Hippocampal morphometry in sudden and unexpected death in epilepsy (SUDEP)

Somani, A.; Zborovschi, A.-B.; Liu, Y.; Patodia, S.; Michalak, Z.; Sisodiya, S.; Thom, M.

doi:10.1101/522300

Home/Archive/bioRxiv

bioRxiv · 10.1101/522300

Hippocampal morphometry in sudden and unexpected death in epilepsy (SUDEP)

Somani, A.·Zborovschi, A.-B.·Liu, Y.·Patodia, S.·Michalak, Z.·Sisodiya, S.·Thom, M.

View original source ↗Export metadata ↓

Abstract

ObjectiveTo determine hippocampal morphometric parameters, including granule cell dispersion and features of malrotation, as potential biomarkers for SUDEP from an archival post-mortem series.\n\nMethodsIn a retrospective study of 187 archival post-mortems from three groups, SUDEP (68; 14 with hippocampal sclerosis (HS)), non-SUDEP epilepsy controls (EP-C =66; 25 with HS) and non-epilepsy controls (NEC= 53), Nissl/H&E stained sections from left and right hippocampus from five coronal levels were digitised. Image analysis was carried out for granule cell layer (GCL) thickness and measurements of hippocampal dimensions (HD) for shape [width (HD1), height (HD2)] and medial hippocampal positioning in relation to the parahippocampal gyrus (PHG) length (HD3). A qualitative evaluation of hippocampal malrotational (HMAL) features, dentate gyrus invaginations (DGI) and subicular/CA1 folds (SCF) was also made.\n\nResultsGCL thickness was increased in HS more than those without (p<0.001). In non-HS cases increased GCL thickness was noted in EP-C compared to NEC (p<0.05) but not between SUDEP and NEC. There was no significant difference in the frequency of DGI, SCF, measurements of hippocampal shape (HD1, HD2 or ratio) or medial positioning between SUDEP, EP-C and NEC groups, when factoring in HS, coronal level and age at death. Comparison between left and right sides within cases showed significantly greater PHG lengths (HD3) on the right side in the SUDEP group only (p=0.018)\n\nConclusionsNo hippocampal morphometric features were identified in support of either excessive granule cell dispersion or features of HMAL as biomarkers for SUDEP. Asymmetries in PHG measurements in SUDEP warrant further investigation as they may indicate abnormal central autonomic networks.

Source connections

Published article ↗

Explore related subjects

pathology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Somani, A., Zborovschi, A.-B., Liu, Y., Patodia, S., Michalak, Z., Sisodiya, S., Thom, M.. 2019-01-17. Hippocampal morphometry in sudden and unexpected death in epilepsy (SUDEP). https://doi.org/10.1101/522300

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗

bioRxiv2019

Detection of apoptosis and matrical degeneration within the intervertebral discs of rats due to passive cigarette smoking.

Although low-back pain is considered to be associated with cigarette smoking, the influence of cigarette smoking on the intervertebral discs (IVD) has not been confirmed. We established a rat model of passive cigarette smoking-induced IVD degeneration, and investigated the cytohistological changes in the IVD and the accompanying changes in gene expression. IVD from rats exposed to 8 weeks of passive cigarette smoking were stained with Elastica van Gieson, and exhibited marked destruction of the supportive structure of the reticular matrix in the nucleus pulposus (NP). Positive signals on safranin O, alcian blue, type II collagen and aggrecan staining were decreased in the destroyed structure. Safranin O and type II collagen signals were also decreased in the cartilage end-plate (CEP) after 4- and 8-weeks of cigarette smoking. In the CEP, the potential for apoptosis was increased significantly, as demonstrated by staining for single-strand DNA. However, there were no signs of apoptosis in the NP or annulus fibrosus cells. Based on these findings, we concluded that passive cigarette smoking-induced stress stimuli first affect the CEP through blood flow due to the histological proximity, thereby stimulating chondrocyte apoptosis and reduction of the extracellular matrix (ECM). This leads to reduction of the ECM in the NP, destroying the NP matrix, which can then progress to IVD degeneration.

pathology↗

bioRxiv2019

Extra-cellular matrix induced by steroids through a G-protein coupled receptor in a Drosophila model of renal fibrosis

Aldosterone is produced by the mammalian adrenal cortex to modulate blood pressure and fluid balance, however excessive, prolonged aldosterone production promotes fibrosis and kidney failure. How aldosterone triggers disease may involve actions that are independent of its canonical mineralocorticoid receptor. Here we present a Drosophila model of renal pathology caused by excess extra-cellular matrix formation, stimulated by exogenous aldosterone and insect ecdysone steroids. Chronic administration of aldosterone or ecdysone induces expression and accumulation of collagen-like pericardin at adult nephrocytes - podocyte-like cells that filter circulating hemolymph. Excess pericardin deposition disrupts nephrocyte (glomerular) filtration and causes proteinuria in Drosophila, hallmarks of mammalian kidney failure. Steroid-induced pericardin arises from cardiomyocytes associated with nephrocytes, reflecting an analogous role of mammalian myofibroblasts in fibrotic disease. Remarkably, the canonical ecdysteroid nuclear hormone receptor, ecdysone receptor EcR, is not required for aldosterone or ecdysone to stimulate pericardin production or associated renal pathology. Instead, these hormones require a cardiomyocyte-associated G-protein coupled receptor, dopamine-EcR (dopEcR), a membrane-associated receptor previously characterized in the fly brain as affecting behavior. This Drosophila renal disease model reveals a novel signaling pathway through which steroids may potentially modulate human fibrosis through proposed orthologs of dopEcR.\n\nSignificance StatementAldosterone regulates salt and fluid homeostasis, yet excess aldosterone contributes to renal fibrosis. Aldosterone acts through a nuclear hormone receptor, but an elusive, G-protein coupled receptor (GPCR) is thought to also mediate the hormones pathology. Here we introduce a Drosophila model of renal fibrosis. Flies treated with human aldosterone produce excess extra-cellular matrix and that causes kidney pathology. Flies treated with the insect steroid ecdysone produce similar pathology, and from this analogous response we identify an alternative receptor through which steroids mediate renal fibrosis -- the GPCR dopamine-Ecdysone Receptor (dopEcR). dopEcR functions in heart muscle cells associated with nephrocytes, analogous to the role of myofibroblasts in human fibrosis. This finding opens avenues to identify mammalian GPCR homologs of dopEcR through which aldosterone mediates renal fibrosis.

pathology↗