Inflammation, psychosis and the brain. What do we really know?

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  • Presenting Author details: kim.do@chuv.chSite de Cery, CH-1008 Prilly-Lausanne, Switzerland,Tel.: +41 21 6436565; fax: +41 21 6436562.

    Converging evidence speak in favor of an abnormal susceptibility tooxidative stress in schizophrenia. A decreased level of glutathione(GSH), the principal non-protein antioxidant and redox regulator,was observed both in cerebrospinal fluid and prefrontal cortex ofschizophrenia patients. Moreover, patients have an abnormal GSHsynthesis most likely of genetic origin: Two independent casecontrol studies showed a significant association between schizo-phrenia and a GAG trinucleotide repeat (TNR) polymorphism in theGSH key synthesizing enzyme glutamatecysteineligase (GCL)catalytic subunit (GCLC) gene. The most common TNR genotype 7/7 was more frequent in controls, whereas the rarest TNR genotype8/8 was three times more frequent in patients. The disease-associatedgenotypes correlated with a decrease in GCLC protein expression,GCL activity and GSH content. These results suggest that GSHsynthesis dysfunction represent a vulnerability factor in schizo-phrenia. Such a redox dysregulation during development couldunderlie the structural and functional anomalies in connectivity: Inexperimental models, GSH deficit induces anomalies similar to thoseobserved in patients.

    (a) Morphology: decrease in normal spines in prefrontal pyramids andin GABAparvalbumine but not of -calretinine immunoreactivity inanterior cingulate.(b) Physiology: impairment of NMDA-dependant synaptic plasticityand of dopamine modulation of NMDA-induced Ca2+ response.(c) Cognition: deficit in olfactory integration and in object recognition.

    In summary, clinical and experimental evidence converge todemonstrate that a genetically induced dysfunction of GSH metabo-lism during development represent a major risk factor contributing tothe disconnectivity syndrome in schizophrenia.

    doi:10.1016/j.schres.2007.12.062

    SENSORYCOGNITIVE PROCESSING IMPAIRMENTS ANDTHEIR RECOVERY IN SCHIZOPHRENIA: EVIDENCE FROMELECTRICAL NEUROIMAGING

    M. Murray 1.

    1EEG Brain Mapping Core, Center for Biomedical Imaging ofLausanne and Geneva and Functional Electrical NeuroimagingLaboratory, Neuropsychology and Neurorehabilitation Service,Radiology Service, Centre Hospitalier Universitaire Vaudois andUniversity of Lausanne, Switzerland

    Presenting Author details: Micah.Murray@chuv.chSite de Cery, CH-1008 Prilly-Lausanne, Switzerland,Tel.: +41 21 6436565; fax: +41 21 6436562.

    Brain imaging methods are improving our general understanding ofthe brain's functional organization in healthy individuals as well aspatients with neuropsychiatric disorders, including schizophrenia.

    Electrical neuroimaging has proven a particularly reliable meansfor identifying sensorycognitive impairments, endophenotypes,and putative rehabilitation strategies in patients with schizophrenia.This technique benefits from real-time temporal information thatreveals the spatio-temporal dynamics of brain (dys)function,including details concerning both when different brain areasbecome active and in what processing step(s) each is involved.Additionally, electrical neuroimaging can reveal effects that maynot forcibly manifest either psychophysically or with neuropsycho-logical batteries. First, evidence will be presented showing thatsensorycognitive impairments in visual processing by patientswith schizophrenia dissociate between functions associated with thedorsal and ventral visual processing streams. Such findings areproviding insights not only regarding the pathophysiology ofschizophrenia, but also for models of object processing in healthyindividuals. Second, evidence will be presented showing recoveryof electrophysiological measures of auditory processing (themismatch negativity; MMN) following treatment with N-acetyl-cysteine (NAC), a glutathione precursor that in turn is likely toimpact NMDA receptor functioning. Following a double-blind andcrossover design, NAC treatment significantly improved MMNgeneration compared with placebo. This improvement wasobserved in the absence of either measurable effects on theP300 response, which was not deficient relative to healthycontrols, or robust changes in assessments of clinical severity.MMN recovery may thus precede changes in standard clinicalmetrics, highlighting the possible utility of electrical neuroimagingas a biomarker of treatment efficacy.

    doi:10.1016/j.schres.2007.12.063

    Special Interest Workshop 12

    INFLAMMATION, PSYCHOSIS AND THE BRAIN. WHAT DOWE REALLY KNOW?

    T. Falcone 1, D. Janigro1, K. Franco1, O. Fattal2.

    1Cleveland Clinic Foundation, Cleveland, USA2Lutheran Hospital, USA

    Presenting Author details: falcont1@ccf.org9500 Euclid Avenue P57, 44195 Cleveland, OH, United States,Tel.: +1 216 5775254.

    This presentation will review current state of the knowledge of theinflammation model in Psychosis. Several lines of evidence havepointed to a link between CNS disorders, and specifically psychosis,and inflammation. Lately, there has been increasing interest in therole of the bloodbrain barrier (BBB) in neurological diseases.Advances in neuroradiology have enhanced our ability to image andstudy the human cerebrovasculature, and further developments in theresearch of metabolic deficiencies linked to brain disorders,neuroinflammation, and multiple sclerosis have amplified thesignificance of the BBB's relationship to acute and chronic diseases.It has not been clear whether BBB failure is a consequence or causeof altered neuronal function. We were the first to demonstrate thatacute breach of the human BBB results in focal motor seizures inotherwise non-predisposed individuals (Marchi et al., Epilepsia,

    30 ABSTRACTS / Schizophrenia Research 98 (2008) 3199

  • 2007). Animal models have shown an etiologic cascade that isinitiated by inflammatory processes leading to BBB and subsequentloss of neuronal homeostasis, suggesting that in principle systemicinflammation may lead to acute or chronic brain disease. The exactnature of these events is poorly understood, but in view of thefindings by a retrospective study in psychotic children at ClevelandClinic it appears that altered immunity is an essential component orcofactor in the onset of acute psychotic episodes in children. Thispresentation will summarize the current understanding of BBBdiseases with special reference to systematic, parallel investigationsin patients and animal models by molecular, radiologic, andpsychiatric methods.

    Chairperson:

    Tatiana Falcone, Neurologic Institute, Cleveland Clinic, Cleveland,OH, United States.

    Speakers:

    Damir Janigro: Bloodbrain barrier, inflammation and psychosis.What do we know?

    Tatiana Falcone: Blood barrier abnormalities in children with firstepisode psychosis

    Kathleen Franco: Immunology and psychosis

    Omar Fattal: The relationship between neuro-inflammation and thephenomenology of psychosis across the life span

    doi:10.1016/j.schres.2007.12.064

    Special Interest Workshop 13

    EVOLUTIONARY INSIGHTS IN FORMING PSYCHOSISRESEARCH AND UNDERSTANDING

    J. Sanjuan 1, T. Crow2, T. Baptista3, J. Burns4, J.J.M. Van Hoof5.

    1Unidad Psiquiatria, Facultad de Medicina, Valencia, Spain2SANE Institute, University of Oxford, UK3Departments of Physiology and Psychiatry, Los Andes UniversityMedical School, Merida, Venezuela4Department of Psychiatry, Nelson R Mandela School of Medicine,University of KwaZulu-Natal, Durban, South Africa5GGZ-Oost-Brabant, Belgium

    Presenting Author details: burns@ukzn.ac.zaDepartment of Psychiatry, Nelson R Mandela School of Medicine,4000 Durban, South Africa,Tel.: +27 31 2604321; fax: +27 31 2604322.

    This workshop brings together five researchers who have used theevolutionary paradigm to influence and direct their research andacademic activities on the psychoses. The purpose of theworkshop is to illustrate research and teaching that is evolu-tionary-based so as to demonstrate the importance of evolutionarythought for this field. Research will be presented usingendophenotypes that have been inspired by evolutionary rationale.For example, Sanjuan and Burns will present genetic researchusing auditory hallucinations and craniofacial dysmorphologyrespectively as endophenotypes. Crow will present his work onthe protocadherin gene and its evolutionary role in lateralisation,language and psychosis. Baptista will discuss his use of the

    evolutionary perspective in teaching and training of psychiatrists. Itis hoped that participants will engage in useful debate that willlead to creative and improved methodologies for evolutionaryapproaches to psychosis research.

    Chairperson:

    Jonathan Burns, University of KwaZulu-Natal, South Africa

    Speakers:

    Julio Sanjuan: Auditory hallucinationsin psychosis: an evolu-tionary genetic explanation

    Timothy Crow: Psychosis as the price that Homo sapiens pays forlanguage

    Trino Baptista: The teaching of the evolutionary approach topsychosis in the psychiatric residency training

    Jonathan Burns: Craniofacial morphology: evolutionary, develop-mental insights for psychosis research

    Jacques Van Hoof: A unitary model for the motor origin ofschizophrenia and bipolar disorders

    doi:10.1016/j.schres.2007.12.065

    A UNITARY MODEL FOR THE MOTOR ORIGIN OFSCHIZOPHRENIA AND BIPOLAR DISORDERS

    J.J.M. Van Hoof 1.

    1GGZ-Oost-Brabant, Belgium

    Presenting Author details: jacquesvanhoof@yahoo.comJoannes Zwijsenlaan 123, 6641 jr Oss, Netherlands,Tel.: +31 412847055; fax: +31 412847199.

    Background: The core problem in brain research of schizophrenia andbipolar disorders is the lack of an adequate physiological model. Anattempt was made to create a new unitary model.

    Methods: Published findings on schizophrenia and bipolar disordersare integrated with more recent data from human and animal studies ofstriatal and cerebellar functions.

    Results: The analysis shows that the relevant problems are themanifestation of an imbalance between two mechanisms in the brain:the first is motor power or drive and the second is steering or guidance.Both mechanisms are used to control movements. The core of thismodel's thesis is that during the normal phylo- and ontogenesis of thehuman brain both of these mechanisms are implemented in a repetitiveway from the how to do motor domain into the what to dointentional (limbic) domain through corticalsubcortical circuits. Thefirst, striatal mechanism is necessary to initiate and calibrate move-ments and intentions, such as intimidation or affiliation. Thisintentional drive mechanism is organized primarily by a circuit locatedin the ventral part of the brain. The second, cerebellar mechanism isnecessary for guidance. This intentional guidance mechanism isorganized primarily in a circuit located in the dorsal part of the brain.The repetitive application of both mechanisms during brain develop-ment allows the creation of unique human capacities. Evidence isaccumulating that the principally genetically based reliance on one orboth types of mechanisms has a bimodal distribution. A geneticallybased insufficient development of one of both mechanisms and an

    31ABSTRACTS / Schizophrenia Research 98 (2008) 3199