Editor's Note: On Friday, 30 March 2007, at the International Congress on Schizophrenia Research in Colorado Springs, Martha Shenton of Harvard Medical School, Boston, chaired a symposium session entitled, “Evidence for endophenotypic markers in schizophrenia." Young Investigator travel awardee Neeltje E.M. van Haren of the University Medical Centre Utrecht, the Netherlands, was there to report for you.
17 April 2007. In this session, the 10 speakers presented a number of findings that were relevant to possible endophenotypic markers in schizophrenia. For example, there were several speakers who presented data from adolescent high-risk samples. Most of these samples consisted of subjects who were relatives (i.e., siblings or twins) of patients, and therefore had an increased risk of developing psychosis.
Larry Seidman from the Harvard Medical School was the first speaker and he reported on cortical thickness measurements in young subjects who were at high risk for developing schizophrenia. Subjects were relatives of patients, and as such carry elevated genetic risk for the illness and might therefore be characterized by milder forms of abnormalities seen in patients. Both cortical thickness and surface area were calculated. These measures were discussed as being possible putative indicators of the integrity of cytoarchitecture in the cortex. Of note, findings showed that thinning in high-risk subjects was found in frontopolar, frontal medial, dorsolateral prefrontal cortex, anterior insula, anterior cingulate and in parahippocampal areas relative to controls. Surprisingly, the most extensive thinning was found in occipital areas. The authors suggested that the most prominent alterations were in areas involved in attention, executive function, olfaction, awareness of self, and in visual processing.
Jonathan Harris from the University of Edinburgh, United Kingdom, also reported on data from a genetic high-risk population. Subjects were identified as 'at high risk' when two family members were diagnosed with psychosis. The researchers assessed a gyrification index (GI), which is considered to be a marker for neurodevelopmental processes. An automated GI method was used to investigate whether GI can predict whether a subject will or will not make the transition to psychosis. Only baseline measurements were used and the subjects who later became psychotic were compared to those subjects who did not. High-risk individuals who subsequently developed schizophrenia were distinguished from the remaining cohort by increased right prefrontal GI.
Data from a third genetic high-risk adolescent sample was presented by Aysenil Belger from the University of North Carolina at Chapel Hill. Many of these adolescents already showed prodromal symptoms. Adolescence is considered to be a critical period for maturation of fronto-limbic and fronto-striatal circuits that are critical for higher order cognitive processes. Belger and her colleagues applied cortical and subcortical parcellation algorithms to obtain volumes of cortical and subcortical structures and ventricles. The authors provided evidence for structural differences and differences in growth curves in high-risk subjects. Group differences were shown in basal ganglia (global pallidus and putamen), cingulum and hippocampus. Age by group interactions were shown for globus pallidus, putamen, hippocampus and total gray matter volume.
Machteld Marcelis from Maastricht University, the Netherlands, also reported on preliminary data from a genetically high-risk sample— unaffected siblings—and compared their fractional anisotropy (FA) values across the brain with those from first episode patients and control subjects. She showed decreased FA in patients relative to controls in the corpus callosum and corona radiata, but not in frontal and temporal white matter areas. In addition, siblings showed decreased FA values in corpus callosum and in the anterior commissure. She concluded that both patients and their unaffected siblings share decreased FA in the corpus callosum.
Michael Harms from Washington University School of Medicine investigated thalamic shape and surface in young schizophrenia patients, their siblings, controls, and their siblings. Thalamic neurogenesis is relevant during early CNS development and volume and shape abnormalities have been reported in schizophrenia. Multivariate analysis did not show a significant group effect, however, in pair-wise analysis although evidence was found for thalamic decreases in patients compared to their siblings and to controls. Using high dimensional brain warping algorithms, anterior and posterior inward deformations were found in patients and in siblings when these groups were compared to controls. These data suggest that genetic influences are involved in thalamic shape abnormalities in patients with schizophrenia and their affected siblings.
Using a longitudinal twin design, where monozygotic and dizygotic twins discordant for schizophrenia and healthy twins were rescanned after an interval of 5 years, Rachel Brans, from University Medical Centre Utrecht showed that genetic or common environmental factors play a role in the whole brain volume decreases reported in schizophrenia. A significantly larger decrease in brain volume during the interval was found in discordant pairs relative to healthy pairs. Using structural equation modeling, Brans and colleagues were able to disentangle the additive genetic and common environmental effects. Heritability (h2) was found to be 67% indicating that the variation in brain volume decrease over time in patients with schizophrenia can for the largest part be explained by genetic factors.
Katie Karlsgodt from UCLA reported on MRI data from a clinically high-risk group, in this case first-episode patients, and a control group. The rationale behind studying clinically high-risk subjects is that it provides the opportunity to focus assessment on the period closest to illness onset. Karlsgodt and colleagues used Diffusion Tensor Imaging (DTI) to gain insight concerning established neurocircuits involved in working memory, i.e., the superior longitudinal fasciculus (SLF) linking working memory areas in the frontal and parietal cortex. Collapsing the FA values across the SLF showed significant decreases in patients in the left and right hemisphere relative to controls. In addition, in the right hemisphere the high-risk group showed decreased FA in comparison to healthy individuals. Furthermore, significant correlations were reported between working memory performance and FA values in controls and patients, but not in the high-risk subjects. It was concluded that white matter integrity in the FLS is disrupted in first-episode schizophrenia and that the high-risk group is intermediate between patients and controls. In first-episode patients FLS integrity might have functional correlates, according to the researchers.
Oliver Gruber from Saarland University, Germany, presented data on the volume of the hippocampus. Based on previous studies, said Gruber, hippocampal volume has proven to fulfill the criteria for being an endophenotype for schizophrenia. Neuregulin is one of the most replicated susceptibility genes in genetic studies in schizophrenia. NRG1 is known for its effect on neuronal glia, synaptogenesis, myelination, and synaptic plasticity. In addition, NRG1 expression influences hippocampal synapse formation, increases neurite outgrowth and arborization in hippocampal neurons. In this study, patients were compared to healthy family members on the presence of the Icelandic haplotype (HAPice). It was shown that carriers of this haplotype have larger hippocampal volumes. No haplotype by diagnosis effect was found. Therefore, it was concluded that the Icelandic NRG1 core at-risk haplotype represents a predisposition for hippocampal volume decrease.
In the recently published study by Motoaki Nakamura and colleagues, from Harvard Medical School (Nakamura et al., 2007), presented by James Levitt, from the same laboratory, patients with schizophrenia and healthy subjects were compared on a measure of orbitofrontal cortex (OFC) sulcogyral pattern. Three types of “H-shaped” sulcogyral patterns were defined using four orbitofrontal sulci: the olfactory, the medial, the lateral, and the transverse orbital sulci. In control subjects it has been shown previously that Type 1 is the most common sulco-gyral pattern, while Type 3 is the least common. Patients with schizophrenia showed a different distribution of OFC sulcogyral pattern in that the Type 3 pattern was significantly more frequent and the Type 1 pattern was less frequent compared to controls. In addition, the presence of a Type 3 pattern was related to poorer socioeconomic status and smaller intracranial volume, which suggests that the Type 3 patients may be a subgroup of patients that evince neurodevelopmental abnormalities.
Peg Nopoulus, from the University of Iowa, was the last speaker. She presented findings from a study that investigated the neuroanatomy of lack of insight in patients with schizophrenia. Lack of insight can be interpreted in the light of anosognosia, which is a neurological disorder characterized by unawareness or denial of the existence of a handicap. Anosognosia appears related to right parietal cortex and posterior insular damage. Nopoulos used an automated approach to parcellate sub-regions in the frontal and parietal lobes. The only significant correlation was found between lack of insight and decreased gray matter volume of the middle frontal gyrus.— Neeltje E.M. van Haren.