A psychoimmunological approach in the understanding of bipolar disorder
03 / 2009 - 03 / 2013
Bipolar disorder (BD) with a lifetime prevalence of 2% is characterized by episodic pathologic disturbances in mood ranging from extreme elation (mania) to severe depression1. There is no (biological) diagnostic marker for BD. Nevertheless, several findings have been found to be associated with BD: hypothalamic-pituitary-adrenal (HPA) axis disturbances2; a higher frequency of autoimmune diseases3; an increase of pro-inflammatory monocyte/macrophage cytokines4; a pro-inflammatory gene signature in the circulating monocytes (and a PDE4B associated pro-inflammatory signature)5; an activated inflammatory response system (IRS) and glucocorticoid insensitivity6 with a linkage between an activated IRS, and disturbances in the tryptophan metabolism7. In bipolar patients an elevated PDE4B associated pro-inflammatory signature in blood occurred in 60% of bipolar cases (15/25, p<0.001 vs. healthy controls) 5 . The finding of the PDE4B associated pro-inflammatory signature may be a cause of neuroinflammation. Besides the pro-inflammatory signature in blood monocytes, PET imaging has revealed activation of microglia in various neurological disorders that are accompanied by brain inflammation8 , 9. Microglia, the terminally differentiated monocytes in the brain are responsible for neuroinflammation. These cells express not only PDE4B under pro-inflammatory conditions10 , 11 but also the peripheral benzodiazepine receptor (PBR). The PBR is accessible for in vivo imaging with positron emission tomography (PET) in humans9 , 12. Activation of the PBR in microglia has also been found in psychiatric disorders. The first study showed a general (grey matter) elevated binding potential of the PBR tracer PK11195 in stable schizophrenic patients 13 . A study has been conducted with patients that suffered from an ongoing psychosis, and a clear focus of inflammation in the hippocampus was found. This region is important for mood, cognition and motivation and may be the origin of hallucinatory perceptions in these patients 14 . The blood and the brain are considered as being two compartments. In the first compartment, the brain, the microglia can be regarded as the primary locus of inflammatory control, with specific expression of PBR as a biomarker that can be imaged with PET. The blood is a secondary but easier accessible compartment. The same holds even more true for the clinical features observed in bipolar disorder, the phonotypical expression of the disorder. White matter disturbances have been found in multiple locations of the brain in bipolar disorder. The orbitofrontal area (OFC)15-17 and frontotemporal area (TP)18 in the dominant hemisphere have been investigated using diffuse tensor magnetic resonance imaging (DTI). A ventral semantic stream has been discovered connecting the TP and OFC through the uncinate and inferior longitudinal fascicule19. Additionally aberrations in fractal anisotropy (a measure of diffusion) were found in limbic system20-22. Using chemicals shift magnetic resonance imaging (CSI), specific biochemical substances were found to be reduced in the caudate heads an lentiform nucleus of bipolar subjects23 and the anterior cingulate cortex and parieto-occipital cortex. A connection between between white matter disturbances and inflammation has been suggested for multiple sclerosis23 , 24. We expect such a link to exist for bipolar disorder as well. This research project aims to investigate two connections concerning the pro-inflammatory state in bipolar disorder.