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BRAIN DEVELOPMENT IN CHILDHOOD ONSET SCHIZOPHRENIA: GENETIC AND ENVIRONMENTAL INFLUENCES
152
Abstracts
netic mechanisms impacting ondistributed neural processing in schizophrenia reporting their work on genomewide association scans (GWAS) associated genes (ZNF804A, CACNA1C) and theirrelationship to disturbances of the connectome in schizophrenia. Dr. David Lewis has agreed to be thediscussant on the panel. doi:10.1016/j.schres.2010.02.145
BRAIN DEVELOPMENT IN CHILDHOOD ONSET SCHIZOPHRENIA: GENETIC AND ENVIRONMENTAL INFLUENCES Nitin Gogtay NIMH Bethesda, MD, USA Structural neuroimaging studies in COS show profound parietofrontal cortical GM loss during adolescence in a pattern that appears exaggeration of the normal GM maturation. At longer term follow up the GM loss slows with age and gets circumscribed to prefrontal and superior temporal cortices(n = 84,197 scans vs controls n = 86, 220 scans; age range 8-28 yrs), mimicking a pattern seen in adult onset schizophrenia. Longitudinal analyses on healthy COS siblings (n = 85,170 scans) also show prefrontal and temporal GM deficits in early ages, which normalize by age 20, suggesting that the GM trajectory itself could be a trait marker. Candidate gene analyses support these observations. For example, initial analyses comparing GM development in 75 COS subjects (176 scans), 44 healthy siblings (92 scans) and 166 healthy controls(402 scans) showed that COS subjects and their healthy siblings with val-COMT allele had accelerated GM loss across prefrontal, cingulated and temporal cortices compared to matched healthy controls who in contrast showed negative GM slow with the met-COMT genotype, suggesting the influence of individual risk genes or cortical GM development in schizophrenia. Sub regional cerebellar maps in 85 COS subjects (206 scans), 78 healthy siblings, and 95 matched healthy controls (225 scans) show significant 'sub regional' decline in volume with age, while the vermal regions showed fixed deficits. The volume loss is shared by healthy COS siblings in the posterior inferior cerebellar regions (compared to the same set of controls) suggesting the trait nature of these changes at sub regional level. Finally, it is important to understand the progressive nature GM changes in the context of underlying white matter (WM) development. Our recent 3-D maps of local WM growth rates in 12 COS patients and 12 healthy controls matched for age, gender and scan interval, over a 5-year period, show up to 2.2% slower WM growth per year in COS(P=0.02, all P-values corrected). The deficits appear early in the frontal regions and later in the parietal regions suggesting a progressive abnormality that follows the normal front to back WM developmental pattern. In addition to highlighting significant WM growth deficits in COS, these findings also suggest that the cortical GM loss in schizophrenia is unlikely to be the result of WM encroachment. doi:10.1016/j.schres.2010.02.146
PROGRESSIVE BRAIN TISSUE LOSS IN MONOZYGOTIC AND DIZYGOTIC TWIN PAIRS DISCORDANT FOR SCHIZOPHRENIA Hilleke Hulshoff Pol University Medical Center Utrecht, Utrecht, Netherlands In contrast to common belief, human brain structure is highly plastic throughout life. That brains of young children and adolescents show constant development is widely accepted. In contrast, the adult
human brain is said to be static, with changes being marginal. But can a static brain account for the continued development of people once they have become adults? That is unlikely. Indeed, recently we found evidence for structural brain plasticity in adulthood that promotes cognitive functioning. Moreover, since we conducted these longitudinal MRI studies in monozygotic and dizygotic twin-pairs, we were able to show that the genetic factors implicated in brain size differ from those implicated in brain structure change. In patients with schizophrenia, who experience cognitive problems, brain plasticity seems compromised. Evidence is accumulating that in patients with schizophrenia there is progressive brain tissue loss, not only in first-episode schizophrenia but also in chronically ill patients (Hulshoff Pol and Kahn, Sz Bull 2008). Recently, we found that the progressive brain changes in schizophrenia are also present in their non-psychotic cotwins, implicating that the progressive brain changes are influenced by genes involved in the disease (particularly in the frontal and temporal cortices), and not due to antipsychotic medication or other disease related circumstances (Brans et al, AGP, 2008). Interestingly, based on our cortical thickness change measurements progressive brain tissue loss in schizophrenia seems to occur predominantly in those brain areas that show continued cortical thickening in healthy adults. Thus, progressive brain tissue loss in adult patients may represent as yet unknown pathophysiology of adult human brain plasticity. doi:10.1016/j.schres.2010.02.147
LONGITUDINAL EFFECTS OF GENETIC RISK FACTORS ON BRAIN MORPHOLOGY
Andrew McIntosh Royal Edinburgh Hospital Edingburgh United Kingdom Background: Schizophrenia and bipolar disorder are highly familial disorders and previous studies suggest that the majority of this risk is shared across disorders. A recent investigation suggested that the effects of shared genetic liability may have longitudinal effects on brain structure. However, there is a lack of studies addressing the relationship between specific gene variants and brain developmental trajectories. Methods: Using imaging data from studies of people at high familial risk of schizophrenia or bipolar disorder we will present evidence relating specific gene variants to altered brain structure and function. In addition, we will consider the timing and longitudinal trajectories of these changes by examining differential relationships with age and by examining serial brain changes over 2-4 years follow-up. Results: Cross-sectional and longitudinal effects of specific genetic variants in BDNF and NRG1 will be presented in studies of affected patients and closely related individuals at high risk of schizophrenia or bipolar disorder. This presentation will also include new data from the recent Scottish Bipolar Family Study. Discussion: Bipolar disorder and schizophrenia are associated with longitudinal effects on medial temporal lobe volume and prefrontal structure that can, in part, be attributed to variants within replicated susceptibility genes common to both conditions. doi:10.1016/j.schres.2010.02.148
GENOME-WIDE SIGNIFICANT NEURAL RISK MECHANISMS FOR SCHIZOPHRENIA AND THE BRAIN CONNECTOME Andreas Meyer-Lindenberg University of Heidelberg, Mannheim, Germany
Abstracts
netic mechanisms impacting ondistributed neural processing in schizophrenia reporting their work on genomewide association scans (GWAS) associated genes (ZNF804A, CACNA1C) and theirrelationship to disturbances of the connectome in schizophrenia. Dr. David Lewis has agreed to be thediscussant on the panel. doi:10.1016/j.schres.2010.02.145
BRAIN DEVELOPMENT IN CHILDHOOD ONSET SCHIZOPHRENIA: GENETIC AND ENVIRONMENTAL INFLUENCES Nitin Gogtay NIMH Bethesda, MD, USA Structural neuroimaging studies in COS show profound parietofrontal cortical GM loss during adolescence in a pattern that appears exaggeration of the normal GM maturation. At longer term follow up the GM loss slows with age and gets circumscribed to prefrontal and superior temporal cortices(n = 84,197 scans vs controls n = 86, 220 scans; age range 8-28 yrs), mimicking a pattern seen in adult onset schizophrenia. Longitudinal analyses on healthy COS siblings (n = 85,170 scans) also show prefrontal and temporal GM deficits in early ages, which normalize by age 20, suggesting that the GM trajectory itself could be a trait marker. Candidate gene analyses support these observations. For example, initial analyses comparing GM development in 75 COS subjects (176 scans), 44 healthy siblings (92 scans) and 166 healthy controls(402 scans) showed that COS subjects and their healthy siblings with val-COMT allele had accelerated GM loss across prefrontal, cingulated and temporal cortices compared to matched healthy controls who in contrast showed negative GM slow with the met-COMT genotype, suggesting the influence of individual risk genes or cortical GM development in schizophrenia. Sub regional cerebellar maps in 85 COS subjects (206 scans), 78 healthy siblings, and 95 matched healthy controls (225 scans) show significant 'sub regional' decline in volume with age, while the vermal regions showed fixed deficits. The volume loss is shared by healthy COS siblings in the posterior inferior cerebellar regions (compared to the same set of controls) suggesting the trait nature of these changes at sub regional level. Finally, it is important to understand the progressive nature GM changes in the context of underlying white matter (WM) development. Our recent 3-D maps of local WM growth rates in 12 COS patients and 12 healthy controls matched for age, gender and scan interval, over a 5-year period, show up to 2.2% slower WM growth per year in COS(P=0.02, all P-values corrected). The deficits appear early in the frontal regions and later in the parietal regions suggesting a progressive abnormality that follows the normal front to back WM developmental pattern. In addition to highlighting significant WM growth deficits in COS, these findings also suggest that the cortical GM loss in schizophrenia is unlikely to be the result of WM encroachment. doi:10.1016/j.schres.2010.02.146
PROGRESSIVE BRAIN TISSUE LOSS IN MONOZYGOTIC AND DIZYGOTIC TWIN PAIRS DISCORDANT FOR SCHIZOPHRENIA Hilleke Hulshoff Pol University Medical Center Utrecht, Utrecht, Netherlands In contrast to common belief, human brain structure is highly plastic throughout life. That brains of young children and adolescents show constant development is widely accepted. In contrast, the adult
human brain is said to be static, with changes being marginal. But can a static brain account for the continued development of people once they have become adults? That is unlikely. Indeed, recently we found evidence for structural brain plasticity in adulthood that promotes cognitive functioning. Moreover, since we conducted these longitudinal MRI studies in monozygotic and dizygotic twin-pairs, we were able to show that the genetic factors implicated in brain size differ from those implicated in brain structure change. In patients with schizophrenia, who experience cognitive problems, brain plasticity seems compromised. Evidence is accumulating that in patients with schizophrenia there is progressive brain tissue loss, not only in first-episode schizophrenia but also in chronically ill patients (Hulshoff Pol and Kahn, Sz Bull 2008). Recently, we found that the progressive brain changes in schizophrenia are also present in their non-psychotic cotwins, implicating that the progressive brain changes are influenced by genes involved in the disease (particularly in the frontal and temporal cortices), and not due to antipsychotic medication or other disease related circumstances (Brans et al, AGP, 2008). Interestingly, based on our cortical thickness change measurements progressive brain tissue loss in schizophrenia seems to occur predominantly in those brain areas that show continued cortical thickening in healthy adults. Thus, progressive brain tissue loss in adult patients may represent as yet unknown pathophysiology of adult human brain plasticity. doi:10.1016/j.schres.2010.02.147
LONGITUDINAL EFFECTS OF GENETIC RISK FACTORS ON BRAIN MORPHOLOGY
Andrew McIntosh Royal Edinburgh Hospital Edingburgh United Kingdom Background: Schizophrenia and bipolar disorder are highly familial disorders and previous studies suggest that the majority of this risk is shared across disorders. A recent investigation suggested that the effects of shared genetic liability may have longitudinal effects on brain structure. However, there is a lack of studies addressing the relationship between specific gene variants and brain developmental trajectories. Methods: Using imaging data from studies of people at high familial risk of schizophrenia or bipolar disorder we will present evidence relating specific gene variants to altered brain structure and function. In addition, we will consider the timing and longitudinal trajectories of these changes by examining differential relationships with age and by examining serial brain changes over 2-4 years follow-up. Results: Cross-sectional and longitudinal effects of specific genetic variants in BDNF and NRG1 will be presented in studies of affected patients and closely related individuals at high risk of schizophrenia or bipolar disorder. This presentation will also include new data from the recent Scottish Bipolar Family Study. Discussion: Bipolar disorder and schizophrenia are associated with longitudinal effects on medial temporal lobe volume and prefrontal structure that can, in part, be attributed to variants within replicated susceptibility genes common to both conditions. doi:10.1016/j.schres.2010.02.148
GENOME-WIDE SIGNIFICANT NEURAL RISK MECHANISMS FOR SCHIZOPHRENIA AND THE BRAIN CONNECTOME Andreas Meyer-Lindenberg University of Heidelberg, Mannheim, Germany