RESUMO
RNA polymerase I transcribes ribosomal DNA to produce precursor 47S rRNA. Post-transcriptional processing of this rRNA generates mature 28S, 18S and 5.8S rRNAs, which form the ribosomes, together with 5S rRNA, assembly factors and ribosomal proteins. We previously reported a homozygous variant in the catalytic subunit of RNA polymerase I, POLR1A, in two brothers with leukodystrophy and progressive course. However, the disease mechanism remained unknown. In this report, we describe another missense variant POLR1A NM_015425.3:c.1925C>A; p.(Thr642Asn) in homozygosity in two unrelated patients. Patient 1 was a 16-year-old male and Patient 2 was a 2-year-old female. Both patients manifested neurological deficits, with brain MRIs showing hypomyelinating leukodystrophy and cerebellar atrophy; and in Patient 1 additionally with hypointensity of globi pallidi and small volume of the basal ganglia. Patient 1 had progressive disease course, leading to death at the age of 16.5 years. Extensive in vitro experiments in fibroblasts from Patient 1 documented that the mutated POLR1A led to aberrant rRNA processing and degradation, and abnormal nucleolar homeostasis. Proteomics data analyses and further in vitro experiments documented abnormal protein homeostasis, and endoplasmic reticulum stress responses. We confirm that POLR1A biallelic variants cause neurodegenerative disease, expand the knowledge of the clinical phenotype of the disorder, and provide evidence for possible pathological mechanisms leading to POLR1A-related leukodystrophy.
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Doenças Neurodegenerativas , RNA Polimerase I , Masculino , Feminino , Humanos , RNA Polimerase I/genética , RNA Polimerase I/metabolismo , Doenças Neurodegenerativas/genética , Proteostase , RNA Ribossômico/metabolismo , Ribossomos , Processamento Pós-Transcricional do RNARESUMO
BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.
Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Morte Súbita/patologia , Epilepsia/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Adulto , Cerebelo/patologia , Criança , Morte Súbita/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/mortalidade , Deficiências do Desenvolvimento/patologia , Epilepsia/mortalidade , Epilepsia/patologia , Anormalidades do Olho/mortalidade , Anormalidades do Olho/patologia , Feminino , Heterozigoto , Humanos , Mutação INDEL , Doenças Renais Císticas/mortalidade , Doenças Renais Císticas/patologia , Masculino , Neuro-Hipófise/metabolismo , Neuro-Hipófise/patologia , Retina/patologia , Sequenciamento Completo do Genoma , Adulto JovemRESUMO
PURPOSE: According to the revised World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) of 2016, oligodendrogliomas are now defined primarily by a specific molecular signature (presence of IDH mutation and 1p19q codeletion). The purpose of our study was to assess the value of dynamic susceptibility contrast MR imaging (DSC-MRI) and diffusion-weighted imaging (DWI) to characterize oligodendrogliomas and to distinguish them from astrocytomas. METHODS: Seventy-one adult patients with untreated WHO grade II and grade III diffuse infiltrating gliomas and known 1p/19q codeletion status were retrospectively identified and analyzed using relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) maps based on whole-tumor volume histograms. The Mann-Whitney U test and logistic regression were used to assess the ability of rCBV and ADC to differentiate between oligodendrogliomas and astrocytomas both independently, but also related to the WHO grade. Prediction performance was evaluated in leave-one-out cross-validation (LOOCV). RESULTS: Oligodendrogliomas showed significantly higher microvascularity (higher rCBVMean ≥ 0.80, p = 0.013) and higher vascular heterogeneity (lower rCBVPeak ≤ 0.044, p = 0.015) than astrocytomas. Diffuse gliomas with higher cellular density (lower ADCMean ≤ 1094 × 10-6 mm2/s, p = 0.009) were more likely to be oligodendrogliomas than astrocytomas. Histogram analysis of rCBV and ADC was able to differentiate between diffuse astrocytomas (WHO grade II) and anaplastic astrocytomas (WHO grade III). CONCLUSION: Histogram-derived rCBV and ADC parameter may be used as biomarkers for identification of oligodendrogliomas and may help characterize diffuse gliomas based upon their genetic characteristics.
Assuntos
Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Oligodendroglioma/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/genética , Astrocitoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Códon , Meios de Contraste , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética , Imagem Ecoplanar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/genética , Oligodendroglioma/patologia , Compostos Organometálicos , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Carga TumoralRESUMO
OBJECTIVES: To compare neuropsychological performances between patients with and without intracranial abnormalities after mild traumatic brain injury (mTBI) and assess the relationship between demographics, injury severity, and self-reported symptom characteristics with improvements in memory and executive functions (8 weeks to 1 year postinjury). SETTING: Inpatient/outpatient followed up at the Department of Physical Medicine and Rehabilitation, Oslo, Norway. PARTICIPANTS: Patients were divided into groups of complicated (n = 73) or uncomplicated mTBIs (n = 77) based on intracranial findings on computed tomographic or magnetic resonance imaging brain scans. DESIGN: Prospective, longitudinal cohort study. MAIN MEASURES: Neuropsychological assessments of memory and executive functions, self-reports of postconcussion, depression, posttraumatic stress symptoms, and general functioning at 8 weeks and 1 year postinjury. RESULTS: Longitudinal data showed that patients with complicated and uncomplicated mTBIs had similar cognitive performance and improvements. Hierarchical linear modeling revealed that individuals with early posttraumatic stress disorder and/or depressive symptoms performed worse on measures of Memory functions, and those with younger age (<40 years) and lower education (<12 years) performed worse on measures of Executive functions. CONCLUSION: Findings are suggestive of a good cognitive outcome following complicated and uncomplicated mTBIs. Early assessments of posttraumatic stress disorder and depression seem useful in identifying those most vulnerable having poorer cognitive outcomes, providing further interventions that may affect emotional and cognitive recovery.
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Concussão Encefálica/reabilitação , Função Executiva , Transtornos da Memória/reabilitação , Recuperação de Função Fisiológica , Adolescente , Adulto , Fatores Etários , Idoso , Encéfalo/diagnóstico por imagem , Concussão Encefálica/diagnóstico por imagem , Estudos de Coortes , Depressão/complicações , Escolaridade , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Noruega , Transtornos de Estresse Pós-Traumáticos/complicações , Tomografia Computadorizada por Raios X , Índices de Gravidade do Trauma , Adulto JovemRESUMO
BACKGROUND: Texture analysis has been done on several radiological modalities to stage, differentiate, and predict prognosis in many oncologic tumors. PURPOSE: To determine the diagnostic accuracy of discriminating glioblastoma (GBM) from single brain metastasis (MET) by assessing the heterogeneity of both the solid tumor and the peritumoral edema with magnetic resonance imaging (MRI) texture analysis (MRTA). MATERIAL AND METHODS: Preoperative MRI examinations done on a 3-T scanner of 43 patients were included: 22 GBM and 21 MET. MRTA was performed on diffusion tensor imaging (DTI) in a representative region of interest (ROI). The MRTA was assessed using a commercially available research software program (TexRAD) which applies a filtration histogram technique for characterizing tumor and peritumoral heterogeneity. The filtration step selectively filters and extracts texture features at different anatomical scales varying from 2 mm (fine) to 6 mm (coarse). Heterogeneity quantification was obtained by the statistical parameter entropy. A threshold value to differentiate GBM from MET with sensitivity and specificity was calculated by receiver operating characteristic (ROC) analysis. RESULTS: Quantifying the heterogeneity of the solid part of the tumor showed no significant difference between GBM and MET. However, the heterogeneity of the GBMs peritumoral edema was significantly higher than the edema surrounding MET, differentiating them with a sensitivity of 80% and specificity of 90%. CONCLUSION: Assessing the peritumoral heterogeneity can increase the radiological diagnostic accuracy when discriminating GBM and MET. This will facilitate the medical staging and optimize the planning for surgical resection of the tumor and postoperative management.
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Neoplasias Encefálicas/diagnóstico por imagem , Imagem de Tensor de Difusão/métodos , Glioblastoma/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Metástase Neoplásica/diagnóstico por imagem , Adulto , Idoso , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/patologia , Neoplasias Encefálicas/patologia , Diagnóstico Diferencial , Feminino , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Sensibilidade e Especificidade , SoftwareRESUMO
OBJECTIVE: According to the new World Health Organization 2016 classification for tumors of the central nervous system, 1p/19q codeletion defines the genetic hallmark that differentiates oligodendrogliomas from diffuse astrocytomas. The aim of our study was to evaluate whether relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) histogram analysis can stratify survival in adult patients with genetic defined diffuse glioma grades II and III. METHODS: Sixty-seven patients with untreated diffuse gliomas World Health Organization grades II and III and known 1p/19q codeletion status were included retrospectively and analyzed using ADC and rCBV maps based on whole-tumor volume histograms. Overall survival and progression-free survival (PFS) were analyzed by using Kaplan-Meier and Cox survival analyses adjusted for known survival predictors. RESULTS: Significant longer PFS was associated with homogeneous rCBV distribution-higher rCBVpeak (median, 37 vs 26 months; hazard ratio [HR], 3.2; P = 0.02) in patients with astrocytomas, and heterogeneous rCBV distribution-lower rCBVpeak (median, 46 vs 37 months; HR, 5.3; P < 0.001) and higher rCBVmean (median, 44 vs 39 months; HR, 7.9; P = 0.003) in patients with oligodendrogliomas. Apparent diffusion coefficient parameters (ADCpeak, ADCmean) did not stratify PFS and overall survival. CONCLUSIONS: Tumors with heterogeneous perfusion signatures and high average values were associated with longer PFS in patients with oligodendrogliomas. On the contrary, heterogeneous perfusion distribution was associated with poor outcome in patients with diffuse astrocytomas.
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Neoplasias Encefálicas/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Glioma/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Intervalo Livre de Doença , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Carga Tumoral , Adulto JovemRESUMO
OBJECTIVES: To examine whether using an amplitude-integrated electroencephalography (aEEG) severity pattern as an entry criterion for therapeutic hypothermia better selects infants with hypoxic-ischemic encephalopathy and to assess the time-to-normal trace for aEEG and magnetic resonance imaging (MRI) lesion load as 24-month outcome predictors. STUDY DESIGN: Forty-seven infants meeting Norwegian therapeutic hypothermia guidelines were enrolled prospectively. Eight-channel EEG/aEEG was recorded from 6 hours until after rewarming, and read after discharge. Neonatal MRI brain scans were scored for summated (range 0-11) regional lesion load. A poor outcome at 2 years was defined as death or a Bayley Scales of Infant-Toddler Development cognitive or motor composite score of <85 or severe hearing or visual loss. RESULTS: Three severity groups were defined from the initial aEEG; continuous normal voltage (CNV; n = 15), discontinuous normal voltage (DNV; n = 18), and a severe aEEG voltage pattern (SEVP; n = 14). Any seizure occurrence was 7% CNV, 50% DNV, and 100% SEVP. Infants with SEVP with poor vs good outcome had a significantly longer median (IQR) time-to-normal trace: 58 hours (9-79) vs 18 hours (12-19) and higher MRI lesion load: 10 (3-10) vs 2 (1-5). A poor outcome was noted in 3 of 15 infants with CNV, 4 of 18 infants with DNV, and 8 of 14 infants with SEVP. Using multiple stepwise linear regression analyses including only infants with abnormal aEEG (DNV and SEVP), MRI lesion load significantly predicted cognitive and motor scores. For the SEVP group alone, time-to-normal trace was a stronger outcome predictor than MRI score. No variable predicted outcome in infants with CNV. CONCLUSIONS: Selection of infants with encephalopathy for therapeutic hypothermia after perinatal asphyxia may be improved by including only infants with an early moderate or severely depressed background aEEG trace.
Assuntos
Encéfalo/patologia , Desenvolvimento Infantil , Eletroencefalografia/métodos , Hipotermia Induzida/métodos , Hipóxia-Isquemia Encefálica/diagnóstico , Transtornos do Neurodesenvolvimento/diagnóstico , Feminino , Humanos , Hipóxia-Isquemia Encefálica/terapia , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Transtornos do Neurodesenvolvimento/etiologia , Noruega , Estudos ProspectivosRESUMO
Neurologic complications are common after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) and affect 30-60% of transplant recipients. The aim of this article is to provide a practical imaging approach based on the timeline and etiology of CNS abnormalities, and neurologic complications related to transplantation of specific organs. The lesions will be classified based upon the interval from HSCT procedure: pre-engraftment period <30 days, early post-engraftment period 30-100 days, late post-engraftment period >100 days, and the interval from SOT procedure: postoperative phase 1-4 weeks, early posttransplant syndromes 1-6 months, late posttransplant syndromes >6 months. Further differentiation will be based on etiology: infections, drug toxicity, metabolic derangements, cerebrovascular complications, and posttransplantation malignancies. In addition, differentiation will be based on complications specific to the type of transplantation: allogeneic and autologous hematopoietic stem cells (HSC), heart, lung, kidney, pancreas, and liver. Thus, in this article we emphasize the strategic role of neuroradiology in the diagnosis and response to treatment by utilizing a methodical approach in the work up of patients with neurologic complications after transplantation.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico por imagem , Transplante de Células-Tronco Hematopoéticas , Transplante de Órgãos , Complicações Pós-Operatórias/diagnóstico por imagem , HumanosRESUMO
AIM: The optimal timing of magnetic resonance imaging (MRI) in encephalopathic infants treated with hypothermia is unknown, and this study examined whether early scans differed from later scans. METHODS: We assessed paired MRI scans carried out on 41 cooled encephalopathic infants at a median of four and 11 days using two scoring systems: the Rutherford injury scores for the basal ganglia and thalami (BGT), white matter and the posterior limb of the internal capsule, and the Bonifacio injury scores for the BGT and watershed area. RESULTS: Both systems produced consistent injury severity scores in 37 of 41 infants on both days, with Rutherford scores predicting poor outcome in six early scans and seven later scans (K = 0.91) and Bonifacio doing the same in seven and nine scans (K = 0.85). A white matter/watershed score of two or a BGT score of one indicated severe changes by day 11 in three infants, but lower scores did not. CONCLUSION: Magnetic resonance imaging scans indicated that the Rutherford and Bonifacio systems produced similar scores in 37 of 41 cooled encephalopathic infants at a median of four and 11 days. Infants with an early white matter/watershed scores of two or a BGT score of one may worsen and should be rescanned.
Assuntos
Encefalopatias/diagnóstico , Encefalopatias/terapia , Hipotermia Induzida , Imageamento por Ressonância Magnética , Neuroimagem , Encéfalo , Feminino , Humanos , Recém-Nascido , Masculino , Estudos Prospectivos , Fatores de TempoRESUMO
BACKGROUND: Volumetric magnetic resonance imaging (MRI) is now widely available and routinely used in the evaluation of high-grade gliomas (HGGs). Ideally, volumetric measurements should be included in this evaluation. However, manual tumor segmentation is time-consuming and suffers from inter-observer variability. Thus, tools for semi-automatic tumor segmentation are needed. PURPOSE: To present a semi-automatic method (SAM) for segmentation of HGGs and to compare this method with manual segmentation performed by experts. The inter-observer variability among experts manually segmenting HGGs using volumetric MRIs was also examined. MATERIAL AND METHODS: Twenty patients with HGGs were included. All patients underwent surgical resection prior to inclusion. Each patient underwent several MRI examinations during and after adjuvant chemoradiation therapy. Three experts performed manual segmentation. The results of tumor segmentation by the experts and by the SAM were compared using Dice coefficients and kappa statistics. RESULTS: A relatively close agreement was seen among two of the experts and the SAM, while the third expert disagreed considerably with the other experts and the SAM. An important reason for this disagreement was a different interpretation of contrast enhancement as either surgically-induced or glioma-induced. The time required for manual tumor segmentation was an average of 16 min per scan. Editing of the tumor masks produced by the SAM required an average of less than 2 min per sample. CONCLUSION: Manual segmentation of HGG is very time-consuming and using the SAM could increase the efficiency of this process. However, the accuracy of the SAM ultimately depends on the expert doing the editing. Our study confirmed a considerable inter-observer variability among experts defining tumor volume from volumetric MRIs.
Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Glioma/patologia , Glioma/terapia , Imageamento por Ressonância Magnética/métodos , Reconhecimento Automatizado de Padrão , Adulto , Idoso , Quimioterapia Adjuvante , Meios de Contraste , Feminino , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Radioterapia AdjuvanteRESUMO
Valuable stimuli are invariably localized in space. While our knowledge regarding the neural networks supporting value assignment and comparisons is considerable, we lack a basic understanding of how the human brain integrates motivational and spatial information. The amygdala is a key structure for learning and maintaining the value of sensory stimuli and a recent non-human primate study provided initial evidence that it also acts to integrate value with spatial location, a question we address here in a human setting. We measured haemodynamic responses (fMRI) in amygdala while manipulating the value and spatial configuration of stimuli in a simple stimulus-reward task. Subjects responded significantly faster and showed greater amygdala activation when a reward was dependent on a spatial specific response, compared to when a reward required less spatial specificity. Supplemental analysis supported this spatial specificity by demonstrating that the pattern of amygdala activity varied based on whether subjects responded to a motivational target presented in the ipsilateral or contralateral visual space. Our data show that the human amygdala integrates information about space and value, an integration of likely importance for assigning cognitive resources towards highly valuable stimuli in our environment.
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Tonsila do Cerebelo/fisiologia , Mapeamento Encefálico/métodos , Tomada de Decisões/fisiologia , Giro do Cíngulo/fisiologia , Recompensa , Percepção Espacial/fisiologia , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Adulto JovemRESUMO
BACKGROUND: Schizophrenia and bipolar disorder are severe mental disorders with overlapping genetic and clinical characteristics, including cognitive impairments. An important question is whether these disorders also have overlapping neuronal deficits. AIMS: To determine whether large-scale brain networks associated with working memory, as measured with functional magnetic resonance imaging (fMRI), are the same in both schizophrenia and bipolar disorder, and how they differ from those in healthy individuals. METHOD: Patients with schizophrenia (n = 100) and bipolar disorder (n = 100) and a healthy control group (n = 100) performed a 2-back working memory task while fMRI data were acquired. The imaging data were analysed using independent component analysis to extract large-scale networks of task-related activations. RESULTS: Similar working memory networks were activated in all groups. However, in three out of nine networks related to the experimental task there was a graded response difference in fMRI signal amplitudes, where patients with schizophrenia showed greater activation than those with bipolar disorder, who in turn showed more activation than healthy controls. Secondary analysis of the patient groups showed that these activation patterns were associated with history of psychosis and current elevated mood in bipolar disorder. CONCLUSIONS: The same brain networks were related to working memory in schizophrenia, bipolar disorder and controls. However, some key networks showed a graded hyperactivation in the two patient groups, in line with a continuum of neuronal abnormalities across psychotic disorders.
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Transtorno Bipolar/fisiopatologia , Encéfalo/fisiopatologia , Memória de Curto Prazo/fisiologia , Rede Nervosa/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Mapeamento Encefálico , Feminino , Neuroimagem Funcional , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto JovemRESUMO
INTRODUCTION: Impaired monitoring of internally generated information has been proposed to be one component in the development and maintenance of delusions. The present study investigated the neural correlates underlying the monitoring processes and whether they were associated with delusions. METHODS: Twenty healthy controls and 19 patients with schizophrenia spectrum disorders were administrated a reality monitoring paradigm during functional magnetic resonance imaging. During encoding participants were instructed to associate a statement with either a presented (viewed condition) or an imagined picture (imagined condition). During the monitoring session in the scanner, participants were presented with old and new statements and their task was to identify whether a given statement was associated with the viewed condition, imagined condition, or if it was new. RESULTS: Patients showed significantly reduced accuracy in the imagined condition with performance negatively associated with degree of delusions. This was accompanied with reduced activity in the left dorsolateral prefrontal cortex and left hippocampus in the patient group. The severity of delusions was negatively correlated with the blood-oxygenation-level dependent response in the left hippocampus. CONCLUSIONS: The results suggest that weakened monitoring is associated with delusions in patients with schizophrenia spectrum disorder, and that this may be mediated by a frontotemporal dysfunction.
Assuntos
Delusões/fisiopatologia , Hipocampo/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Mapeamento Encefálico , Estudos de Casos e Controles , Feminino , Humanos , Imaginação/fisiologia , Imageamento por Ressonância Magnética , Masculino , Psicologia do Esquizofrênico , Adulto JovemRESUMO
OBJECTIVE: There was more than a 10-fold increase in the incidence of narcolepsy type 1 (NT1) after the H1N1 mass vaccination in 2009/2010 in several countries. NT1 is associated with loss and increase of cell groups in the hypothalamus which may be associated with secondary affected sub-cortical and cortical gray matter. We performed a case-control comparison of MRI-based global and sub-cortical volume and cortical thickness in post-H1N1 NT1 patients compared with controls. METHODS: We included 54 post-H1N1 NT1 patients (51 with confirmed hypocretin-deficiency; 48 H1N1-vaccinated with Pandemrix®; 39 females, mean age 21.8 ± 11.0 years) and 114 healthy controls (77 females, mean age 23.2 ± 9.0 years). 3T MRI brain scans were obtained, and the T1-weighted MRI data were processed using FreeSurfer. Group differences among three global, 10 sub-cortical volume measures and 34 cortical thickness measures for bilateral brain regions were tested using general linear models with permutation testing. RESULTS: Patients had significantly thinner brain cortex bilaterally in the temporal poles (Cohen's d = 0.68, p = 0.00080), entorhinal cortex (d = 0.60, p = 0.0018) and superior temporal gyrus (d = 0.60, p = 0.0020) compared to healthy controls. The analysis revealed no significant group differences for sub-cortical volumes. CONCLUSIONS: Post-H1N1(largely Pandemrix®-vaccinated) NT1 patients have significantly thinner cortex in temporal brain regions compared to controls. We speculate that this effect can be partly attributed to the hypothalamic neuronal change in NT1, including loss of function of the widely projecting hypocretin-producing neurons and secondary effects of the abnormal sleep-wake pattern in NT1 or could be specific for post-H1N1 (largely Pandemrix®-vaccinated) NT1 patients.
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Vírus da Influenza A Subtipo H1N1 , Narcolepsia , Feminino , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Orexinas , Estudos de Casos e Controles , Narcolepsia/etiologia , Imageamento por Ressonância Magnética , EncéfaloRESUMO
Background: Evaluation of molecular markers (IDH, pTERT, 1p/19q codeletion, and MGMT) in adult diffuse gliomas is crucial for accurate diagnosis and optimal treatment planning. Dynamic Susceptibility Contrast (DSC) and Arterial Spin Labeling (ASL) perfusion MRI techniques have both shown good performance in classifying molecular markers, however, their performance has not been compared side-by-side. Methods: Pretreatment MRI data from 90 patients diagnosed with diffuse glioma (54 men/36 female, 53.1 ± 15.5 years, grades 2-4) were retrospectively analyzed. DSC-derived normalized cerebral blood flow/volume (nCBF/nCBV) and ASL-derived nCBF in tumor and perifocal edema were analyzed in patients with available IDH-mutation (n = 67), pTERT-mutation (n = 39), 1p/19q codeletion (n = 33), and MGMT promoter methylation (n = 31) status. Cross-validated uni- and multivariate logistic regression models assessed perfusion parameters' performance in molecular marker detection. Results: ASL and DSC perfusion parameters in tumor and edema distinguished IDH-wildtype (wt) and pTERT-wt tumors from mutated ones. Univariate classification performance was comparable for ASL-nCBF and DSC-nCBV in IDH (maximum AUROCC 0.82 and 0.83, respectively) and pTERT (maximum AUROCC 0.70 and 0.81, respectively) status differentiation. The multivariate approach improved IDH (DSC-nCBV AUROCC 0.89) and pTERT (ASL-nCBF AUROCC 0.8 and DSC-nCBV AUROCC 0.86) classification. However, ASL and DSC parameters could not differentiate 1p/19q codeletion or MGMT promoter methylation status. Positive correlations were found between ASL-nCBF and DSC-nCBV/-nCBF in tumor and edema. Conclusions: ASL is a viable gadolinium-free replacement for DSC for molecular characterization of adult diffuse gliomas.
RESUMO
BACKGROUND: Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are important structural components of neural cellular membranes and possess anti-inflammatory properties. Very preterm infants are deprived of the enhanced placental supply of these fatty acids, but the benefit of postnatal supplementation on brain development is uncertain. The aim of this study was to test the hypothesis that early enteral supplementation with ARA and DHA in preterm infants improves white matter (WM) microstructure assessed by diffusion-weighted MRI at term equivalent age. METHODS: In this double-blind, randomized controlled trial, infants born before 29 weeks gestational age were allocated to either 100 mg/kg ARA and 50 mg/kg DHA (ARA:DHA group) or medium chain triglycerides (control). Supplements were started on the second day of life and provided until 36 weeks postmenstrual age. The primary outcome was brain maturation assessed by diffusion tensor imaging (DTI) using Tract-Based Spatial Statistics (TBSS) analysis. RESULTS: We included 120 infants (60 per group) in the trial; mean (range) gestational age was 26+3 (22+6 - 28+6) weeks and postmenstrual age at scan was 41+3 (39+1 - 47+0) weeks. Ninety-two infants underwent MRI imaging, and of these, 90 had successful T1/T2 weighted MR images and 74 had DTI data of acceptable quality. TBSS did not show significant differences in mean or axial diffusivity between the groups, but demonstrated significantly higher fractional anisotropy in several large WM tracts in the ARA:DHA group, including corpus callosum, the anterior and posterior limb of the internal capsula, inferior occipitofrontal fasciculus, uncinate fasciculus, and the inferior longitudinal fasciculus. Radial diffusivity was also significantly lower in several of the same WM tracts in the ARA:DHA group. CONCLUSION: This study suggests that supplementation with ARA and DHA at doses matching estimated fetal accretion rates improves WM maturation compared to control treatment, but further studies are needed to ascertain any functional benefit. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov; ID:NCT03555019.
Assuntos
Recém-Nascido Prematuro , Substância Branca , Gravidez , Lactente , Recém-Nascido , Humanos , Feminino , Ácidos Docosa-Hexaenoicos , Imagem de Tensor de Difusão/métodos , Placenta , Substância Branca/diagnóstico por imagem , Suplementos Nutricionais , Ácido Araquidônico , Encéfalo/diagnóstico por imagemRESUMO
Several lines of evidence suggest that common polygenic variation influences brain function in humans. Combining high-density genetic markers with brain imaging techniques is constricted by the practicalities of collecting sufficiently large brain imaging samples. Pathway analysis promises to leverage knowledge on function of genes to detect recurring signals of moderate effect. We adapt this approach, exploiting the deep information collected on brain function by fMRI methods, to identify molecular pathways containing genetic variants which influence brain activation during a commonly applied experiment based on a face matching task (n=246) which was developed to study neural processing of faces displaying negative emotions. Genetic markers moderately associated (p<10(-4)) with whole brain activation phenotypes constructed by applying principal components to contrast maps, were tested for pathway enrichment using permutation based methods. The most significant pathways are related to post NMDA receptor activation events, driven by genetic variants in calcium/calmodulin-dependent protein kinase II (CAMK2G, CAMK2D) and a calcium-regulated nucleotide exchange factor (RASGRF2) in which all are activated by intracellular calcium/calmodulin. The most significant effect of the combined polygenic model were localized to the left inferior frontal gyrus (p=1.03 × 10(-9)), a region primarily involved in semantic processing but also involved in processing negative emotions. These findings suggest that pathway analysis of GWAS results derived from principal component analysis of fMRI data is a promising method, to our knowledge, not previously described.
Assuntos
Encéfalo/metabolismo , Cálcio/fisiologia , Imageamento por Ressonância Magnética , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , Redes e Vias Metabólicas/genética , Polimorfismo de Nucleotídeo Único , Adulto , Face , Feminino , Marcadores Genéticos , Humanos , MasculinoRESUMO
Ewing sarcoma (ES) is a malignant small round cell tumor, accounting for 10-15% of all primary bone tumors and approximately 3% of all pediatric cancers. Primary ES of the cranial bone is unusual with reported incidence from 1% to 6% of all ES cases. This report shows a rare case of primary ES of the squamous temporal bone in a 12-year-old boy with a history of swelling of the right temporal region and symptoms of increased intracranial pressure. We illustrate the extremely unusual radiological presentation of this primary ES of temporal bone associated with large aneurysmal bone cyst-like (ABC-like) changes. The boy was successfully treated according to Euro Ewing 2012 protocol. He is alive with no evidence of recurrence and metastasis after 16 months of completed treatment.
RESUMO
STUDY OBJECTIVES: Narcolepsy type 1 (NT1) is a neurological sleep disorder. Postmortem studies have shown 75%-90% loss of the 50 000-70 000 hypocretin-producing neurons and 64%-94% increase in the 64 000-120 000 histaminergic neurons and conflicting indications of gliosis in the hypothalamus of NT1 patients. The aim of this study was to compare MRI-based volumes of the hypothalamus in patients with NT1 and controls in vivo. METHODS: We used a segmentation tool based on deep learning included in Freesurfer and computed the volume of the whole hypothalamus, left/right part of the hypothalamus, and 10 hypothalamic subregions. We included 54 patients with post-H1N1 NT1 (39 females, mean age 21.8 ± 11.0 years) and 114 controls (77 females, mean age 23.2 ± 9.0 years). Group differences were tested with general linear models using permutation testing in Permutation Analysis of Linear Models and evaluated after 10 000 permutations, yielding two-tailed P-values. Furthermore, a stepwise Bonferroni correction was performed after dividing hypothalamus into smaller regions. RESULTS: The analysis revealed larger volume for patients compared to controls for the whole hypothalamus (Cohen's d = 0.71, p = 0.0028) and for the left (d = 0.70, p = 0.0037) and right part of the hypothalamus (d = 0.65, p = 0.0075) and left (d = 0.72, p = 0.0036) and right tubular-inferior (d = 0.71, p = 0.0037) hypothalamic subregions. CONCLUSIONS: In conclusion, patients with post-H1N1 NT1 showed significantly larger hypothalamic volume than controls, in particular in the tubular-inferior subregions which could reflect several processes as previous studies have indicated neuroinflammation, gliosis, and changes in the numbers of different cell types.
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Vírus da Influenza A Subtipo H1N1 , Narcolepsia , Feminino , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Gliose , Hipotálamo/diagnóstico por imagem , Orexinas , SonoRESUMO
INTRODUCTION: Predicting impairment in preterm children is challenging. Our aim is to explore the association between MRI at term-equivalent age (TEA) and neurocognitive outcomes in late childhood and to assess whether the addition of EEG improves prognostication. METHODS: This prospective observational study included forty infants with gestational age 24 + 0-30 + 6. Children were monitored with multichannel EEG for 72 h after birth. Total absolute band power for the delta band on day 2 was calculated. Brain MRI was performed at TEA and scored according to the Kidokoro scoring system. At 10-12 years of age, we evaluated neurocognitive outcomes with Wechsler Intelligence Scale for Children 4th edition, Vineland adaptive behavior scales 2nd edition and Behavior Rating Inventory of Executive Function. We performed linear regression analysis to examine the association between outcomes and MRI and EEG, respectively, and multiple regression analysis to explore the combination of MRI and EEG. RESULTS: Forty infants were included. There was a significant association between global brain abnormality score and composite outcomes of WISC and Vineland test, but not the BRIEF test. The adjusted R2 was 0.16 and 0.08, respectively. For EEG, adjusted R2 was 0.34 and 0.15, respectively. When combining MRI and EEG data, adjusted R2 changed to 0.36 for WISC and 0.16 for the Vineland test. CONCLUSION: There was a small association between TEA MRI and neurocognitive outcomes in late childhood. Adding EEG to the model improved the explained variance. Combining EEG and MRI data did not have any additional benefit over EEG alone.