Dataset Information

Glial regenerative cell types in the superficial cortex in cortical dysplasia subtypes.

ABSTRACT:

Purpose

Focal Cortical Dysplasias (FCD) are localized malformative brain lesions in epilepsy. FCD3a associated with hippocampal sclerosis, affects the superficial cortex and is presumed to have an 'acquired' rather than developmental origin. Precursor cells may arise outside neurogenic zones including cortical layer I. Our aim was to characterise subsets of glial progenitor cells in the superficial cortical layers, known to be involved in gliosis and gliogenesis and that could distinguish FCD3a from other subtypes.

Methods

Using immunohistochemistry we quantified the density of glial progenitor subsets in superficial cortex layers using markers against PAX6, GFAP, Olig2 and PDGFR? and proliferation marker MCM2 in ten FCD3a cases compared to 18 other FCD types and 11 non-FCD controls.

Key findings

Glial progenitor cells types were present in the cortical layer I and II in all FCD groups. GFAP cells frequently expressed PAX6 and significantly higher GFAP/PAX6 than GFAP/MCM2 cell densities were identified in the FCD3a group (p < 0.05). Olig2 cell densities were significantly higher in FCD3b than FCD3a (p = 0.002) and significantly higher GFAP/MCM2 compared to PDGFR?/MCM2 cell densities were identified in both FCD3b and FCD2 groups. There was no correlation between cell densities and the age of patients at surgery and between cortical regions.

Significance

Immature and proliferative glial populations across FCD variants reflect reactive cell types and differences may provide insight into underlying pathomechanisms. Higher PAX6 expression in astroglial cells in FCD3a may indicate a switch to astrocytic maturation and enhanced superficial gliosis. Higher Olig2 and GFAP/MCM2 densities in FCD3b may reflect margins of the tumour infiltration zone rather than true cortical dysplasia.

SUBMITTER: Liu JYW

PROVIDER: S-EPMC7829594 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Glial regenerative cell types in the superficial cortex in cortical dysplasia subtypes.

Liu Joan Y W JYW Reeves Cheryl C van der Pijl Rianne R Thom Maria M

Epilepsy research 20201210

<h4>Purpose</h4>Focal Cortical Dysplasias (FCD) are localized malformative brain lesions in epilepsy. FCD3a associated with hippocampal sclerosis, affects the superficial cortex and is presumed to have an 'acquired' rather than developmental origin. Precursor cells may arise outside neurogenic zones including cortical layer I. Our aim was to characterise subsets of glial progenitor cells in the superficial cortical layers, known to be involved in gliosis and gliogenesis and that could distinguis ...[more]

PMID: 33370704

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Project description:Background and Purpose- We investigated cortical superficial siderosis (cSS) progression and its clinical relevance for incident lobar intracerebral hemorrhage (ICH) risk, in probable cerebral amyloid angiopathy presenting with neurological symptoms and without ICH at baseline. Methods- Consecutive patients meeting modified Boston criteria for probable cerebral amyloid angiopathy from a single-center cohort who underwent magnetic resonance imaging (MRI) at baseline and during follow-up were analyzed. cSS progression was assessed by comparison of the baseline and follow-up images. Patients were followed prospectively for incident symptomatic ICH. cSS progression and first-ever ICH risk were investigated in Cox proportional hazard models adjusting for confounders. Results- The cohort included 118 probable cerebral amyloid angiopathy patients: 72 (61%) presented with transient focal neurological episodes and 46 (39%) with cognitive complaints prompting the baseline MRI investigation. Fifty-two patients (44.1%) had cSS at baseline. During a median scan interval of 2.2 years (interquartile range, 1.2-4.4 years) between the baseline (ie, first) MRI and the latest MRI, cSS progression was detected in 33 (28%) patients. In multivariable logistic regression, baseline cSS presence (odds ratio, 4.04; 95% CI, 1.53-10.70; P=0.005), especially disseminated cSS (odds ratio, 9.12; 95% CI, 2.85-29.18; P<0.0001) and appearance of new lobar microbleeds (odds ratio, 4.24; 95% CI, 1.29-13.9; P=0.017) were independent predictors of cSS progression. For patients without an ICH during the interscan interval (n=105) and subsequent follow-up (median postfinal MRI time, 1.34; interquartile range, 0.3-3 years), cSS progression independently predicted increased symptomatic ICH risk (hazard ratio, 3.76; 95% CI, 1.37-10.35; P=0.010). Conclusions- Our results suggest that cSS evolution may be a useful biomarker for assessing disease progression and ICH risk in cerebral amyloid angiopathy patients and a candidate biomarker for clinical studies and trials.

Project description:Introduction: Focal cortical dysplasias (FCDs) are a group of malformations of cortical development that constitute a common cause of drug-resistant epilepsy, often subjected to neurosurgery, with a suboptimal long-term outcome. The past few years have witnessed a dramatic leap in our understanding of the molecular basis of FCD. This study aimed to provide an updated review on the genomic and epigenetic advances underlying FCD etiology, to understand a genotype-phenotype correlation and identify priorities to lead future translational research. Methods: A scoping review of the literature was conducted, according to previously described methods. A comprehensive search strategy was applied in PubMed, Embase, and Web of Science from inception to 07 May 2020. References were screened based on title and abstract, and posteriorly full-text articles were assessed for inclusion according to eligibility criteria. Studies with novel gene variants or epigenetic regulatory mechanisms in patients that underwent epilepsy surgery, with histopathological diagnosis of FCD type I or II according to Palmini's or the ILAE classification system, were included. Data were extracted and summarized for an overview of evidence. Results: Of 1,156 candidate papers, 39 met the study criteria and were included in this review. The advent of next-generation sequencing enabled the detection in resected FCD tissue of low-level brain somatic mutations that occurred during embryonic corticogenesis. The mammalian target of rapamycin (mTOR) signaling pathway, involved in neuronal growth and migration, is the key player in the pathogenesis of FCD II. Somatic gain-of-function variants in MTOR and its activators as well as germline, somatic, and second-hit mosaic loss-of-function variants in its related repressors have been reported. However, the genetic background of FCD type I remains elusive, with a pleomorphic repertoire of genes affected. DNA methylation and microRNAs were the two epigenetic mechanisms that proved to have a functional role in FCD and may represent molecular biomarkers. Conclusion: Further research into the possible pathogenic causes of both FCD subtypes is required, incorporating single-cell DNA/RNA sequencing as well as methylome and proteomic analysis. The collected data call for an integrated clinicopathologic and molecular genetic diagnosis in current practice not only to improve diagnostic accuracy but also to guide the development of future targeted treatments.

Dataset Information

Glial regenerative cell types in the superficial cortex in cortical dysplasia subtypes.

Purpose

Methods

Key findings

Significance

Publications

Glial regenerative cell types in the superficial cortex in cortical dysplasia subtypes.

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