Gavin P. Reynolds

Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains

Abstract: The regional distributions of iron, copper, zinc, magnesium, and calcium in parkinsonian brains were compared with those of matched controls. In mild Parkinsons disease (PD), there were no significant differences in the content of total iron between the two groups, whereas there was a significant increase in total iron and iron (III) in substantia nigra of severely affected patients. Although marked regional distributions of iron, magnesium, and calcium were present, there were no changes in magnesium, calcium, and copper in various brain areas of PD. The most notable finding was a shift in the iron (II)/iron (III) ratio in favor of iron (III) in substantia nigra and a significant increase in the iron (III)‐binding protein, ferritin. A significantly lower glutathione content was present in pooled samples of putamen, globus pallidus, substantia nigra, nucleus basalis of Meynert, amygdaloid nucleus, and frontal cortex of PD brains with severe damage to substantia nigra, whereas no significant changes were observed in clinicopathologically mild forms of PD. In all these regions, except the amygdaloid nucleus, ascorbic acid was not decreased. Reduced glutathione and the shift of the iron (II)/iron (III) ratio in favor of iron (III) suggest that these changes might contribute to pathophysiological processes underlying PD.

Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain.

Significant differences in the content of iron (III) and total iron were found in post mortem substantia nigra of Parkinsons disease. There was an increase of 176% in the levels of total iron and 255% of iron (III) in the substantia nigra of the parkinsonian patients compared to age matched controls. In the cortex (Brodmann area 21), hippocampus, putamen, and globus pallidus there was no significant difference in the levels of iron (III) and total iron. Thus the changes in total iron, iron (III) and the iron (II)/iron (III) ratio in the parkinsonian substantia nigra are likely to be involved in the pathophysiology and treatment of this disorder.

Frontal Cortical and Left Temporal Glutamatergic Dysfunction in Schizophrenia

Abstract: Glutamatergic mechanisms have been investigated in postmortem brain samples from schizophrenics and controls. D‐[3H]Aspartate binding to glutamate uptake sites was used as a marker for glutamatergic neurones, and [3H]kainate binding for a subclass of postsynaptic glutamate receptors. There were highly significant increases in the binding of both ligands to membranes from orbital frontal cortex on both the left and right sides of schizophrenic brains. The changes are unlikely to be due to antemortem neuroleptic drug treatment, because no similar changes were recorded in other areas. A predicted left‐sided reduction in D‐[3H]aspartate binding was refuted at 5% probability, but not at 10%. Previously reported high concentrations of dopamine in left amygdala were strongly associated with low concentrations of D‐[3H]aspartate binding in left polar temporal cortex in the schizophrenics. The findings are compatible with an overabundant glutamatergic innervation of orbital frontal cortex in schizophrenia. The results also suggest that schizophrenia may involve left‐sided abnormalities in the relationship between temporal glutamatergic and dopaminergic projections to amygdala.

Association of antipsychotic druginduced weight gain with a 5-HT2C receptor gene polymorphism

A side-effect of treatment with antipsychotic drugs for schizophrenia is increased body fat, which leads to further morbidity and poor adherence to treatment. The 5-hydroxytryptamine 2C receptor (5-HT2C) has been associated with this effect; we aimed to establish whether a genetic polymorphism of the promoter region of this receptor affects weight gain after drug treatment in first-episode patients with schizophrenia. We noted significantly less weight gain in patients with the -759T variant allele (p=0.0003) than in those without this allele, who were more likely to have substantial (>7%) weight gain (p=0.002). We have identified a genetic factor that is associated with antipsychotic drug-induced weight gain.

Neurochemical characteristics of early and late onset types of Alzheimer's disease.

Brains of 49 patients who had died with Alzheimers disease and 54 controls were examined. The Alzheimer group exhibited noticeably reduced activity of the cholinergic marker enzyme choline acetyltransferase in the cerebral cortex, but cortical concentrations of noradrenaline, gamma-aminobutyric acid, and somatostatin were also significantly reduced. Analysis of the results according to age at death showed that the older patients, dying in their 9th and 10th decades, had a relatively pure cholinergic deficit confined to temporal lobe and hippocampus, together with a reduced concentration of somatostatin confined to temporal cortex. By contrast, the younger patients, dying in their 7th and 8th decades, had a widespread and severe cholinergic deficit together with the abnormalities of noradrenaline, gamma-aminobutyric acid, and somatostatin, and the younger patients accounted for most of the abnormalities in these systems observed in the overall group. Comparison of the young subjects with Alzheimers disease with the older controls did not support the concept of Alzheimers disease representing an acceleration of the aging process. These results suggest that Alzheimers disease in people aged under 80 may represent a distinct form of presenile dementia which differs in important respects from the dementia of old age.

A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia

Neuropathological studies have demonstrated deficits of GABAergic interneurons in the hippocampus in schizophrenia. and selective deficits in some GABAergic sub-populations defined by calcium-binding proteins (CBPs) have been reported in the cortex in schizophrenia. In the present study, the relative densities of cells immunoreactive for the CBPs parvalbumnin (PV) and calretinin (CR) were determined in hippocampal tissue sections taken from patients with schizophrenia, bipolar disorder and major depression and from matched control subjects (15 per group). No significant difference in the density of CR-immunoreactive neurons was found between subject groups. Relative to normal controls, schizophrenic patients showed a significant and profound deficit in the relative density of PV-immunoreactive neurons in all hippocampal sub-fields. These reductions were more apparent in male than female schizophrenic patients, and were unrelated to antipsychotic drug treatment, age or duration of illness. The density of PV-immunoreactive neurons did not differ significantly from controls in the depression group, although a trend toward decreased relative density of PV-immunoreactive neurons was apparent in bipolar disorder that reached significance in one sub-field. The findings provide further evidence to support a profound and selective abnormality of a sub-population of GABAergic neurons in the hippocampus in schizophrenia.

Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins.

BACKGROUND Postmortem studies have provided evidence for abnormalities of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia, including deficits of GABA-containing interneurons. The calcium-binding proteins parvalbumin, calbindin, and calretinin can be used as markers for specific subpopulations of cortical GABAergic interneurons. METHODS Following our previous observation of a reduction in the density of parvalbumin- but not calretinin-immunoreactive cells in the prefrontal cortex (Brodmann area 10) in schizophrenia, we have quantified the laminar density of neurons immunoreactive for the calcium-binding proteins parvalbumin, calbindin, and calretinin in a further prefrontal cortical region (Brodmann area 9) in patients with schizophrenia, bipolar disorder, major depression, and in matched control subjects (each group n = 15). RESULTS Initial statistical analysis revealed reductions in the total cortical density of parvalbumin- and calbindin- but not calretinin-immunoreactive neurons in schizophrenia relative to control subjects. Further analysis comparing individual laminar densities between groups indicated that, following correction for multiple comparisons, only a reduction in calbindin-immunoreactive neurons in cortical layer II in the schizophrenic group attained statistical significance. CONCLUSIONS These findings suggest that deficits of specific GABAergic neurons, defined by the presence of calcium-binding proteins, are present in schizophrenia. Trends toward similar reductions are observed in bipolar disorder.

Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer's, Parkinson's, and Huntington's diseases

Because dopamine D2 receptors are known to be elevated in schizophrenic brain striata, this study examined whether a similar dopamine receptor elevation occurred in other diseases including neuroleptic-treated Alzheimers and Huntingtons diseases. The average D1 density in postmortem striata from Alzheimers patients was 17.6 +/- 0.1 pmol/g, similar to an age-matched control density of 16.6 +/- 0.4 pmol/g. The average D1 density in schizophrenia patients was 19.0 +/- 0.6 pmol/g, similar to the age-matched control density of 17.9 +/- 0.6 pmol/g. In Parkinsons disease patients, however, the D1 receptor density was elevated, with values of 22.8 +/- 1.2 pmol/g (in patients not receiving L-DOPA) and 19.6 +/- 1.5 pmol/g (in patients receiving L-DOPA) compared to the age-matched control density of 16.0 +/- 0.4 pmol/g. The D2 receptors in Alzheimers striata averaged 13.4 +/- 0.6 pmol/g (in patients who had not received neuroleptics), almost identical to the control density of 12.7 +/- 0.3 pmol/g. The average D2 density in neuroleptic-treated Alzheimers striata was 16.7 +/- 0.7 pmol/g, an elevation of 31%, the individual values of which had a normal distribution. In Parkinsons disease patients, the D2 densities were elevated in tissues from patients not receiving L-DOPA (19.9 +/- 1.5 pmol/g in putamen and 14.8 +/- 1.2 pmol/g in striatum) compared to the age-matched control values of 13.0 +/- 0.4 pmol/g and 12.6 +/- 0.3 pmol/g, respectively. In Huntingtons disease patients, the D2 density averaged 7.5 +/- 0.4 pmol/g in patients who had not received neuroleptics, but was 10.3 +/- 0.6 pmol/g in those who had. Although all of the D1 and D2 densities in each of the above diseases and subgroups revealed a normal distribution pattern, the D2 densities in schizophrenia displayed a bimodal distribution pattern, with 48 striata having a mode at 14 pmol/g, and the other 44 striata having a mode at 26 pmol/g. Thus, compared to the neuroleptic-induced and unimodal elevations in D2 of 31% in Alzheimers disease and 37% in Huntingtons disease, the schizophrenic striata with a mode of 26 pmol/g (105% above control) appear to contain more D2 receptors than can be accounted for by the neuroleptic administration alone.

Metabolic side effects of antipsychotic drug treatment - pharmacological mechanisms.

Obesity and metabolic syndrome, with increased risk of eventual cardiovascular disease and type II diabetes, are significant problems for patients receiving antipsychotic drugs and are likely contribute to their decreased life expectancy. Several drug-related mechanisms may contribute to these problems, including effects both influencing food intake and on glucose and lipid metabolism. The metabolic consequences of different antipsychotic drugs vary substantially; these variations reflect differences in receptor pharmacology and provide clues as to the underlying pharmacological mechanisms. The two drugs with the greatest effects on body weight, olanzapine and clozapine, also have high affinity for the 5-HT2C and histamine H1 receptors, which implicate these receptors in antipsychotic-induced weight gain, while peripheral M3 muscarinic receptor antagonism as well as central 5-HT2C effects may contribute to obesity-independent diabetes. Other receptor mechanisms may have additive or synergistic effects; dopamine D2 receptor antagonism can enhance 5-HT2C-mediated effects on food intake, as well as influencing lipid and glucose metabolism via disinhibition of prolactin secretion. Pharmacogenetic associations of drug-induced weight gain with 5-HT2C receptor and leptin gene polymorphisms, among others, have provided further clues. Elevated leptin secretion in the absence of a decrease in food intake indicates drug-induced leptin insensitivity in the hypothalamus. The minimal weight gain seen with ziprasidone and aripiprazole may reflect their having further pharmacological effects that protect against changes in food intake and related metabolic factors. Understanding the pharmacology of metabolic consequences of current antipsychotic drug treatment is clearly the key to developing improved pharmacotherapies that avoid these problematic and limiting adverse effects.

Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis.

Objectives Weight gain, leading to further morbidity and poor treatment adherence, is a common consequence of treatment with antipsychotic drugs. Two recent studies in the same cohort of Chinese Han subjects have shown that polymorphisms of the promoter regions of both the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor and the leptin genes, are associated with antipsychotic-induced weight gain over 10 weeks. We have investigated whether these effects remain true in a Caucasian population and following longer term treatment. Methods Seventy-three Spanish caucasian patients with a first-episode psychosis and initially drug-naive were genotyped for the 5-HT2C receptor −759C/T and leptin −2548A/G polymorphisms. Body mass index and plasma leptin levels were monitored after 6 weeks, 3 months and 9 months of antipsychotic treatment. Results Patients with the −759T variant allele showed significantly less weight gain than those without this allele. This effect held true in the smaller group of patients receiving olanzapine. The −2548 leptin polymorphism was not associated with short-term (6 week and 3 month) weight increases but did show significant association with 9-month antipsychotic-induced weight gain. The 5-HT2C −759 genotype was significantly associated with pre-treatment plasma leptin levels. Conclusions These findings confirm the importance of two genetic factors associated with long-term antipsychotic-induced weight increases in schizophrenia, and implicate a role for leptin in the 5-HT receptor-mediated weight regulation.