NEUROPSYCHOLOGICAL IMPAIRMENT IN INDIVIDUALS AT FAMILIAL RISK FOR SCHIZOPHRENIA. SEARCHING FOR THE NEUROCOGNITIVE ENDOPHENOTYPE

Background. Studies on nonpsychotic biological first-degree relatives of patients with schizophrenia (SCZRELs) can be considered as a useful tool for detecting cognitive markers for the illness vulnerability. Furthermore, identifying different subtypes of schizophrenia (e.g. Deficit Syndrome) could allow a better characterization of the different profiles of vulnerability to schizophrenia. It is currently unclear whether some observed similarity in schizophrenia and affective psychosis may be a reflection of a dimensional continuum detectable through cognitive vulnerability. Aims. This dissertation includes four different studies addressing the role of neurocognitive functioning in healthy first-degree relatives of patients with schizophrenia. The underlying assumption is that neurocognition may be viewed as a putative marker of vulnerability to psychosis. Specifically, Study1 reviews the literature on neurocognitive impairments exhibited by SCZRELs as an indicator of susceptibility to schizophrenia; Study2 aims to identify specific cognitive deficits in subsamples of SCZRELs; the purpose of the Study3 is to detect cognitive differences in subgroups of SCZRELs of Deficit/Nondeficit schizophrenia patients (DS/NonDS); Study4 focuses on the possible overlap in memory dysfunction in samples of youth at familial high-risk for schizophrenia (HRSCZ) and affective psychosis (HRAFF). Methods. Study2-3 addressed adults SCZRELs (aged 18-60), and Study4 addressed Child and Adolescent (aged 13-25). Study2 was conducted at Verona MHCS and concerned neurocognitive endophenotypes in a sample of SCZRELs with tasks involving memory, attention and executive functions. Study3 clustered the sample of patients with schizophrenia according to the “Deficit/Nondeficit” subtype criteria, verifying whether the cognitive profile of DS relatives is more impaired than that of Nondeficit relatives, Finally, Study4 is part of the Harvard Adolescent High Risk project and was conducted in Boston to assess the memory profile (verbal and non-verbal memory) of HRSCZ and HRAFF by directly comparing neuropsychological measures. Clinical measures were also considered in all conducted studies; moreover, the samples considered in the studies were compared with normal control ones. Results. Consistent with the literature review on SCZRELs (Study1), our SCZRELs sample exhibited more impairments on executive tasks than the controls; moreover, negative symptoms occurred more frequently in the relatives and were correlated with the cognitive impairment (Study2). The subgroup of relatives, stratified according to the Deficit syndrome of their ill relatives, showed evidences of more specifically impaired clinical and cognitive measures as compared with the Non DS relatives, who were to some extent similar to controls (Study3). Both HRSCZ and HRAFF were more impaired on both verbal and visuo-spatial memory tasks and exhibited a higher psychopathological profile compared to controls (Study 4). Discussion. Among the putative candidates as cognitive intermediate endophenotypes for schizophrenia (Study1), our findings add evidence of impaired executive functions in the healthy SCZRELs. This impairment was found associated with negative symptoms, suggesting a specific responsibility of prefrontal area mechanisms as deficient information processing for schizophrenia vulnerability (Study2). The detailed examination of the sample of relatives, according to the Deficit/Nondeficit patients’ subtypes, may point to the occurrence of distinct profiles of vulnerability for different subtypes of schizophrenia (Study3). Additionally, an abnormal executive cognitive processing, substantially unrelated to psychopathological symptoms, seems to affect verbal and nonverbal memory performances of people at familial risk for both affective and nonaffective psychosis (Study4). Conclusions. Consistent with current available data on individuals at risk for schizophrenia (Study1), we show that an underlying executive deficit may play an important endophenotypic role for the familial vulnerability to this psychosis (Study2). Our studies further suggest that distinct profiles of familial liability may be accounted for the heterogeneity of schizophrenia (Study3). Our results also suggest that the heterogeneity of schizophrenic manifestations can stem from heterogeneity of familial liability profile (Study4). Finally, we point to the presence of an underlying organizational deficit, common to schizophrenia and affective psychosis that may serve as developmental indicator of liability even in absence of full-blown clinical manifestations.