Isolated Craniocervical Dystonia Without Initial Neuropsychiatric Manifestations Associated with NMDA-Receptor Antibodies.
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ABSTRACT:
SUBMITTER: Waller SE
PROVIDER: S-EPMC10105100 | biostudies-literature | 2023 Apr
REPOSITORIES: biostudies-literature
Publications
Isolated Craniocervical Dystonia Without Initial Neuropsychiatric Manifestations Associated with NMDA-Receptor Antibodies.
Waller Sophie E SE Williams Laura L Lee Adrian Y S AYS Lin Ming-Wei MW McCusker Elizabeth E Morales-Briceño Hugo H Fung Victor S C VSC
Movement disorders clinical practice 20220809 4
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Project description:ObjectiveTo evaluate the relationship between health-related quality of life (HR-QoL) and both physical and psychiatric factors in a large, international, multicentre cohort of patients with isolated dystonia, the Dystonia Coalition.MethodsNatural history data from 603 patients with isolated dystonia (median age 57 years (IQR: 48 to 64 years), 67.0% women) were prospectively acquired and analysed. HR-QoL (RAND 36-Item Health Survey), severity of depressive symptoms, generalised anxiety (Hospital Anxiety and Depression Scale) and social anxiety (Liebowitz Social Anxiety Scale) were assessed. Dystonia severity (Burke-Fahn-Marsden Dystonia Rating Scale) and dystonic tremor were examined. Statistical predictors of HR-QoL were calculated using saturated path analysis.ResultsReduced HR-QoL was strongly associated with the degree of depressive symptoms and generalised and social anxiety (8/8 RAND 36 subscales, p≤0.001). Increased dystonia severity was associated with worse physical functioning, physical and emotional role functioning and social functioning (all p≤0.001). The presence of tremor correlated with worse physical functioning and pain (all p≤0.006). Younger age was associated with reduced emotional well-being and vitality (all p≤0.006). There were no HR-QoL differences between sexes.ConclusionHR-QoL in isolated dystonia is strongly associated with psychiatric and physical features. While current standard of care focus on motor aspects of dystonia, comprehensive care should address both physical and mental aspects of health.
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Project description:This study was conducted to explore hippocampal structural changes and their possible associations with clinical characteristics, emotional status, and treatment regimens in patients with systemic lupus erythematosus (SLE) without major neuropsychiatric manifestations (non-NPSLE). Eighty-five non-NPSLE patients with normal conventional magnetic resonance imaging (MRI) and seventy-seven matched healthy control (HC) subjects were recruited. All participants underwent the standard high-resolution volumetric MRI. The bilateral hippocampal volume (HIPV) and hippocampal density (HIPD) were calculated, respectively, for each participant. We found that the bilateral HIPV and HIPD of the SLE patient group were significantly less than those of the HC group. The bilateral HIPV of female patients were significantly less than those of male patients. The SLE disease activity index (SLEDAI) was negatively correlated with the bilateral HIPV and the right HIPD. Urine protein quantity was negatively correlated with the bilateral HIPV and HIPD. Hydroxychloroquine (HCQ) showed a protective effect on right HIPV. In conclusion, we found that the early hippocampal atrophy could occur before obvious neuropsychiatric manifestations and might be associated with SLE disease activity and organ damages. Early detection and intervention of hippocampal damage might prevent the progression to NPSLE. More studies are needed to fully understand the underlying mechanisms of hippocampal atrophy in SLE.
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Project description:ImportanceMutations in the GNAL gene have recently been shown to cause primary torsion dystonia. The GNAL-encoded protein (Gαolf) is important for dopamine D1 receptor function and odorant signal transduction. We sequenced all 12 exons of GNAL in 461 patients from Germany, Serbia, and Japan, including 318 patients with dystonia (190 with cervical dystonia), 51 with hyposmia and Parkinson disease, and 92 with tardive dyskinesia or acute dystonic reactions.ObservationsWe identified the following two novel heterozygous putative mutations in GNAL: p.Gly213Ser in a German patient and p.Ala353Thr in a Japanese patient. These variants were predicted to be pathogenic in silico, were absent in ethnically matched control individuals, and impaired Gαolf coupling to D1 receptors in a bioluminescence energy transfer (BRET) assay. Two additional variants appeared to be benign because they behaved like wild-type samples in the BRET assay (p.Ala311Thr) or were detected in ethnically matched controls (p.Thr92Ala). Both patients with likely pathogenic mutations had craniocervical dystonia with onset in the fifth decade of life. No pathogenic mutations were detected in the patients with hyposmia and Parkinson disease, tardive dyskinesias, or acute dystonic reactions.Conclusions and relevanceMutations in GNAL can cause craniocervical dystonia in different ethnicities. The BRET assay may be a useful tool to support the pathogenicity of identified variants in the GNAL gene.
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Project description:Scrub typhus is caused by Orientia tsutsugamushi characterized by focal or disseminated vasculitis and perivasculitis which may involve the lungs, heart, liver, spleen and central nervous system. It was thought to have been eradicated from India. Recently it is being reported from many areas of India. The clinical picture and severity of the symptoms varies widely. The neurological manifestations of scrub typhus are not uncommon but are diverse. Meningoencephalitis is classical manifestation of scrub typhus but cerebellitis, cranial nerve palsies, plexopathy, transverse myelitis, neuroleptic malignant syndrome and Guillan-Barré syndrome are other manifestations reported in literature. The availability of literature on the neurological manifestations of scrub typhus is limited to case reports mainly. This article reviews various neurological manifestations of scrub typhus reported in literature.
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Project description:Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the main causes of death in patients with systemic lupus erythematosus (SLE). Signs and symptoms of NPSLE are heterogeneous, and it is hard to diagnose, and treat NPSLE patients in the early stage. We conducted this study to explore the possible brain activity changes using resting state functional magnetic resonance imaging (rs-fMRI) in SLE patients without major neuropsychiatric manifestations (non-NPSLE patients). We also tried to investigate the possible associations among brain activity, disease activity, depression, and anxiety. In our study, 118 non-NPSLE patients and 81 healthy controls (HC) were recruited. Rs-fMRI data were used to calculate the regional homogeneity (ReHo) in all participants. We found decreased ReHo values in the fusiform gyrus and thalamus and increased ReHo values in the parahippocampal gyrus and uncus. The disease activity was positively correlated with ReHo values of the cerebellum and negatively correlated with values in the frontal gyrus. Several brain areas showed correlations with depressive and anxiety statuses. These results suggested that abnormal brain activities might occur before NPSLE and might be the foundation of anxiety and depression symptoms. Early detection and proper treatment of brain dysfunction might prevent the progression to NPSLE. More studies are needed to understand the complicated underlying mechanisms.
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Project description:Depressive and anxiety disorders are frequently observed in patients with Systemic Lupus Erythematosus (SLE). However, the underlying mechanisms are still unknown. We conducted this survey to understand the prevalence of depression and anxiety in SLE patients without major neuropsychiatric manifestations (non-NPSLE) and to explore the relationship between emotional disorders, symptoms, autoantibodies, disease activity, and treatments in SLE. 176 SLE patients were included, and SLE disease activity index (SLEDAI), Hamilton Depression Rating Scale (HAMD), and Hamilton Anxiety Rating Scale (HAMA) were recorded to evaluate their disease activity and emotional status. We found that depressive and anxiety disorders were common among SLE patients: 121 (68.8%) patients were in depression status while 14 (8.0%) patients could be diagnosed with depression. Accordingly, 101 (57.4%) were in anxiety status and 21 (11.9%) could be diagnosed with anxiety. Depression was associated with disease activity, and anxiety was associated with anti-P0 antibody, while both of them were associated with proteinuria. HAMA and HAMD scores were in strong positive correlation and they were independent risk factors of each other. We concluded that the high prevalence of depression and anxiety and the association between depression and SLE disease activity might reveal the covert damage of central nervous system in SLE. The role of anti-P0 antibody in SLE patients with emotional disorders warrants more researches.
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Project description:To investigate brain perfusion patterns in systemic lupus erythematosus (SLE) patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE and non-NPSLE, respectively) and to identify biomarkers for the diagnosis of NPSLE using noninvasive three-dimensional (3D) arterial spin labeling (ASL). Thirty-one NPSLE and 24 non-NPSLE patients and 32 age- and sex-matched normal controls (NCs) were recruited. Three-dimensional ASL-MRI was applied to quantify cerebral perfusion. Whole brain, gray (GM) and white matter (WM), and voxel-based analysis (VBA) were performed to explore perfusion characteristics. Correlation analysis was performed to find the relationship between the perfusion measures, lesion volumes, and clinical variables. Receiver operating characteristic (ROC) analysis and support vector machine (SVM) classification were applied to differentiate NPSLE patients from non-NPSLE patients and healthy controls. Compared to NCs, NPSLE patients showed increased cerebral blood flow (CBF) within WM but decreased CBF within GM, while non-NPSLE patients showed increased CBF within both GM and WM. Compared to non-NPSLE patients, NPSLE patients showed significantly reduced CBF in the frontal gyrus, cerebellum, and corpus callosum. CBF within several brain regions such as cingulate and corpus callosum showed significant correlations with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics (SLICC) damage index scores. ROC analysis showed moderate performance in distinguishing NPSLE from non-NPSLE patients with AUCs > 0.7, while SVM analysis demonstrated that CBF within the corpus callosum achieved an accuracy of 83.6% in distinguishing NPSLE from non-NPSLE patients. Different brain perfusion patterns were observed between NPSLE and non-NPSLE patients. CBF measured by noninvasive 3D ASL could be a useful biomarker for the diagnosis and disease monitoring of NPSLE and non-NPSLE patients.
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Project description:The NMDA receptor (NMDAR) subunit GluN1 is critical for receptor function and plays a pivotal role in synaptic plasticity. Mounting evidence has shown that pathogenic autoantibody targeting of the GluN1 subunit of NMDARs, as in anti-NMDAR encephalitis, leads to altered NMDAR trafficking and synaptic localization. However, the underlying signaling pathways affected by antibodies targeting the NMDAR remain to be fully delineated. It remains unclear whether patient antibodies influence synaptic transmission via direct effects on NMDAR channel function. Here, we show using short-term incubation that GluN1 antibodies derived from patients with anti-NMDAR encephalitis label synapses in mature hippocampal primary neuron culture. Miniature spontaneous calcium transients (mSCaTs) mediated via NMDARs at synaptic spines are not altered in pathogenic GluN1 antibody exposed conditions. Unexpectedly, spine-based and cell-based analyses yielded distinct results. In addition, we show that calcium does not accumulate in neuronal spines following brief exposure to pathogenic GluN1 antibodies. Together, these findings show that pathogenic antibodies targeting NMDARs, under these specific conditions, do not alter synaptic calcium influx following neurotransmitter release. This represents a novel investigation of the molecular effects of anti-NMDAR antibodies associated with autoimmune encephalitis.
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Project description:NMDA-receptor antibodies (NMDAR-Abs) cause an autoimmune encephalitis with a diverse range of EEG abnormalities. NMDAR-Abs are believed to disrupt receptor function, but how blocking this excitatory synaptic receptor can lead to paroxysmal EEG abnormalities-or even seizures-is poorly understood. Here we show that NMDAR-Abs change intrinsic cortical connections and neuronal population dynamics to alter the spectral composition of spontaneous EEG activity and predispose brain dynamics to paroxysmal abnormalities. Based on local field potential recordings in a mouse model, we first validate a dynamic causal model of NMDAR-Ab effects on cortical microcircuitry. Using this model, we then identify the key synaptic parameters that best explain EEG paroxysms in pediatric patients with NMDAR-Ab encephalitis. Finally, we use the mouse model to show that NMDAR-Ab-related changes render microcircuitry critically susceptible to overt EEG paroxysms when these key parameters are changed, even though the same parameter fluctuations are tolerated in the in silico model of the control condition. These findings offer mechanistic insights into circuit-level dysfunction induced by NMDAR-Ab.
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