Progressive Brain Volume Loss During Adolescence in Childhood-Onset Schizophrenia

Sporn, Alexandra; Greenstein, Deanna; Gogtay, Nitin; Jeffries, Neal; Lenane, Marge; Gochman, Peter; Clasen, Liv S.; Blumenthal, Jonathan D.; Giedd, Jay N.; Rapoport, Judith L.

doi:10.1176/appi.ajp.160.12.2181

Cited by 177 publications

(120 citation statements)

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“…21 Finally, COS patients show a striking loss of gray matter volume as measured on serial MRI scanning through adolescence when compared with normal controls. The rate of reduction was related to premorbid impairment and baseline symptom severity, 22 and is also a greater rate of loss than reported for adult-onset cases. 23 In order to follow-up on the positive association observed between haplotypes in the GAD1 gene and two family samples of adult-onset schizophrenia, 24,25 we tested SNPs at this locus for association in the childhood-onset sample.…”

mentioning

confidence: 65%

“…22 Volumes of the cerebrum and total and regional gray matter were obtained by using automated analysis, and percent change in volume across time was calculated. The rate of total and frontal gray matter volume change was calculated for the subjects with COS, who had at least two MRI scans available before age 21 (N ¼ 39).…”

Section: Methodsmentioning

confidence: 99%

“…The total gray matter slope was defined as the follow-up scan value minus the first scan value divided by time elapsed between scans and expressed as milliliters per year (a negative value representing cortical volume reduction). This measure has been presented previously (see Sporn et al, 2003). 22 Nucleic acid purification and PCR Genomic DNA was extracted from immortalized lymphoblastoid cells using the QIAamp DNA Extraction Kit (Qiagen, Inc., Valencia, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…This measure has been presented previously (see Sporn et al, 2003). 22 Nucleic acid purification and PCR Genomic DNA was extracted from immortalized lymphoblastoid cells using the QIAamp DNA Extraction Kit (Qiagen, Inc., Valencia, CA, USA). SNPs in and around the GAD1 and GAD2 genes were selected from the Celera (http://www.celeradiscoverysystem.…”

Section: Methodsmentioning

confidence: 99%

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GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

Addington¹,

Gornick²,

et al. 2004

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Postmortem brain studies have shown deficits in the cortical c-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD 67 ) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD 67 , were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n ¼ 72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5 0 upstream region of GAD1 showed a positive pairwise association with illness in these families (P ¼ 0.022-0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P ¼ 0.003-0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD 67 may be a common risk factor for schizophrenia. Molecular Psychiatry (2005) 10, 581-588.

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confidence: 65%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

Addington¹,

Gornick²,

et al. 2004

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“…11 COS patients show a striking loss of gray matter volume, which plateaus in adolescence. 12,13 Although rare, the higher rates of familial illness or biological markers of illness, extreme severity and 10% rate of chromosomal abnormalities seen in this sample 14 suggest that genetic influences may be more salient. 6 NRG1 participates in glutamatergic signaling by regulating the N-methyl-D-aspartate (NMDA) receptor through the interaction of the NRG1 protein and its receptors.…”

Section: Introductionmentioning

confidence: 80%

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Addington¹,

Gornick²,

Shaw³

et al. 2006

Mol Psychiatry

110

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Childhood-onset schizophrenia (COS), defined as onset of psychosis by the age of 12, is a rare and malignant form of the illness, which may have more salient genetic influence. Since the initial report of association between neuregulin 1 (NRG1) and schizophrenia in 2002, numerous independent replications have been reported. In the current study, we genotyped 56 markers (54 single-nucleotide polymorphisms (SNPs) and two microsatellites) spanning the NRG1 locus on 78 COS patients and their parents. We used family-based association analysis for both diagnostic (extended transmission disequilibrium test) and quantitative phenotypes (quantitative transmission disequilibrium test) and mixed-model regression. Most subjects had prospective anatomic brain magnetic resonance imaging (MRI) scans at 2-year intervals. Further, we genotyped a sample of 165 healthy controls in the MRI study to examine genetic risk effects on normal brain development. Individual markers showed overtransmission of alleles to affecteds (P = 0.009-0.05). Further, several novel four-marker haplotypes demonstrated significant transmission distortion. There was no evidence of epistasis with SNPs in erbB4. The risk allele (0) at 420M9-1395 was associated with poorer premorbid social functioning. Further, possession of the risk allele was associated with different trajectories of change in lobar volumes. In the COS group, risk allele carriers had greater total gray and white matter volume in childhood and a steeper rate of subsequent decline in volume into adolescence. By contrast, in healthy children, possession of the risk allele was associated with different trajectories in gray matter only and was confined to frontotemporal regions, reflecting epistatic or other illness-specific effects mediating NRG1 influence on brain development in COS. This replication further documents the role of NRG1 in the abnormal brain development in schizophrenia. This is the first demonstration of a disease-specific pattern of gene action in schizophrenia.

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Progressive Brain Changes in Children and Adolescents With First-Episode Psychosis

Arango¹

2012

Arch Gen Psychiatry

134

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Progressive Brain Volume Loss During Adolescence in Childhood-Onset Schizophrenia

Abstract: Striking loss of cerebral gray matter is seen through adolescence in patients with childhood-onset schizophrenia. The rate of reduction was related to premorbid impairment and baseline symptom severity, but it may also be in part a plastic response to illness.

Cited by 177 publications

References 47 publications

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss

Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories

Progressive Brain Changes in Children and Adolescents With First-Episode Psychosis

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