No abstract

2Genetic determinants of cognition are poorly characterized and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here, we used a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities including memory. Using exome sequence data from 6,871 trios, we find that M3 genes are also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease genes in the developed human brain, and provide empirical support for a convergent generegulatory network influencing cognition and neurodevelopmental disease.Cognition refers to human mental abilities such as memory, attention, processing speed, reasoning and executive function. Performance on cognitive tasks varies between individuals and is highly heritable 1 and polygenic 2,3 . However, to date, progress in identifying molecular genetic contributions to healthy human cognitive abilities has been limited 4,5 .A distinction can be made between cognitive domains such as the ability to apply acquired knowledge and learned skills (so called crystallized abilities) and fluid cognitive abilities such as the capacity to establish new memories, reason in novel situations or perform cognitive tasks accurately and quickly 6 . Notably, within individuals, performance on different measures of cognitive ability tend to be positively correlated such that people who do well in one domain, such as memory, tend to do well in other domains 7 . Seemingly disparate domains of cognitive ability also show high levels of genetic correlation in twin studies, typically in excess of 0.6 8 , and analyses using genome-wide similarity between unrelated individuals 3 (genome-wide complex trait analysis, GCTA) has also demonstrated substantial genetic correlation between diverse cognitive and learning abilities 9,10 . These studies suggest genes that influence human cognition may exert pleiotropic effects across diverse cognitive domains, such that genes regulating one cognitive ability might influence other cognitive abilities.Since impairment of cognitive function is a core clinical feature of many neurodevelopmental diseases including schizophrenia 11 , autism 12 , epilepsy 13 and intellectual disability (by definition), we sought to investigate gene-regulatory networks for human cognition and to determine their relationship to neurodevelopmental disease. An overview of our experimental design is provided in Supplementary Fig. 1. RESULTS Gene co-expression network a...

Reoperation after failed resective epilepsy surgery led to approximately 70% long-time seizure freedom and reasonable neuropsychological outcome. There is an increased risk of permanent postoperative neurological deficits, which should be taken into consideration when counselling for reoperation.

Melanotic tumors of the nervous system show overlapping histological characteristics but differ substantially in their biological behavior. In order to achieve a better delineation of such tumors, we performed an in-depth molecular characterization. Eighteen melanocytomas, 12 melanomas, and 14 melanotic and 14 conventional schwannomas (control group) were investigated for methylome patterns (450k array), gene mutations associated with melanotic tumors and copy number variants (CNVs). The methylome fingerprints assigned tumors to entity-specific groups. Methylation groups also showed a substantial overlap with histology-based diagnosis suggesting that they represent true biological entities. On the molecular level, melanotic schwannomas were characterized by a complex karyotype with recurrent monosomy of chromosome 22q and variable whole chromosomal gains and recurrent losses commonly involving chromosomes 1, 17p and 21. Melanocytomas carried GNAQ/11 mutations and presented with CNV involving chromosomes 3 and 6. Melanomas were frequently mutated in the TERT promoter, harbored additional oncogene mutations and showed recurrent chromosomal losses involving chromosomes 9, 10 and 6q, as well as gains of 22q. Together, melanotic nervous system tumors have several distinct mutational and chromosomal alterations and can reliably be distinguished by methylome profiling.

Summary Purpose Intracerebral vascular malformations including cavernous angiomas (CAs) and arteriovenous malformations (AVMs) are an important cause of chronic pharmacoresistant epilepsies. Little is known about the pathogenetic basis of epilepsy in patients with vascular malformations. Intracerebral deposits of iron-containing blood products have been generally regarded as responsible for the strong epileptogenic potential of CAs. Here, we have analyzed whether blood–brain barrier (BBB) dysfunction and subsequent astrocytic albumin uptake, recently described as critical trigger of focal epilepsy, represent pathogenetic factors in vascular lesion–associated epileptogenesis. Methods We examined the correlation between hemosiderin deposits, albumin accumulation, and several clinical characteristics in a series of 80 drug-refractory epilepsy patients with CAs or AVMs who underwent surgical resection. Analysis of clinical parameters included gender, age of seizure onset, epilepsy frequency, duration of epilepsy before surgery, and postoperative seizure outcome classification according to Engel class scale. Hemosiderin deposits in the adjacent brain tissue of the vascular lesion were semiquantitatively analyzed. Fluorescent double-immunohistochemistry using GFAP/albumin costaining was performed to study albumin extravasation. Key Findings Our results suggest that a shorter duration of preoperative epilepsy is correlated with significantly better postsurgical outcome (p < 0.05), whereas no additional clinical or neuropathologic parameter correlated significantly with the postsurgical seizure situation. Intriguingly, we observed strong albumin immunoreactivity within the vascular lesion and in perilesional astrocytes (57.65 ± 4.05%), but not in different control groups. Significance Our present data on albumin uptake in brain tissue adjacent to AVMs and CAs suggests BBB dysfunction and accumulation of albumin within astrocytes as a new pathologic feature potentially associated with the epileptogenic mechanism for vascular lesions and provides novel therapy perspectives for antiepileptogenesis in affected patients.