1John D. Hamilton MD,
2Robert Asarnow PhD,
3Nitin Gogtay MD,
3Judith L. Rapoport MD, 4Paul M. Thompson PhD
1University of California, Davis, CA
2UCLA Neuropsychiatric Instiute, Los Angeles, CA
3Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD
4Laboratory of Neuro Imaging, Brain Mapping Division, Dept. Neurology, UCLA School of Medicine, Los Angeles, CA
This Symposium offers a look at recent findings in the neurobiology of early-onset schizophrenia as observed through three separate but validating windows: genetic studies, brain imaging, and sibling studies.
In genetic studies, the National Institute of Mental Health's Intramural Research Program (IRP) has recruited 68 COS probands with severe chronic schizophrenia with onset by age 12, along with their first degree relatives. This recruitment was performed despite the fact that childhood-onset schizophrenia (COS) is relatively rare with only 1/300th the prevalence of adult-onset schizophrenia. An advantage to studying this group is that data indicates very early onset illnesses have more salient genetic causes (Childs and Scriver, 1986), suggesting that if there is a continuum of genetic risk for schizophrenia, COS schizophrenia should be associated with greater genetic loading.
In imaging studies, a novel image analysis technique was applied to serial images of the same subjects over time, to map brain changes in the COS cohort. Also scans of genetic twins were used to help understand genetic influences in brain development and disease. For example, one used a twin sample discordant for schizophrenia allowing comparison between cortex maps in genetically similar subjects with and without the illness (Cannon et al., 2002). And mathematical strategies can map how genes influence normal brain structure (Thompson et al., 2001a).
In sibling studies, 62 full siblings of 67 youth with COS have been studied with diagnostic interviews, neuropsychological testing, eyetracking measures, and MRI scans.
Genetic studies show an increased rate of schizophrenia spectrum disorders in first degree relatives of COS subjects, with relative risk of 8 to community controls (vs. RR 4 of AOS subjects to community controls). The frequency and pattern of eye movement abnormalities were similar between AOS and the parents of COS subjects. 5/65 (6%) of COS subjects have clinical cytogenetic abnormalities vs. only 1/100 consecutive ADHD children. In particular, the chromosome 22q11 deletion may be more common in COS subjects than AOS. A collaborative study with Dr. Maria Karayiorgou examined single nucleotide pair (SNP) markers for 1.5 megabase (1500 base) region flanked by markers D22S427 and D22S264 for the COS sample and for an AOS sample. In both these independent populations Haplotype Relative Risk (HRR) analysis showed significant association between schizophrenia and the proline dehydrogenase allene 2 of SNP21945. Similar results were obtained using the Transmission Disequilibrium Test (TDT), and were supported by more extensive analysis. Three centers have also reported partial or complete transient autism preceding COS even though COS and autism are usually conceptualized as separate disorders.
Imaging studies show that, in repeated scans of normal children age 3 to 15, a rostro-caudal wave of growth was detected in the corpus callosum. Earlier growth (age 3 to 6) occurred in those callosum circuits innervating frontal cortices. Later growth rates (6 to puberty) peaked in the callosal isthmus circuits innervating perisylvian association and language cortices, while during this same time period a severe, spatially localized loss of gray matter occurred in the basal ganglia. In COS subjects these novel brain mapping techniques detected striking anatomical profiles of accelerated gray matter loss (Thompson et al., 2001b). Prospective re-scanning of COS subjects showed earliest deficits in parietal brain regions, progressing over 5 years into the temporal lobes, sensorimotor and dorsolateral pre-frontal cortices, and frontal eye fields. These patterns correlated with psychotic symptom severity. Temporal gray matter loss was pervasive only late in the disease.
Sibling studies show that siblings of COS patients have high rates of schizophrenia spectrum diagnosis (27%). Siblings with no diagnosis, compared to matched community controls, perform more poorly on Trails B and have smaller parietal gray matter volumes (p=.003). Compared to matched community controls, younger siblings (mean age 14, N=8) show structural alterations in the parietal lobe whereas adult siblings (mean age 24, N=7) show total and frontal gray matter trends towards smaller volume (p=.081, .074).
Even with limited sample size, results suggest that the genetic signal at some loci may be stronger in COS than in AOS subjects. Recent advances in genetics suggest candidate genes for further study. Brain imaging provides a powerful tool to identify complex brain changes in normal and abnormal development. Dynamic and genetic brain maps, as described in this Symposium, show enormous promise in revealing how genes and environment interact to induce these changes. A reasonable speculation is that gray matter loss in healthy siblings follows the same dynamic pattern of a posterior to anterior "wave" of gray matter loss seen in COS probands. Abnormal loss of cortical tissue and abnormalities in neurocognitive functioning in healthy siblings may be developmental trait markers.
Cannon T, Thompson P, van Erp T, Toga A, Poutanen V-P, Huttunen M, Lonnqvist J, Standertskjold-Nordenstam C-G, Narr K, Khaledy M, Zoumalan C, Dail R, Kaprio J (2002), Cortex Mapping Reveals Regionally-Specific Pattern of Genetic and Disease-Specific Gray Matter Deficits in Twins Discordant for Schizophrenia. Proceedings of the National Academy of Sciences of the USA In press
Childs B, Scriver CR (1986), Age at onset and causes of disease. Perspect Biol Med 29: 437-60
Thompson P, Cannon T, Narr K, van Erp T, Khaledy M, Poutanen V-P, Huttunen M, Lonnqvist J, Standertskjold-Nordenstam C-G, Kaprio J, Dail R, Zoumalan C, Toga A (2001a), Genetic Influencs on Brain Structure. Nature Neuroscience 4: 1253-8
Thompson P, Vidal C, Giedd J, Gochman P, Blumenthal J, Nicolson R, Toga A, Rapoport J (2001b), Mapping Adolescent Brain Change Reveals Dynamic Wave of Accelerated Gray Matter Loss in Very Early-Onset Schizophrenia. Proceedings of the National Academy of Sciences of the USA 98: 11650-11655
Paul Thompson, Ph.D.
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