Linda Scoriels - Academia.edu (original) (raw)

Papers by Linda Scoriels

Psychotic disorders such as schizophrenia are biologically complex and carry huge population morb... more Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.

Background: Emotional impairments are important determinants of functional outcome in psychosis, ... more Background: Emotional impairments are important determinants of functional outcome in psychosis, and current treatments are not particularly effective. Modafinil is a wake-promoting drug that has been shown to improve emotion discrimination in healthy individuals and attention and executive function in schizophrenia. We aimed to establish whether modafinil might have a role in the adjuvant treatment of emotional impairments in the first episode of psychosis, when therapeutic endeavor is arguably most vital.

Schizophrenia Research, 2014

Current Pharmaceutical Design, 2014

The world population is growing older and age-related cognitive decline is becoming a burden of s... more The world population is growing older and age-related cognitive decline is becoming a burden of societal importance. D-serine is an endogenous amino acid that activates the co-agonist site of the NMDA-glutamate receptor, which is related to cognitive functions, such as learning and memory. Studies in aged rodents have shown a marked decrease in the levels of D-serine in brain regions such as the hippocampus, a key region for encoding memory. Exogenous administration of D-serine in rodents has demonstrated pro-cognitive effects in several brain functions, including memory and executive function. Further to animal studies, our group has observed an agerelated decrease in D-serine in the blood of healthy adults and elderly. The oral administration of D-serine induced significant improvement in executive function and spatial problem solving in elderly, some of the key cognitive domains affected by aging. In this review we propose the activation of the co-agonist site of NMDA receptors as a target to remediate features of the age-related cognitive decline. The cognitive effects of other agents targeting the co-agonist site of NMDA receptors are also discussed.

Schizophrenia research, 2014

Schizophrenia Research, 2008

Psychological Medicine, 2013

2013). Speed of facial affect intensity recognition as an endophenotype of rst-episode psychosis... more 2013). Speed of facial affect intensity recognition as an endophenotype of rst-episode psychosis and associated limbic-cortical grey matter systems. Psychological Medicine, null, pp 591-602

Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2013

Cannabis is a widely used recreational drug. Its effect on human health and psychosis remains con... more Cannabis is a widely used recreational drug. Its effect on human health and psychosis remains controversial. In this study, we aimed to explore the possibility that cannabis use influenced CCL11 plasma levels. Increased CCL11 chemokine has been reported in schizophrenia and cannabis is a known trigger of schizophrenia. Additionally, plasma levels of the chemokine CCL11 have recently been shown to increase with age and with cognitive deficits and hippocampal neurogenesis. For this study, a total of 87 healthy volunteers (68% men, age range 18-35 years) completed the Cannabis Experience Questionnaire that included information on sociodemographic and morphometric data and provided a blood sample for CCL11 measurement. 'Current users' of cannabis (n = 18) had significantly higher CCL11 plasma levels compared to 'past users' (n = 33) and 'never users' (n = 36) [F(3,84) = 3.649; p = 0.030]. The latter two groups had similar CCL11 levels. Higher CCL11 plasma levels could not be attributed to gender, age, body mass index, physical activity or use of other legal/illegal drugs. These results suggest that cannabis use increases CCL11 plasma levels and the effects are reversible when cannabis use ceases.

Proceedings of the National Academy of Sciences, 2004

Cholinergic axons and nicotinic receptors are abundant in all layers of the olfactory bulb (OB), ... more Cholinergic axons and nicotinic receptors are abundant in all layers of the olfactory bulb (OB), the main region of newborn neuron integration in the adult brain. Here, we report that the OB granule cell layer in mice lacking the predominant form of brain highaffinity nicotinic acetylcholine receptors (␤ 2 ؊/؊ mice) displayed nearly 50% more newborn neurons and significantly fewer apoptotic cells than did ␤2 ؉/؉ mice. Conversely, in vivo chronic nicotine exposure significantly decreased the number of newborn granule cells in ␤2 ؉/؉ but not ␤2 ؊/؊ adult mice, confirming that the survival of newborn neurons can be controlled by the activation of ␤2containing nicotinic acetylcholine receptors. Unexpectedly, investigating the behavioral consequence of an increased number of granule cells in ␤2 ؊/؊ mice revealed that these animals have a less robust short-term olfactory memory than their wild-type counterparts. Taken together, these results provide evidence that highaffinity nicotinic receptors are involved in the maturation of adult OB local circuits. They also indicate that an increase in the number of granule cells does not necessarily correlate with better olfactory performance and further highlight the importance of cholinergic afferents for olfactory processing.

European Neuropsychopharmacology, 2013

European Neuropsychopharmacology, 2009

European Archives of Psychiatry and Clinical Neuroscience, 2009

In this review, we present the main findings of the 6th Symposium for the Search for the Causes o... more In this review, we present the main findings of the 6th Symposium for the Search for the Causes of Schizophrenia, which took place between 3 and 6 February 2009, in Sao Paulo, Brazil. In a few short years, the landscape of the causes of schizophrenia has changed dramatically. The flat and featureless epidemiological horizon has developed undulating contours, which promise new avenues for research, particularly if we are able to integrate such findings with tantalising new findings from genetics as novel methods for identifying genuine sites of genetic risk emerge. The Search highlighted and fostered the emerging acknowledgement that we will need to integrate knowledge across traditionally disparate disciplines in psychiatry in order to develop complex, testable hypotheses in the search for the causes of schizophrenia. Such challenges are beginning to be addressed. From epidemiology, gene-environment studies are becoming more sophisticated, while neuroscience is increasingly concerned about social organisation and how social factors impinge upon biological pathways to potentially lead to psychosis. Tantalising new insights from genome-wide association studies offer new clues about rare genetic mutations, which have large effect sizes for schizophrenia, including copy number variants and de novo mutations. It is only through forums such as the 6th Symposium for the Search for the Causes of Schizophrenia that the seeds of integrated collaborations across disciplines can be sown to address the complex polyfactorial basis of schizophrenia.

Biological Psychiatry, 2008

Cognitive endophenotypes may further our understanding of the genetic basis of psychiatric disord... more Cognitive endophenotypes may further our understanding of the genetic basis of psychiatric disorders, and the catechol-O-methyltransferase (COMT) gene is a promising candidate gene for both cognitive function and disorder. We conducted a meta-analysis of reported associations between the COMT Val158/108Met polymorphism and measures of memory and executive function. The PubMed database was searched for studies relating cognitive functions and the COMT Val158/108Met polymorphism. This enabled meta-analyses of six cognitive phenotypes (Trail Making task, verbal recall, verbal fluency, IQ score, n-back task, and Wisconsin Card Sorting Test). Data were extracted by two reviewers and included cognitive scores by COMT genotype, publication year, diagnostic status, ancestry, proportion of male participants, and whether genotype frequencies were consistent with Hardy-Weinberg equilibrium. We found no association between COMT genotype and the majority of phenotypes. There was evidence of association with IQ score (d = .06), which did not differ significantly by ancestry, sex, average sample age, or patient status. For the n-back task, there was no robust evidence for genetic association, but the effect size was significantly larger in patient (d = .40) than nonpatient (d = -.27) populations, larger in both samples with fewer male subjects, and those of greater average age. There was also evidence of publication bias and decreasing effect sizes with later publication. Despite initially promising results, the COMT Val158/108Met polymorphism appears to have little if any association with cognitive function. Publication bias may hamper attempts to understand the genetic basis of psychological functions and psychiatric disorders.

Biological Psychiatry, 2011

1. Biol Psychiatry. 2011 Jan 25. [Epub ahead of print] Reply to: With Great Power Comes Great Res... more 1. Biol Psychiatry. 2011 Jan 25. [Epub ahead of print] Reply to: With Great Power Comes Great Responsibility: Meta-Analytic Proof for a Timeless Insight. Barnett JH, Scoriels L, Munafò MR. Department of Psychiatry, University ...

Background: D-serine is an endogenous co-agonist of the N-Methyl D-Aspartate Receptor (NMDAR) tha... more Background: D-serine is an endogenous co-agonist of the N-Methyl D-Aspartate Receptor (NMDAR) that plays a crucial role in cognition including learning processes and memory. Decreased D-serine levels have been associated with age-related decline in mechanisms of learning and memory in animal studies. Here, we asked whether D-serine administration in older adults improves cognition. Methods: Fifty healthy older adults received D-serine and placebo in a randomized, double blind, placebo-controlled, crossover design study. We studied the effect of D-serine administration on the performance of cognitive tests and an analogue mood scale. We also collected blood samples to measure D-serine, L-serine, glutamate and glutamine levels. Results: D-serine administration improved performance in the Groton Maze learning test of spatial memory and learning and problem solving (F (3, 38) = 4.74, p = 0.03). Subjects that achieved higher increases in plasma D-serine levels after administration improved more in test performance (r 2 =-0.19 p = 0.009). D-serine administration was not associated with any significant changes in the other cognitive tests or in the mood of older adults (p > 0.05). Conclusions: D-serine administration may be a strategy to improve spatial memory, learning and problem solving in healthy older adults. Future studies should evaluate the impact of long-term D-serine administration on cognition in older adults.

Objective: Autoantibodies against N-methyl-D-aspartate receptor (anti-NMDAR) and ribo-somal-P (an... more Objective: Autoantibodies against N-methyl-D-aspartate receptor (anti-NMDAR) and ribo-somal-P (anti-P) antigens are potential pathogenic factors in the frequently observed diffuse brain dysfunctions in patients with systemic lupus erythematosus (SLE). Although studies have been conducted in this area, the role of anti-NMDAR antibodies in SLE cognitive dysfunction remains elusive. Moreover, the specific contribution of anti-P antibodies has not been reported yet. The present study attempts to clarify the contribution of anti-NMDAR and anti-P antibodies to cognitive dysfunction in SLE. Methods: The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to assess a wide range of cognitive function areas in 133 Chilean women with SLE. ANCOVA models included auto-antibodies, patient and disease features. Results: Cognitive deficit was found in 20%. Higher SLEDAI-2K scores were associated with impairment in spatial memory and learning abilities, whereas both anti-NMDAR and anti-P antibodies contributed to deficits in attention and spatial planning abilities, which reflect fronto-parietal cortex dysfunctions. Conclusions: These results reveal an association of active disease together with specific circulating autoantibodies, such as anti-NMDAR and anti-P, with cognitive dysfunction in SLE patients. Lupus (2014) 0, 1–11.