Expression of neurodegenerative disease‐related proteins and caspase‐3 in glioneuronal tumours

Prabowo, Avanita S.; Iyer, Anand M.; Veersema, Tim J.; Anink, Jasper J.; Meeteren, Antoinette Y. N. Schouten–van; Spliet, Wim G.M.; Rijen, P.C. van; Ferrier, Cyrille H.; Thom, Maria; Aronica, Eleonora

doi:10.1111/nan.12143

Cited by 26 publications

(17 citation statements)

References 88 publications

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“…In ganglioglioma controls, Tbr1 nuclear labelling of dysmorphic neurons was noted in one case (Supporting Information Figure 1A); a variable proportion also showed cytoplasmic OTX1 positive labelling (Supporting Information Figure 1B) but more consistent labelling was observed with SOX2 (Supporting Information Figure 1C). Little evidence of nuclear labelling of gangliogliomas for OLIG2 was seen (Supporting Information Figure 1D) but strong labelling with calbindin as previously noted (Supporting Information Figure 1E) and also with p62 as previously reported . Dysmorphic cells in ganglioglioma infrequently labelled with MCM2 in contrast to MVNT (Supporting Information Figure 1F).…”

Section: Resultssupporting

confidence: 79%

Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?

et al. 2017

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Multinodular and vacuolating neuronal tumor (MVNT) is a new pattern of neuronal tumour included in the recently revised WHO 2016 classification of tumors of the CNS. There are 15 reports in the literature to date. They are typically associated with late onset epilepsy and a neoplastic vs. malformative biology has been questioned. We present a series of ten cases and compare their pathological and genetic features to better characterized epilepsy‐associated malformations including focal cortical dysplasia type II (FCDII) and low‐grade epilepsy‐associated tumors (LEAT). Clinical and neuroradiology data were reviewed and a broad immunohistochemistry panel was applied to explore neuronal and glial differentiation, interneuronal populations, mTOR pathway activation and neurodegenerative changes. Next generation sequencing was performed for targeted multi‐gene analysis to identify mutations common to epilepsy lesions including FCDII and LEAT. All of the surgical cases in this series presented with seizures, and were located in the temporal lobe. There was a lack of any progressive changes on serial pre‐operative MRI and a mean age at surgery of 45 years. The vacuolated cells of the lesion expressed mature neuronal markers (neurofilament/SMI32, MAP2, synaptophysin). Prominent labelling of the lesional cells for developmentally regulated proteins (OTX1, TBR1, SOX2, MAP1b, CD34, GFAPδ) and oligodendroglial lineage markers (OLIG2, SMI94) was observed. No mutations were detected in the mTOR pathway genes, BRAF, FGFR1 or MYB. Clinical, pathological and genetic data could indicate that MVNT aligns more with a malformative lesion than a true neoplasm with origin from a progenitor neuro‐glial cell type showing aberrant maturation.

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Section: Resultssupporting

confidence: 79%

Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?

et al. 2017

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“…We are aware that some techniques, such as western blot, are more suitable to quantify protein abundance (GFAP and CS‐56), and for this reason we named our evaluation as semiquantitative. However, if properly done, immunohistochemistry can be quantified and several studies have done so …”

Section: Discussionmentioning

confidence: 99%

Temporal lobe epilepsy patients with severe hippocampal neuron loss but normal hippocampal volume: Extracellular matrix molecules are important for the maintenance of hippocampal volume

et al. 2015

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SUMMARYObjective: Hippocampal sclerosis is a common finding in patients with temporal lobe epilepsy (TLE), and magnetic resonance imaging (MRI) studies associate the reduction of hippocampal volume with the neuron loss seen on histologic evaluation. Astrogliosis and increased levels of chondroitin sulfate, a major component of brain extracellular matrix, are also seen in hippocampal sclerosis. Our aim was to evaluate the association between hippocampal volume and chondroitin sulfate, as well as neuronal and astroglial populations in the hippocampus of patients with TLE. Methods: Patients with drug-resistant TLE were subdivided, according to hippocampal volume measured by MRI, into two groups: hippocampal atrophy (HA) or normal volume (NV) cases. Hippocampi from TLE patients and age-matched controls were submitted to immunohistochemistry to evaluate neuronal population, astroglial population, and chondroitin sulfate expression with antibodies against neuron nuclei protein (NeuN), glial fibrillary acidic protein (GFAP), and chondroitin sulfate (CS-56) antigens, respectively. Results: Both TLE groups were clinically similar. NV cases had higher hippocampal volume, both ipsilateral and contralateral, when compared to HA. Compared to controls, NV and HA patients had reduced neuron density, and increased GFAP and CS-56 immunopositive area. There was no statistical difference between NV and HA groups in neuron density or immunopositive areas for GFAP and CS-56. Hippocampal volume correlated positively with neuron density in CA1 and prosubiculum, and with immunopositive areas for CS-56 in CA1, and negatively with immunopositive area for GFAP in CA1. Multiple linear regression analysis indicated that both neuron density and CS-56 immunopositive area in CA1 were statistically significant predictors of hippocampal volume. Significance: Our findings indicate that neuron density and chondroitin sulfate immunopositive area in the CA1 subfield are crucial for the hippocampal volume, and that chondroitin sulfate is important for the maintenance of a normal hippocampal volume in some cases with severe neuron loss.

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“…Several studies revealed an association of dentate gyrus (DG) pathological changes with long-term seizure histories and cognitive dysfunction suggesting a compromised regenerative capacity of the DG in a subpopulation of TLE patients (Blumcke et al, 2009; Coras et al, 2010). Further evidence suggests similar mechanisms underlying cellular aging and neurodegeneration are also widespread in other forms of epilepsy such as in developmental lesions associated with chronic intractable epilepsy (Iyer et al, 2014; Prabowo et al, 2014). …”

Section: Glial Activation – a Common Histopathological Finding In mentioning

confidence: 99%

Comorbidities in Neurology: Is adenosine the common link?

Boison

Aronica

2015

Neuropharmacology

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Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the ‘adenosine hypothesis of comorbidities’ implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic ‘comorbidity model’, in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain comorbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.

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Expression of neurodegenerative disease‐related proteins and caspase‐3 in glioneuronal tumours

Abstract: Our observations in GNT provide evidence of premature activation of mechanisms of neurodegeneration which are associated with the clinical course of epilepsy in patient with GG.

Cited by 26 publications

References 88 publications

Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?

Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?

Temporal lobe epilepsy patients with severe hippocampal neuron loss but normal hippocampal volume: Extracellular matrix molecules are important for the maintenance of hippocampal volume

Comorbidities in Neurology: Is adenosine the common link?

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