Original articleDecreased N-Acetylaspartate in children with familial bipolar disorder
Introduction
Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive procedure using magnetic resonance technology, which provides data regarding levels of neuronal substrates, including N-acetylaspartate (NAA), choline (Cho), myoinositol (mI), and creatine/phosphocreatine (Cr) (Miller et al 1991). NAA is an amino acid found in high concentrations within neurons, and not within glial cells, and therefore may serve as a marker of neuronal density or integrity (Urenjak et al 1993). Cr is distributed within gray and white matter and is commonly used as a reference for the amount of brain tissue contained within the analyzed voxel (Ross and Michaelis 1994). Relatively low NAA/Cr ratios may indicate decreased neuronal density or viability.
Dorsolateral prefrontal (DLPF) levels of NAA have been found to be decreased in adults with bipolar disorder (BD) compared to healthy controls (Winsberg et al 2000). This finding, implying decreased neuronal density in DLPF in BD, was supported by a histopathological study of postmortem brains reporting decreased neuronal and glial density in the dorsolateral prefrontal cortex (DLPFC) of BD patients (Rajkowska et al 2001). Decreased density may furthermore represent decreased functioning, as a functional magnetic resonance imaging (fMRI) study found decreased activation of right DLPFC in adults with BD viewing fearful faces as compared to controls (Yurgelun-Todd et al 2000).
Other studies have implicated prefrontal regions in the pathophysiology of BD. Decreased subgenual prefrontal gray matter, glia, and blood flow have been reported in familial BD patients Drevets et al 1997, Ongur et al 1998. Positron emission tomography (PET) studies have supported decreased prefrontal metabolism and blood flow in bipolar depressed states Baxter et al 1989, Ketter et al 2001, Martinot et al 1990, Reischies et al 1989.
Early neuroimaging studies of pediatric mood disorders also implicate prefrontal abnormalities. In a magnetic resonance imaging (MRI) study, children with nonfamilial major depressive disorder had larger left prefrontal volumes than controls (Nolan et al 2002). Another study reported decreased left subgenual prefrontal cortex volume in adolescent females with MDD compared to controls (Botteron et al 2002). These studies support children and adolescents with mood disorders having prefrontal abnormalities similar to adults with mood disorders.
In pediatric BD, there have been two published 1H-MRS studies. The first study found no differences between subjects and controls in levels of NAA in frontal and temporal cortex (Castillo et al 2000). This negative finding involved primarily nonlimbic areas such as temporal cortex; hence, lower neuronal density in BD could be specific to limbic and paralimbic areas such as DLPF. The second study was of acutely manic children, reporting decreased mI concentrations in anterior cingulate cortex (ACC) after lithium treatment (Davanzo et al 2001). No differences in NAA/Cr levels were found in ACC of bipolar subjects compared to controls either before or after lithium treatment. There have been no prefrontal 1H-MRS studies of euthymic bipolar children, but children with MDD have been reported to have elevated Cho levels in left anterior medial cortex (Steingard et al 2000) and left DLPFC (Farchione et al 2002).
Therefore, we wished to use 1H-MRS to study DLPF NAA/Cr ratios in children and adolescents with BD. We studied subjects with BD who had at least one biological parent with BD, a more homogenous cohort that may represent a highly heritable form of BD and therefore perhaps a form with distinct neurobiological findings. We hypothesized that DLPF NAA/Cr ratios would be lower in bipolar offspring with BD than in healthy controls.
Section snippets
Methods and materials
This protocol was approved by the Stanford University Panel of Medical Research in Human Subjects. Fifteen patients and 11 healthy volunteers were recruited from an ongoing study of bipolar offspring and from the community. After obtaining oral and written informed consent from parents and oral and written assent from their offspring, semistructured interviews were conducted. Patients had at least one parent with bipolar I or II disorder as diagnosed by the Structured Clinical Interview for
Cohort
Mean age was 12.6 ± 2.9 years for both patients and controls; age range was 9.1 years to 18.2 years for both groups. Groups did not differ significantly by age. The bipolar group had more males numerically than the control group (87% vs. 55%), but this was not a significant difference (χ2 = 3.3, df = 1, p = .09, Fisher exact). Furthermore, there was no significant interaction of gender with NAA/Cr ratios (F = 3.2, df = 1, p = .09).
Mean YMRS score for the bipolar group was 11.1 ± 9.1 and mean
Discussion
We found decreased NAA/Cr ratios in right prefrontal cortex in children with BD who had at least one parent with BD compared to healthy volunteers. This finding is similar to results obtained from 1H-MRS studies of adults with BD (Winsberg et al 2000) and schizophrenia (Bertolino et al 1998). An overall regional decrease in NAA/Cr may indicate lower neuronal density or viability and therefore dysfunction in the DLPF. The DLPF has been suggested to have a role in mediation of affect and has been
Acknowledgements
This work was supported in part by National Institutes of Health Grants MH01142, MH19908, MH050047, and HD31715 (Dr. Reiss); a NARSAD Young Investigators Award and National Institutes of Health Grant MH64460-01 (Dr. Chang); and by a grant from the Stanley Foundation (Dr. Ketter).
References (40)
- et al.
The effect of treatment with antipsychotic drugs on brain N-acetylaspartate measures in patients with schizophrenia
Biol Psychiatry
(2001) - et al.
Cerebral hypoperfusion in medication resistant, depressed patients assessed by Tc99 m HMPAO SPECT
J Affect Disord
(1996) - et al.
Volumetric reduction in left subgenual prefrontal cortex in early onset depression
Biol Psychiatry
(2002) - et al.
Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder
Neuropsychopharmacology
(2001) - et al.
Is comorbidity with ADHD a marker for juvenile-onset mania?
J Am Acad Child Adolesc Psychiatry
(1997) - et al.
Proton magnetic resonance spectroscopic imaging in pediatric major depression
Biol Psychiatry
(2002) - et al.
Reliability of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) mania and rapid cycling sections
J Am Acad Child Adolesc Psychiatry
(2001) - et al.
Prepubertal and young adolescent bipolarity versus ADHDAssessment and validity using the WASH-U-KSADS, CBCL AND TRF
J Affect Disord
(1998) - et al.
Attention-deficit disorder in adults with or without hyperactivityWhere is the difference? A study in humans using short echo (1)H- magnetic resonance spectroscopy
Neurosci Lett
(2001) - et al.
Striatal neuronal loss or dysfunction and choline rise in children with attention-deficit hyperactivity disorderA 1H-magnetic resonance spectroscopy study
Neurosci Lett
(2001)
Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL)Initial reliability and validity data
J Am Acad Child Adolesc Psychiatry
Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder
Biol Psychiatry
Lithium increases N-acetyl-aspartate in the human brainIn vivo evidence in support of bcl-2’s neurotrophic effects?
Biol Psychiatry
Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder
Biol Psychiatry
Clinical correlates of cerebral blood flow in depression
Psychiatry Res
Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy
Biol Psychiatry
Choline ingestion increases the resonance of choline-containing compounds in the human brainAn in vivo proton magnetic resonance spectroscopy study
Biol Psychiatry
Changes in regional cerebral blood flow demonstrated by single photon emission computed tomography in depressive disordersComparison of unipolar vs. bipolar subtypes
Psychiatry Res
Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder
Biol Psychiatry
The family history method using diagnostic criteria. Reliability and validity
Arch Gen Psychiatry
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