NRSF and BDNF polymorphisms as biomarkers of cognitive dysfunction in adults with newly diagnosed epilepsy

Abstract

Cognitive dysfunction is a common comorbidity in people with epilepsy, but its causes remain unclear. It may be related to the etiology of the disorder, the consequences of seizures, or the effects of antiepileptic drug treatment. Genetics may also play a contributory role. We investigated the influence of variants in the genes encoding neuron-restrictive silencer factor (NRSF) and brain-derived neurotrophic factor (BDNF), proteins previously associated with cognition and epilepsy, on cognitive function in people with newly diagnosed epilepsy. A total of 82 patients who had previously undergone detailed neuropsychological assessment were genotyped for single nucleotide polymorphisms (SNPs) across the NRSF and BDNF genes. Putatively functional SNPs were included in a genetic association analysis with specific cognitive domains, including memory, psychomotor speed, and information processing. Cross-sectional and longitudinal designs were used to explore genetic influences on baseline cognition at diagnosis and change from baseline over the first year since diagnosis, respectively. We found a statistically significant association between genotypic variation and memory function at both baseline (NRSF: rs1105434, rs2227902 and BDNF: rs1491850, rs2030324, rs11030094) and in our longitudinal analysis (NRSF: rs2227902 and BDNF: rs12273363). Psychomotor speed was also associated with genotype (NRSF rs3796529) in the longitudinal assessment. In line with our previous work on general cognitive function in the healthy aging population, we observed an additive interaction between risk alleles for the NRSF rs2227902 (G) and BDNF rs6265 (A) polymorphisms which was again consistent with a significantly greater decline in delayed recall over the first year since diagnosis. These findings support a role for the NRSF–BDNF pathway in the modulation of cognitive function in patients with newly diagnosed epilepsy.

News about the Role of the Transcription Factor REST in Neurons: From Physiology to Pathology

“…Another property of recently established cognitive dysfunctions of epileptic patients is due to the establishment of new alterations of hippocampal neurons governed by REST. The results confirmed a role of REST polymorphism in the modulation of cognitive functions [39].…”

“…During the last few years, the therapeutic potential of REST has attracted attention concerning both specific conditions and their deacetylases (examples in [57,58]). Recent therapeutic attempts have been included in numerous studies reporting neurodegenerative diseases [31][32][33][34] and epilepsy [38,39]. These studies, however, concerned primarily pathology, not therapies of diseases.…”

WONOEP appraisal: Biomarkers of epilepsy‐associated comorbidities

“…Cognitive performance was evaluated in newly diagnosed epilepsy patients (baseline) and again 12 months later. They found that genetic variants of NRSF and BDNF were associated with greater impairment in memory functions and in psychomotor speed either at epilepsy diagnosis and in the subsequent follow up (e.g., 12 months later) …”

“…58 Such polymorphism is associated with high messenger RNA (mRNA) levels of BIN1. 58 Warburton et al 59 enrolled a subgroup of subjects from the Standard and New Antiepileptic Drugs (SANAD) trial and they evaluated the presence of polymorphisms in the neuron-restrictive silencer factor (NRSF) and brain-derived neurotrophic factor (BDNF) genes and their association with cognitive functions. Cognitive performance was FDG-PET coregistration with MRI in a patient with ASD, intellectual disability, and epilepsy.…”

“…They found that genetic variants of NRSF and BDNF were associated with greater impairment in memory functions and in psychomotor speed either at epilepsy diagnosis and in the subsequent follow up (e.g., 12 months later). 59 MicroRNA (miRNA) are noncoding small RNA emerging as the master regulator of gene expression. A relatively novel area of research concerns the regulation of miRNA by learning and memory, as well as in patients with psychiatric disorders.…”