Bipolar disorder shares symptoms and pathological pathways with other neurodegenerative diseases, including frontotemporal dementia (FTD). Since TAR DNA-binding protein 43 (TDP-43) is a neuropathological marker of frontotemporal dementia and it is involved in synaptic transmission, we explored the role of TDP-43 as a molecular feature of bipolar disorder (BD). Homogenates were acquired from frozen hippocampus of postmortem brains of bipolar disorder subjects. TDP-43 levels were quantified using an ELISA-sandwich method and compared between the postmortem brains of bipolar disorder subjects and age-matched control group. We found higher levels of TDP-43 protein in the hippocampus of BD (n = 15) subjects, when compared to controls (n = 15). We did not find associations of TDP-43 with age at death, postmortem interval, or age of disease onset. Our results suggest that protein TDP-43 may be potentially implicated in behavioral abnormalities seen in BD. Further investigation is needed to validate these findings and to examine the role of this protein during the disease course and mood states.

Background

Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive actions, that presents the involvement of the cortico-striatal areas. The contribution of environmental risk factors to OCD development suggests that epigenetic mechanisms may contribute to its pathophysiology. DNA methylation changes and gene expression were evaluated in post-mortem brain tissues of the cortical (anterior cingulate gyrus and orbitofrontal cortex) and ventral striatum (nucleus accumbens, caudate nucleus and putamen) areas from eight OCD patients and eight matched controls.

Results

There were no differentially methylated CpG (cytosine-phosphate-guanine) sites (DMSs) in any brain area, nevertheless gene modules generated from CpG sites and protein-protein-interaction (PPI) showed enriched gene modules for all brain areas between OCD cases and controls. All brain areas but nucleus accumbens presented a predominantly hypomethylation pattern for the differentially methylated regions (DMRs). Although there were common transcriptional factors that targeted these DMRs, their targeted differentially expressed genes were different among all brain areas. The protein-protein interaction network based on methylation and gene expression data reported that all brain areas were enriched for G-protein signaling pathway, immune response, apoptosis and synapse biological processes but each brain area also presented enrichment of specific signaling pathways. Finally, OCD patients and controls did not present significant DNA methylation age differences.

Conclusions

DNA methylation changes in brain areas involved with OCD, especially those involved with genes related to synaptic plasticity and the immune system could mediate the action of genetic and environmental factors associated with OCD.

The human brain undergoes non-uniform changes during aging. The substantia nigra (SN), the source of major dopaminergic pathways in the brain, is particularly vulnerable to changes in the progression of several age-related neurodegenerative diseases. To establish normative data for high-resolution imaging, and to further clinical and anatomical studies we analyzed SNs from 15 subjects aged 50-91 cognitively normal human subjects without signs of parkinsonism. Complete brains or brainstems with substantia nigra were formalin-fixed, celloidin-mounted, serially cut and Nissl-stained. The shapes of all SNs investigated were reconstructed using fast, high-resolution computer-assisted 3D reconstruction software. We found a negative correlation between age and SN volume (p = 0.04, rho = -0.53), with great variability in neuronal numbers and density across participants. The 3D reconstructions revealed SN inter- and intra-individual variability. Furthermore, we observed that human SN is a neuronal reticulum, rather than a group of isolated neuronal islands. Caution is required when using SN volume as a surrogate for SN status in individual subjects. The use of multimodal sequences including those for fiber tracts may enhance the value of imaging as a diagnostic tool to assess SN in vivo. Further studies with a larger sample size are needed for understanding the structure-function interaction of human SN.

The choroid plexus (CP) is an important structure for the brain. Besides its major role in the production of cerebrospinal fluid (CSF), it conveys signals originating from the brain, and from the circulatory system, shaping brain function in health and in pathology. Previous studies in rodents have revealed altered transcriptome both during aging and in various diseases of the central nervous system, including Alzheimer's disease. In the present study, a high-throughput sequencing of the CP transcriptome was performed in postmortem samples of clinically healthy individuals aged 50's through 80's. The data shows an age-related profile, with the main changes occurring in the transition from the 50's to the 60's, stabilizing thereafter. Specifically, neuronal and membrane functions distinguish the transcriptome between the 50's and the 60's, while neuronal and axon development and extracellular structure organization differentiate the 50's from the 70's. These findings suggest that changes in the CP transcriptome occur early in the aging process. Future studies will unravel whether these relate with processes occurring in late- onset brain diseases.