RESUMO
Systemic lupus erythematosus (SLE) is an auto-immune disease characterized by multi-organ involvement. Although uncommon, central nervous system involvement in SLE, termed neuropsychiatric SLE (NPSLE), is not an exception. Current knowledge on underlying pathogenic mechanisms is incomplete, however, neuroinflammation is thought to play a critical role. Evidence from neurodegenerative diseases and multiple sclerosis suggests that neuroinflammation is correlated with brain iron accumulation, making quantitative susceptibility mapping (QSM) a potential hallmark for neuroinflammation in vivo. This study assessed susceptibility values of the thalamus and basal ganglia in (NP)SLE patients and further investigated the in vivo findings with histological analyses of postmortem brain tissue derived from SLE patients. We used a 3T MRI scanner to acquire single-echo T2*-weighted images of 44 SLE patients and 20 age-matched healthy controls. Of the 44 patients with SLE, all had neuropsychiatric complaints, of which 29 were classified as non-NPSLE and 15 as NPSLE (seven as inflammatory NPSLE and eight as ischemic NPSLE). Mean susceptibility values of the thalamus, caudate nucleus, putamen, and globus pallidus were calculated. Formalin-fixed paraffin-embedded post-mortem brain tissue including the putamen and globus pallidus of three additional SLE patients was obtained and stained for iron, microglia and astrocytes. Susceptibility values of SLE patients and age-matched controls showed that iron levels in the thalamus and basal ganglia were not changed due to the disease. No subgroup of SLE showed higher susceptibility values. No correlation was found with disease activity or damage due to SLE. Histological examination of the post-mortem brain showed no increased iron accumulation. Our results suggest that neuroinflammation in NPSLE does not necessarily go hand in hand with iron accumulation, and that the inflammatory pathomechanism in SLE may differ from the one observed in neurodegenerative diseases and in multiple sclerosis.
Assuntos
Lúpus Eritematoso Sistêmico , Vasculite Associada ao Lúpus do Sistema Nervoso Central , Gânglios da Base/diagnóstico por imagem , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico por imagem , Imageamento por Ressonância Magnética , Tálamo/diagnóstico por imagemRESUMO
The hypothalamus is at the core of the stress responses systems of the brain. Most interestingly, even though changes of HPA-function have been observed in opiate addiction not much is known about structural changes of the hypothalamus. Volumes of hypothalamus in heroin addicts (n = 14) and healthy controls (n = 12) were assessed by using morphometry of serial whole-brain sections. Total brain volume was larger in the heroin group (mean 1478.85 ± 62.34 cm3 vs. mean 1352.38 ± 103.24 cm3), as the heroin group was more than 10 years younger (p = 0.001). Thus, diagnosis-related effects in the hypothalamus were assessed using the hypothalamus volume relative to whole brain volume showing reduced volumes of the hypothalamus in the heroin group (0.201 ± 0.074 × 10-3 vs. 0.267 ± 0.048 × 10-3; ANOVA: F(1,23) = 6.211, p = 0.020) with a strong hemispheric effect (left side: about 20% reduction 0.209 ± 0.080 × 10-3 vs. 0.264 ± 0.049 × 10-3; F = 4.109; p = 0.054; right side: about 27% reduction, 0.198 ± 0.069 × 10-3 vs. 0.271 ± 0.050 × 10-3; F = -8.800; p = 0.007). Our results provide further evidence for structural and not only functional deficits of the hypothalamus in addiction.
Assuntos
Diagnóstico , Dependência de Heroína/patologia , Hipotálamo/patologia , Adulto , Autopsia , Seguimentos , Lateralidade Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Adulto JovemRESUMO
Repetitive transorbital alternating current stimulation (rtACS) improves vision in patients with chronic visual impairments and an acute treatment increased survival of retinal neurons after optic nerve crush (ONC) in rodent models of visual system injury. However, despite this protection no functional recovery could be detected in rats, which was interpreted as evidence of "silent survivor" cells. We now analysed the mechanisms underlying this "silent survival" effect. Using in vivo microscopy of the retina we investigated the survival and morphology of fluorescent neurons before and after ONC in animals receiving rtACS or sham treatment. One week after the crush, more neurons survived in the rtACS-treated group compared to sham-treated controls. In vivo imaging further revealed that in the initial post-ONC period, rtACS induced dendritic pruning in surviving neurons. In contrast, dendrites in untreated retinae degenerated slowly after the axonal trauma and neurons died. The complete loss of visual evoked potentials supports the hypothesis that cell signalling is abolished in the surviving neurons. Despite this evidence of "silencing", intracellular free calcium imaging showed that the cells were still viable. We propose that early after trauma, complete dendritic stripping following rtACS protects neurons from excitotoxic cell death by silencing them.
Assuntos
Sobrevivência Celular , Dendritos/metabolismo , Estimulação Elétrica , Neurônios/metabolismo , Traumatismos do Nervo Óptico/metabolismo , Animais , Axônios/metabolismo , Morte Celular , Modelos Animais de Doenças , Terapia por Estimulação Elétrica , Potenciais Evocados Visuais , Camundongos , Microscopia Confocal , Plasticidade Neuronal , Traumatismos do Nervo Óptico/etiologia , Traumatismos do Nervo Óptico/patologia , Traumatismos do Nervo Óptico/terapia , Ratos , Retina/citologia , Retina/metabolismoRESUMO
BACKGROUND: The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups. METHODS: In this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analysed for progression-free survival outcomes by the Kaplan-Meier method. The DNA methylation-based and WHO classification schema were compared using the Brier prediction score, analysed in an independent cohort with WHO grading, progression-free survival, and disease-specific survival data available, collected at the Medical University Vienna (Vienna, Austria), assessing methylation patterns with an alternative methylation chip. FINDINGS: We retrospectively collected 497 meningiomas along with 309 samples of other extra-axial skull tumours that might histologically mimic meningioma variants. Unsupervised clustering of DNA methylation data clearly segregated all meningiomas from other skull tumours. We generated genome-wide DNA methylation profiles from all 497 meningioma samples. DNA methylation profiling distinguished six distinct clinically relevant methylation classes associated with typical mutational, cytogenetic, and gene expression patterns. Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours (p=0·0096) from the Brier prediction test). We validated this finding in our independent cohort of 140 patients with meningioma. INTERPRETATION: DNA methylation-based meningioma classification captures clinically more homogenous groups and has a higher power for predicting tumour recurrence and prognosis than the WHO classification. The approach presented here is potentially very useful for stratifying meningioma patients to observation-only or adjuvant treatment groups. We consider methylation-based tumour classification highly relevant for the future diagnosis and treatment of meningioma. FUNDING: German Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.
Assuntos
Metilação de DNA , Neoplasias Meníngeas/classificação , Neoplasias Meníngeas/genética , Meningioma/classificação , Meningioma/genética , Recidiva Local de Neoplasia/genética , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Progressão da Doença , Intervalo Livre de Doença , Feminino , Genoma , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Neurofibromina 2/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-akt/genética , Estudos Retrospectivos , Análise de Sequência de RNA , Receptor Smoothened/genética , Taxa de Sobrevida , Fatores de Transcrição/genética , Transcriptoma , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genéticaRESUMO
Systemic chemotherapeutic treatment for unresectable and/or aggressive meningiomas is still unsatisfying. PDGF receptor (PDGFR)-mediated activation of mitogenic signalling has been shown to be active in meningiomas. Therefore, we evaluate in vitro and in vivo the effects of inhibiting PDGFR using the clinically well-characterised tyrosine kinase inhibitors sorafenib or regorafenib in meningioma models. IOMM-Lee meningioma cells were used to assess cytotoxic effects, inhibition of proliferation, induction of apoptosis, as well as inhibition of migration and motility by sorafenib and regorafenib. Using an orthotopic mouse xenograft model, growth inhibition as monitored by magnetic resonance imaging, and overall survival of sorafenib- or regorafenib-treated mice compared with control animals was determined. Treatment of malignant IOMM-Lee cells resulted in significantly reduced cell survival and induction of apoptosis following regorafenib and sorafenib treatment. Western blots showed that both drugs target phosphorylation of p44/42 ERK via downregulation of the PDGFR. Both drugs additionally showed significant inhibition of cell motility and invasion. In vivo, mice with orthotopic meningioma xenografts showed a reduced volume (n.s.) of signal enhancement in MRI (mainly tumour) following sorafenib and regorafenib treatment. This was translated in a significantly increased overall survival time (p ≤ 0.05) for regorafenib-treated mice. Analyses of in vivo-grown tumours demonstrated again reduced PDGFR expression and expression/phosphorylation of p44/42. Sorafenib and regorafenib show antitumour activity in vitro and in vivo by targeting PDGFR and p44/42 ERK signalling.
Assuntos
Neoplasias Meníngeas/tratamento farmacológico , Meningioma/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Depsipeptídeos , Modelos Animais de Doenças , Humanos , Neoplasias Meníngeas/patologia , Meningioma/patologia , Camundongos , Invasividade Neoplásica , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Células Tumorais CultivadasRESUMO
Postmortem and positron emission tomography studies have indicated the pathophysiological involvement of microglial cells in schizophrenia. We hypothesized that the microglial production of quinolinic acid (QUIN), an endogenous N-methyl-d-aspartate receptor (NMDAR) agonist, may be linked to the previously described glutamatergic deficits in the hippocampus of schizophrenia patients. We performed a semi-quantitative assessment of QUIN-immunoreactive microglial cells in schizophrenia patients and matched controls in the CA1, CA2/3, and dentate gyrus (DG) area of the posterior hippocampal formation. Complementary immunostaining of the commonly used microglial surface marker HLA-DR was performed in adjacent histological sections. Fewer QUIN-immunoreactive microglial cells were observed in the CA1 hippocampal subregion of schizophrenia patients compared to controls (left p=0.028, right p=0.018). No significant diagnosis-dependent changes were observed in the CA2/3 and DG regions. These results were controlled for potential confounds by age, duration of disease, autolysis time, psychotropic medication, and hippocampal volume. No diagnosis-related differences were observed for the overall density of microglial cells (HLA-DR expression). Our findings suggest that reduced microglial QUIN content in the hippocampal CA1 region is associated with schizophrenia. We hypothesize that this association may contribute to impaired glutamatergic neurotransmission in the hippocampus of schizophrenia patients.
Assuntos
Região CA1 Hipocampal/química , Agonistas de Aminoácidos Excitatórios/análise , Microglia/química , Ácido Quinolínico/análise , Receptores de N-Metil-D-Aspartato/agonistas , Esquizofrenia/metabolismo , Adulto , Região CA1 Hipocampal/imunologia , Região CA1 Hipocampal/patologia , Contagem de Células , Feminino , Ácido Glutâmico/fisiologia , Antígenos HLA-DR/análise , Hipocampo/química , Hipocampo/imunologia , Hipocampo/patologia , Humanos , Masculino , Microglia/imunologia , Pessoa de Meia-Idade , Neuroimunomodulação/fisiologia , Especificidade de Órgãos , Esquizofrenia/imunologia , Esquizofrenia/patologia , Transmissão SinápticaRESUMO
In recent years, the hypothalamus, amygdala and hippocampus have attracted increased interest with regard to the effects of stress on neurobiological systems in individuals with depression and suicidal behaviour. A large body of evidence indicates that these subcortical regions are involved in the pathogenetic mechanisms of mood disorders and suicide. The current neuroimaging techniques inadequately resolve the structural components of small and complex brain structures. In previous studies, our group was able to demonstrate a structural and neuronal pathology in mood disorders. However, the impact of suicide remains unclear. In the current study we used volumetric measurements of serial postmortem sections with combined Nissl-myelin staining to investigate the hypothalamus, amygdala and hippocampus in suicide victims with mood disorders (n = 11), non-suicidal mood disorder patients (n = 9) and control subjects (n = 23). Comparisons between the groups by using an ANCOVA showed a significant overall difference for the hypothalamus (p = 0.001) with reduced volumes in non-suicidal patients compared to suicide victims (p = 0.018) and controls (p = 0.006). To our surprise, the volumes between the suicide victims and controls did not differ significantly. For the amygdala and hippocampus no volume changes between the groups could be detected (all p values were n. s.). In conclusion our data suggest a structural hypothalamic pathology in non-suicidal mood disorder patients. The detected differences between suicidal and non-suicidal patients suggest that suicidal performances might be related to the degree of structural deficits.
Assuntos
Tonsila do Cerebelo/patologia , Hipocampo/patologia , Hipotálamo/patologia , Transtornos do Humor/patologia , Suicídio , Adulto , Idoso , Atrofia/complicações , Atrofia/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/complicações , Suicídio/psicologiaRESUMO
Protein expression of VGF (nonacronymic) is induced by nerve/brain-derived growth factor, neurotrophin 3, and insulin. VGF is synthesized by neurons in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. After enzymatic processing, smaller VGF-derived peptides are secreted into the cerebrospinal fluid (CSF) or blood. These peptides play important roles by improving synaptic plasticity, neurogenesis, and energy homeostasis, which are impaired in schizophrenia. Based on previous observations of neuroendocrine and hypothalamic deficits in schizophrenia and to determine whether increased levels of the VGF fragment 23-62 in CSF, which have been described in a recent study, were related to changes in hypothalamic VGF expression, an immunohistochemical study was performed in 20 patients with schizophrenia and 19 matched control subjects. N- (D-20) and C-terminal (R-15) VGF antibodies yielded similar results and immunolabeled a vast majority of PVN and SON neurons. Additionally, D20-VGF immunohistochemistry revealed immunostained fibers in the pituitary stalk and neurohypophysis that ended at vessel walls, suggesting axonal transport and VGF secretion. The cell density of D20-VGF-immunoreactive neurons was reduced in the left PVN (P = 0.002) and SON (P = 0.008) of patients with schizophrenia. This study provides the first evidence for diminished hypothalamic VGF levels in schizophrenia, which might suggest increased protein secretion. Our finding was particularly significant in subjects without metabolic syndrome (patients with a body mass index ≤28.7 kg/m(2)). In conclusion, apart from beneficial effects on synaptic plasticity and neurogenesis, VGF may be linked to schizophrenia-related alterations in energy homeostasis.