Early surgery prolongs professional activity in IDH mutant low-grade glioma patients: a policy change analysis

BackgroundUntil 2015, Dutch guidelines recommended follow-up and biopsy rather than surgery as initial care for suspected low-grade gliomas (LGG). Given evidence that surgery could extend patient survival, our center stopped following this guideline on January 1, 2010 and opted for early maximal safe resection of LGG. The effects of early surgery on the ability of patients to work remains little documented. MethodsA total of 104 patients operated on at our center between January 2000 and April 2013 and diagnosed with the WHO 2016 grade 2 astrocytoma, IDH mutant or oligodendroglioma, IDH mutant and deleted 1p19q were included. The clinical characteristics, survival, and work history of patients operated on before or after January 2010 were obtained from the patients' records and compared. The minimal follow-up was 8 years. ResultsAs per policy change, the interval between radiological diagnosis and first surgery decreased significantly after 2010. Likewise, before 2010, 25.8% of tumors were initially biopsied, 51.6% were resected under anesthesia, and 22.5% under awake conditions versus 14.3%, 23.8%, and 61.9% after this date (p < 0.001). The severity of permanent postoperative neurological deficits decreased after 2010. In total, 82.5% of the patients returned to work postoperatively before 2010 versus 100% after 2010. The postoperative control of epilepsy increased significantly after 2010 (74.4% vs. 47.9%). The median time from diagnosis to a definitive incapacity to work increased by more than 2 years after 2010 (88.7 vs. 62.2 months). ConclusionA policy shift towards early aggressive surgical treatment of IDH mutant LGG is safe and prolongs the patients' ability to work

Differential expression patterns of chloride transporters, Na+-K+-2Cl--cotransporter and K+-Cl--cotransporter, in epilepsy-associated malformations of cortical development.

Malformations of cortical development are recognized causes of chronic medically intractable epilepsy. An increasing number of observations suggests an important role for cation-chloride co-transporters (CCTs) in controlling neuronal function. Deregulation of their expression may contribute to the mechanisms of hyperexcitability that lead to seizures. In the present study the expression and cell-specific distribution of Na+-K+-2Cl--cotransporter (NKCC1) and K+-Cl--cotransporter (KCC2) were studied immunocytochemically in different developmental lesions, including focal cortical dysplasia (FCD) type IIB (n=9), hemimegalencephaly (HMEG, n=6) and ganglioglioma (GG, n=9) from patients with medically intractable epilepsy and in age-matched controls. In normal control adult cortex, NKCC1 displayed low neuronal and glial expression levels. In contrast KCC2 showed strong and diffuse neuropil staining. Notable glial immunoreactivity (IR) was not found for KCC2. NKCC1 was highly expressed in the majority of FCD, HMEG and GG specimens. NKCC1 IR was observed in neurons of different size, including large dysplastic neurons, in balloon cells (in FCD and HMEG cases) and in glial cells with astrocytic morphology. The immunoreactivity pattern of KCC2 in FCD, HMEG and GG specimens was characterized by less neuropil staining and more intrasomatic IR compared with control. KCC2 IR was observed in neurons of different size, including large dysplastic neurons, but not in balloon cells or in glial cells with astrocytic morphology. Double-labeling experiments confirmed the differential cellular distribution of the two CCTs and their expression in GABA(A) receptor (alpha1 subunit)-positive dysplastic neurons. The cellular distribution of CCTs, with high expression of NKCC1 in dysplastic neurons and altered subcellular distribution of KCC2 resembles that of immature cortex and suggests a possible contribution of CCTs to the high epileptogenicity of malformations of cortical development

FLAIR images at 7 Tesla MRI highlight the ependyma and the outer layers of the cerebral cortex.

Objectives: Fluid-attenuated inversion recovery (FLAIR) imaging is an important clinical ‘work horse’ for brain MRI and has proven to facilitate imaging of both intracortical lesions as well as cortical layers at 7 T MRI. A prominent observation on 7 T FLAIR images is a hyperintense rim at the cortical surface and around the ventricles.We aimed to clarify the anatomical correlates and underlying contrast mechanisms of this hyperintense rim. Materials and Methods: Two experiments with post-mortem human brain tissue were performed. FLAIR and T2-weighted imageswere obtained at typical in vivo (0.8mmisotropic) and high resolution (0.25mmisotropic). At one location the cortical surfacewas partly removed, and scanned again. Imagingwas followed by histological and immunohistochemical analysis. Additionally, several simulations were performed to evaluate the potential contribution from an artifact due to water diffusion. Results: The hyperintense rim corresponded to the outer – glia rich – layer of the cortex and disappeared upon removal of that layer. At the ventricles, the rim corresponded to the ependymal layer, and was not present at white matter/fluid borders at an artificial cut. The simulations supported the hypothesis that the hyperintense rim reflects the tissue properties in the outer cortical layers (or ependymal layer for the ventricles), and is not merely an artifact, although not all observations were explained by the simulated model of the contrast mechanism. Conclusions: 7 T FLAIR seems to amplify the signal from layers I–III of the cortex and the ependyma around the ventricles. Although diffusion of water from layer I into CSF does contribute to this effect, a long T2 relaxation time constant in layer I, and probably also layer II–III, is most likely themajor contributor, since the rimdisappears upon removal of that layer. This knowledge can help the interpretation of imaging results in cortical development and in patients with cortical pathology

White Matter Lesions Are Not Related to beta-Amyloid Deposition in an Autopsy-Based Study.

Contains fulltext : 96523.pdf (publisher's version ) (Open Access)Population-based studies have investigated the relation between beta-amyloid levels in cerebrospinal fluid or plasma and white matter lesions (WMLs). However, these circulating levels of beta-amyloid in cerebrospinal fluid or plasma may not reliably reflect the actual degree of amyloid present in the brain. Therefore, we investigated the relation between WMLs and beta-amyloid plaques and amyloid angiopathy in brain tissue. WML on MRI or CT were rated in 28 nondemented patients whose neuroimaging was available prior to death. beta-amyloid in plaques and arterioles were immunohistochemically stained and quantified in postmortem brain necropsies. WMLs were present in 43% of the total population. Both cortex and periventricular region showed no differences for beta-amyloid deposition in either plaques or blood vessel walls in patients with WMLs compared to those without WMLs. Thus, our results indicate that there is no relation between the degree of WMLs and beta-amyloid deposition in the brain

Increased matrix metalloproteinases expression in tuberous sclerosis complex: modulation by microRNA 146a and 147b<i> in vitro</i>

Aim: Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) control proteolysis within the extracellular matrix (ECM) of the brain. Dysfunction of this enzymatic system due to brain inflammation can disrupt the blood-brain barrier (BBB) and has been implicated in the pathogenesis of epilepsy. However, this has not been extensively studied in the epileptogenic human brain. Methods: We investigated the expression and cellular localization of major MMPs (MMP2, MMP3, MMP9 and MMP14) and TIMPs (TIMP1, TIMP2, TIMP3 and TIMP4) using quantitative real-time polymerase chain reaction (RT-PCR) and immunohistochemistry in resected epileptogenic brain tissue from patients with tuberous sclerosis complex (TSC), a severe neurodevelopmental disorder characterized by intractable epilepsy and prominent neuroinflammation. Furthermore, we determined whether anti-inflammatory microRNAs, miR146a and miR147b, which can regulate gene expression at the transcriptional level, could attenuate dysregulated MMP and TIMP expression in TSC tuber-derived astroglial cultures. Results: We demonstrated higher mRNA and protein expression of MMPs and TIMPs in TSC tubers compared to control and perituberal brain tissue, particularly in dysmorphic neurons and giant cells, as well as in reactive astrocytes, which was associated with BBB dysfunction. More importantly, IL-1β-induced dysregulation of MMP3, TIMP2, TIMP3 and TIMP4 could be rescued by miR146a and miR147b in tuber-derived TSC cultures. Conclusions: This study provides evidence of dysregulation of the MMP/TIMP proteolytic system in TSC, which is associated with BBB dysfunction. As dysregulated MMP and TIMP expression can be ameliorated in vitro by miR146a and miR147b, these miRNAs deserve further investigation as a novel therapeutic approach

Landscape of chromosomal copy number aberrations in gangliogliomas and dysembryoplastic neuroepithelial tumours

Item does not contain fulltextAIM: Gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumours (DNTs) represent the most common histological entities within the spectrum of glioneuronal tumours (GNTs). The wide variability of morphological features complicates histological classification, including discrimination from prognostically distinct diffuse low-grade astrocytomas (AIIs). This study was performed to increase our understanding of these tumours. METHODS: We studied chromosomal copy number aberrations (CNAs) by genome-wide sequencing in a large cohort of GNTs and linked these to comprehensive histological analysis and clinical characteristics. One hundred fourteen GNTs were studied: 50 GGs and 64 DNTs. Also, a data set of CNAs from 38 diffuse AIIs was included. RESULTS: The most frequent CNAs in both GGs and DNTs were gains at chromosomes 5 and 7, often concurrent, and gain at chromosome 6. None of the CNAs was linked to histological subtype, immunohistochemical features or to clinical characteristics. Comparison of AIIs and diffuse GNTs revealed that gain at whole chromosome 5 is only observed in GNTs. CNA patterns indicative of chromothripsis were detected in three GNTs. CONCLUSION: We conclude that GNTs with diverse morphologies share molecular features, and our findings support the need to improve classification and differential diagnosis of tumour entities within the spectrum of GNTs, as well as their distinction from other gliomas

miR147b: A novel key regulator of interleukin 1 beta-mediated inflammation in human astrocytes

Astrocytes are important mediators of inflammatory processes in the brain and seem to play an important role in several neurological disorders, including epilepsy. Recent studies show that astrocytes produce several microRNAs, which may function as crucial regulators of inflammatory pathways and could be used as therapeutic target. We aim to study which miRNAs are produced by astrocytes during IL-1β mediated inflammatory conditions in vitro, as well as their functional role and to validate these findings in human epileptogenic brain tissue. Sequencing was used to assess miRNA and mRNA expression in IL-1β-stimulated human fetal astrocyte cultures. miRNAs were overexpressed in cell cultures using miRNA mimics. Expression of miRNAs in resected brain tissue from patients with tuberous sclerosis complex or temporal lobe epilepsy with hippocampal sclerosis was examined using in situ hybridization. Two differentially expressed miRNAs were found: miR146a and miR147b, which were associated with increased expression of genes related to the immune/inflammatory response. As previously reported for miR146a, overexpression of miR147b reduced the expression of the pro-inflammatory mediators IL-6 and COX-2 after IL-1β stimulation in both astrocyte and tuberous sclerosis complex cell cultures. miR146a and miR147b overexpression decreased proliferation of astrocytes and promoted neuronal differentiation of human neural stem cells. Similarly to previous evidence for miR146a, miR147b was increased expressed in astrocytes in epileptogenic brain. Due to their anti-inflammatory effects, ability to restore aberrant astrocytic proliferation and promote neuronal differentiation, miR146a and miR147b deserve further investigation as potential therapeutic targets in neurological disorders associated with inflammation, such as epilepsy