Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder

Abstract

Background: N-acetyl aspartate (NAA) is an amino acid present in high concentrations in neurons and is thus a putative neuronal marker. In vivo proton magnetic resonance spectroscopy (¹H MRS) studies have shown lower NAA concentrations in patients with various neurodegenerative disorders, suggesting decreased neuronal number, size, or function. Dorsolateral prefrontal (DLPF) NAA has not been extensively assessed in bipolar disorder patients, but it could be decreased in view of consistent reports of decreased DLPF cerebral blood flow and metabolism in mood disorders. We measured DLPF NAA in patients with bipolar disorder and healthy control subjects using in vivo ¹H MRS.

Methods: We obtained ratios of NAA, choline, and myoinositol (mI) to creatine-phosphocreatine (Cr-PCr) in bilateral DLPF 8-mL voxels of 20 bipolar patients (10 Bipolar I, 10 Bipolar II) and 20 age- and gender-matched healthy control subjects using ¹H MRS.

Results: DLPF NAA/Cr-PCr ratios were lower on the right hemisphere(p < .03) and the left hemisphere (p < .003) in bipolar disorder patients compared with healthy control subjects.

Conclusions: These preliminary data suggest that bipolar disorder patients have decreased DLPF NAA/Cr-PCr. This finding could represent decreased neuronal density or neuronal dysfunction in the DLPF region.

Introduction

In vivo proton magnetic resonance spectroscopy (¹H MRS) is a noninvasive means of determining concentrations of several brain metabolites including N-acetyl aspartate (NAA), choline-containing compounds (Cho), myoinositol (mI), and creatine/phosphocreatine (Cr) Dager and Steen 1992, Keshavan et al 1991, Miller 1991. NAA is the second most prominent peak in the proton spectrum after water and the second most abundant amino acid in the brain after glutamate. It is found in high (8–10 mmol/L) concentrations in neurons and is absent in mature glial cells; it is thus a putative neuronal marker (Urenjak et al 1993).

Although NAA is thought to provide a measure of neuronal integrity, its specific role in neuronal function remains to be established. Putative roles for NAA include involvement in de novo fatty acid synthesis, protein synthesis initiation, N-acetyl aspartate glutamate (NAAG) metabolism, and aspartate storage (Tsai and Coyle 1995).

Studies using ¹H MRS have shown decreased NAA in various conditions involving neuronal cell damage and loss, including stroke, multiple sclerosis, Alzheimer’s disease, and epilepsy (Howe et al 1993). Thus, NAA may provide a marker for neuronal integrity and viability and may be more sensitive to neuronal loss than structural magnetic resonance imaging (MRI) Ende et al 1996, Guimaraes et al 1995.

Membrane phospholipid metabolism constituents, such as glycerophosphocholine and phosphocholine, contribute to the ¹H MRS Cho signal. The Cho signal has reportedly been increased in states of accelerated membrane phospholipid turnover, and it has been suggested that decreased NAA, along with an elevated Cho signal, may be an indicator of neuronal loss associated with increased membrane turnover versus neuronal loss without active neurodegeneration found with decreased NAA and no changes in Cho (Deicken et al 1998).

Multiple lines of evidence implicate prefrontal circuits in the pathophysiology of mood disorders (George et al 1994). Cerebral blood flow and metabolism studies have most often revealed DLPF hypometabolism in patients with mood disorders (Ketter et al 1996). In postmortem studies Rajkowska has reported histopathological evidence to support previous neuroimaging findings of decreased volume and altered metabolism in the dorsolateral prefrontal (DLPF) cortex in major depressive disorder, that is, marked reductions in the density and size of DLPFC cortex neurons and glial cells (Rajkowska et al 1999). DLPF NAA has not been extensively assessed in bipolar disorder patients but could be decreased in view of consistent reports of decreased DLPF cerebral blood flow and metabolism in mood disorders.

Using in vivo ¹H MRS, Bertolino et al demonstrated bilateral decreases in NAA/Cr in the DLPF and hippocampal regions of schizophrenia patients (Bertolino et al 1996). Renshaw et al found bilateral temporal lobe NAA/Cr decreases in 13 patients with first-episode psychosis, including 6 patients with bipolar disorder (Renshaw et al 1995). The ¹H MRS studies in affective disorders have demonstrated variable results. Several studies have shown increased choline containing compounds in the basal ganglia of bipolar disorder patients Kato et al 1994, Kato et al 1996, Lafer et al 1994, Sharma et al 1992, but there have been no consistent findings with regard to NAA. Few studies have examined NAA in unmedicated or medication-naive patients, and to our knowledge no studies have examined NAA exclusively in unmedicated bipolar disorder patients. Relationships between ¹H MRS NAA findings and bipolar illness characteristics such as illness subtype, duration, and treatment history remain to be elucidated.

The purpose of this study is to determine whether unmedicated bipolar patients show evidence of abnormal frontal lobe neuronal function, as measured by ¹H MRS NAA/Cr, similar to that observed in schizophrenia. Based on evidence of hypofrontality in positron emission tomography (PET) studies of mood disorder patients, the DLPF region was selected for spectroscopic analysis. We therefore studied ratios of DLPF NAA, Cho, and mI to Cr in unmedicated bipolar disorder patients and age- and gender-matched healthy controls using ¹H MRS.