Doublecortin-expressing cell types in temporal lobe epilepsy

Doublecortin (DCX) is widely regarded as a marker of immature and migrating neurons during development. While DCX expression persists in adults, particularly in the temporal lobe and neurogenic regions, it is unknown how seizures influence its expression. The aim of the present study was to explore the distribution and characteristics of DCX-expressing cells in surgical and postmortem samples from 40 adult and paediatric patients, with epilepsy and with or without hippocampal sclerosis (HS), compared to post mortem controls. The hippocampus (pes and body), parahippocampal gyrus, amygdala, temporal pole and temporal cortex were examined with DCX immunohistochemistry using four commercially-available DCX antibodies, labelled cells were quantified in different regions of interest as well as their co-expression with cell type specific markers (CD68, Iba1, GFAP, GFAP∂, nestin, SOX2, CD34, OLIG2, PDGFRβ, NeuN) and cell cycle marker (MCM2). Histological findings were compared with clinical data, as well as gene expression data obtained from the temporal cortex of 83 temporal lobe epilepsy cases with HS. DCX immunohistochemistry identified immature (Nestin-/NeuN-) neurons in layer II of the temporal neocortex in patients with and without epilepsy. Their number declined significantly with age but was not associated with the presence of hippocampal sclerosis, seizure semiology or memory dysfunction. DCX+ cells were prominent in the paralaminar nuclei and periamygdalar cortex and these declined with age but were not significantly associated with epilepsy history. DCX expressing cells with ramified processes were prominent in all regions, particularly in the hippocampal subgranular zone, where significantly increased numbers were observed in epilepsy samples compared to controls. DCX ramified cells co-expressed Iba1, CD68 and PDGFRβ, and less frequently MCM2, OLIG2 and SOX2, but no co-localization was observed with CD34, nestin or GFAP/GFAP ∂. Gene expression data from neocortical samples in patients with TLE and HS supported ongoing DCX expression in adults. We conclude that DCX identifies a range of morphological cell types in temporal lobe epilepsy, including immature populations, glial and microglial cell types. Their clinical relevance and biological function requires further study but we show some evidence for alteration with age and in epilepsy

A Genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology

We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of "amyloid" transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and "TAU" transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org

PAX6, brain structure and function in human adults: Advanced MRI in aniridia

Objective PAX6 is a pleiotropic transcription factor essential for the development of several tissues including the eyes, central nervous system, and some endocrine glands. Recently it has also been shown to be important for the maintenance and functioning of corneal and pancreatic tissues in adults. We hypothesized that PAX6 is important for the maintenance of brain integrity in humans, and that adult heterozygotes may have abnormalities of cortical patterning analogous to those found in mouse models. Methods We used advanced magnetic resonance imaging techniques, including surface-based morphometry and region-of-interest analysis in adult humans heterozygously mutated for PAX6 mutations (n = 19 subjects and n = 21 controls). Using immunohistochemistry, we also studied PAX6 expression in the adult brain tissue of healthy subjects (n = 4) and patients with epilepsy (n = 42), some of whom had focal injuries due to intracranial electrode track placement (n = 17). Results There were significant reductions in frontoparietal cortical area after correcting for age and intracranial volume. A greater decline in thickness of the frontoparietal cortex with age, in subjects with PAX6 mutations compared to controls, correlated with age-corrected, accelerated decline in working memory. These results also demonstrate genotypic effects: those subjects with the most severe genotypes have the most widespread differences compared with controls. We also demonstrated significant increases in PAX6-expressing cells in response to acute injury in the adult human brain. Interpretation These findings suggest a role for PAX6 in the maintenance and consequent functioning of the adult brain, homologous to that found in other tissues. This has significant implications for the understanding and treatment of neurodegenerative diseases

The impact of brain-derived neurotrophic factor Val66Met polymorphism on cognition and functional brain networks in patients with intractable partial epilepsy

INTRODUCTION: Medial temporal lobe epilepsy (mTLE) is the most common refractory focal epilepsy in adults. Around 30%-40% of patients have prominent memory impairment and experience significant postoperative memory and language decline after surgical treatment. BDNF Val66Met polymorphism has also been associated with cognition and variability in structural and functional hippocampal indices in healthy controls and some patient groups. AIMS: We examined whether BDNF Val66Met variation was associated with cognitive impairment in mTLE. METHODS: In this study, we investigated the association of Val66Met polymorphism with cognitive performance (n = 276), postoperative cognitive change (n = 126) and fMRI activation patterns during memory encoding and language paradigms in 2 groups of patients with mTLE (n = 37 and 34). RESULTS: mTLE patients carrying the Met allele performed more poorly on memory tasks and showed reduced medial temporal lobe activation and reduced task-related deactivations within the default mode networks in both the fMRI memory and language tasks than Val/Val patients. CONCLUSIONS: Although cognitive impairment in epilepsy is the result of a complex interaction of factors, our results suggest a role of genetic factors on cognitive impairment in mTLE

Soluble Fibrinogen Triggers Non-cell Autonomous ER Stress-Mediated Microglial-Induced Neurotoxicity

Aberrant or chronic microglial activation is strongly implicated in neurodegeneration, where prolonged induction of classical inflammatory pathways may lead to a compromised blood-brain barrier (BBB) or vasculature, features of many neurodegenerative disorders and implicated in the observed cognitive decline. BBB disruption or vascular disease may expose the brain parenchyma to “foreign” plasma proteins which subsequently impact on neuronal network integrity through neurotoxicity, synaptic loss and the potentiation of microglial inflammation. Here we show that the blood coagulation factor fibrinogen (FG), implicated in the pathogenesis of dementias such as Alzheimer’s disease (AD), induces an inflammatory microglial phenotype as identified through genetic microarray analysis of a microglial cell line, and proteome cytokine profiling of primary microglia. We also identify a FG-mediated induction of non-cell autonomous ER stress-associated neurotoxicity via a signaling pathway that can be blocked by pharmacological inhibition of microglial TNFα transcription or neuronal caspase-12 activity, supporting a disease relevant role for plasma components in neuronal dysfunction

L\u27adaptation de l\u27organe visu el aux intermittences lumineuses et aux phosphènes électriques papillotants

U vezi s problemom mehanizma vidnih osjeta i s pitanjem, kako djeluje svijetlo na vidnu funkciju. izvršene su tri serije eksperimenata, i to: 1. ispitano je, kojom brzinom i u kojim granicama dolazi do adaptacije na treperenje izazvano isprekidanim svijetlom odnosno isprekidanim električnim podražajima oka; 2. ispitano je, kako utječe na kritičnu frekvenciju prethodno podraživanje oka treptavim svijetlom različite frekvencije a stalnog trajanja; i 3. ispitan je utjecaj intermitentnih električnih fosfena na frekvenciju fuzije svijetla. Rezultati tih pokusa bili su: a) pri podraživanju oka isprekidanom električnom strujom dolazi mnogo brže do adaptacije na treperenje i opseg adaptacije znatno je veći, nego kad se oko podražuje isprekidanim svijetlom; b) prethodno podraži van je vidnog organa različitim subfuzionalnim frekvencijama svijetla smanjuje kritičnu frekvenciju za svijetlo. Maksimalno smanjenje nađene je nakon ekspozicije na treptave svijetlo od oko 20/sek. sa simetričnim opadanjem smanjenja za brže i sporije frekvencije; c) prethodno podraživanje oka isprekidanom strujom različite frekvencije ne utječe na kritičnu frekvenciju za svijetlo. Na osnovi tih rezultata autor se priklanja hipotezi, da je brza adaptacija na intermitentne električne fosfene uvjetovana u prvom redu inhibicijom, koja nastaje u živčanim elementima retine, dok bi relativno uska adaptacija na treperenje svijetla bila rezultat prvenstveno pogoršanja u funkcionalnom stanju vidnog korteksa. Kod normalnog kontinuiranog podraživanja svijetlom dolazi do zaštitne inhibicije u· centrima, koja sprečava da kortikalne strukture dođu u takvo stanje uzbuđenja, koje ih iscrpljuje. Naprotiv diskontinuirano uzbuđivanje sprečava, da se ta zaštitna inhibicija razvije u dovoljnoj mjeri, a to tada dovodi do smanjenja funkcionalne sposobnosti centara, što se očituje u subjektivnoj fuziji isprekidanih podražaja, odnosno u sniženju kritične frekvencije. Maksimalno sniženje kritične frekvencije nakon ekspozicije na treperenje svijetla od oko 20/sek odgovara pristizanju grupiranih živčanih impulsa u momentima, kad se vidni korteks nalazi u svojoj supranormalnoj fazi podražljivosti.Dans le cadre des problèmes concernant le mécanisme de la vision et l\u27influence de la lumière intermittente nous avons étudié: 1) l\u27adaptation au papillotement produit soit par la lumière intermittente soit par la stimulation électrique interrompue à des fréquences préfusionnelles: 2) les changements de la fréquence critique sous J\u27influence des stimulations lumineuses intermittentes de diverses cadences et d\u27une durée de 30 sec.; et 3) l\u27influence des stimulations intermittentes électriques sur la fréquence de fusion de la lumière. Les résultats ont montré; a) l\u27adaptation au papillotement provoqué par une stimulation intermittente électrique (courant continu interrompu) se produit beaucoup plus vite et dans une marge des fréquences beaucoup plus grande que l\u27adaptation aux intermittences lumineuses. En général, l\u27adaptation au papillotement est d\u27autant plus rapide que la fréquence d\u27intermittences est plus grande. Le nombre total d\u27intermittences nécessaires à la disparition du papillotement augmente proportionnellement à la diminution de la fréquence; b) la stimulation préalable de l\u27oeil par la lumière à des fréquences préfusionnelles diminue la fréquence de fusion. La diminution maximum de la fréquence de fusion était obtenue après une stimulation à la cadence d\u27environ 20 cycles par sec. L\u27influence de la stimulation intermittente préalable sur la fréquence de fusion décroît presque symétriquement pour les fréquences de stimulation supérieures ou inférieures à 20/sec. L\u27exposition préalable de l\u27oeil aux fréquences suprafusionnelles ne change pas la fréquence de fusion; c) la stimulation électrique interrompue ne modifie pas la fréquence critique de la lumière. L\u27auteur émet l\u27hypothèse que l\u27adaptation rapide aux phosphènes électriques intermittents, qui se manifeste par la disparation des phosphènes, pourrait être attribuée à. l\u27inhibition des éléments rétiniens. Au contraire, l\u27adaptation lente au papillotement lumineux (homogénéisation apparente de stimulus) - l\u27adaptation que l\u27on peut obtenir seulement avec des fréquences assez voisines à la fréquence de fusion - serait plutôt l\u27effet d\u27une détérioration des éléments corticaux. Des modifications centrales semblables pourraient être aussi responsables de la diminution de la fréquence de fusion après l\u27exposition aux intermittences lumineuses

Peripheral Serotonin 1B Receptor Transcription Predicts the Effect of Acute Tryptophan Depletion on Risky Decision-Making

BACKGROUND: The effects of acute tryptophan depletion on human decision-making suggest that serotonin modulates the processing of rewards and punishments. However, few studies have assessed which of the many types of serotonin receptors are responsible. METHODS: Using a within-subject, double-blind, sham-controlled design in 26 subjects, we examined whether individual differences in serotonin system gene transcription, measured in peripheral blood, predicted the effect of acute tryptophan depletion on decision-making. Participants performed a task in which they chose between successive pairs of fixed, lower-stakes (control) and variable, higher-stakes (experimental) gambles, each involving wins or losses. In 21 participants, mRNA from 9 serotonin system genes was measured in whole blood prior to acute tryptophan depletion: 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT3A, 5-HT3E, 5-HT7 (serotonin receptors), 5-HTT (the serotonin transporter), and tryptophan hydroxylase 1. RESULTS: Acute tryptophan depletion did not significantly influence participants' sensitivity to probability, wins, or losses, although there was a trend for a lower tendency to choose experimental gambles overall following depletion. Significant positive correlations, which survived correction for multiple comparisons, were detected between baseline 5-HT1B mRNA levels and acute tryptophan depletion-induced increases in both the overall tendency to choose the experimental gamble and sensitivity to wins. No significant relationship was observed with any other peripheral serotonin system markers. Computational analyses of decision-making data provided results consistent with these findings. CONCLUSIONS: These results suggest that the 5-HT1B receptor may modulate the effects of acute tryptophan depletion on risky decision-making. Peripheral levels of serotonin markers may predict response to treatments that act upon the serotonin system, such as selective serotonin reuptake inhibitors

Association Analysis in African Americans of European-Derived Type 2 Diabetes Single Nucleotide Polymorphisms From Whole-Genome Association Studies

OBJECTIVE— Several whole-genome association studies have reported identification of type 2 diabetes susceptibility genes in various European-derived study populations. Little investigation of these loci has been reported in other ethnic groups, specifically African Americans. Striking differences exist between these populations, suggesting they may not share identical genetic risk factors. Our objective was to examine the influence of type 2 diabetes genes identified in whole-genome association studies in a large African American case-control population

Genomic Risk Profiling of Ischemic Stroke: Results of an International Genome-Wide Association Meta-Analysis

Introduction: Familial aggregation of ischemic stroke derives from shared genetic and environmental factors. We present a meta-analysis of genome-wide association scans (GWAS) from 3 cohorts to identify the contribution of common variants to ischemic stroke risk.Methods: This study involved 1464 ischemic stroke cases and 1932 controls. Cases were genotyped using the Illumina 610 or 660 genotyping arrays; controls, with Illumina HumanHap 550Kv1 or 550Kv3 genotyping arrays. Imputation was performed with the 1000 Genomes European ancestry haplotypes (August 2010 release) as a reference. A total of 5,156,597 single-nucleotide polymorphisms (SNPs) were incorporated into the fixed effects meta-analysis. All SNPs associated with ischemic stroke (P < 1 x 10(-5)) were incorporated into a multivariate risk profile model.Results: No SNP reached genome-wide significance for ischemic stroke (P < 5 x 10(-8)). Secondary analysis identified a significant cumulative effect for age at onset of stroke (first versus fifth quintile of cumulative profiles based on SNPs associated with late onset, beta = 14.77 [10.85, 18.68], P = 5.5 x 10(-12)), as well as a strong effect showing increased risk across samples with a high propensity for stroke among samples with enriched counts of suggestive risk alleles (P < 5 x 10(-6)). Risk profile scores based only on genomic information offered little incremental prediction.Discussion: There is little evidence of a common genetic variant contributing to moderate risk of ischemic stroke. Quintiles based on genetic loading of alleles associated with a younger age at onset of ischemic stroke revealed a significant difference in age at onset between those in the upper and lower quintiles. Using common variants from GWAS and imputation, genomic profiling remains inferior to family history of stroke for defining risk. Inclusion of genomic (rare variant) information may be required to improve clinical risk profiling

The 9p21 susceptibility locus for coronary artery disease and the severity of coronary atherosclerosis

<p>Abstract</p> <p>Background</p> <p>Case-control Genome-Wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) at the 9p21 locus as risk factors for coronary artery disease (CAD). The locus does not contain a clear candidate gene. Hence, the results of GWAS have raised an intense interest in delineating the basis for the observed association. We analyzed association of 4 SNPs at the 9p21 locus with the severity and progression of coronary atherosclerosis, as determined by serial quantitative coronary angiograms (QCA) in the well-characterized Lipoprotein Coronary Atherosclerosis Study (LCAS) population. The LCAS is a randomized placebo-control longitudinal follow-up study in patients with CAD conducted to test the effects of fluvastatin on progression or regression of coronary atherosclerosis.</p> <p>Methods</p> <p>Extensive plasma lipid levels were measured at the baseline and 2 1/2 years after randomization. Likewise serial QCA was performed at the baseline and upon completion of the study. We genotyped the population for 4 SNPs, previously identified as the susceptibility SNPs for CAD in GWAS, using fluorogenic 5' nuclease assays. We reconstructed the haplotypes using Phase 2, analyzed SNP and haplotype effects using the Thesias software as well as by the conventional statistical methods.</p> <p>Results</p> <p>Only Caucasians were included since they comprised 90% of the study population (332/371 with available DNA sample). The 4 SNPs at the 9p21 locus were in tight linkage disequilibrium, leading to 3 common haplotypes in the LCAS population. We found no significant association between quantitative indices of severity of coronary atherosclerosis, such as minimal lumen diameter and number of coronary lesions or occlusions and the 9p21 SNPs and haplotypes. Likewise, there was no association between quantitative indices of progression of coronary atherosclerosis and the SNPs or haplotypes. Similarly, we found no significant SNP or haplotype effect on severity and progression of coronary atherosclerosis.</p> <p>Conclusion</p> <p>We conclude the 4 SNPs at the 9p21 locus analyzed in this study do not impart major effects on the severity or progression of coronary atherosclerosis. The effect size may be very modest or the observed association of the CAD with SNPs at the 9p21 locus in the case-control GWAS reflect involvement of vascular mechanisms not directly related to the severity or progression of coronary atherosclerosis.</p