Multivariate prediction of schizophrenia in adulthood utilizing childhood neurological data

Ph.D. University of Hawaii at Manoa 2012.Includes bibliographical references.Research has highlighted numerous benefits of identifying at-risk individuals before they develop schizophrenia. Longitudinal studies have elucidated a number of neurological deficits present in people with schizophrenia that can be measured premorbidly. Most of these studies, however, have suffered from methodological limitations, including only incorporating a single neurological variable, small sample size, and truncated follow-up assessment period. The objective of the current study was to examine the ability of multiple neurological variables to predict adult psychiatric status in high risk individuals and healthy controls. Data were derived from a longitudinal dataset of a large Danish cohort study begun in 1959, and included information on offspring of parents hospitalized with schizophrenia as well as age-matched controls. In adulthood, 32 offspring were diagnosed with a schizophrenia-spectrum disorder, 79 with a non-psychotic diagnosis and 133 with no diagnosable mental illness. The most accurate prediction model correctly classified 65.6% of schizophrenia-spectrum outcomes based on risk status and neurological data. Minor physical anomalies, a marker of pre-or perinatal complications, were the single most significant neurological predictor of schizophrenia-spectrum outcomes, followed by neuromotor dysfunction. Ocular alignment deficits, abnormal cerebral lateralization, and delayed developmental milestones contributed the least to predicting outcome diagnoses relative to other proxies of neurological dysfunction. Results are discussed with respect to the two-hit model of schizophrenia etiology

Youth-caregiver Agreement on Clinical High-risk Symptoms of Psychosis

Early identification of individuals who will go on to develop schizophrenia is a difficult endeavor. The variety of symptoms experienced by clinical high-risk youth make it difficult to identify who will eventually develop schizophrenia in the future. Efforts are being made, therefore, to more accurately identify at-risk individuals and factors that predict conversion to psychosis. As in most assessments of children and adolescents, however, both youth and parental report of symptomatology and resulting dysfunction are important to assess. The goals of the current study were to assess the extent of cross-informant agreement on the Structured Interview for Prodromal Symptoms (SIPS), a widely-used tool employed to determine clinical high-risk status. A total of 84 youth-caregiver pairs participated. Youth and caregiver raters displayed moderate overall agreement on SIPS-rated symptoms. Both youth and caregiver ratings of youth symptomatology contributed significantly to predicting conversion to psychosis. In addition, youth age and quality of youth-caregiver relationships appear to be related to cross-informant symptom ratings. Despite differences on individual SIPS domains, the majority of dyads agreed on youth clinical high-risk status. Results highlight the potential clinical utility of using caregiver informants to determine youth psychosis risk

Premorbid multivariate markers of neurodevelopmental instability in the prediction of adult schizophrenia-spectrum disorder:a high-risk prospective investigation

The authors examined whether multiple childhood indicators of neurodevelopmental instability known to relate to schizophrenia-spectrum disorders could predict later schizophrenia-spectrum outcomes. A standardized battery of neurological and intellectual assessments was administered to a sample of 265 Danish children in 1972, when participants were 10–13 years old. Parent psychiatric diagnoses were also obtained in order to evaluate the predictive strength of neurodevelopmental factors in combination with genetic risk. Participants were grouped into three categories indicating level of genetic risk: children with a parent with schizophrenia (n=94); children with a parent with a non-psychotic mental health diagnosis (n=84); and children with a parent with no records of psychiatric hospitalization (n=66). Variables measured included minor physical anomalies (MPAs), coordination, ocular alignment, laterality, and IQ. Adult diagnoses were assessed through psychiatric interviews in 1992, as well as through a scan of the national psychiatric registry through 2007. Adult diagnostic information was available for 244 members of the sample. Through a combination of multiple childhood predictors, the model correctly classified 73% (24 of 33) of the participants who eventually developed a schizophrenia-spectrum outcome in adulthood. Results suggest that, with replication, multivariate premorbid prediction could potentially be a useful complementary approach to identifying individuals at risk for developing a schizophrenia-spectrum disorder. Genetic risk, MPAs, and other markers of neurodevelopmental instability may be useful for comprehensive prediction models

Atrophin contributes to the negative regulation of epidermal growth factor receptor signaling in Drosophila.

Dentato-rubral and pallido-luysian atrophy (DRPLA) is a dominant, progressive neurodegenerative disease caused by the expansion of polyglutamine repeats within the human Atrophin-1 protein. Drosophila Atrophin and its human orthologue are thought to function as transcriptional co-repressors. Here, we report that Drosophila Atrophin participates in the negative regulation of Epidermal Growth Factor Receptor (EGFR) signaling both in the wing and the eye imaginal discs. In the wing pouch, Atrophin loss of function clones induces cell autonomous expression of the EGFR target gene Delta, and the formation of extra vein tissue, while overexpression of Atrophin inhibits EGFR-dependent vein formation. In the eye, Atrophin cooperates with other negative regulators of the EGFR signaling to prevent the differentiation of surplus photoreceptor cells and to repress Delta expression. Overexpression of Atrophin in the eye reduces the EGFR-dependent recruitment of cone cells. In both the eye and wing, epistasis tests show that Atrophin acts downstream or in parallel to the MAP kinase rolled to modulate EGFR signaling outputs. We show that Atrophin genetically cooperates with the nuclear repressor Yan to inhibit the EGFR signaling activity. Finally, we have found that expression of pathogenic or normal forms of human Atrophin-1 in the wing promotes wing vein differentiation and acts as dominant negative proteins inhibiting endogenous fly Atrophin activity