- Email: [email protected]
8.1 Brain Abnormalities and IQ in Offspring Related to Those in Siblings, Co-Twins, and Parents of Patients With Schizophrenia
SYMPOSIA 8.1 — 8.3
illness suggest that early cognitive and brain abnormalities are present in atrisk youths well before the age at which psychosis typically manifests and that early behavioral cognitive markers are predictive of the later development of psychotic illness.
PSY, IMAGS, BD http://dx.doi.org/10.1016/j.jaac.2017.07.618
8.1 BRAIN ABNORMALITIES AND IQ IN OFFSPRING RELATED TO THOSE IN SIBLINGS, CO-TWINS, AND PARENTS OF PATIENTS WITH SCHIZOPHRENIA Neeltje van Haren, PhD, University Medical Center Utrecht, N. [email protected] Objectives: Offspring of patients with schizophrenia have an increased genetic and environmental vulnerability to develop a severe mental illness themselves. Therefore, patients with schizophrenia serve as a valuable population to study the clinical, biological, and behavioral changes close to but before the onset of symptoms of the disease. This is one model that allows us to examine individuals who are at increased risk for developing future psychopathology. To investigate the generalizability of findings from offspring studies to other familial at-risk subjects, we compare global and local measures of the brain between different types of relatives of patients with schizophrenia. Methods: A total of 1,011 participants were included from five family studies on schizophrenia: 342 relatives [unaffected for psychosis; 41 offspring, 211 siblings, 44 parents, 26 dizygotic (DZ) co-twins, 20 monozygotic (MZ) co-twins], each with their own control group (HC, 438 in total). FreeSurfer was used to estimate brain measures from MRI. We included total brain (TB), gray matter (GM), white matter (WM) volume, global and local cortical thickness (CT), and surface area (SA). Age and gender effects were regressed out per cohort, and standardized residuals were calculated. Linear-mixed model analyses were performed comparing each relative group with their own control group, taking family relatedness into account. Effect sizes were calculated. To investigate the role of IQ, all analyses were repeated with correcting for IQ. Results: Comparing the different relative types, patients with schizophrenia showed the greatest effect sizes compared with HC in all measures, with the exception of CT where MZ co-twins showed the largest effect. Locally, patients with schizophrenia showed reduced CT and smaller SA, particularly in the frontal and temporal cortex. Reduced CT was also present in the other relative types (except siblings), whereas smaller SA was only present in siblings. After IQ correction, most effects were less pronounced or disappeared. Conclusions: These results suggest a familial (possibly genetic) component to GM, TB, WM, and SA decreases in schizophrenia. Results indicate that patients with schizophrenia show more abundant brain abnormalities compared with parents, siblings, and twins, which is in line with a high relative risk for developing schizophrenia. It is noteworthy that brain abnormalities in relatives became less prominent when correcting for IQ, suggesting that genetic vulnerability for schizophrenia is also related to IQ.
COG, IMAGS, PSY http://dx.doi.org/10.1016/j.jaac.2017.07.619
8.2 IDENTIFICATION OF EARLY CHILDHOOD BEHAVIOR PROBLEMS AND NEUROCOGNITION IN THE DEVELOPMENT OF SCHIZOPHRENIA AND AFFECTIVE PSYCHOSES Synthia Guimond, PhD, Harvard Medical School at Beth Israel Deaconess Medical Center, [email protected]; Larry J. Seidman, PhD [deceased], Harvard Medical School at Beth Israel Deaconess Medical Center, [email protected] Objectives: It is now well known that neurocognitive and behavioral problems precede adolescent and adult psychotic disorders by a number of years. Identification of early predictors of conversion to psychosis is a major public health concern and is necessary for the development of more effective, earlier
JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 56 NUMBER 10S OCTOBER 2017
interventions. The extent to which childhood behavioral impairments are present before onset of illness is less well studied than is childhood IQ, and the concurrent relationship of childhood behavior problems and IQ with subsequent psychotic disorder has not been established. We investigated whether early childhood behavior problems are associated with increased risk for adult schizophrenia (SZ) or affective psychosis (AFF), independently and in combination with IQ. Methods: The study included individuals with SZ (N ¼ 47) and AFF (N ¼ 45), as well as control subjects with no psychosis (N ¼ 101) and a larger sample group of control subjects (N ¼ 1,496) from the New England Family Study. Behavioral problems at ages 4 and 7 years were prospectively assessed from standardized observations by the clinician. IQ was assessed at age 4 years with the StanfordBinet and age 7 years with the Wechsler Intelligence Scale for Children. Results: We found externalizing problems at age 4 years, and externalizing and internalizing problems at age 7 years, were associated with later SZ; and both internalizing and externalizing problems at ages 4 and 7 years were associated with later development of AFF. Lower IQ at ages 4 and 7 years was associated with SZ, whereas lower IQ was associated with AFF at age 7 years only. Examined simultaneously, both lower IQ and behavioral problems remained associated with a risk of SZ, whereas only behavioral problems remained associated with AFF. Of the tested individuals at age 7 years, data analyses revealed neurocognitive impairment in 42.2 percent of those with SZ, 22.9 percent of persons with bipolar psychosis (BP), and 7 percent of control subjects. The presence of psychosis in first-degree relatives significantly increased the severity of childhood neurocognitive impairment for SZ, but not for those with BP. Conclusions: Behavioral problems seem to be a general marker of risk of adult psychotic disorder, whereas lower childhood IQ is more specific to the risk of SZ, especially compared with BP. Future research should clarify the premorbid evolution of behavior and cognitive problems into adult psychosis, as well as the perinatal contributions to these developmental patterns.
COG, DEV, PSY Supported by the Stanley Medical Research Institute, National Association for Research on Schizophrenia and Depression, and NIMH Grants MH-63951, MH-56956, MH-50647, and T32 MH- 017119 http://dx.doi.org/10.1016/j.jaac.2017.07.620
8.3 CONNECTIVITY AND BRAIN NETWORK ALTERATIONS IN YOUNG OFFSPRING OF PATIENTS WITH SCHIZOPHRENIA AND BIPOLAR DISORDER Guusje Collin, PhD, University Medical Centre Utrecht, G. [email protected]; Manon Hillegers, MD, PhD, University Medical Center Utrecht, [email protected] Objectives: Emerging evidence suggests that the neurobiology of psychotic disorders involves abnormalities in connectivity and brain network, or “connectome,” organization. As these disorders are genetically mediated, studying offspring of patients provides a valuable paradigm to explore brain development in relation to psychiatric vulnerability. The objective of this study is to examine connectome organization in unaffected at-risk offspring. Methods: Diffusion-weighted MRI and resting-state fMRI scans were collected from 127 offspring of a parent diagnosed with schizophrenia (SZ-offspring; N ¼ 28) or BD (BD-offspring; N ¼ 60), and community control subjects (N ¼ 39). Participants were 13.5 years of age on average (age range 8–18 years). Anatomical and functional brain networks were reconstructed for each individual subject, analyzed using graph theory, and compared between subject groups. Results: SZ-offspring demonstrated anatomical connectivity deficits of connections linking central brain hubs (F ¼ 3.90, P ¼ 0.023), with post hoc tests showing a significant difference compared with both control subjects (t ¼ 2.39, P ¼ 0.018) and BD-offspring (t ¼ 2.61, P ¼ 0.010). The disruption in anatomical hub-to-hub connectivity was associated with increased modularity of the functional connectome (r ¼ 0.59, P ¼ 0.020). Relative to control subjects, high-risk offspring showed abnormal coupling between structural and functional connectivity of long-distance connections (F ¼ 7.23, P ¼ 0.001), with post hoc tests indicating a significant effect in both offspring groups (SZoffspring, F ¼ 3.17, P ¼ 0.002; BD-offspring, F ¼ 3.27, p ¼ 0.002).
www.jaacap.org
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illness suggest that early cognitive and brain abnormalities are present in atrisk youths well before the age at which psychosis typically manifests and that early behavioral cognitive markers are predictive of the later development of psychotic illness.
PSY, IMAGS, BD http://dx.doi.org/10.1016/j.jaac.2017.07.618
8.1 BRAIN ABNORMALITIES AND IQ IN OFFSPRING RELATED TO THOSE IN SIBLINGS, CO-TWINS, AND PARENTS OF PATIENTS WITH SCHIZOPHRENIA Neeltje van Haren, PhD, University Medical Center Utrecht, N. [email protected] Objectives: Offspring of patients with schizophrenia have an increased genetic and environmental vulnerability to develop a severe mental illness themselves. Therefore, patients with schizophrenia serve as a valuable population to study the clinical, biological, and behavioral changes close to but before the onset of symptoms of the disease. This is one model that allows us to examine individuals who are at increased risk for developing future psychopathology. To investigate the generalizability of findings from offspring studies to other familial at-risk subjects, we compare global and local measures of the brain between different types of relatives of patients with schizophrenia. Methods: A total of 1,011 participants were included from five family studies on schizophrenia: 342 relatives [unaffected for psychosis; 41 offspring, 211 siblings, 44 parents, 26 dizygotic (DZ) co-twins, 20 monozygotic (MZ) co-twins], each with their own control group (HC, 438 in total). FreeSurfer was used to estimate brain measures from MRI. We included total brain (TB), gray matter (GM), white matter (WM) volume, global and local cortical thickness (CT), and surface area (SA). Age and gender effects were regressed out per cohort, and standardized residuals were calculated. Linear-mixed model analyses were performed comparing each relative group with their own control group, taking family relatedness into account. Effect sizes were calculated. To investigate the role of IQ, all analyses were repeated with correcting for IQ. Results: Comparing the different relative types, patients with schizophrenia showed the greatest effect sizes compared with HC in all measures, with the exception of CT where MZ co-twins showed the largest effect. Locally, patients with schizophrenia showed reduced CT and smaller SA, particularly in the frontal and temporal cortex. Reduced CT was also present in the other relative types (except siblings), whereas smaller SA was only present in siblings. After IQ correction, most effects were less pronounced or disappeared. Conclusions: These results suggest a familial (possibly genetic) component to GM, TB, WM, and SA decreases in schizophrenia. Results indicate that patients with schizophrenia show more abundant brain abnormalities compared with parents, siblings, and twins, which is in line with a high relative risk for developing schizophrenia. It is noteworthy that brain abnormalities in relatives became less prominent when correcting for IQ, suggesting that genetic vulnerability for schizophrenia is also related to IQ.
COG, IMAGS, PSY http://dx.doi.org/10.1016/j.jaac.2017.07.619
8.2 IDENTIFICATION OF EARLY CHILDHOOD BEHAVIOR PROBLEMS AND NEUROCOGNITION IN THE DEVELOPMENT OF SCHIZOPHRENIA AND AFFECTIVE PSYCHOSES Synthia Guimond, PhD, Harvard Medical School at Beth Israel Deaconess Medical Center, [email protected]; Larry J. Seidman, PhD [deceased], Harvard Medical School at Beth Israel Deaconess Medical Center, [email protected] Objectives: It is now well known that neurocognitive and behavioral problems precede adolescent and adult psychotic disorders by a number of years. Identification of early predictors of conversion to psychosis is a major public health concern and is necessary for the development of more effective, earlier
JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT P SYCHIATRY VOLUME 56 NUMBER 10S OCTOBER 2017
interventions. The extent to which childhood behavioral impairments are present before onset of illness is less well studied than is childhood IQ, and the concurrent relationship of childhood behavior problems and IQ with subsequent psychotic disorder has not been established. We investigated whether early childhood behavior problems are associated with increased risk for adult schizophrenia (SZ) or affective psychosis (AFF), independently and in combination with IQ. Methods: The study included individuals with SZ (N ¼ 47) and AFF (N ¼ 45), as well as control subjects with no psychosis (N ¼ 101) and a larger sample group of control subjects (N ¼ 1,496) from the New England Family Study. Behavioral problems at ages 4 and 7 years were prospectively assessed from standardized observations by the clinician. IQ was assessed at age 4 years with the StanfordBinet and age 7 years with the Wechsler Intelligence Scale for Children. Results: We found externalizing problems at age 4 years, and externalizing and internalizing problems at age 7 years, were associated with later SZ; and both internalizing and externalizing problems at ages 4 and 7 years were associated with later development of AFF. Lower IQ at ages 4 and 7 years was associated with SZ, whereas lower IQ was associated with AFF at age 7 years only. Examined simultaneously, both lower IQ and behavioral problems remained associated with a risk of SZ, whereas only behavioral problems remained associated with AFF. Of the tested individuals at age 7 years, data analyses revealed neurocognitive impairment in 42.2 percent of those with SZ, 22.9 percent of persons with bipolar psychosis (BP), and 7 percent of control subjects. The presence of psychosis in first-degree relatives significantly increased the severity of childhood neurocognitive impairment for SZ, but not for those with BP. Conclusions: Behavioral problems seem to be a general marker of risk of adult psychotic disorder, whereas lower childhood IQ is more specific to the risk of SZ, especially compared with BP. Future research should clarify the premorbid evolution of behavior and cognitive problems into adult psychosis, as well as the perinatal contributions to these developmental patterns.
COG, DEV, PSY Supported by the Stanley Medical Research Institute, National Association for Research on Schizophrenia and Depression, and NIMH Grants MH-63951, MH-56956, MH-50647, and T32 MH- 017119 http://dx.doi.org/10.1016/j.jaac.2017.07.620
8.3 CONNECTIVITY AND BRAIN NETWORK ALTERATIONS IN YOUNG OFFSPRING OF PATIENTS WITH SCHIZOPHRENIA AND BIPOLAR DISORDER Guusje Collin, PhD, University Medical Centre Utrecht, G. [email protected]; Manon Hillegers, MD, PhD, University Medical Center Utrecht, [email protected] Objectives: Emerging evidence suggests that the neurobiology of psychotic disorders involves abnormalities in connectivity and brain network, or “connectome,” organization. As these disorders are genetically mediated, studying offspring of patients provides a valuable paradigm to explore brain development in relation to psychiatric vulnerability. The objective of this study is to examine connectome organization in unaffected at-risk offspring. Methods: Diffusion-weighted MRI and resting-state fMRI scans were collected from 127 offspring of a parent diagnosed with schizophrenia (SZ-offspring; N ¼ 28) or BD (BD-offspring; N ¼ 60), and community control subjects (N ¼ 39). Participants were 13.5 years of age on average (age range 8–18 years). Anatomical and functional brain networks were reconstructed for each individual subject, analyzed using graph theory, and compared between subject groups. Results: SZ-offspring demonstrated anatomical connectivity deficits of connections linking central brain hubs (F ¼ 3.90, P ¼ 0.023), with post hoc tests showing a significant difference compared with both control subjects (t ¼ 2.39, P ¼ 0.018) and BD-offspring (t ¼ 2.61, P ¼ 0.010). The disruption in anatomical hub-to-hub connectivity was associated with increased modularity of the functional connectome (r ¼ 0.59, P ¼ 0.020). Relative to control subjects, high-risk offspring showed abnormal coupling between structural and functional connectivity of long-distance connections (F ¼ 7.23, P ¼ 0.001), with post hoc tests indicating a significant effect in both offspring groups (SZoffspring, F ¼ 3.17, P ¼ 0.002; BD-offspring, F ¼ 3.27, p ¼ 0.002).
www.jaacap.org
S313