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Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients.

ABSTRACT: Focal cortical dysplasia (FCD) is a malformation of the cerebral cortex with poorly-defined epileptogenic zones (EZs), and poor surgical outcome in FCD is associated with inaccurate localization of the EZ. Hence, identifying novel epileptogenic markers to aid in the localization of EZ in patients with FCD is very much needed. High-throughput gene expression studies of FCD samples have the potential to uncover molecular changes underlying the epileptogenic process and identify novel markers for delineating the EZ. For this purpose, we, for the first time performed RNA sequencing of surgically resected paired tissue samples obtained from electrocorticographically graded high (MAX) and low spiking (MIN) regions of FCD type II patients and autopsy controls. We identified significant changes in the MAX samples of the FCD type II patients when compared to non-epileptic controls, but not in the case of MIN samples. We found significant enrichment for myelination, oligodendrocyte development and differentiation, neuronal and axon ensheathment, phospholipid metabolism, cell adhesion and cytoskeleton, semaphorins, and ion channels in the MAX region. Through the integration of both MAX vs non-epileptic control and MAX vs MIN RNA sequencing (RNA Seq) data, PLP1, PLLP, UGT8, KLK6, SOX10, MOG, MAG, MOBP, ANLN, ERMN, SPP1, CLDN11, TNC, GPR37, SLC12A2, ABCA2, ABCA8, ASPA, P2RX7, CERS2, MAP4K4, TF, CTGF, Semaphorins, Opalin, FGFs, CALB2, and TNC were identified as potential key regulators of multiple pathways related to FCD type II pathology. We have identified novel epileptogenic marker elements that may contribute to epileptogenicity in patients with FCD and could be possible markers for the localization of EZ.

SUBMITTER: Srivastava A

PROVIDER: S-EPMC8305866 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients.

Srivastava Arpna A Kumar Krishan K Banerjee Jyotirmoy J Tripathi Manjari M Dubey Vivek V Sharma Devina D Yadav Nitin N Sharma M C MC Lalwani Sanjeev S Doddamani Ramesh R Chandra P Sarat PS Dixit Aparna Banerjee AB

Molecular brain 20210723 1

Focal cortical dysplasia (FCD) is a malformation of the cerebral cortex with poorly-defined epileptogenic zones (EZs), and poor surgical outcome in FCD is associated with inaccurate localization of the EZ. Hence, identifying novel epileptogenic markers to aid in the localization of EZ in patients with FCD is very much needed. High-throughput gene expression studies of FCD samples have the potential to uncover molecular changes underlying the epileptogenic process and identify novel markers for d ...[more]

PMID: 34301297

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Project description:Dendritic spines are the postsynaptic sites for most excitatory glutamatergic synapses. We previously demonstrated a severe spine loss and synaptic reorganization in human neocortices presenting Type II focal cortical dysplasia (FCD), a developmental malformation and frequent cause of drug-resistant focal epilepsy. We extend the findings, investigating the potential role of complement components C1q and C3 in synaptic pruning imbalance. Data from Type II FCD were compared with those obtained in focal epilepsies with different etiologies. Neocortical tissues were collected from 20 subjects, mainly adults with a mean age at surgery of 31 years, admitted to epilepsy surgery with a neuropathological diagnosis of: cryptogenic, temporal lobe epilepsy with hippocampal sclerosis, and Type IIa/b FCD. Dendritic spine density quantitation, evaluated in a previous paper using Golgi impregnation, was available in a subgroup. Immunohistochemistry, in situ hybridization, electron microscopy, and organotypic cultures were utilized to study complement/microglial activation patterns. FCD Type II samples presenting dendritic spine loss were characterized by an activation of the classical complement pathway and microglial reactivity. In the same samples, a close relationship between microglial cells and dendritic segments/synapses was found. These features were consistently observed in Type IIb FCD and in 1 of 3 Type IIa cases. In other patient groups and in perilesional areas outside the dysplasia, not presenting spine loss, these features were not observed. In vitro treatment with complement proteins of organotypic slices of cortical tissue with no sign of FCD induced a reduction in dendritic spine density. These data suggest that dysregulation of the complement system plays a role in microglia-mediated spine loss. This mechanism, known to be involved in the removal of redundant synapses during development, is likely reactivated in Type II FCD, particularly in Type IIb; local treatment with anticomplement drugs could in principle modify the course of disease in these patients.

Project description:ObjectiveFavorable seizure outcome is reported following resection of bottom-of-sulcus dysplasia (BOSD). We assessed the distribution of epileptogenicity and dysplasia in and around BOSD to better understand this clinical outcome and the optimal surgical approach.MethodsWe studied 27 children and adolescents with magnetic resonance imaging (MRI)-positive BOSD who underwent epilepsy surgery; 85% became seizure-free postresection (median = 5.0 years follow-up). All patients had resection of the dysplastic sulcus, and 11 had additional resection of the gyral crown (GC) or adjacent gyri (AG). Markers of epileptogenicity were relative cortical hypometabolism on preoperative 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and spiking, ripples, fast ripples, spike-high-frequency oscillation cross-rate, and phase amplitude coupling (PAC) on preresection and postresection electrocorticography (ECoG), all analyzed at the bottom-of-sulcus (BOS), top-of-sulcus (TOS), GC, and AG. Markers of dysplasia were increased cortical thickness on preoperative MRI, and dysmorphic neuron density and variant allele frequency of somatic MTOR mutations in resected tissue, analyzed at similar locations.ResultsRelative cortical metabolism was significantly reduced and ECoG markers were significantly increased at the BOS compared to other regions. Apart from spiking and PAC, which were greater at the TOS compared to the GC, there were no significant differences in PET and other ECoG markers between the TOS, GC, and AG, suggesting a cutoff of epileptogenicity at the TOS rather than a tapering gradient on the cortical surface. MRI and tissue markers of dysplasia were all maximal in the BOS, reduced in the TOS, and mostly absent in the GC. Spiking and PAC reduced significantly over the GC after resection of the dysplastic sulcus.SignificanceThese findings support the concept that dysplasia and intrinsic epileptogenicity are mostly limited to the dysplastic sulcus in BOSD and support resection or ablation confined to the MRI-visible lesion as a first-line surgical approach. 18 F-FDG PET and ECoG abnormalities in surrounding cortex seem to be secondary phenomena.

Project description:OBJECTIVE:Focal cortical dysplasia (FCD) lesion detection and subtyping remain challenging on conventional MRI. New diffusion models such as the spherical mean technique (SMT) and neurite orientation dispersion and density imaging (NODDI) provide measurements that potentially produce more specific maps of abnormal tissue microstructure. This study aims to assess the SMT and NODDI maps for computational and radiological lesion characterization compared to standard fractional anisotropy (FA) and mean diffusivity (MD). METHODS:SMT, NODDI, FA, and MD maps were calculated for 33 pediatric patients with suspected FCD (18 histologically confirmed). Two neuroradiologists scored lesion visibility on clinical images and diffusion maps. Signal profile changes within lesions and homologous regions were quantified using a surface-based approach. Diffusion parameter changes at multiple cortical depths were statistically compared between FCD type IIa and type IIb. RESULTS:Compared to fluid-attenuated inversion recovery (FLAIR) or T1-weighted imaging, lesions conspicuity on NODDI intracellular volume fraction (ICVF) maps was better/equal/worse in 5/14/14 patients, respectively, while on SMT intra-neurite volume fraction (INVF) in 3/3/27. Compared to FA or MD, lesion conspicuity on the ICVF was better/equal/worse in 27/4/2, while on the INVF in 20/7/6. Quantitative signal profiling demonstrated significant ICVF and INVF reductions in the lesions, whereas SMT microscopic mean, radial, and axial diffusivities were significantly increased. FCD type IIb exhibited greater changes than FCD type IIa. No changes were detected on FA or MD profiles. SIGNIFICANCE:FCD lesion-specific signal changes were found in ICVF and INVF but not in FA and MD maps. ICVF and INVF showed greater contrast than FLAIR in some cases and had consistent signal changes specific to FCD, suggesting that they could improve current presurgical pediatric epilepsy imaging protocols and can provide features useful for automated lesion detection.

Dataset Information

Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients.

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Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients.

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