myelin-basic-protein and Bipolar-Disorder

The pathogenesis of bipolar affective disorder is associated with immunological imbalances, a general pro-inflammatory status, neuroinflammation, and impaired white matter integrity. Myelin basic protein (MBP) is one of the major proteins in the myelin sheath of brain oligodendrocytes. For the first time, we have shown that IgGs isolated from sera of bipolar patients can effectively hydrolyze human myelin basic protein (MBP), unlike other test proteins. Several stringent criteria were applied to assign the studied activity to serum IgG. The level of MBP-hydrolyzing activity of IgG from patients with bipolar disorder was statistically significantly 1.6-folds higher than that of healthy individuals. This article presents a detailed characterization of the catalytic properties of MBP-hydrolyzing antibodies in bipolar disorder, including the substrate specificity, inhibitory analysis, pH dependence of hydrolysis, and kinetic parameters of IgG-dependent MBP hydrolysis, providing the heterogeneity of polyclonal MBP-hydrolyzing IgGs and their difference from canonical proteases. The ability of serum IgG to hydrolyze MBP in bipolar disorder may become an additional link between the processes of myelin damage and inflammation.

Topics: Antibodies, Catalytic; Bipolar Disorder; Humans; Immunoglobulin G; Multiple Sclerosis; Myelin Basic Protein

Psychotic disorders affect ~3% of the general population and are among the most severe forms of mental diseases. In early stages of psychosis, clinical aspects may be difficult to distinguish from one another. Undifferentiated psychopathology at the first-episode of psychosis (FEP) highlights the need for biomarkers that can improve and refine differential diagnosis. We investigated gene expression differences between patients with FEP-schizophrenia spectrum (SCZ; N=53) or FEP-Mania (BD; N=16) and healthy controls (N=73). We also verified whether gene expression was correlated to severity of psychotic, manic, depressive symptoms and/or functional impairment. All participants were antipsychotic-naive. After the psychiatric interview, blood samples were collected and the expression of 12 psychotic-disorder-related genes was evaluated by quantitative PCR. AKT1 and DICER1 expression levels were higher in BD patients compared with that in SCZ patients and healthy controls, suggesting that expression of these genes is associated more specifically to manic features. Furthermore, MBP and NDEL1 expression levels were higher in SCZ and BD patients than in healthy controls, indicating that these genes are psychosis related (independent of diagnosis). No correlation was found between gene expression and severity of symptoms or functional impairment. Our findings suggest that genes related to neurodevelopment are altered in psychotic disorders, and some might support the differential diagnosis between schizophrenia and bipolar disorder, with a potential impact on the treatment of these disorders.

Topics: Adult; Bipolar Disorder; Carrier Proteins; Case-Control Studies; DEAD-box RNA Helicases; Diagnosis, Differential; Female; Gene Expression Regulation; Humans; Male; Myelin Basic Protein; Proto-Oncogene Proteins c-akt; Psychiatric Status Rating Scales; Psychometrics; Psychotic Disorders; Reference Values; Ribonuclease III; Schizophrenia; Schizophrenic Psychology; Statistics as Topic; Young Adult

Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.

Topics: Adult; Age Factors; Antipsychotic Agents; Axons; Biomarkers; Bipolar Disorder; Brain; Fatty Acid Binding Protein 3; Fatty Acid-Binding Proteins; Female; Humans; Lamotrigine; Linear Models; Lithium Compounds; Male; Middle Aged; Myelin Basic Protein; Neurofilament Proteins; Psychiatric Status Rating Scales; Psychotropic Drugs; S100 Calcium Binding Protein beta Subunit; Sex Factors; Triazines

It is difficult for clinicians to diagnose schizophrenia solely based on interviews. We explored the diagnostic efficiency and predictive capability of serum biomarkers for schizophrenia.. Levels of β nerve growth factor (β-NGF), brain-derived neurotrophic factor (BDNF), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), calcium binding protein S100β, myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) were measured in the sera of 278 schizophrenia patients, 240 depression and bipolar disorder patients, and 260 healthy controls. DSM-IV-TR criteria were used as the diagnostic criteria for schizophrenia and depressive and bipolar disorders. The diagnostic efficiency was high in patients with schizophrenia compared with the healthy controls. Receiver operating characteristic (ROC) curve analysis was used to ascertain the diagnostic efficiency of the 8 proteins. Data were collected between July 2010 and December 2012.. One-way analysis of variance significantly demonstrated lower serum BDNF, MBP, and GFAP levels (F = 16.504, P < .001; F = 207.209, P < .001; F = 33.668, P < .001, respectively) but higher serum IL-6 and S100β concentrations (F = 15.250, P < .001; F = 12.751, P < .001, respectively) among patients with schizophrenia. ROC analysis of the discriminant scores of the serum β-NGF, BDNF, IL-6, S100β, MBP, and GFAP levels resulted in significant discrimination between the schizophrenia and control groups (AUC = 0.922) and the depressive/bipolar disorder and control groups (AUC = 0.762).. Serum levels of 6 proteins (but not TNF-α and IFN-γ) contribute most to the diagnosis of schizophrenia. These proteins may prove to be useful adjuncts for the clinical assessment of this disease.

Topics: Adult; Biomarkers; Bipolar Disorder; Brain-Derived Neurotrophic Factor; Case-Control Studies; Depressive Disorder; Female; Glial Fibrillary Acidic Protein; Humans; Interferon-gamma; Interleukin-6; Male; Myelin Basic Protein; Nerve Growth Factor; Psychiatric Status Rating Scales; ROC Curve; S100 Calcium Binding Protein beta Subunit; Schizophrenia; Tumor Necrosis Factor-alpha; Young Adult

Most brain gene expression studies of schizophrenia have been conducted in the frontal cortex or hippocampus. The extent to which alterations occur in other cortical regions is not well established. We investigated primary visual cortex (Brodmann area 17) from the Stanley Neuropathology Consortium collection of tissue from 60 subjects with schizophrenia, bipolar disorder, major depression, or controls. We first carried out a preliminary array screen of pooled RNA, and then used RT-PCR to quantify five mRNAs which the array identified as differentially expressed in schizophrenia (myelin basic protein [MBP], myelin-oligodendrocyte glycoprotein [MOG], β-actin [ACTB], thymosin β-10 [TB10], and superior cervical ganglion-10 [SCG10]). Reduced mRNA levels were confirmed by RT-PCR for MBP, ACTB and TB10. The MBP reduction was limited to transcripts containing exon 2. ACTB and TB10 mRNAs were also decreased in bipolar disorder. None of the transcripts were altered in subjects with major depression. Reduced MBP mRNA in schizophrenia replicates findings in other brain regions and is consistent with oligodendrocyte involvement in the disorder. The decreases in expression of ACTB, and the actin-binding protein gene TB10, suggest changes in cytoskeletal organisation. The findings confirm that the primary visual cortex shows molecular alterations in schizophrenia and extend the evidence for a widespread, rather than focal, cortical pathophysiology.

Topics: Actins; Adult; Bipolar Disorder; Demography; Depressive Disorder, Major; Female; Gene Expression Regulation; Genes, Essential; Humans; Male; Middle Aged; Myelin Basic Protein; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Schizophrenia; Visual Cortex

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Adult; Bipolar Disorder; Blood Cells; Female; Gene Expression Regulation; Humans; Male; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; RNA, Messenger; Schizophrenia

Myelination of the frontal and temporal lobes occurs at a similar time period as symptom onset in schizophrenia. To assess this potential relationship, we compared myelination and oligodendrocyte numbers in the hippocampal formation of controls and matched subjects with schizophrenia and bipolar disorder. The levels and distribution of the myelin marker myelin basic protein (MBP) and the oligodendrocyte marker adenomatous polyposis coli (APC) were measured using immunocytochemistry. MBP immunoreactivity (IR) was increased in several hippocampal subregions of control females versus control males. Female subjects with schizophrenia and bipolar disorder exhibited decreased myelination in the hippocampal formation while male subjects with bipolar disorder showed increased MBP levels in the superior medullary lamina. In contrast, the number of APC immunoreactive cells did not differ in any disorder or region. Our results demonstrate an interaction between gender, mental illness, and myelination, and may be related to cognitive deficits seen in schizophrenia and bipolar disorder.

Topics: Adenomatous Polyposis Coli Protein; Adult; Aged; Aged, 80 and over; Bipolar Disorder; Densitometry; Dentate Gyrus; Female; Hippocampus; Humans; Immunohistochemistry; Male; Middle Aged; Myelin Basic Protein; Myelin Sheath; Paraffin Embedding; Schizophrenia; Sex Characteristics

Reports of elevated Gs alpha subunit (alpha(s)) immunolabeling and cAMP-mediated hyper-functionality in autopsied cerebral cortical brain regions from bipolar affective disorder (BD) patients suggest signal transduction abnormalities occur in this disorder. Because covalent modification of alpha(s) can affect its turnover and levels, we determined whether CTX-catalyzed and endogenous [(32)P] adenosine diphosphate (ADP)-ribosylation of alpha(s) isoforms are altered in temporal and occipital cortical regions, which show elevated alpha(s) levels in BD as compared to nonpsychiatric subjects. Reduced CTX-catalyzed [(32)P]ADP-ribosylated alpha(s-S) and endogenous [(32)P]ADP-ribosylation of a 39-kDa alpha(s)-like protein were found in BD temporal cortex compared to controls. These findings suggest that clearance of these alpha(s) isoforms through ADP-ribosylation may be decreased in BD temporal cortex. Although no differences were observed in mean levels of endogenous and CTX-catalyzed [(32)P]ADP-ribosylation of alpha(s-L) in BD temporal cortex, alpha(s-L) immunolabeling was elevated significantly and correlated inversely with the degree of endogenous [(32)P]ADP-ribosylation of this subunit. In addition, endogenous [(32)P]ADP-ribosylation of an exogenous substrate, myelin basic protein, was similar in BD and comparison subject temporal cortex. Taken together, these observations suggest that elevations of alpha(s) in BD brain are more likely related to factors affecting the disposition or availability of alpha(s) to this posttranslational enzymatic modification.

Topics: Adenosine Diphosphate; Adult; Aged; Aged, 80 and over; Bipolar Disorder; Cholera Toxin; Female; Heterotrimeric GTP-Binding Proteins; Humans; Immunohistochemistry; Lithium; Male; Middle Aged; Myelin Basic Protein; Neurons; Occipital Lobe; Phosphorus Isotopes; Temporal Lobe

Topics: Bipolar Disorder; Gene Expression Profiling; Gene Expression Regulation; Humans; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin Sheath; Myelin-Associated Glycoprotein; Oligodendroglia; Oligonucleotide Array Sequence Analysis; Schizophrenia

Two related patients with similar clinical features consisting of a few dysmorphic signs and psychiatric disturbance were reported to have a partial trisomy of chromosomes 15(pter-q13.3) and 18(q23-qter) deriving from a familial translocation t(15;18). One patient is affected by bipolar disorder and the other by schizoaffective disorder. Both cases have a predominantly affective course; nevertheless, a clear diagnosis is difficult in the first patient, who is 15 years of age, and only a longitudinal course will allow us to establish a definite diagnosis. The possibility that these two pathologies belong to a single category is discussed, and the presence of a susceptibility locus on chromosome 18 is hypothesized. Cytogenetic data, FISH, and DNA studies indicate that the myelin basic protein (MPB) gene is not involved in the translocation, and localize it centromeric to the breakpoint on chromosome 18(q22.3). Thus, it is unlikely to be involved in the disease.

Topics: Adolescent; Aspartic Acid Endopeptidases; Base Sequence; Bipolar Disorder; Cells, Cultured; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 18; DNA Primers; Female; Humans; In Situ Hybridization, Fluorescence; Leukocytes, Mononuclear; Male; Middle Aged; Molecular Sequence Data; Myelin Basic Protein; Pedigree; Schizophrenia; Translocation, Genetic