Stella G. Giakoumaki

Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Recent evidence suggests that prepulse inhibition (PPI) levels relate to executive function possibly by a prefrontal cortex (PFC) dopamine (DA) link. We explored the effects of enhanced PFC DA signaling by the nonstimulant catechol-O-methyltransferase (COMT) inhibitor tolcapone, on PPI and working memory of subjects homozygous for the Val (low PFC DA) and the Met (high PFC DA) alleles of the COMT Val158Met polymorphism. Twelve Val/Val and eleven Met/Met healthy male subjects entered the study. Tolcapone 200 mg was administered in two weekly sessions, according to a balanced, crossover, double-blind, placebo-controlled design. PPI was assessed with 5 dB and 15 dB above background prepulses, at 30-, 60-, and 120 ms prepulse–pulse intervals. Subjects also underwent the n-back and the letter–number sequencing (LNS) tasks. PPI was lower in the Val/Val compared to the Met/Met group in the placebo condition. Tolcapone increased PPI significantly in the Val/Val group and tended to have the opposite effect in the Met/Met group. Baseline startle was not affected by tolcapone in the Val/Val group but it was slightly increased in the Met/Met group. Tolcapone improved performance in the n-back and LNS tasks only in the Val/Val group. Enhancement of PFC DA signaling with tolcapone improves both PPI and working memory in a COMT Val158Met genotype-specific manner. These results suggest that early information processing and working memory may both depend on PFC DA signaling, and that they may both relate to PFC DA levels according to an inverted U-shaped curve function.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

The CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males

Roussos P, Giakoumaki SG, Georgakopoulos A, Robakis NK, Bitsios P. The CACNA1C and ANK3 risk alleles impact on affective personality traits and startle reactivity but not on cognition or gating in healthy males.
Bipolar Disord 2011: 13: 250–259.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT)

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Prepulse inhibition of the startle reflex depends on the catechol O-methyltransferase Val158Met gene polymorphism.

BACKGROUND Recent evidence suggests that dopamine (DA) agonist-induced disruption of prepulse inhibition (PPI) depends on basal PPI values, in a manner that suggests an inverted U-shaped relationship between PPI and prefrontal DA levels. This is the first study to examine possible genetic determinants of PPI and the catechol O-methyltransferase (COMT) Val158Met polymorphism, the main catabolic pathway of released DA in the prefrontal cortex (PFC). METHOD PPI was measured in 93 healthy males presented with 75-dB and 85-dB prepulses at 60-ms and 120-ms prepulse-pulse intervals. Subjects were grouped according to their COMT status into a Val/Val, a Val/Met and a Met/Met group. RESULTS ANOVAs showed that at all prepulse and interval conditions, Val/Val individuals had the lowest PPI, Met/Met the highest, and Val/Met were intermediate. CONCLUSIONS These results suggest that PPI is regulated by DA neurotransmission in the PFC and its levels depend on the COMT Val158Met gene polymorphism. These findings enhance the value of the PPI paradigm in examining individual variability of early information processing in healthy subjects and psychiatric disorders associated with changes in PFC DA activity and attentional deficits such as schizophrenia.

The level of prepulse inhibition in healthy individuals may index cortical modulation of early information processing

This study examined whether baseline PPI levels reflect individual efficiency in tasks associated with routine versus supervisory attentional systems (SAS). PPI and neuropsychological data were collected from 30 healthy male subjects. High PPI was associated with shorter movement times on the 5-choice Reaction Time and shorter Subsequent Thinking Times in the Stockings of Cambridge test. These data suggest that high-PPI status reflects greater efficiency in tasks that engage SAS.

Planning, decision-making and the COMT rs4818 polymorphism in healthy males

Recent evidence suggests that a synonymous polymorphism within the COMT gene (rs4818 C/G) accounts for a greater variation of COMT activity compared to the functional Val158Met polymorphism. This is the first study on the effects of the rs4818 C/G polymorphism on cognition. One hundred and seven healthy males were tested with the Stockings of Cambridge (SoC) and the Iowa Gambling Task (IGT) and then grouped according to their COMT rs4818 C/G status into three groups (G/G, C/G, C/C). ANOVAs showed that C/C individuals had the best performance in the SoC, G/G the worse, while C/G were intermediate. G/G individuals had strikingly better performance in the IGT compared to the other two groups and their performances in the two tasks were inversely related. These results show that the rs4818 C/G polymorphism imparts strong and differential effects on PFC functions. Low prefrontal dopamine levels are disadvantageous for planning in non-emotional problem solving but lead to optimal effects in emotionally informed decision-making. While high prefrontal dopamine levels may be advantageous for non-emotional problem solving, they lead to disadvantageous choices when decision-making depends on processing of emotional feedback.

Evidence of Disrupted Prepulse Inhibition in Unaffected Siblings of Bipolar Disorder Patients

BACKGROUND Prepulse inhibition (PPI) of the startle response refers to a reduction in the response to a strong stimulus (pulse) if preceded shortly by a weak stimulus (prepulse). Disrupted PPI is thought to reflect abnormalities in the inhibitory control of information processing. Reduced PPI has been reported in mania, although it is not clear whether it represents a trait feature of bipolar disorder (BD). To address this issue, the present study examined whether disrupted PPI is present in individuals at high risk for BD. METHODS Twenty-one remitted BD patients and 19 of their unaffected siblings were compared with 17 age- and gender-matched healthy volunteers on tests of acoustic startle reactivity and PPI of the startle response. RESULTS There were no group differences in startle reactivity. Compared with healthy individuals, BD patients and their unaffected siblings showed lower PPI. In the patient group, no significant correlations were found between PPI and measures of symptom and disease severity or medication. CONCLUSIONS This is the first study to report reduced PPI in remitted BD patients and their unaffected first-degree relatives. This finding, although in need of replication, suggests that PPI disruption may represent a trait deficit in BD associated with genetic predisposition.

Tolcapone effects on gating, working memory, and mood interact with the synonymous catechol-O-methyltransferase rs4818c/g polymorphism.

BACKGROUND The functional catechol-O-methyltransferase (COMT) valine158methionine (val158met) polymorphism determines prepulse inhibition (PPI) levels and working memory performance and the effects of tolcapone on these functions. Here, we explored the effects of the synonymous COMT rs4818 C/G polymorphism and tolcapone on PPI and working memory. METHODS Thirteen G/G (low prefrontal cortex [PFC] dopamine [DA]) and 12 C/C (high PFC DA) healthy male subjects entered and completed the study. Subjects participated in two weekly sessions associated with either acute oral tolcapone (200 mg) or placebo according to a balanced, crossover, double-blind design. Prepulse inhibition was assessed with 5 dB and 15 dB above background prepulses at 30-msec, 60-msec, and 120-msec intervals. Subjective mood and working memory performance (n-back and letter-number sequencing) were also assessed. RESULTS Prepulse inhibition was lower and reaction time in the n-back was slower in the G/G compared with the C/C group in the placebo condition. Tolcapone increased PPI and improved performance in both working memory tasks in the G/G group only. Baseline startle was greater in the C/C group and was not affected by tolcapone. Mood profile was worse in the C/C group and tended to deteriorate with tolcapone. Status of val158met alone could not explain these results. CONCLUSIONS Catechol-O-methyltransferase haplotype analyses are essential in future research. Prepulse inhibition and working memory may both relate to PFC DA levels according to an inverted U-shaped curve function. Tolcapone could be potentially useful in the treatment of conditions with deficient sensorimotor gating and working memory such as schizophrenia and prodromal states but only in a genotype-specific manner.

The Influence of Schizophrenia-Related Neuregulin-1 Polymorphisms on Sensorimotor Gating in Healthy Males

BACKGROUND Neuregulin-1 (NRG1) variations have been shown to modulate schizophrenia candidate endophenotypes related to brain structure and function. The objective of this cross-sectional genetic association study was to determine the relationship of six core single-nucleotide polymorphisms within the NRG1 gene identified as promising schizophrenia risk genes (rs6994992, SNP8NRG221132, SNP8NRG241930, rs3924999, rs2439272 and rs10503929) to prepulse inhibition (PPI) of the acoustic startle reflex, a well validated schizophrenia endophenotype. METHODS PPI was tested in a highly homogeneous study entry cohort (n = 445) of carefully screened healthy, young male army conscripts originating from the Greek LOGOS project (Learning on Genetics of Schizophrenia Spectrum). The QTPHASE from the UNPHASED package was used for the association analysis of each single-nucleotide polymorphisms or haplotype data. RESULTS Reduced PPI, particularly at 75-dB_120-msec and 85-dB_60-msec trials, was related to the SNP8NRG241930 G allele and especially the rs6994992 T allele and rs2439272 C allele. Haplotype analysis followed up by risk versus no-risk groups Analysis of variance confirmed that the rs10503929 and rs3924999 SNPs were also associated with PPI reductions, when combined with rs2439272. CONCLUSIONS We provide solid evidence for a role of NRG1 risk genotype variations in PPI reductions in a large and demographically and genetically highly homogeneous cohort of healthy young males. These results further validate NRG1 as a candidate gene for the schizophrenia and spectrum disorders and improve our understanding of its functional mechanisms within the human brain because they suggest an influence of the gene in the neural substrate mediating sensorimotor gating.