Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of ...atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology with the increasing interest in early detection and prevention. First, we explore the role of
-methyl-d-aspartate receptors in a subpopulation of cortical parvalbumin-containing interneurons (PVIs). Postmortem and preclinical data has implicated these neurons in the positive and negative symptoms, as well as the cognitive dysfunction present in schizophrenia. These neurons also appear to be sensitive to inflammation and oxidative stress during the perinatal and peripubertal periods, which may be mediated in large part by aberrant synaptic pruning. After exploring some of the molecular mechanisms through which neuroinflammation and oxidative stress are thought to exert their effects, we highlight the progress that has been made in identifying psychosis prior to onset through the identification of individuals at clinical high risk for psychosis (CHR). By combining our understanding of psychosis pathogenesis with the increasing characterization of endophenotypes that precede frank psychosis, it may be possible to identify patients before they present with psychosis and intervene to reduce the burden of the disease to both patients and families.
Abstract Despite its debilitating symptoms, the pathophysiology of bipolar disorder (BD) remains unclear. One consistently compelling finding, however, has been the presence of oxidative stress. In ...the present investigation, we conducted a meta-analysis of studies that measured oxidative stress markers in BD patients compared to healthy controls. Search terms and selection criteria were determined a priori to identify and include all studies that measured a marker of oxidative stress in BD compared to healthy controls. Eight markers were included: superoxide dismutase, catalase, protein carbonyl, glutathione peroxidase, 3-nitrotyrosine, lipid peroxidation, nitric oxide, and DNA/RNA damage. A meta-analysis of standardized means was conducted using a random-effects model with generic inverse weighting. Between-study heterogeneity, publication bias, and sensitivity analyses were also examined for each marker. Twenty-seven papers were included in the meta-analysis, which comprised a total of 971 unique patients with BD and 886 healthy controls. Lipid peroxidation, DNA/RNA damage, and nitric oxide were significantly increased in BD patients compared to healthy controls. Additionally, the effect size for lipid peroxidation was very high. Publication bias was not detected for any of the markers. The main limitations in this meta-analysis are the high degree of heterogeneity between studies and the small number of studies used in the analysis of some markers. Additionally, the sensitivity analysis indicated that some results are not very robust. The results from this meta-analysis support the role of oxidative stress in bipolar disorder, especially to DNA, RNA, and lipids.
Mitochondrial disease prevalence has been estimated at 1 in 4000 in the United States, and 1 in 5000 worldwide. Prevalence in Canada has not been established, though multi-linked health ...administrative data resources present a unique opportunity to establish robust population-based estimates in a single-payer health system. This study used administrative data for the Ontario, Canada population between April 1988 and March 2019 to measure mitochondrial disease prevalence and describe patient characteristics and health care costs.
3069 unique individuals were hospitalized with mitochondrial disease in Ontario and eligible for the study cohort, representing a period prevalence of 2.51 per 10,000 or 1 in 3989. First hospitalization was most common between ages 0-9 or 50-69. The mitochondrial disease population experiences a high need for health care and incurred high costs (mean = CAD$24,023 in 12 months before first hospitalization) within the single-payer Ontario health care system.
This study provides needed insight into mitochondrial disease in Canada, and demonstrates the high health burden on patients. The methodology used can be adapted across jurisdictions with similar routine collection of health data, such as in other Canadian provinces. Future work should seek to validate this approach via record linkage of existing disease cohorts in Ontario, and identify specific comorbidities with mitochondrial disease that may contribute to high health resource utilization.
Bipolar disorder (BD) is a debilitating mood disorder with no specific biological marker. No novel treatment has been developed specifically for BD in the last several decades. Although the ...pathophysiology of BD remains unclear, there is strong evidence in the literature supporting the role of mitochondrial dysfunction in BD. In this systematic review, we identified and investigated 12 studies that measure lactate, which is a direct marker for mitochondrial dysfunction, in BD patients and healthy controls. Six studies measured lactate levels in the brain through proton echo‐planar spectroscopy or magnetic resonance spectroscopy and five of these studies reported significantly elevated lactate levels in patients with BD. Two studies reporting cerebrospinal fluid lactate levels also found significantly elevated lactate in BD compared to healthy controls. Two other studies that reported peripheral lactate levels did not demonstrate significant findings. The meta‐analysis, using standardized means and a random‐effect model for five studies that measured brain lactate levels, corroborated the findings of the systematic review. Although the meta‐analysis had a nearly significant overall effect (Z = 1.97, P = 0.05), high statistical heterogeneity (I2 = 86%) and possible publication bias suggest that the results should be interpreted with caution. To validate lactate abnormalities in BD, further studies should be carried out, including larger sample sizes, not excluding female patients, and using standardized methodologies. Peripheral lactate levels and other bioenergetic markers should be thoroughly studied to better understand the role of mitochondrial dysfunction in BD and to help develop more objective diagnostic tools.
Bipolar disorder (BD) is a chronic psychiatric illness described by severe changes in mood. Extensive research has been carried out to understand the aetiology and pathophysiology of BD. Several ...hypotheses have been postulated, including alteration in genetic factors, protein expression, calcium signalling, neuropathological alteration, mitochondrial dysfunction and oxidative stress in BD. In the following paper, we will attempt to integrate these data in a manner which is to understand targets of treatment and how they may be, in particular, relevant to combination treatment. In summary, the data suggested that BD might be associated with neuronal and glial cellular impairment in specific brain areas, including the prefrontal cortex. From molecular and genetics: (1) alterations in dopaminergic system, through catechol-O-aminotransferase; (2) decreased expression and polymorphism on brain-derived neurotrophic factor; (3) alterations cyclic-AMP responsive element binding; (4) dysregulation of calcium signalling, including genome-wide finding for voltage-dependent calcium channel α-1 subunit are relevant findings in BD. Future studies are now necessary to understand how these molecular pathways interact and their connection to the complex clinical manifestations observed in BD.
Accruing data suggest that oxidative stress may be a factor underlying the pathophysiology of bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Glutathione (GSH) is the ...major free radical scavenger in the brain. Diminished GSH levels elevate cellular vulnerability towards oxidative stress; characterized by accumulating reactive oxygen species. The aim of this study was to determine if mood disorders and SCZ are associated with abnormal GSH and its functionally related enzymes. Post-mortem prefrontal cortex from patients with BD, MDD, SCZ, and from non-psychiatric comparison controls were provided by the Stanley Foundation Neuropathology Consortium. Spectrophotometric analysis was utilized for the quantitative determination of GSH, while immunoblotting analyses were used to examine expression of glutamyl-cysteine ligase (GCL), GSH reductase (GR), and GSH peroxidase (GPx). We found that the levels of reduced, oxidized, and total GSH were significantly decreased in all psychiatric conditions compared to the control group. Although GCL and GR levels did not differ between groups, the levels of GPx were reduced in MDD and SCZ compared to control subjects. Since oxidative damage has been demonstrated in MDD, BD, and SCZ, our finding that GSH levels are reduced in post-mortem prefrontal cortex suggests that these patient groups may be more susceptible to oxidative stress.
First described over 50 years ago, Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by mutations of the X-linked
gene. RTT affects predominantly females, and has a prevalence of ...roughly 1 in every 10,000 female births. Prior to the discovery that mutations of
are the leading cause of RTT, there were suggestions that RTT could be a mitochondrial disease. In fact, several reports documented altered mitochondrial structure, and deficiencies in mitochondrial enzyme activity in different cells or tissues derived from RTT patients. With the identification of
as the causal gene, interest largely shifted toward defining the normal function of MeCP2 in the brain, and how its absence affects the neurodevelopment and neurophysiology. Recently, though, interest in studying mitochondrial function in RTT has been reignited, at least in part due to observations suggesting systemic oxidative stress does play a contributing role in RTT pathogenesis. Here we review data relating to mitochondrial alterations at the structural and functional levels in RTT patients and model systems, and present a hypothesis for how the absence of MeCP2 could lead to altered mitochondrial function and elevated levels of cellular oxidative stress. Finally, we discuss the prospects for treating RTT using interventions that target specific aspects of mitochondrial dysfunction and/or oxidative stress.
Large-scale microarray studies on post-mortem brain tissues have been utilized to investigate the complex molecular pathology of bipolar disorder. However, a major challenge in characterizing the ...dysregulation of gene expression in patients with bipolar disorder includes the lack of convergence between different studies, limiting comprehensive understanding from individual results. In this study, we aimed to identify genes that are both validated in published literature and are important classification features of unsupervised machine learning analysis of Stanley Brain Bank microarray database, followed by augmented intelligence method to identify distinct patient molecular subgroups. Through combining traditional literature approaches and machine learning, we identified TBL1XR1, SMARCA2, and CHMP5 to be replicated in 3 of the 4 studies included our analysis. The expression of these genes segregated unique subgroups of patients with bipolar disorder. Our study suggests the involvement of PPARγ pathway regulation in patients with bipolar disorder.
Previously, we found decreased mitochondrial complex I subunits levels and increased protein oxidation and nitration in postmortem prefrontal cortex (PFC) from patients with bipolar disorder (BD) and ...schizophrenia (SCZ). The objectives of this study were to replicate our findings in an independent sample of subjects with BD, and to examine more specifically oxidative and nitrosative damage to mitochondrial and synaptosomal proteins and lipid peroxidation in myelin. We isolated mitochondria, synaptosomes, and myelin using a percoll gradient from postmortem PFC from patients with BD, SCZ, and healthy controls. Levels of mitochondrial complex I and III proteins, protein oxidation (carbonylation), and nitration (3‐nitrotyrosine) were assessed using immunobloting analysis. Lipid peroxidation lipid hydroperoxides (LPH), 8‐isoprostane (8‐Iso), 4‐hydroxy‐2‐nonenal (4‐HNE) were measured using colorimetric or ELISA assays. We found decreased complex I subunits levels in BD subjects compared with control (CTL), but no difference in complex III subunits. Carbonylation was increased in synaptosomes from BD group while 3‐nitrotyrosine was increased in mitochondria from BD and SCZ groups. 8‐Iso was found increased in the BD group while 4‐HNE was increased in both SCZ and BD when compared with controls with no differences in LPH. Our results suggest that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins.
Oxidative stress has been shown to be higher in the brain of patients with bipolar disorder (BD). Here, we demonstrated increased levels of protein oxidation in synaptosomes from postmortem prefrontal cortex from patients from BD group, while 3‐nitrotyrosine was increased in mitochondria from BD and schizophrenia (SCZ) groups. Moreover, lipid peroxidation was found increased in the BD when compared with controls; suggesting that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins.
Oxidative stress has been shown to be higher in the brain of patients with bipolar disorder (BD). Here, we demonstrated increased levels of protein oxidation in synaptosomes from postmortem prefrontal cortex from patients from BD group, while 3‐nitrotyrosine was increased in mitochondria from BD and schizophrenia (SCZ) groups. Moreover, lipid peroxidation was found increased in the BD when compared with controls; suggesting that in BD mitochondrial proteins are more susceptible to potentially reversible nitrosative damage while more longstanding oxidative damage occurs to synaptic proteins.
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