"For the first time, our study supports the idea that there may be on-going damage to certain regions of the brain as the illness progresses," said the study's lead author Raymond Deicken, MD. Deicken is the medical director of the Psychiatric Partial Hospital Program at the San Francisco VA Medical Center and UCSF associate professor of psychiatry.
The study appears in the May issue of the American Journal of Psychiatry.
More than 2 million Americans suffer from bipolar disorder, commonly known as manic depression. To date, there are no physiological markers used to diagnose the disease. Instead, it is identified by behavioral symptoms, including frequent mood swings between high-energy mania and severe depression.
Deicken and his colleagues compared brain scans of 15 non-symptomatic male patients with familial bipolar I disorder to those of 20 healthy male comparison subjects. Male subjects were chosen to control for the effects of gender. In addition, test subjects were chosen based on several previous studies showing that patients who have inherited the disorder have more prominent changes in brain structure and function.
Researchers determined chemical signatures of different brain structures in these two groups using proton magnetic resonance spectroscopy. One finding focused on the level of an amino acid called N-acetylaspartate, or NAA, in the hippocampus, which is made up of a right and left half and is part of a complex of neural circuits in the brain that regulate emotion and memory.
The study found significantly lower concentrations of NAA in the right hippocampus of males with bipolar disorder when compared to the control group. They also found that for the right hippocampus, bipolar patients who had the disease the longest had the lowest levels of the amino acid. This association between length of illness and NAA appears to be confined to certain brain regions since it was not found in previous studies that involved the frontal lobe and thalamus.
NAA is the second most abundant amino acid--next to glutamate--present in brain tissue. It is a biochemical indicator of the presence of neurons and axons, plays an important role in the synthesis of neuronal proteins, and is a precursor of myelin, which acts as insulation around neurons in the brain.
"Low NAA is an indication that the integrity of neurons and/or axons has been compromised in some way, either by damage, loss or dysfunction," Deicken said. The decrease of hippocampal NAA over time in the test subjects indicates a progressive nature of this disease. Decreasing levels of NAA are also seen in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and multiple sclerosis.
According to Deicken, the findings also confirm the important role of the hippocampus in bipolar disorder. Brain imaging studies of patients suffering from major depression have demonstrated smaller hippocampi. Given that bipolar disorder also affects mood and emotion, it is not surprising that this study provides evidence for hippocampal damage or dysfunction in the disorder.
The hippocampus is also important from a therapeutic standpoint since it is one of two brain regions where new neuronal growth, or neurogenesis, can occur, offering hope for reversal of damage.
NAA measurements may also help us to understand how medications work in bipolar disorder. "Lithium has been around for a long time and nobody really knows how it works," Deicken said. However, he points out that long-term lithium treatment has been recently shown to exert powerful protective effects in the rat brain, including damage from stroke. It has also been shown in humans to increase both the amount of NAA and gray matter in the brain.
Finally, Deicken predicts that the monitoring of NAA levels will become invaluable in the evaluation of treatments for bipolar disorder and other psychiatric diseases--such as schizophrenia and major depression--which involve neuronal loss or dysfunction. "We'll know we're onto a potential treatment if a medication or other intervention manages to boost low levels of NAA toward more normal values, indicating neuronal repair or a recovery of function," Deicken said.
Additional authors of the study include Robert Feiwell, MD, UCSF assistant clinical professor of radiology; Brain Soher, PhD, SFVAMC Magnetic Resonance Unit; Mary P. Pegues, MSW, and Susan Anzalone, BA, research associates, SFVAMC Psychiatry Service.
Deicken's research was supported by the National Institute of Mental Health and a Stanley Foundation Research Award from the National Alliance for the Mentally Ill.
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