BACKGROUND: Gli Endofenotipi sono componenti stabili ed ereditabili dei disturbi psicotici, misurabili in laboratorio con metodi quantitativi di analisi. I marker di risonanza magnetica, i deficit neuropsicologici, la prepulse inhibition del riflesso di startle (PPI) e i neurological soft signs (NSS) sono alcuni tra gli endofenotipi più studiati per la schizofrenia. Un’evoluzione del concetto di endofenotipo è quella di “endofenotipo esteso” che definisce l'unione tra più endofenotipi funzionalmente associati tra loro. OBIETTIVI: Il presente progetto di Dottorato si pone lo scopo di: 1) condurre per la prima volta una revisione sistematica allo scopo di individuare potenziali "endofenotipi estesi", formati da deficit neuropsicologici e alterazioni cerebrali strutturali, associati al polimorfismo Val158Met del gene COMT; 2) testare per la prima volta, in una coorte di pazienti affetti da psicosi, l'ipotesi che i pazienti con alti livelli di NSS (sensory integration and sequencing of complex motor act), rilevati da una valutazione neurologica, hanno più elevati deficit di PPI e che i pazienti con elevati deficit di PPI e elevati livelli di NSS hanno maggiori sintomi negativi; 3) valutare per la prima volta, in una coorte di pazienti affetti da psicosi se i pazienti con il genotipo Val/Val del polimorfismo Val158Met del gene COMT hanno più elevati livelli di NSS (sensory integration and sequencing of complex motor act) e una minore prestazione nelle funzioni esecutive. E' stata inoltre valutata l'ipotesi di un'associazione tra elevati livelli di NSS e basse funzioni esecutive. Infine è stato ipotizzata un'associazione tra il genotipo Val/Val della COMT e contemporaneamente elevati livelli di NSS (sensory integration and sequencing of complex motor act) e basse prestazioni nelle funzioni cognitive. METODI: Per il primo obiettivo è stata condotta una revisione sistematica sui database Medline e PubMed per individuare i test neuropsicologici e le alterazioni cerebrali strutturali legati al polimorfimso Val158Met del gene COMT e per verificare se gli endofenotipi cerebrali strutturali e neuropsicologici individuati sono associati tra loro. Infine sono stati proposti alcuni "endofenotipi estesi". Per il secondo obiettivo è stata reclutata una coorte di pazienti psicotici in contatto con il Servizio di Salute Mentale di Verona Sud (Italia) ed è stata sottoposta alle valutazioni della PPI e dei NSS. Inoltre è stato reclutato un gruppo di controllo. Per il terzo obiettivo, è stata reclutata una coorte di pazienti affetti da psicosi, che hanno donato il loro DNA e sono stati sottoposti alla valutazione dei NSS e a una valutazione neuropsicologica. I dati sono stati raccolti nell'ambito di tre studi epidemiologici multicentrici, condotti rispettivamente in Veneto (Italia) e a Londra Sud, Nottingham e Bristol (Regno Unito): il "Psychosis Incident Cohort Outcome Study" (PICOS), l'"Aetiology and Ethnicity in Schizophrenia and Other Psychoses study (AESOP) " and il "Genetics and Psychotic Illness study (GAP)". Inoltre è stata inclusa una coorte di pazienti psicotici in contatto con il Servizio di Salute Mentale di Verona Sud, Italia. RISULTATI: Rispetto al primo obiettivo, sono stati proposti tre "endofenotipi estesi" associati al polimorfismo Val158Met del gene COMT; un endofenotipo caratterizzato da: 1) la performance all'N-back e il volume della corteccia prefrontale, 2) la performance all'N-back e il volume del lobo mediale temporale, 3) la performance al CPT e il volume della corteccia prefrontale. Rispetto al secondo obiettivo, sono stati sottoposti alle valutazioni della PPI e dei NSS quindici pazienti affetti da psicosi con una durata di malattia uguale o inferiore a cinque anni e quindici soggetti di controllo. I risultati hanno dimostrato che nei pazienti non erano evidenziabili maggiori livelli di deficit di PPI ma solo più elevati livelli di NSS (p<0.01), rispetto ai soggetti controllo. Più elevati livelli di NSS non erano associati a deficit di PPI. I deficit di PPI non erano correlati con nessuna caratteristica clinica; al contrario i NSS sensory integration signs erano correlati positivamente ai sintomi negativi (p<0,01). Rispetto al terzo obiettivo, sono stati inclusi nel nostro studio quattrocentonovantotto pazienti affetti da psicosi. I risultati hanno evidenziato che il genotipo Met/Met era associato ad alti livelli di NSS sequencing of complex motor acts (p=0,034) e a basse prestazioni nelle funzioni esecutive (p<0,01) nei soggetti Caucasici ma non negli Africani e Afro-caraibici. I pazienti Caucasici con NSS sequencing of complex motor acts più elevati dimostravano anche peggiori funzioni esecutive (p<0,05). Tra i pazienti Caucasici che presentavano sia alti livelli di NSS sequencing of complex motor acts sia basse funzioni esecutive è stata riscontrata una più elevata percentuale del genotipo Met/Met, mentre il genotipo Val/Val era maggiormente presente nei pazienti che presentavano sia bassi livelli di NSS sequencing of complex motor acts sia alte funzioni cognitive e il genotipo Val/Met era più frequenti tra i pazienti che presentavano o alti livelli di NSS sequencing of complex o basse funzioni esecutive (Chi quadrato p=0,016). CONCLUSIONI: Concludendo, lo scopo di questo progetto è quello di contribuire a chiarire i potenziali meccanismi sottostanti l'esordio della psicosi, al fine di migliorare l'assessment e contribuire a definire nuove strategie di prevenzione e migliori trattamenti per tale disturbo.
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.
EXTENDED ENDOPHENOTYPES IN EARLY PSYCHOSIS: IS THERE AN ASSOCIATION AMONG BRAIN STRUCTURES, NEUROLOGICAL SOFT SIGNS, NEUROPSYCHOLOGY, PREPULSE INHIBITION AND GENETICS?
IRA, Elisa
2012-01-01
Abstract
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.File | Dimensione | Formato | |
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