Structural brain correlates of an operationally defined high-risk phenotype for schizophrenia: a population based study

Schizophrenia is THE major psychiatric disorder and it affects around 1% of the population in their lifetime with devastating effects. Key ?psychotic? symptoms include hallucinations, and delusions as well as problems with emotions, motivation and intellect. It has recently been shown that many people have similar symptoms but only a few go on to develop the full-blown illness. Studying people with symptoms alone who are ?at risk? of schizophrenia is likely to teach us a lot about what it is that causes the illness. One way of doing this is to make use of a large survey of the population known as the Avon Longitudinal Study of Parents and Children (ALSPAC). This has been following several thousand people born in Avon to see what health problems they might develop. The people in ALSPAC are now about 17 years old and are being studied to see which of them has these psychotic-like symptoms. We propose to build on this work by selecting a representative group of those with and those without symptoms and asking them to have an MRI scan. MRI is a commonly used and very safe brain scanning technique. It shows up the detailed structured of the brain, both grey and white matter. Statistical techniques can then be applied which will pick out any areas that are different between the two groups. We predict that certain areas will be abnormal and if so this will greatly increase our understanding of the illness and may even lead to new treatments or ways of preventing the clinical disorder manifesting itself.

Schizophrenia affects around 1% of the population in their lifetime but its neurobiological basis is poorly understood. One potential risk factor is psychosis-like symptoms occurring in adolescence. These symptoms are much more common in the population than clinically identified psychosis. We propose to characterise the neural substrate of an operationally defined high risk (HR) phenotype for the later development of schizophrenia based on such symptoms using structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Previous work using MRI in prodromal patients and those at high genetic risk for schizophrenia has shown subtle abnormalities in grey and white matter. However, such studies are subject to several confounding factors, such as treatment effects, selection bias and limits to generalizability, and the results lack consistency. We plan to build on ongoing work identifying high-risk mental states in late adolescence (17? years) in the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC is a population based cohort and has a wealth of relevant data critically relevant to this proposal including cognitive testing during childhood and stored DNA and the cohort members will be at a crucial stage of adolescent development just prior to the sharp in incidence of schizophrenia in early adulthood. We propose to select at random 125 young people with and 125 without psychosis-like symptoms from the ALSPAC cohort and invite them to undergo MRI. We will carry out voxel-based morphometry and DTI to examine differences between the groups in terms of regional grey matter density/volume and the integrity of white matter. We will also map myelin water fraction from analysis of quantitative relaxometry data which will provide deeper insights into the nature of the white matter changes. We predict that significant changes will be detected in the HR group with symptoms, which will reflect abnormal neurodevelopment (synaptic pruning) - particularly in frontal and medial temporal lobe grey matter and white matter tracts connecting them - and hence a vulnerability to develop a clinical psychotic illness. We will also test the hypothesis and changes in hippocampus do not occur in HR subjects but only in patients with established schizophrenia. In addition, we will be in a position to explore the association between these findings and genetic variation. This project has the potential to deliver important advances in our understanding of the biological basis of schizophrenia and related psychotic disorders, and perhaps to inform the development of therapeutic interventions.