The neuropathology of bipolar disorder: systematic review and meta-analysis

Abstract

Various neuropathological findings have been reported in bipolar disorder (BD). However, it is unclear which findings are well established. To address this gap, we carried out a systematic review of the literature. We searched over 5000 publications, identifying 103 data papers, of which 81 were eligible for inclusion. Our main findings can be summarised as follows. First, most studies have relied on a limited number of brain collections, and have used relatively small sample sizes (averaging 12 BD cases and 15 controls). Second, surprisingly few studies have attempted to replicate closely a previous one, precluding substantial meta-analyses, such that the latter were all limited to two studies each, and comprising 16-36 BD cases and 16-74 controls. As such, no neuropathological findings can be considered to have been established beyond reasonable doubt. Nevertheless, there are several replicated positive findings in BD, including decreased cortical thickness and glial density in subgenual anterior cingulate cortex, reduced neuronal density in some amygdalar nuclei, and decreased calbindin-positive neuron density in prefrontal cortex. Many other positive findings have also been reported, but with limited or contradictory evidence. As an important negative result, it can be concluded that gliosis is not a feature of BD; neither is there neuropathological evidence for an inflammatory process.

Cellular calcium in bipolar disorder: systematic review and meta-analysis

“…It therefore cannot be excluded that VGCCs have a role in [Ca 2+ ] regulation in many cell types, although this would seem likely to be at most a minor contribution to the results reported here, especially since VGCCs are not expressed in platelets or their megakaryocyte precursors [75]. Finally, it would be of interest to study intracellular [Ca 2+ ] in glia in bipolar disorder, since these cells are implicated in its pathophysiology [76,77], and Ca 2+ dysregulation in the disorder may involve these cells as well as the presumed primary neuronal locus of dysfunction. Despite the uncertainties as to its cause and molecular basis, the increase in intracellular [Ca 2+ ] found in bipolar disorder is broadly supportive of the possibility that novel calcium channel antagonists, or related drugs acting upon calcium signalling, could be of potential therapeutic value, especially if designed to be brain selective [78][79][80].…”

Longitudinal Cortical Thickness Changes in Bipolar Disorder and the Relationship to Genetic Risk, Mania, and Lithium Use

“…A recent meta-analysis of postmortem studies in BD suggests cortical tissue alterations in several brain areas as detected by staining of calcium-binding proteins (94). Lithium has been shown to attenuate calcium dysregulation, possibly underlying its neuroprotective effects (28,92,95).…”

A case of bipolar disorder developing into atypical parkinsonism and presenting with frontotemporal asymmetrical brain degeneration. A TREDEM Registry Case Report

“…However, illness trajectories are largely variable and scarcely predictable. Moreover, no clear neuropathological marker can be ascribable to BD . In a recent study, the longitudinal trajectories of frontotemporal dementia (FTD) and psychiatric disorders with behavioural symptoms were examined and the results provide strong evidence of a faster worsening of the symptoms in FTD, with a stable profile in psychiatric conditions.…”

“…Moreover, no clear neuropathological marker can be ascribable to BD. 1 In a recent study, the longitudinal trajectories of frontotemporal dementia (FTD) and psychiatric disorders with behavioural symptoms were examined and the results provide strong evidence of a faster worsening of the symptoms in FTD, with a stable profile in psychiatric conditions. This may provide grounds to assume that our patient's clinical trajectory is due to a frontal lobe neurodegeneration, rather than the evolution of a purely psychiatric condition.…”