Dataset Information

Inflammasome induction in Rasmussen's encephalitis: cortical and associated white matter pathogenesis.

ABSTRACT:

Background

Rasmussen's encephalitis (RE) is an inflammatory encephalopathy of unknown cause defined by seizures with progressive neurological disabilities. Herein, the pathogenesis of RE was investigated focusing on inflammasome activation in the brain.

Methods

Patients with RE at the University of Alberta, Edmonton, AB, Canada, were identified and analyzed by neuroimaging, neuropsychological, molecular, and pathological tools. Primary human microglia, astrocytes, and neurons were examined using RT-PCR, enzyme-linked immunosorbent assay (ELISA), and western blotting.

Results

Four patients with RE were identified at the University of Alberta. Magnetic resonance imaging (MRI) disclosed increased signal intensities in cerebral white matter adjacent to cortical lesions of RE patients, accompanied by a decline in neurocognitive processing speed (P <0.05). CD3?, HLA-DRA, and TNF? together with several inflammasome-associated genes (IL-1?, IL-18, NLRP1, NLRP3, and CASP1) showed increased transcript levels in RE brains compared to non-RE controls (n?=?6; P <0.05). Cultured human microglia displayed expression of inflammasome-associated genes and responded to inflammasome activators by releasing IL-1?, which was inhibited by the caspase inhibitor, zVAD-fmk. Major histocompatibility complex (MHC) class II, IL-1?, caspase-1, and alanine/serine/cysteine (ASC) immunoreactivity were increased in RE brain tissues, especially in white matter myeloid cells, in conjunction with mononuclear cell infiltration and gliosis. Neuroinflammation in RE brains was present in both white matter and adjacent cortex with associated induction of inflammasome components, which was correlated with neuroimaging and neuropsychological deficits.

Conclusion

Inflammasome activation likely contributes to the disease process underlying RE and offers a mechanistic target for future therapeutic interventions.

SUBMITTER: Ramaswamy V

PROVIDER: S-EPMC3881507 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inflammasome induction in Rasmussen's encephalitis: cortical and associated white matter pathogenesis.

Ramaswamy Vijay V Walsh John G JG Sinclair D Barry DB Johnson Edward E Tang-Wai Richard R Wheatley B Matt BM Branton William W Maingat Ferdinand F Snyder Thomas T Gross Donald W DW Power Christopher C

Journal of neuroinflammation 20131213

<h4>Background</h4>Rasmussen's encephalitis (RE) is an inflammatory encephalopathy of unknown cause defined by seizures with progressive neurological disabilities. Herein, the pathogenesis of RE was investigated focusing on inflammasome activation in the brain.<h4>Methods</h4>Patients with RE at the University of Alberta, Edmonton, AB, Canada, were identified and analyzed by neuroimaging, neuropsychological, molecular, and pathological tools. Primary human microglia, astrocytes, and neurons were ...[more]

PMID: 24330827

Similar Datasets

Project description:Vanishing white matter (VWM) is a leukodystrophy caused by biallelic pathogenic variants in eukaryotic translation initiation factor 2B. Neuropathology includes lack of reactive gliosis, paucity of myelin, and axonal abnormalities. Alteration in proteins involved in cellular metabolism has also been implicated in the disease. It, however, remains unclear which factors contribute to VWM pathogenesis. Here, we aimed at gaining insight into the basis of VWM pathogenesis using the 2b5ho mouse model of VWM. We first investigated the temporal proteome in the cerebellum, corpus callosum, cortex, and brainstem of 2b5ho and wild type (WT) mice. Protein changes observed in 2b5ho mice were then cross-referenced with published proteomic datasets from post mortem VWM patient brain tissue to define alterations relevant to the human disease. By comparing 2b5ho mice with their region- and age-matched WT counterparts, we identified region-specific protein changes associated with disease development and progression. We showed that the proteome in the cerebellum and cortex of 2b5ho mice was already deregulated prior to pathology development, whereas proteome changes in the corpus callosum only occurred after onset of pathology. Remarkably, protein changes in the brainstem were transient, indicating that a compensatory mechanism might occur in this region throughout the disease course. Gene ontology overrepresentation analysis revealed that proteome changes observed in 2b5ho mouse brains reflect alterations in features well-known in VWM. Side-by-side comparison of the 2b5ho mouse and VWM patient brain proteomes revealed that part of protein changes were the same as in VWM patients. These could represent relevant changes that contribute to the disease or even drive its progression in VWM patients. Taken together, we show that the proteome in the brain of 2b5ho mice is affected in a region-specific and time-dependent manner. We found that the 2b5ho mouse model partly replicates the human disease at the protein level, and provides a spatiotemporal proteome resource to study aspects of VWM pathogenesis. This resource highlights alterations presenting from early to late disease stages, and those that possibly drive disease progression.

Project description:BackgroundWhile gross measures of brain structure have shown alterations with increasing body mass index (BMI), the extent and nature of such changes has varied substantially across studies. Here, we sought to determine whether small-scale morphometric measures might prove more sensitive and reliable than larger scale measures and whether they might offer a valuable opportunity to link cortical changes to underlying white matter changes. To examine this, we explored the association of BMI with millimetre-scale Gaussian curvature, in addition to standard measures of morphometry such as cortical thickness, surface area and mean curvature. We also assessed the volume and integrity of the white matter, using white matter signal intensity and fractional anisotropy (FA). We hypothesised that BMI would be linked to small-scale changes in Gaussian curvature and that this phenomenon would be mediated by changes in the integrity of the underlying white matter.MethodsThe association of global measures of T1-weighted cortical morphometry with BMI was examined using linear regression and mediation analyses in two independent groups of healthy young to middle aged human subjects (n1 = 52, n2 = 202). In a third dataset of (n3 = 897), which included diffusion tensor images, we sought to replicate the significant associations established in the first two datasets, and examine the potential mechanistic link between BMI-associated cortical changes and global FA.ResultsGaussian curvature of the white matter surface showed a significant, positive association with BMI across all three independent datasets. This effect was mediated by a negative association between the integrity of the white matter and BMI.ConclusionsIncreasing BMI is associated with changes in white matter microstructure in young to middle-aged healthy adults. Our results are consistent with a model whereby BMI-linked cortical changes are mediated by the effects of BMI on white matter microstructure.

Dataset Information

Inflammasome induction in Rasmussen's encephalitis: cortical and associated white matter pathogenesis.

Background

Methods

Results

Conclusion

Publications

Inflammasome induction in Rasmussen's encephalitis: cortical and associated white matter pathogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets