The relationship between inflammatory markers and hippocampal and extra-hippocampal atrophy patterns in patients with temporal lobe epilepsy

Orientadores: Fernando Cendes, Ana Carolina CoanTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Introdução: A epilepsia atinge 1 a 2 % da população mundial, sendo a epilepsia de lobo temporal associada a esclerose hipocampal (ELT-EH) a forma mais frequente em adultos. Estudos de imagem já determinaram que a ELT-EH apresenta redução volumétrica cerebral difusa, não sendo restrita à região do hipocampo. Há evidências de que a inflamação tem um importante papel na neuroexcitabilidade e que alterações na regulação inflamatória podem gerar degeneração neuronal e induzir crises convulsivas Objetivos: Definir a associação de marcadores inflamatórios séricos e epilepsias, além de características clínicas, de EEG e padrões de alteração de neuroimagem em pacientes com ELT. Materias e Métodos: Foram incluídos no estudo 490 pacientes com diagnóstico clínico e eletroencefalográfico de epilepsia e um grupo de 166 controles sem doenças neurológicas. Os pacientes foram divididos entre os com ELT (246) e pacientes com outras epilepsias. Os indivíduos foram submetidos a coleta de sangue para a avaliação dos marcadores inflamatórios e 86 desses realizaram ressonância magnética (RM) de crânio. O volume de estruturas subcorticais e espessura de regiões corticais foram analisadas pelo programa FreeSurfer. Os marcadores inflamatórios (IL-1, IL-2, IL-4, IL-6, IL-10, IL-17, TNF? e seus receptores sTNFr1 e sTNFr2, BDNF, CTNF, IFN?, NGF, GDNF) foram analisados de maneira cega aos dados clínicos pelas técnicas Enzyme-Linked Immunosorbent Assay (ELISA) e Cytometric Bead Array (CBA). Resultados: Os fatores inflamatórios não estão correlacionados com a idade e gênero dos indivíduos e nem com o tempo de doença dos pacientes (r>0,3; p>0,05). Os níveis séricos de BDNF, NGF, sTNFr2 e a NT3 foram elevados enquanto que os níveis de TNF, sTNFr1, IFN? e das interleucinas foram reduzidos quando avaliamos os pacientes, em geral ou os grupos ELT e outras epilepsias em relação aos controles. Mesmo padrão foi observado quando avaliados apenas os pacientes com malformação do desenvolvimento cortical, exceto o sTNR1 e IL10 que não foram significativos nessa última análise. O CNTF, NT4/5 e GDNF não foram diferentes entre pacientes e controles. O sTNFr2 se demonstrou um bom marcador para diferenciar pacientes e controles (curva ROC com AUC de 0,858). Analisando apenas os pacientes com ELT, O GDNF foi maior nos pacientes com pouca atividade epileptiforme ao EEG. O IL2 e o IL4 foram elevados nos pacientes com maior frequência de crises. Em relação à imagem, o TNF? sérico apresentou correlação inversa ao volume do tálamo ipsilateral. Discussão: Nosso estudo é um dos primeiros a avaliar uma extensa coorte de pacientes e realizar uma avaliação exploratória sobre a relação de marcadores inflamatórios, dados clínicos e de neuroimagem. Os marcadores inflamatórios apresentam diferentes papéis no sistema nervoso central e sua medição sérica nos ajuda a compreender melhor o papel desses nas epilepsias. Conclusão: Os marcadores inflamatórios estão claramente envolvidos na epilepsia e na perda neuronal, porém são necessários estudos específicos para compreender se estes são epifenômenos ou consequências das crisesAbstract: Introduction: Epilepsy affects 1% to 2% of the world population and temporal lobe epilepsy associated with hippocampal sclerosis (TLE-HS) is the most common epilepsy in adults. Imaging studies have already demonstrated that TLE patients present diffuse gray and white matter atrophy, not restricted to hippocampal region. Inflammation perform an important role in neuroexcitability. Changes on inflammatory regulation can lead to neuronal degeneration and induce seizures. Objectives: To define the association of serum inflammatory markers and epilepsies, as well as clinical characteristics, EEG and neuroimaging patterns in patients with TLE. Subjects and Methods: The study included 490 patients with clinical and electroencephalographic (EEG) diagnosis of epilepsy and a group with 166 controls without neurological diseases. The patients were classified as TLE-HS (246) and other epilepsies. All participants were invited to perform blood sampling (blood serum for inflammatory markers) and 86 performed magnetic resonance imaging (MRI). MRI cortical thickness and subcortical structures were analyzed with FreeSurfer software. The blood serum analysis of IL-1, IL-2, IL-4, IL-6, IL-10, IL-17, TNF? ,sTNFr1, sTNFr2, BDNF, CTNF, IFN?, NGF, GDNF was performed by Enzyme-Linked Immunosorbent Assay (ELISA) and Cytometric Bead Array (CBA). Results: The inflammatory markers did not present correlation with age and gender, or with epilepsy duration. The blood serum levels of BDNF, NGF, sTNFr2 e a NT3 were higher while TNF, sTNFr1, IFN? and interleukines were reduced in patients with epilepsy, TLE-HS and other epilepsies when compared with controls. The same pattern was observed in patients with malformation of cortical development, except for sTNFr1 and IL10. The CTNF, NT4/5 and GDNF were not different between patients and controls in any group. In ROC analysis the sTNFr2 was a good marker to separate patients from controls (AUC =0,858). Considering just patients, the GDNF presented higher serum levels in patients with less interictal epileptiform activity at EEG; and blood serum IL2 and IL4 were higher in patients with more frequent seizures. TNF? presented an inverse correlation with ipsilateral thalamus volume. Discussion: Our study is one of the first to evaluate an extensive cohort of patients and perform an exploratory assessment on the relationship between inflammatory markers, clinical data and imaging. Inflammatory markers play different roles in central nervous system and their serum measurement helps in better comprehending their relationship with epilepsy. Conclusion: The inflammatory markers are associated with epilepsy, but more specific studies are necessary to determine if they are epiphenomena or consequence of seizuresDoutoradoFisiopatologia MédicaDoutora em Ciências2015/17066-0;FAPESPCAPE

Tribunal do Júri: funcionamento e a influência da mídia nas decisões dos jurados

The Jury Court is one of the oldest institutions when it comes to democratic relevance. With worldwide application and repercussion, it is considered a solidified and essential tool in the maintenance of the brazilian legal system. It will be analyzed, in counterpoint, the role of the media in forming the opinion of the jury participants and the strength of the public outcry with regard to court decisions. An attempt will be made to present possible ways of solving the obstacle, in addition to exposing the peculiarities that surround the institute. In this stir, the descriptive research method will be to fulfill this endeavor.O Tribunal do Júri é uma das mais antigas instituições de apelo democrático do direito. Com aplicação e repercussão mundial, é ferramenta considerada solidificada e primordial na manutenção do ordenamento jurídico pátrio. Será analisado, em contraponto, a atuação da mídia na formação de opinião dos participantes do júri e a força do clamor público no que tange às decisões judiciais. Tentar-se-á apresentar possíveis formas de solução do entrave, além de expor as peculiaridades que circundam o instituto. Nesta celeuma, o método de pesquisa descritiva será disposto a este fim

A REGIONAL VENDA NOVA (BH) E O PROCESSO DE REESTRUTURAÇÃO URBANA DO VETOR NORTE DA REGIÃO METROPOLITANA DE BELO HORIZONTE (RMBH\MG)

O objetivo geral deste artigo é compreender os motivos da localização de empreendimentos de grande porte na Regional Venda Nova e nos municípios inseridos no Vetor Norte da Região Metropolitana de Belo Horizonte (RMBH). Como aporte teórico consta uma breve discussão dos conceitos: Espaço, Reestruturação e Planejamento Urbano, e para a análise foram elaborados mapas de localização, com os empreendimentos e equipamentos urbanos localizados neste vetor. Os resultados da pesquisa apontaram para o fato de que na reestruturação urbana do Vetor Norte da RMBH a atuação de agentes imobiliários e fundiários, mas também do Estado, chama a atenção. Mesmo porque este processo estava previsto no Plano Metropolitano da RMBH, em que consta que as transformações ocorridas no Vetor Norte da RMBH influenciam também suas áreas adjacentes e contribuem para a superação de seus problemas urbano

Sleep onset uncovers thalamic abnormalities in patients with idiopathic generalised epilepsy

The thalamus is crucial for sleep regulation and the pathophysiology of idiopathic generalised epilepsy (IGE), and may serve as the underlying basis for the links between the two. We investigated this using EEG-fMRI and a specific emphasis on the role and functional connectivity (FC) of the thalamus. We defined three types of thalamic FC: thalamocortical, inter-hemispheric thalamic, and intra-hemispheric thalamic. Patients and controls differed in all three measures, and during wakefulness and sleep, indicating disorder-dependent and state-dependent modification of thalamic FC. Inter-hemispheric thalamic FC differed between patients and controls in somatosensory regions during wakefulness, and occipital regions during sleep. Intra-hemispheric thalamic FC was significantly higher in patients than controls following sleep onset, and disorder-dependent alterations to FC were seen in several thalamic regions always involving somatomotor and occipital regions. As interactions between thalamic sub-regions are indirect and mediated by the inhibitory thalamic reticular nucleus (TRN), the results suggest abnormal TRN function in patients with IGE, with a regional distribution which could suggest a link with the thalamocortical networks involved in the generation of alpha rhythms. Intra-thalamic FC could be a more widely applicable marker beyond patients with IGE. Keywords: Functional connectivity, Generalised epilepsy, Sleep, Thalamic reticular nucleus thalamu

MicroRNA Hsa-miR-134 is a circulating biomarker for mesial temporal lobe epilepsy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Epilepsy is misdiagnosed in up to 25% of patients, leading to serious and long-lasting consequences. Recently, circulating microRNAs have emerged as potential biomarkers in a number of clinical scenarios. The purpose of this study was to identify and to validate circulating microRNAs that could be used as biomarkers in the diagnosis of epilepsy. Quantitative real-time PCR was used to measure plasma levels of three candidate microRNAs in two phases of study: an initial discovery phase with 14 patients with mesial temporal lobe epilepsy (MTLE), 13 with focal cortical dysplasia (FCD) and 16 controls; and a validation cohort constituted of an independent cohort of 65 patients with MTLE and 83 controls. We found hsa-miR-134 downregulated in patients with MTLE (p = 0.018) but not in patients with FCD, when compared to controls. Furthermore, hsa-miR-134 expression could be used to discriminate MTLE patients with an area under the curve (AUC) of 0.75. To further assess the robustness of hsa-miR-134 as a biomarker for MTLE, we studied an independent cohort of 65 patients with MTLE, 27 of whom MTLE patients were responsive to pharmacotherapy, and 38 patients were pharmacoresistant and 83 controls. We confirmed that hsa-miR-134 was significantly downregulated in the plasma of patients with MTLE when compared with controls (p < 0.001). In addition, hsa-miR-134 identified patients with MTLE regardless of their response to pharmacotherapy or the presence of MRI signs of hippocampal sclerosis. We revealed that decreased expression of hsa-miR-134 could be a potential non-invasive biomarker to support the diagnosis of patients with MTLE.Epilepsy is misdiagnosed in up to 25% of patients, leading to serious and long-lasting consequences. Recently, circulating microRNAs have emerged as potential biomarkers in a number of clinical scenarios. The purpose of this study was to identify and to v124FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIORCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)2013/07559-3; 2013/00099-7sem informaçãosem informaçã

HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction

High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein released by glia and neurons upon inflammasome activation and activates receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR) 4 on the target cells. HMGB1/TLR4 axis is a key initiator of neuroinflammation. In recent days, more attention has been paid to HMGB1 due to its contribution in traumatic brain injury (TBI), neuroinflammatory conditions, epileptogenesis, and cognitive impairments and has emerged as a novel target for those conditions. Nevertheless, HMGB1 has not been portrayed as a common prognostic biomarker for these HMGB1 mediated pathologies. The current review discusses the contribution of HMGB1/TLR4/RAGE signaling in several brain injury, neuroinflammation mediated disorders, epileptogenesis and cognitive dysfunctions and in the light of available evidence, argued the possibilities of HMGB1 as a common viable biomarker of the above mentioned neurological dysfunctions. Furthermore, the review also addresses the result of preclinical studies focused on HMGB1 targeted therapy by the HMGB1 antagonist in several ranges of HMGB1 mediated conditions and noted an encouraging result. These findings suggest HMGB1 as a potential candidate to be a common biomarker of TBI, neuroinflammation, epileptogenesis, and cognitive dysfunctions which can be used for early prediction and progression of those neurological diseases. Future study should explore toward the translational implication of HMGB1 which can open the windows of opportunities for the development of innovative therapeutics that could prevent several associated HMGB1 mediated pathologies discussed herein

Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed

Event-based modelling in temporal lobe epilepsy demonstrates progressive atrophy from cross-sectional data

OBJECTIVE: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multi-centre cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features. METHODS: We extracted regional measures of cortical thickness, surface area and subcortical brain volumes from T1-weighted (T1W) MRI scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1,625 healthy controls from 25 centres. Features with a moderate case-control effect size (Cohen's d≥0.5) were used to train an Event-Based Model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age of onset and anti-seizure medicine (ASM) resistance. RESULTS: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume and, finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated to duration of illness (Spearman's ρ=0.293, p=7.03x10-16 ), age of onset (ρ=-0.18, p=9.82x10-7 ) and ASM resistance (AUC=0.59, p=0.043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM stage zero, which represents MTLE-HS with mild or non-detectable abnormality on T1W MRI. SIGNIFICANCE: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features

Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-Analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = \uc3\ua2 '0.24 to \uc3\ua2 '0.73; P < 1.49 \uc3\u97 10 \uc3\ua2 '4), and lower thickness in the precentral gyri bilaterally (d = \uc3\ua2 '0.34 to \uc3\ua2 '0.52; P < 4.31 \uc3\u97 10 \uc3\ua2 '6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = \uc3\ua2 '1.73 to \uc3\ua2 '1.91, P < 1.4 \uc3\u97 10 \uc3\ua2 '19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = \uc3\ua2 '0.36 to \uc3\ua2 '0.52; P < 1.49 \uc3\u97 10 \uc3\ua2 '4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = \uc3\ua2 '0.29 to \uc3\ua2 '0.54; P < 1.49 \uc3\u97 10 \uc3\ua2 '4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = \uc3\ua2 '0.27 to \uc3\ua2 '0.51; P < 1.49 \uc3\u97 10 \uc3\ua2 '4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < \uc3\ua2 '0.0018; P < 1.49 \uc3\u97 10 \uc3\ua2 '4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder