous system (CNS) and other tissues. Next-generating sequencing further identified diverse mutations in viral genomes that can potentially contribute to viral pathogenesis. This study presents an EV-A71 oral infection murine model that efficiently infects weaned mice and allows tracking of viral spread, features that can facilitate research into viral pathogenesis and neuroinvasion via the natural route of infection. IMPORTANCE Enterovirus A71 (EV-A71), a positive-strand RNA virus of the Picornaviridae, poses a persistent global public health problem. EV-A71 is primarily transmitted through the fecal-oral route, and thus suitable animal models of oral infection are needed to investigate viral pathogenesis. We present an animal model of EV-A71 infection that enables the natural route of oral infection in weaned and nonimmunocompromised 21-day-old hSCARB2 transgenic mice. Our results demonstrate that severe disease and death could be stably induced, and viral invasion of the CNS could be replicated in this model, similar to severe real-world EV-A71 infections. We also developed a nanoluciferase-containing EV-A71 virus that can be used with this animal model to track viral spread after oral infection in real time. Such a model offers several advantages over existing animal models and can facilitate future research into viral spread, tissue tropism, and viral pathogenesis, all pressing issues that remain unaddressed for EV-A71 infections.
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Sistema Nervoso Central/virologia , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/complicações , Proteínas de Membrana Lisossomal/genética , Boca/virologia , Doenças do Sistema Nervoso/virologia , Receptores Depuradores/genética , Animais , Modelos Animais de Doenças , Enterovirus Humano A/genética , Infecções por Enterovirus/patologia , Infecções por Enterovirus/virologia , Genoma Viral , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Tropismo Viral , Replicação Viral , DesmameRESUMO
BACKGROUND: 18 F-APN-1607 is a novel tau PET tracer characterized by high binding affinity for 3- and 4-repeat tau deposits. Whether 18 F-APN-1607 PET imaging is clinically useful in PSP remains unclear. OBJECTIVES: The objective of this study was to investigate the clinical utility of 18 F-APN-1607 PET in the diagnosis, differential diagnosis, and assessment of disease severity in patients with PSP. METHODS: We enrolled 3 groups consisting of patients with PSP (n = 20), patients with α-synucleinopathies (MSA with predominant parkinsonism, n = 7; PD, n = 10), and age- and sex-matched healthy controls (n = 13). The binding patterns of 18 F-APN-1607 in PET/CT imaging were investigated. Regional standardized uptake ratios were compared across groups and examined in relation to their utility in the differential diagnosis of PSP versus α-synucleinopathies. Finally, the relationships between clinical severity scores and 18 F-APN-1607 uptake were investigated after adjustment for age, sex, and disease duration. RESULTS: Compared with healthy controls, patients with PSP showed increased 18 F-APN-1607 binding in several subcortical regions, including the striatum, putamen, globus pallidus, thalamus, subthalamic nucleus, midbrain, tegmentum, substantia nigra, pontine base, red nucleus, raphe nuclei, and locus coeruleus. We identified specific regions that were capable of distinguishing PSP from α-synucleinopathies. The severity of PSP was positively correlated with the amount of 18 F-APN-1607 uptake in the subthalamic nucleus, midbrain, substantia nigra, red nucleus, pontine base, and raphe nuclei. CONCLUSIONS: 18 F-APN-1607 PET imaging holds promise for the diagnosis, differential diagnosis, and assessment of disease severity in patients with PSP. © 2021 International Parkinson and Movement Disorder Society.
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Núcleo Subtalâmico , Paralisia Supranuclear Progressiva , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Putamen , Paralisia Supranuclear Progressiva/diagnóstico por imagemRESUMO
Objective: We aimed to characterize the cognitive profiles in multiple system atrophy (MSA) and explore the cerebral metabolism related to the cognitive decline in MSA using 18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET). Methods: In this study, 105 MSA patients were included for cognitive assessment and 84 of them were enrolled for 18F-FDG PET analysis. The comprehensive neuropsychological tests covered five main domains including execution, attention, memory, language, and visuospatial function. The cognitive statuses were classified to MSA with normal cognition (MSA-NC) and MSA with cognitive impairment (MSA-CI), including dementia (MSA-D), and mild cognitive impairment (MSA-MCI). With 18F-FDG PET imaging, the cerebral metabolism differences among different cognitive statuses were analyzed using statistical parametric mapping and post-hoc analysis. Results: Among 84 MSA patients, 52 patients were found with MSA-CI, including 36 patients as MSA-MCI and 16 patients as MSA-D. In detail, the cognitive impairments were observed in all the five domains, primarily in attention, executive function and memory. In 18F-FDG PET imaging, MSA-D and MSA-MCI patients exhibited hypometabolism in left middle and superior frontal lobe compared with MSA-NC (p < 0.001). The normalized regional cerebral metabolic rate of glucose (rCMRglc) in left middle frontal lobe showed relative accuracy in discriminating MSA-CI and MSA-NC [areas under the curve (AUC) = 0.750; 95%CI = 0.6391-0.8609]. Conclusions: Cognitive impairments were not rare in MSA, and the hypometabolism in frontal lobe may contribute to such impairments.
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ABSTRACT: A correct clinical diagnosis of motor dysfunction accompanied by cognitive impairment remains challenging. Recent advances in molecular imaging biomarkers hold promise to overcome this issue. A 37-year-old woman presenting with parkinsonism and cognitive impairment underwent both multimodal neuroimaging and genetic testing. Her main findings on PET included diffuse tau accumulation in the cerebral cortex and left putamen, increased cerebellar amyloid deposits, asymmetrically reduced dopamine transporter binding, and mild hypermetabolism in the putamen. Genetic analysis revealed the presence of a presenilin-1 mutation (C.1157T>G). These findings suggested a diagnosis of early-onset autosomal dominant Alzheimer disease accompanied by parkinsonism.
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Doença de Alzheimer , Disfunção Cognitiva , Transtornos Parkinsonianos , Adulto , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Feminino , Humanos , Imageamento por Ressonância Magnética , Imagem Multimodal , Mutação , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/genética , Tomografia por Emissão de Pósitrons , Presenilina-1/genéticaRESUMO
BACKGROUND: The recent developed PET ligands for amyloid-ß (Aß) and tau allow these two neuropathological hallmarks of Alzheimer's disease (AD) to be mapped and quantified in vivo and to be examined in relation to cognition. OBJECTIVE: To assess the associations among Aß, tau, and cognition in non-demented subjects. METHODS: Three hundred eighty-nine elderly participants without dementia from the Alzheimer's Disease Neuroimaging Initiative underwent tau and amyloid PET scans. Cross-sectional comparisons and longitudinal analyses were used to evaluate the relationship between Aß and tau accumulation. The correlations between biomarkers of both pathologies and performance in memory and executive function were measured. RESULTS: Increased amyloid-PET retention was associated with greater tau-PET retention in widespread cortices. We observed a significant tau increase in the temporal composite regions of interest over 24 months in Aß+ but not Aß- subjects. Finally, tau-PET retention but not amyloid-PET retention significantly explained the variance in memory and executive function. Higher level of tau was associated with greater longitudinal memory decline. CONCLUSION: These findings suggested PET-detectable Aß plaque pathology may be a necessary antecedent for tau-PET signal elevation. Greater tau-PET retention may demonstrate poorer cognition and predict prospective memory decline in non-demented subjects.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cognição , Disfunção Cognitiva/metabolismo , Estudos Transversais , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Placa AmiloideRESUMO
BACKGROUND: Objective motor ratings and subjective motor complaints are both widely used in Parkinson's disease (PD). However, the objective basis to the self-perceived mobility quality is still not well elucidated. PURPOSES: We aimed to figure out the relevancy between the UPDRS motor scores and PDQ39 mobility sub-scores, and further explore whether physician-assessed motor dysfunctions and patients-reported mobility deficits have some shared mechanisms. METHODS: 49 patients with PD who completed the PDQ39 scale were retrospectively included. The relevancy between mobility quality and UPDRS scores was assessed, as well as the related presynaptic dopaminergic binding (11C-CFT) and glucose metabolism (18F-FDG) in this dual-tracer PET imaging study. RESULTS: Modest correlation was found between UPDRS motor score and the PDQ39 mobility sub-score (r = 0.440, p = 0.002). No correlation was found between PDQ39 mobility SI and the dopaminergic lesions in putamen; however, the strict correlation was found with the UPDRS motor scores. In terms of global PD related pattern (PDRP) scores, the two motor scores both correlated strictly. In the further regional metabolism exploration, cerebellum correlated positively with PDQ39 mobility sub-scores, and the frontal and parietal regions mainly correlated negatively with the motor quality scores. CONCLUSION: UPDRS motor scores and PDQ39 mobility scores were only modestly correlated. The mechanisms involved under mobility quality were beyond dopaminergic deficiency, including motor related cerebellum hyper-metabolism and non-motor related frontal hypo-metabolism. Conclusively, the self-reported mobility experience may have the neurophysiological basis related to both motor and non-motor manifestations in PD.
RESUMO
In December 2019, an outbreak of coronavirus infection emerged in Wuhan, Hubei Province of China, which is now named Coronavirus Disease 2019 (COVID-19). The outbreak spread rapidly within mainland China and globally. This paper reviews the different imaging modalities used in the diagnosis and treatment process of COVID-19, such as chest radiography, computerized tomography (CT) scan, ultrasound examination, and positron emission tomography (PET/CT) scan. A chest radiograph is not recommended as a first-line imaging modality for COVID-19 infection due to its lack of sensitivity, especially in the early stages of infection. Chest CT imaging is reported to be a more reliable, rapid, and practical method for diagnosis of COVID-19, and it can assess the severity of the disease and follow up the disease time course. Ultrasound, on the other hand, is portable and involves no radiation, and thus can be used in critically ill patients to assess cardiorespiratory function, guide mechanical ventilation, and identify the presence of deep venous thrombosis and secondary pulmonary thromboembolism. Supplementary information can be provided by PET/CT. In the absence of vaccines and treatments for COVID-19, prompt diagnosis and appropriate treatment are essential. Therefore, it is important to exploit the advantages of different imaging modalities in the fight against COVID-19.