Grey matter changes over time in high risk subjects developing schizophrenia
Introduction
The Edinburgh High Risk Study (EHRS) is the first to prospectively examine the changes in brain structure of people at high risk of schizophrenia for familial reasons, before any individuals fall ill (Johnstone et al., 2000). We compared the changes over time in high risk subjects who had two scans about 2 years apart, in the three groups: well controls (n = 19), high-risk subjects without any psychotic symptoms (n = 47), and high-risk subjects with transient or isolated psychotic symptoms (n = 18). Eight of the people from the transient or isolated psychotic symptoms group have subsequently developed schizophrenia, on average 2.34 years after their first scan.
Previous cross-sectional imaging studies in schizophrenia found reduced GMD compared to controls, particularly in the temporal lobes, in people with established disease and in the first-episode of illness (Lawrie and Abukmeil, 1998, Lawrie et al., 1999, Shenton et al., 1992, Suddath et al., 1990, Wright et al., 2000). These studies show that structural brain changes are present around the time of onset of psychosis, but the chronology is unknown. However, post-mortem schizophrenia studies have shown mixed findings; some report no change or an increase in GMD in the ventral striatum (Lauer et al., 2001), no change specifically in the amygdala (Chance et al., 2002), whilst others find decreases in GMD (McDonald et al., 2000) in the left parahippocampal gyrus and left fusiform gyrus, similar to those found in MRI studies. The schizophrenic subjects in these post-mortem studies differ greatly from most patients and particularly our high-risk group in age, illness and medication duration, (family history), and are therefore not directly comparable. Further to this, there are differences in the analysis methods used by each approach. Post-mortem studies have to account for individual and regional tissue shrinkage, differences in time to fixation and the fixation period itself, and they measure volume, not maximal points of change, as in VBM.
Structural MRI of the brain at first scan in the subjects in this sample revealed that there was lower GMD in the amygdala–hippocampal complex (AHC) in people at high risk, but even less in first-episode patients, compared to healthy controls (Job et al., 2002, Job et al., 2003, Lawrie et al., 1999, Lawrie et al., 2001). A subgroup of those high-risk subjects and controls were scanned on a second occasion approximately 2 years later. Some of the high-risk participants had experienced transient or isolated psychotic symptoms during this time. Subsequently, 8 of the high-risk participants went on to develop schizophrenia (Johnstone et al., 2000). We therefore tested a three-part hypothesis in this report. Firstly, we determined whether or not people at high risk of schizophrenia, as a group, show reductions in GMD in the temporal lobes and AHC over time, compared with a control group, that might indicate a general and probably genetic effect. Secondly, we examined whether these structures showed greater reductions in GMD in high-risk participants with transient or isolated psychotic symptoms, than in those without any psychotic symptoms. Thirdly, we examined changes over time in the 8 high-risk participants who have since developed schizophrenia, for reductions that are evident preceding illness onset.
Section snippets
Subjects
The subjects were recruited for the EHRS (Hodges et al., 1999, Johnstone et al., 2000). A total of 162 high risk subjects who had at least two first or second degree relatives with schizophrenia, were recruited over a period of 4 years. Of this group, 66 people and 19 healthy controls, matched group wise for age, had a structural MRI scan of the whole brain which was repeated after approximately 2 years in the first 5 years of the study. Others were either recruited too late or became ill too
Results
In our first comparison, we constructed statistical maps of changes over time in the high-risk and control groups. Using the same statistical analysis (a repeated measures ANOVA, for group × time interactions) as used in our previous ROI study, there were no significant differences in GMD changes, over 2 years, between the control and the high-risk group, in keeping with our previous ROI study (Lawrie et al., 2002). However, when we examine the changes over time in the high risk group alone,
Discussion
We did not find evidence to support the first part of our hypothesis, namely a reduction in temporal lobe volumes in all high-risk individuals as compared to controls. However, using exclusive masking, a statistical technique used more often in functional MRI (Cabeza et al., 2004, Critchley et al., 2000, Davis and Johnsrude, 2003, Farrer et al., 2003, Morcom et al., 2003), the within group analyses do provide information that may be useful for early diagnostic purposes. This masking technique
Acknowledgment
This project was funded by a Medical Research Council of Great Britain programme grant.
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