Elaine Walker - US grants

The present research is concerned with the developmental precursors of schizophrenia. It utilizes a novel methodology that will facilitate the study of premorbid factors at a detailed level of analysis that has not been possible with previous approaches. Childhood home movies and developmental information will serve as the data base for the study of early behavioral phenomena in individuals diagnosed as suffering from schizophrenia in adulthood. There will be three comparison groups: Healthy siblings of patients, patients suffering from affective disorders, and subjects from families with no mental illness. The first phase of this research program will use the home movies to study molar behavioral characteristics of the subjects at 1 to 2 years of age and to develop rating scales for examining the molecular aspects of neuromotor, attentional and socioemotional functions. Based upon past findings and current theoretical models, it is predicted that constitutional vulnerability to schizophrenia will be manifested in infancy on the molar behavioral level as well as in specific functional domains. On the molar level, it is predicted that preschizophrenic children will show decreased levels of communicative and motor behavior when compared to control subjects. The methodology of the present study holds promise for addressing many other questions that are of critical relevance to our understanding of the etiology of schizophrenia. The rating scales devised in the first phase of the research program will be used in subsequent work to examine the development of neuromotor, attentional and socioemotional functions. This will permit molecular analyses of these functional domains across childhood and will provide data for determining: 1) the earliest period at which deviations are apparent in the developmental trajectory of schizophrenia, 2) the extent to which the development of schizophrenic and affective patients is distinguishable, 3) the sequence of emergence of developmental deviations in the three domains, and 4) the relation between early developmental factors and the later clinical course of the disorder.

The proposed research is a series of investigations of the developmental precursors of schizophrenia and their relation with clinical outcome characteristics -- symptoms, neuropsychological profiles and brain morphology. Using childhood home-movies, the neuromotor and socioemotional aspects of schizophrenic patients' development will be documented from infancy through adolescence, and contrasted with that of sibling and nonfamilial controls as well as patients with affective disorders. The relation between the various aspects of childhood development and the characteristics of patients as adults will be examined. The research will also explore the roles of prenatal and perinatal factors and family history of mental illness in predicting developmental course and clinical outcome.

The research described in this proposal is concerned with identifying developmental precursors of schizophrenia and examining the relation between developmental factors and neuropsychological and neuroanatomical characteristics of schizophrenia. The research uses a methodology that is best described as an archival, observational approach; childhood home- movies will serve as the primary data-base on neuromotor and socioemotional aspects of development, beginning in infancy and extending through early adolescence. Subjects are individuals who succumbed to schizophrenia in late adolescence/early adulthood. There will be three comparison groups; patients diagnosed with affective disorder, healthy siblings of patients, and subjects from nuclear families with no mental illness. In addition to the childhood home-movies, extensive developmental and family history data are collected on all subjects. Patients and their sibling controls will also receive a neuropsychological assessment and magnetic resonance image (MRI) scan of the brain. Previously awarded grants will cover the collection of archival data and assessments of subjects. This proposal requests funds to cover the costs of personnel for extensive observational analyses of videotapes and organization, storage and analyses of data. The chief goals of the project are to: 1) chart the development trajectories leading to schizophrenia, 2@determine the relation between potential etiologic factors (perinatal complications and family history of mental illness) and developmental characteristics, and 3) examine the relations among etiologic factors, developmental characteristics, and neuropsychological and neuroanatomical aspects of the subjects as adults. Because the methodology of the study will allow for direct microlevel analyses of behavior across the childhood years, it holds promise for yielding a broader view of preschizophrenic development than has been possible with previous approaches.

The long-term objective of the principal investigator is the elucidation of the genetic epidemiology of opportunistic pathogens. The epidemiological data necessary to assess the means of transmission, virulence, and reservoirs of a pathogen provide a strong foundation for managing disease, but this data is often not available for 'minor' pathogens. Moraxella catarrhalis, an oropharyngeal commensal with pathogenic potential, will serve as a model system for genetic epidemiological analysis. Multi-locus DNA typing provides a means of assessing the genetic diversity and genetic identity in a population of bacteria. Correlation of genotype with other epidemiological factors provides a means of inferring associations between specific genotypes and transmissibility, disease state of the host, and virulence. The specific aims of this project include I) the analysis of genetic diversity in a nine year collection of M. catarrhalis isolates recovered from a Veterans Administration medical center. A random sample of M. catarrhalis isolates from each year will be genotyped using restriction fragment length polymorphisms detected by pulsed field gel electrophoresis and Southern blot analysis. Genotypic data will be entered into a data matrix, and will be used to construct a dendrogram of genetic relatedness among strains. 2) An outbreak may be due to a common source of a pathogen; this can be inferred by a concurrent increased incidence one strain. The PI will test the hypothesis that a three year peak in isolates at the Mountain Home VAMC was due to increased nosocomial transmission. This will be inferred by a decrease in genetic diversity due to the emergence of one or a few strains. In order to detect less common strains a more extensive sampling of strains recovered during the peak will be performed. 3) Genetic data will be tested for correlation with factors of epidemiological significance. Chart reviews of patient records will provide data on patient residence at the time of isolation, date of admission for in- patients, date of culture, and patient risk factors. The data will be analyzed for correlation between genetically related strains and location within the hospital, physical and temporal proximity of the patients, and specific patient risk factors. Statistically significant correlation will be used to infer the roles of transmission, environmental reservoirs, and the interaction of patient risk factors with specific strains in successful infection/colonization.

The research described in this proposal is concerned with identifying developmental precursors of schizophrenia and examining the relation between developmental factors and neuropsychological and neuroanatomical characteristics of schizophrenia. The research uses a methodology that is best described as an archival, observational approach; childhood home- movies will serve as the primary data-base on neuromotor and socioemotional aspects of development, beginning in infancy and extending through early adolescence. Subjects are individuals who succumbed to schizophrenia in late adolescence/early adulthood. There will be three comparison groups; patients diagnosed with affective disorder, healthy siblings of patients, and subjects from nuclear families with no mental illness. In addition to the childhood home-movies, extensive developmental and family history data are collected on all subjects. Patients and their sibling controls will also receive a neuropsychological assessment and magnetic resonance image (MRI) scan of the brain. Previously awarded grants will cover the collection of archival data and assessments of subjects. This proposal requests funds to cover the costs of personnel for extensive observational analyses of videotapes and organization, storage and analyses of data. The chief goals of the project are to: 1) chart the development trajectories leading to schizophrenia, 2@determine the relation between potential etiologic factors (perinatal complications and family history of mental illness) and developmental characteristics, and 3) examine the relations among etiologic factors, developmental characteristics, and neuropsychological and neuroanatomical aspects of the subjects as adults. Because the methodology of the study will allow for direct microlevel analyses of behavior across the childhood years, it holds promise for yielding a broader view of preschizophrenic development than has been possible with previous approaches.

DESCRIPTION (provided by applicant): Interest in the possibility of preventing the onset of psychosis has grown in recent years. The identification of individuals at risk will be a critical first step in the development of early prevention trials. It is well established that the clinical onset of psychosis is usually preceded by significant behavioral dysfunction, which becomes most pronounced during adolescence. In fact, the vast majority of patients manifest adjustment problems during adolescence; often a 'prodromal' behavioral syndrome similar to SPD. To date, prospective studies of youth with prodromal signs have shown a high rate of Axis I outcomes (30 to 40 percent) within one to three years, lending support to the utility of behavioral risk indicators. In order to improve predictive validity beyond that achieved with behavioral criteria, a multifactorial approach that includes biological risk factors may be needed. Findings from our preliminary research indicate that adolescents with schizotypal personality disorder (SPD) manifest several physical indicators that have been observed in schizophrenia patients, including dysmorphic features, movement abnormalities, and elevated cortisol. Further, SPD adolescents with more pronounced dysmorphic features, movement abnormalities and cortisol elevations are more likely to show symptom exacerbation or Axis I disorder within two to three years. The proposed research represents a replication and extension of this study. The chief goals are to elucidate the predictive validity of putative behavioral and biological indicators of risk for psychotic disorders, and 2) to shed light on neuromaturational processes that might be involved in the emergence of prodromal features. Of particular interest is the particular role of the hypothalamic-pituitary-adrenal (HPA) axis as a moderating neural system that influences the expression of latent vulnerabilities. The study will explore the direct and interactive effects of dysmorphic features (minor physical and dermal abnormalities), movement abnormalities, and cortisol secretion on the developmental course of adolescents with SPD and other Axis II disorders. Participants will be followed for a four-year period to chart behavioral development, psychiatric symptoms and HPA activity. The resultant data will allow us to address key questions about the development and prediction of psychotic disorders in at-risk youth. In the long-term, the research holds promise for yielding findings that have implications for our conceptualization of the prodromal course of schizophrenia and other psychoses, and for approaches to preventive intervention.

[unreadable] DESCRIPTION (provided by applicant): Schizophrenia and other forms of psychosis affect approximately 3% of the population with a disorder that is usually chronic and disabling. The peak age of onset is between ages 18-30, occurring just as life's most productive years are beginning. Although genetic liability and abnormal brain development are known contributing factors, the etiology and pathophysiology of schizophrenia and related syndromes is largely unknown. To date, prospective observation of onset, i.e., the transition from vulnerability to disorder has not been possible because most persons at true risk cannot be identified premorbidly. This has hampered efforts at prevention. However, recent progress in risk ascertainment methodology has enabled reliable identification of help-seeking persons with pre-psychotic or "prodromal" clinical syndromes who develop psychosis within 1-2 years at rates between 20%-50%. Thus, clinical high-risk populations are now available for tracking prospectively the development and emergence of psychosis. However, because of the low incidence of schizophrenia and the heterogeneity of outcomes in clinical high-risk cases, single site studies cannot efficiently exploit the risk criteria in identifying predictors and mechanisms of psychosis. The NAPLS consortium was created to solve this problem. Eight NIMH-funded sites in North America studying prodromal patients using a common prodromal assessment instrument pooled data to create the largest sample of such persons worldwide (N=291), 35% of whom converted to psychosis after 2 years. An algorithm of baseline data was generated predicting psychosis with about 80% positive predictive power and 40% sensitivity. In this revised proposal, we describe a collaborative prospective study for which we will recruit 800 cases and 400 appropriate controls over 5 years using common, standardized clinical and neurobiological measures. The aim is to collect a sample with sufficient size and power to rigorously test elements critical to the liability for and development of psychosis in the biomarker domains of brain structure, electrophysiology, stress hormones, and genomics, and in the clinical domains of prodromal presentation and epidemiology. The revised proposal addresses reviewers' concerns, including the integration of the research plan and measures into a unifying framework. The findings will enhance our ability to identify persons at high risk for imminent psychosis, by refining predictors of conversion, and expanding our understanding of the underlying neural mechanisms. Such knowledge is critical for future efforts at early detection, intervention and prevention of psychotic disorders. PUBLIC HEALTH RELEVANCE: Preventing schizophrenia and other psychoses could relieve an enormous burden of personal and family suffering and economic losses to society. This 8-site project aims to increase our ability to identify high-risk individuals prior to onset and to pinpoint neurobiological changes that underlie the emergence of a psychotic disorder. These efforts are critical to the development of effective preventative intervention strategies for psychotic disorders. [unreadable] [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): Schizophrenia and other psychotic disorders are serious and debilitating mental illnesses that incur substantial suffering for patients and major challenges to our health care system. The clinical high-risk (CHR) prodromal phase is the period prior to the onset of psychosis when clinical symptoms gradually emerge and function declines. The presence of a CHR syndrome in young adults is associated with heightened risk (~30%) for the later development of psychosis. The North American Prodrome Longitudinal Study (NAPLS) and other CHR studies have made substantial progress towards predicting psychosis, and in showing an accelerated reduction in prefrontal cortex (PFC) gray matter (GM) density in CHR converters from pre- to post-psychosis onset, but the mechanisms driving conversion remain elusive, partly because no studies include repeated measures prior to the onset of psychosis. In NAPLS2, we found that disrupted resting-state (rs) thalamo- cortical functional connectivity prior to psychosis predicts conversion and correlates with rate of GM decline, but we do not know if rs-dysconnectivity is progressive during the prodrome. Furthermore, in NAPLS2, plasma markers of pro-inflammatory cytokines at baseline predicted the rate of GM loss in converters; these same markers also correlated with rs-dysconnectivity. We do not yet know whether these inflammatory markers drive the changes in brain structure/function or are consequences of these changes. Similarly, higher levels of cortisol, and lower mismatch negativity predicted psychosis and the rate of PFC GM decline and were correlated with each other and with measures of rs-connectivity and cytokines. This application is a competitive renewal for a nine-site, longitudinal study aimed at identifying the brain processes underlying the progression of the clinical syndromes that characterize the psychosis prodrome. The goals are: 1) to determine the pre-onset trajectories of GM decline and disrupted resting-state brain connectivity in CHR individuals who develop psychosis using MRI, and 2) to identify inflammatory and plasticity mechanisms associated with transition to psychosis. Over a two-year period, the study will repeatedly measure these indicators, and at the same time examine changes in physiological indices of brain function, social and cognitive functioning, and symptom progression. The multi-site collaboration will follow large CHR (n= 378) and demographically matched comparison (n= 162) samples that will undergo comprehensive assessments of biological and behavioral changes. This approach will answer important questions about the origins of the brain changes that give rise to psychosis and will provide insights into likely approaches to halting or mitigatig the pathological process and advance our understanding of risk prediction, both critical steps in prevention.