EXTENDED ENDOPHENOTYPES IN EARLY PSYCHOSIS: IS THERE AN ASSOCIATION AMONG BRAIN STRUCTURES, NEUROLOGICAL SOFT SIGNS, NEUROPSYCHOLOGY, PREPULSE INHIBITION AND GENETICS?

BACKGROUND: Endophenotypes are defined as heritable and stable components of the psychotic disorder, with the advantage of being measurable with quantitative methods and amenable to laboratory assessment. Examples of currently investigated endophenotypes in schizophrenia are neuroimaging markers, neuropsychological deficit, prepulse inhibition of the startle reflex (PPI), and neurological soft signs (NSS). In multigenerational families with schizophrenia, a co-segregation between some endophenotypes, such as magnetic resonance imaging (MRI) and neuropsychological measures, has been found. Moving from this observation, some authors have recently introduced the concept of “extended endophenotype”, referring to the proposal of combining multiple endophenotypes functionally associated with each other. AIMS: The present PhD project aims at: 1) performing for the first time a systematic review of the potential role of neuropsychological impairments and brain structural abnormalities in relation to the COMT Val158Met polymorphism as potential “extended endophenotypes” in psychosis; 2) testing for the first time, in a cohort of patients with psychosis that patients with higher levels of NSS sensory integration and NSS motor sequencing signs elicited by a neurological evaluation show higher PPI deficits and that patients with PPI deficits and high NSS scores have high level of negative symptoms. 3) investigating for the first time, in cohort of patients with psychosis, that patients with the Val/Val genotype of the COMT Val158Met polymorphism have higher score of NSS (sensory integration and sequencing of complex motor acts) and lower executive function. The hypothesis of an association between high NSS and lower executive function was also tested. Moreover, we hypothesized that the COMT Val/Val genotype would be associated with both higher NSS (sensory integration and sequencing of complex motor acts) and poorer executive function. METHODS: For the Aim 1, we searched the PubMed and Medline databases to systematically identify the neuropsychological tasks and brain structural variations related to COMT Val158Met across psychosis spectrum disorders and to verify if the neuropsychological and the brain structural endophenotypes identified were associated with each other. Finally we propose some "extended endophenotypes". For the Aim 2 a cohort of psychotic patients in contact with the South Verona Community-based Mental Health Service (CMHS), Italy, during a period of three years, was recruited and underwent PPI and NSS evaluations. Moreover a group of matched healthy controls was recruited. For the Aim 3, 4 cohort of subjects with psychosis were recruited, gave their DNA, underwent NSS and neuropsychological evaluation. The data were collected within the framework of three multisite epidemiological studies of first episode psychosis, conducted respectively in Veneto (Italy) and South London, Nottingham and Bristol (UK): the Psychosis Incident Cohort Outcome Study (PICOS), the Aetiology and Ethnicity in Schizophrenia and Other Psychoses (AESOP) study and the Genetics and Psychotic Illness study (GAP). Moreover a cohort of psychotic patients in contact with the South Verona Community-based Mental Health Service (CMHS), Italy, was included. RESULTS: Regarding the 1st aim, three proposals of extended endophenotypes associated with COMT Val158Met polymorphism were identified; an extended endophenotype characterised by: 1) N-back performance and prefrontal cortex volumes, 2) N-back performance and medial temporal lobe volumes and 3) CPT performance, prefrontal volumes. Regarding the 2nd aim fifteen subjects affected by psychosis with a duration of illness equal or less than 5 years and fifteen healthy controls underwent PPI and NSS evaluations. Results showed that the patients did not exhibit higher levels of PPI deficits but only higher levels of NSS (p<0.01), as compared to healthy controls. Higher NSS rates were not associated with PPI deficits. PPI deficits did not correlate with any clinical characteristic; inversely, NSS sensory integration signs correlated positively with negative symptoms (p<0.01). Regarding the 3rd aim, four hundred ninety eight patients with psychosis were included in our study. We found that the Met/Met genotype is associated with higher sequencing of complex motor acts signs (p=0,034) and with lower executive function (p<0,01) in Caucasian but not in African and African-Caribbean individuals. Patients with higher sequencing of complex motor acts signs exhibited also lower executive function in Caucasians (p<0,05). Caucasian patients with both higher sequencing of complex motor acts signs and poorer executive function showed an higher percentage of Met/Met genotype, whereas the percentage of Val/Val individuals was higher in patients with both lower sequencing of complex motor acts signs and higher executive function and the Val/Met genotype was more frequent among patients with either higher sequencing of complex motor acts signs or poorer executive function (Chi Square, p=0,016). CONCLUSION: In conclusion, the purpose of this project is to contribute to clarifying the potential mechanisms underlying the onset of psychosis, in order to improve the assessment of the illness and to contribute to defining new prevention strategies and better treatment interventions for psychosis.