Yarema B. Bezchlibnyk

Gene expression differences in bipolar disorder revealed by cDNA array analysis of post-mortem frontal cortex.

Previous studies have implicated a number of biochemical pathways in the etiology of bipolar disorder (BD). However, the precise abnormalities underlying this disorder remain to be established. To investigate novel factors that may be important in the pathophysiology of BD, we utilized cDNA expression arrays to examine differences in expression of up to 1200 genes known to be involved in potentially relevant biochemical processes. This investigation was undertaken in post‐mortem samples of frontal cortex tissue from patients with BD and matched controls, obtained (n = 10/group) from the Stanley Foundation Neuropathology Consortium. Results include significant (greater than 35% change in signal intensity) differences between BD and controls in a number of genes (n = 24). Selected targets were analyzed by RT‐PCR, which confirmed a decrease in transforming growth factor‐beta1 (TGF‐β1), and an increase in both caspase‐8 precursor (casp‐8) and transducer of erbB2 (Tob) expression in BD. We further observed a significant decrease of TGF‐β1 mRNA levels in BD by RT‐PCR in individual post‐mortem samples. Given the neuroprotective role attributed to this inhibitory cytokine, our results suggest that the down‐regulation of TGF‐β1 may lead to various neurotoxic insults potentially involved in the etiology of certain mood disorders.

The neurobiology of bipolar disorder: focus on signal transduction pathways and the regulation of gene expression.

Objective: This article presents an overview of signal transduction path ways and re views the re search under taken to study these systems in clinically relevant samples from patients with bipolar disorder (BD). Method: We re viewed the published findings from studies of post mortem brain tissue and blood samples from patients with BD. Results: Al though the ex act biochemical abnormalities have yet to be identified, the presented findings strongly suggest that BD may be due, at least in part, to abnormalities in signal transduction mechanisms. In particular, altered levels or function, or both, of G-protein a subunits and effector molecules such as protein kinase A (PKA) and protein kinase C (PKC) have consistently been associated with BD both in peripheral cells and in post mortem braintis sue, while more re cent studies implicate disruption in novel second-messenger cascades, such as the ERK/MAPK path way. Conclusions: De spite the difficulties inherent in biochemical studies of clinically relevant tissue samples, numerous investigations have illuminated the signal transduction mechanisms in patients with BD. These studies also suggest that BD may be due to the interaction of many abnormalities. In this con text, novel techniques enabling the study of gene expression promise to assist in untangling these complex interactions, through visualizing the end result of these changes at the level of gene transcription.

Myelin oligodendrocyte glycoprotein (MOG) gene is associated with obsessive-compulsive disorder

Obsessive‐compulsive disorder (OCD) is a severe neuropsychiatric disorder with a strong genetic component, and may involve autoimmune processes. Support for this latter hypothesis comes from the identification of a subgroup of children, described by the term pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS), with onset of OCD symptoms following streptococcal infections. Genes involved in immune response therefore represent possible candidate genes for OCD, including the myelin oligodendrocyte glycoprotein (MOG) gene, which plays an important role in mediating the complement cascade in the immune system. Four polymorphisms in the MOG gene, a dinucleotide CA repeat (MOG2), a tetranucleotide TAAA repeat (MOG4), and 2 intronic single nucleotide polymorphisms, C1334T and C10991T, were investigated for the possibility of association with OCD using 160 nuclear families with an OCD proband. We examined the transmission of alleles of these four polymorphisms with the transmission disequilibrium test (TDT). A biased transmission of the 459‐bp allele (allele 2: χ2 = 5.255, P = 0.022) of MOG4 was detected, while MOG2, C1334T, and C10991T showed no statistically significant bias in the transmission of alleles. The transmission of the C1334T.MOG2.C10991T.MOG4 haplotype 1.13.2.2 (χ2 = 6.426, P = 0.011) was also significant. Quantitative analysis using the family‐based association test (FBAT) was significant for MOG4 in total Yale‐Brown Obsessive‐Compulsive Scale severity score (allele 2: z = 2.334, P = 0.020). Further investigations combining genetic, pathological, and pharmacological strategies, are warranted.

Amygdala cyclic adenosine monophosphate response element binding protein phosphorylation in patients with mood disorders: effects of diagnosis, suicide, and drug treatment.

BACKGROUND Signal transduction abnormalities have been identified in patients with bipolar (BD) and major depressive (MDD) disorders and are targets for lithium and antidepressant drugs. A key downstream target for signal transduction pathways is the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Therefore, we measured the levels of phosphorylated CREB (pCREB) in the amygdala, a region critical to emotional processing and important in the pathophysiology of both BD and MDD. METHODS Human postmortem amygdala sections were generously provided by the Stanley Foundation Neuropathology Consortium. Samples consisted of subjects with MDD, BD, schizophrenia (SCZ), and nonpsychiatric-nonneurologic comparison subjects (n = 15 per group). Levels of pCREB were measured by immunohistochemistry, relative to total cell number. RESULTS There were no differences between diagnostic groups--control subjects and subjects with BD, MDD, or SCZ--but increased numbers of pCREB stained cells were found in several amygdalar nuclei in subjects who had died by suicide. In contrast, patients treated with lithium at the time of death had significantly lower pCREB levels in the same region. CONCLUSIONS These results suggest that CREB activity may be an important factor in the neurobiology of suicide and the well-documented antisuicidal effect of lithium.

Decreased expression of insulin-like growth factor binding protein 2 in the prefrontal cortex of subjects with bipolar disorder and its regulation by lithium treatment

Insulin-like growth factors (IGFs) regulate cellular proliferation and death, and their bioactivity is controlled by IGF binding proteins (IGFBPs). Since IGFBP-2 is the major brain resident IGFBP, and we have demonstrated lithium-mediated changes in its mRNA and protein levels in neuronal cultures, we examined IGFBP-2 expression in prefrontal cortex postmortem brain tissue from subjects with mood disorders. We found decreased IGFBP-2 expression in bipolar disorder patients compared with controls; this was especially pronounced in subjects not treated with lithium. These results suggest a role for IGFBPs in the etiology and pharmacotherapy of mood disorders.

Immunoreactivity of 43 kDa growth-associated protein is decreased in post mortem hippocampus of bipolar disorder and schizophrenia.

Impairment of neuroplasticity is considered to play a role in the pathogenesis of psychiatric disorders. To further characterize the impairment of neuroplasticity in psychiatric disorders, expression of the neuronal plasticity marker 43 kDa growth-associated protein (GAP-43) was detected in postmortem hippocampal sub-regions from psychiatric patients including major depressive disorder, bipolar disorder and schizophrenia subjects, and matched control subjects. We found that GAP-43 protein levels in the hippocampal hilar region were significantly lower in bipolar disorder and schizophrenia subjects than in control subjects. We also found that GAP-43 protein levels in the inner molecular layer of the dentate gyrus and the stratum radiatum of CA2 region were reduced in a trend in bipolar disorder and schizophrenia subjects when compared with control subjects. These results suggest that impairment of neuroplasticity may occur in the hippocampus of bipolar disorder and schizophrenia patients.

Subgenual Cingulate Deep Brain Stimulation for Treatment-Resistant Depression

Abstract Neuroimaging studies in patients with depression have been critical in identifying a network of brain regions involved in the symptomatology and treatment of depression. Since a substantial proportion of patients are resistant to conventional treatments, including antidepressant and psychological therapy, these studies have spurred attempts to reregulate the network via targeted neuromodulation, including deep brain stimulation of the subgenual cingulate cortex.

A neurosurgeon`s view: Laser interstitial thermal therapy of mesial temporal lobe structures

Stereotactic laser ablation of mesial temporal structures is a promising new surgical intervention for patients with mesial temporal lobe epilepsy (MTLE). Since this procedure was first used to treat MTLE in 2010, the literature contains reports of 37 patients that underwent MR-guided stereotactic laser amygdalohippocampotomy (SLAH) using Laser Interstitial Thermal Therapy (LITT) with at least 1year of follow-up. This early body of data suggests that SLAH is a safe and effective treatment for MTLE in properly selected patients. Moreover, SLAH is substantially less invasive when compared with open surgical procedures including standard anterior temporal lobectomy and its more selective variants, results in immediate destruction of tissue in contrast to radiosurgical treatments for MTLE, and can more readily ablate larger volumes of tissue than is possible with techniques employing radiofrequency ablation. Finally, evidence is accruing that SLAH is associated with lower overall risk of neuropsychological deficits compared to open surgery. Thus, LITT constitutes a novel minimally invasive tool in the neurosurgeons armamentarium for managing medically refractory seizures that may draw eligible patients to consider surgical interventions to manage their seizures.