Regionally-specific changes in levels of tumour necrosis factor in the dorsolateral prefrontal cortex obtained postmortem from subjects with major depressive disorder.

Background: From studies in the periphery, changed levels of tumour necrosis factor (TNF) have been implicated in the pathophysiology of major depressive disorders (MDD). Therefore we decided to determine whether TNF was altered in the frontal cortex (Brodmann's areas (BA) 24 and 46) from 10 subjects with MDD and 10 control subjects.

Methods: Tissue homogenates were prepared from the left hemisphere and levels of TNF trans-membrane (tmTNF) and TNF soluble (sTNF) forms measured by Western blots.

Pharmacotherapeutic targets in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by an increasing impairment in normal memory and cognitive processes that significantly diminishes a person's daily functioning. Despite decades of research and advances in our understanding of disease aetiology and pathogenesis, there are still no effective disease-modifying drugs available for the treatment of AD. However, numerous compounds are currently undergoing pre-clinical and clinical evaluations.

Drug development based on the metals hypothesis of Alzheimer's disease.

The recent report of positive results from a Phase IIa clinical trial of PBT2, a novel drug that targets amyloid-beta-metal interactions, underscores the value of abnormal transition metal metabolism as a potential therapeutic target in Alzheimer's disease. The Metals Hypothesis of Alzheimer's disease is based upon observations of the precipitation of amyloid-beta by zinc and its radicalization by copper. Both metals are markedly enriched in plaques.

Levels of [(3)H]pirenzepine binding in Brodmann's area 6 from subjects with schizophrenia is not associated with changes in the transcription factor SP1 or BACE1.

Decreased muscarinic M1 receptor (CHRM1) mRNA has been reported in Brodmann's area (BA) 6 from subjects with schizophrenia. We have extended this study by measuring levels of CHRM1 ([(3)H]pirenzepine binding), CHRM3 ([(3)H]4-DAMP binding), the transcription factor SP1 and the CHRM1 downstream target beta-site APP-cleaving enzyme 1 (BACE1) in BA 6 from 19 subjects with schizophrenia and 19 control subjects. Radioligand binding was quantified using either in situ radioligand binding with autoradiography or, in cohorts of 10 control subjects and 10 subjects with schizophrenia, membrane enriched fraction (MEF) CNS ([(3)H]pirenzepine binding only).

Using differential solubilization and 2-D gel electrophoresis to visualize increased numbers of proteins in the human cortex and caudate nucleus and putamen.

The aim of this study was to determine if differential solubilization of human CNS proteins would increase the total number of proteins that could be visualized using 2-D gel electrophoresis. Hence, proteins were solubilized into Tris, CHAPS and SB3-10 before separation across a pH 4-7 IEF gradient and a 12-14% SDS polyacrylamide gel, which could be achieved with a run-to-run variation of 35% in spot intensity. Because Western blot analyses suggested proteins could be in more than one detergent fraction, we completed a conservative analyses of our 2-D gels assuming spots that appeared on multiple gels at the same molecular weight and pI were the same protein.

Evidence for altered post-receptor modulation of the serotonin 2a receptor in schizophrenia.

We have shown a decrease in cortical serotonin(2A) receptors using tissue sections, but not with washed membranes, from the same cohort of subjects. These discrepant findings led us to determine if we could obtain similar results using samples from the same tissue block. Our studies used single-point saturation analyses to estimate the total number of [(3)H]ketanserin binding sites in tissue sections, crude homogenate, membrane-enriched and cytosol-enriched tissue samples from Brodmann's area 9.

Therapeutics for Alzheimer's disease based on the metal hypothesis.

Alzheimer's disease is the most common form of dementia in the elderly, and it is characterized by elevated brain iron levels and accumulation of copper and zinc in cerebral beta-amyloid deposits (e.g., senile plaques).

Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta.

As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta within hours and improving cognitive performance to exceed that of normal littermate controls within days.

N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial.

Background: Treatment-resistant subthreshold depression is a major problem in bipolar disorder. Both depression and bipolar disorder are complicated by glutathione depletion. We hypothesized that treatment with N-acetyl cysteine (NAC), a safe, orally bioavailable precursor of glutathione, may improve the depressive component of bipolar disorder.

Acting on harmful command hallucinations in psychotic disorders: an integrative approach.

Although harmful command hallucinations have been linked to violent behavior, few studies have examined factors mediating this relationship. The principal aim of this study was to examine a range of factors potentially associated with acting on harmful command hallucinations using a multivariate approach. The sample comprised 75 participants drawn from community and forensic services.

N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial.

Background: Brain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.

Plasma apolipoprotein E is decreased in schizophrenia spectrum and bipolar disorder.

We have shown that plasma apolipoprotein E is significantly decreased in treatment-free subjects with schizophrenia spectrum and bipolar disorder but increases after treatment in bipolar disorder. Levels of apolipoprotein D were not changed by treatment. Hence changed apolipoprotein E could be involved in abnormalities in lipid homeostasis in some subjects with psychiatric diseases.

Increased levels of serotonin 2A receptors and serotonin transporter in the CNS of neuregulin 1 hypomorphic/mutant mice.

Changes in neuregulin 1 expression have been reported in the CNS from subjects with schizophrenia. As neuregulin 1 is important in cortical development we postulated that changes in neuregulin 1 expression may contribute towards changes in cholinergic, glutamatergic and serotonergic markers that are well documented in the CNS of subjects with that disorder. To begin to test this hypothesis, we used in situ radioligand binding to measure levels of muscarinic M1/M4 receptors, the kainate receptor, the NMDA receptor, the serotonin 2A receptor, the serotonin 1A receptor and the serotonin transporter in the CNS from heterozygous transmembrane domain neuregulin 1 mutant mice.

Treatment with haloperidol and diazepam alters GABA(A) receptor density in the rat brain.

A significant body of data suggests that GABA(A) receptors are altered in the CNS of subjects with schizophrenia. However, subjects with schizophrenia are treated with antipsychotic drugs and, in some cases, antipsychotic drugs and benzodiazepines. It has therefore been suggested that the changes in GABA(A) receptors in the CNS of subjects with schizophrenia are due to such drug treatments.

Inhibitory control and spatial working memory in Parkinson's disease.

Patients with Parkinson's disease (PD) have difficulty performing tasks relying on inhibitory control and working memory, functions of the prefrontal cortex. Eye movement paradigms can be used to investigate basic sensorimotor functions and higher order cognitive aspects of motor control. This study investigated inhibitory control and spatial working memory in the saccadic system of 13 individuals with mild-moderate PD and 13 age-matched controls.

The voices acceptance and action scale (VAAS): Pilot data.

Acceptance and mindfulness methods that emphasise the acceptance rather than control of symptoms are becoming more central to behavioural and cognitive therapies. Acceptance and Commitment Therapy (ACT) is the most developed of these methods; recent applications of ACT to psychosis suggest it to be a promising therapeutic approach. However, investigation of the mechanisms of therapy within this domain is difficult because there are no acceptance-based measures available specifically for psychotic symptoms.

CNS 14-3-3zeta: changes with sex but not psychiatric diagnoses or psychotropic drug treatment.

mRNA for 14-3-3zeta, an abundant signalling protein in human CNS, is reported as decreased or unchanged in cortex from subjects with schizophrenia. Addressing this dichotomy, using Western blot analyses, we measured levels of 14-3-3zeta proteins in cortex and caudate nucleus from subjects with schizophrenia, bipolar disorder, age/sex matched controls and in analogous CNS regions from rats treated with psychotropic drugs. Anti-14-3-3zeta antibody bound to three proteins (molecular weights: 27, 54 and 70 kDa), in all CNS tissue.

Packaging of prions into exosomes is associated with a novel pathway of PrP processing.

Prion diseases are fatal, transmissible neurodegenerative disorders associated with conversion of the host-encoded prion protein (PrP(C)) into an abnormal pathogenic isoform (PrP(Sc)). Following exposure to the infectious agent (PrP(Sc)) in acquired disease, infection is propagated in lymphoid tissues prior to neuroinvasion and spread within the central nervous system. The mechanism of prion dissemination is perplexing due to the lack of plausible PrP(Sc)-containing mobile cells that could account for prion spread between infected and uninfected tissues.

Differential effects of antipsychotic drugs on serotonin-1A receptor-mediated disruption of prepulse inhibition.

Serotonin-1A (5-HT(1A)) receptors have been implicated in the symptoms of schizophrenia. However, there is limited in vivo evidence for an interaction of antipsychotic drugs with 5-HT(1A) receptor-mediated behavioral effects. We therefore investigated in rats the action of several antipsychotic drugs on prepulse inhibition (PPI), a measure of sensorimotor gating that is deficient in schizophrenia.

Metals and Alzheimer's disease.

There is increasing evidence to support a role for both the amyloid beta-protein precursor (AbetaPP) and its proteolytic fragment, amyloid beta (Abeta), in metal ion homeostasis. Furthermore, metal ions such as zinc and copper can interact with both AbetaPP and Abeta to potentiate Alzheimer's disease by participating in the aggregation of these normal cellular proteins and in the generation of reactive oxygen species. In addition, metal ions may interact on several other AD-related pathways, including those involved in neurofibrillary tangle formation, secretase cleavage of AbetaPP and proteolytic degradation of Abeta.

La lunga attesa: towards a molecular approach to neuroimaging and therapeutics in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are Aβ amyloid plaques, neurofibrillary tangles (NFT), synaptic loss and reactive gliosis. Current diagnosis of AD is made by clinical, neuropsychologic, and neuroimaging assessments.