Striatal dopaminergic markers in dementia with Lewy bodies, Alzheimer's and Parkinson's diseases: rostrocaudal distribution.

Dementia with Lewy bodies (DLB) is a neuropsychiatric disease associated with extrapyramidal features which differ from those of Parkinson's disease, including reduced effectiveness of L-dopa and severe sensitivity reactions to neuroleptic drugs. Distinguishing Alzheimer's disease from DLB is clinically relevant in terms of prognosis and appropriate treatment. Dopaminergic activities have been investigated at coronal levels along the rostrocaudal striatal axis from a post-mortem series of 25 DLB, 14 Parkinson's disease and 17 Alzheimer's disease patients and 20 elderly controls. [(3)H]Mazindol binding to the dopamine uptake site was significantly reduced in the caudal putamen in DLB compared with controls (57%), but not as extensively as in Parkinson's disease (75%), and was unchanged in Alzheimer's disease. Among three dopamine receptors measured (D1, D2 and D3), the most striking changes were apparent in relation to D2. In DLB, [(3)H]raclopride binding to D2 receptors was significantly reduced in the caudal putamen (17%) compared with controls, and was significantly lower than in Parkinson's disease at all levels. D2 binding was significantly elevated at all coronal levels in Parkinson's disease compared with controls, most extensively in the rostral putamen (71%). There was no change from the normal pattern of D2 binding in Alzheimer's disease. The only significant alteration in D1 binding ([(3)H]SCH23390) in the groups examined was an elevation (30%) in the caudal striatum in Parkinson's disease. There were no differences in D3 binding, measured using [(3)H]7-OH-DPAT, in DLB compared with controls. A slight, significant decrease in D3 binding in the caudal striatum of Parkinson's disease (13%) patients and an increase in Alzheimer's disease (20%) in the dorsal striatum at the level of the nucleus accumbens were found. The concentration and distribution of dopamine were disrupted in both DLB and Parkinson's disease, although in the caudate nucleus the loss of dopamine in DLB was uniform whereas in Parkinson's disease the loss was greater caudally. In the caudal putamen, dopamine was reduced by 72% in DLB and by 90% in Parkinson's disease. The homovanillic acid : dopamine ratio, a metabolic index, indicated compensatory increased turnover in Parkinson's disease, which was absent in DLB despite the loss of substantia nigra neurons (49%), dopamine and uptake sites. These differences between DLB, Parkinson's disease and Alzheimer's disease may explain some characteristics of the extrapyramidal features of DLB and its limited response to L-dopa and severe neuroleptic sensitivity. The distinct changes in the rostrocaudal pattern of expression of dopaminergic parameters are relevant to the interpretation of the in vivo imaging and diagnosis of DLB.

Dopaminergic activities in the human striatum: rostrocaudal gradients of uptake sites and of D1 and D2 but not of D3 receptor binding or dopamine.

The human striatum, which receives dopaminergic innervation from the substantia nigra and ventral tegmental area (cell groups A8, A9 and A10), has structural and functional subdivisions both rostrocaudally and dorsoventrally. These relate to motor and non-motor origins of cortical projections and the specific areas of the substantia nigra and ventral tegmental area providing dopaminergic innervation. In the present study, we have evaluated the distribution of a number of dopaminergic parameters in the caudate, putamen and nucleus accumbens at separate coronal levels in a post mortem study in a series of elderly normal individuals aged 55-94 years, with analysis of the effect of post mortem variables. Dopamine D1 receptor density displayed a rostrocaudally declining gradient in the putamen but not in the caudate, such that at levels posterior to the anterior commissure, there was significantly lower D1 binding in the putamen compared to the caudate. The density of dopamine D2 receptors was similar in the putamen and caudate, increasing rostrocaudally. The density of dopamine uptake sites exhibited an increasing rostrocaudal gradient in the caudate, especially ventrally, but not in the putamen, where binding was more constant. The dopamine D3 receptor was concentrated in the ventral striatum, particularly the nucleus accumbens, although there was no evidence of a rostrocaudal gradient. With respect to striosome-matrix compartmentalization, there was no complete segregation, although D1 and D3 receptors were concentrated in striosomes, whereas D2 receptors and uptake sites showed higher density in the matrix. Levels of dopamine were similar in the caudate and putamen, and were significantly elevated at levels including the nucleus accumbens and the anterior commissure. Homovanillic acid and the metabolic index (homovanillic acid/dopamine ratio) were significantly higher in the putamen compared to the caudate, especially at levels from and caudal to the anterior commissure. These distributions of dopamine receptors and metabolic indicators, reflecting the different functional domains of the striatum, are relevant to the interpretation of current in vivo imaging of the dopamine transporter and receptors in neurological and psychiatric disorders. They provide information to assist in the detection of perturbations in expression, in specific diseases, at particular points on rostrocaudal, lateromedial and dorsoventral axes, a level of resolution beyond current neuroimaging capability.

Nigrostriatal dopaminergic activities in dementia with Lewy bodies in relation to neuroleptic sensitivity: comparisons with Parkinson's disease.

BACKGROUND: In dementia with Lewy bodies (DLB) mild extrapyramidal symptoms are associated with moderate reductions in substantia nigra neuron density and concentration of striatal dopamine. Many DLB patients treated with typical neuroleptics suffer severe adverse reactions, which result in decreased survival. METHODS: In a series of DLB cases, with and without neuroleptic sensitivity, substantia nigra neuron densities, striatal dopamine and homovanillic acid concentrations, and autoradiographic [3H]mazindol and [3H]raclopride binding (to the dopamine transporter and D2 receptor, respectively) were analyzed and compared to control and idiopathic Parkinson's disease cases. RESULTS: D2 receptors were up-regulated in neuroleptictolerant DLB and Parkinson's disease compared to DLB without neuroleptic exposure and controls. D2 receptors were not up-regulated in DLB cases with severe neuroleptic reactions. Dopamine uptake sites were reduced concomitantly with substantia nigra neuron density in Parkinson's disease compared to controls, but there was no significant correlation between substantia nigra neuron density and [3H]mazindol binding in DLB groups. There was no significant difference in substantia nigra neuron density, [3H]mazindol binding, and dopamine or homovanillic acid concentration between neuroleptic-tolerant and -sensitive groups. CONCLUSIONS: Failure to up-regulate D2 receptors in response to neuroleptic blockade or reduced dopaminergic innervation may be the critical factor responsible for neuroleptic sensitivity.

Dopamine and nicotinic receptor binding and the levels of dopamine and homovanillic acid in human brain related to tobacco use.

Reports of a reduction in the risk of developing Parkinson's disease and Alzheimer's disease in tobacco smokers, together with the loss of high-affinity nicotine binding in these diseases, suggest that consequences of nicotinic cholinergic transmission may be neuroprotective. Changes in brain dopaminergic parameters and nicotinic receptors in response to tobacco smoking have been assessed in this study of autopsy samples from normal elderly individuals with known smoking histories and apolipoprotein E genotype. The ratio of homovanillic acid to dopamine, an index of dopamine turnover, was reduced in elderly smokers compared with age matched non-smokers (P<0.05) in both the caudate and putamen. Dopamine levels were significantly elevated in the caudate of smokers compared with non-smokers (P<0.05). However there was no significant change in the numbers of dopamine (D1, D2 and D3) receptors or the dopamine transporter in the striatum, or for dopamine D1 and D2 receptors in the hippocampus in smokers compared with non-smokers or ex-smokers. The density of high-affinity nicotine binding was higher in smokers than non-smokers in the hippocampus, entorhinal cortex and cerebellum (elevated by 51-221%) and to a lesser extent in the striatum (25-55%). The density of high-affinity nicotine binding in ex-smokers was similar to that of the non-smokers in all the areas investigated. The differences in high-affinity nicotine binding between smokers and the non- and ex-smokers could not be explained by variation in apolipoprotein E genotype. There were no differences in alpha-bungarotoxin binding, measured in hippocampus and cerebellum, between any of the groups. These findings suggest that chronic cigarette smoking is associated with a reduction of the firing of nigrostriatal dopaminergic neurons in the absence of changes in the numbers of dopamine receptors and the dopamine transporter. Reduced dopamine turnover associated with increased numbers of high-affinity nicotine receptors is consistent with attenuated efficacy of these receptors in smokers. A decrease in striatal dopamine turnover may be a mechanism of neuroprotection in tobacco smokers that could delay basal ganglia pathology. The current findings are also important in the interpretation of measurements of nicotinic receptors and dopaminergic parameters in psychiatric conditions such as schizophrenia, in which there is a high prevalence of cigarette smoking.

Striatal dopaminergic loss without parkinsonism in a case of corticobasal degeneration.

Neurochemical analyses of post-mortem brain from cases of corticobasal degeneration are extremely rare although nearly 100 cases have been reported in the literature. We detail findings of neurotransmitter derangement in the basal ganglia of a case of neuropathologically confirmed corticobasal degeneration, who presented with dementia. The implications of severe neuronal loss in the substantia nigra and extremely low levels of dopamine and its metabolites in the striatum are considered in relation to the absence of an intrinsic extrapyramidal syndrome.

Serotonergic neurotransmission in the spinal cord and motor cortex of patients with motor neuron disease and controls: quantitative autoradiography for 5-HT1a and 5-HT2 receptors.

Serotonin 5-HT is a potent modulator of motor neuron excitability in the spinal cord. Serotonergic neurotransmission, because of its effects on glutamatergic excitation, may be relevant to the pathogenesis and therapy of motor neuron disease (MND). The human motor system was studied at two levels, spinal cord and motor cortex, by autoradiography for the 5-HT1A and 5-HT2 receptor subclasses. In addition, biochemical estimations of indole metabolites were performed in the spinal cord. Post mortem tissue from control cases and MND patients showed a reduction in 5-HT1A receptor binding in the cervical (p < 0.01) but not lumbar ventral horn in MND. 5-HT2 receptors were preserved in the ventral horn at both levels and were focally abundant around motor neuron somata. Tissue levels of 5-HT were unchanged in the spinal cord in MND. The metabolite 5-HIAA was increased in the cervical spinal cord in MND as was the molar ratio of 5HIAA:5-HT, implying that there may be an increased turnover of 5HT. In the motor cortex and premotor cortex the 5-HT1A receptor remained unchanged in MND. There was a 20% reduction in 5-HT2 receptor binding sites (p < 0.05) across all the cortical laminae with preservation of the normal pattern of laminar binding. These changes in two levels of the motor system in MND most likely represent physiological adaptations in the spinal cord and motor cortex rather than primary involvement of the serotonergic system in the pathogenesis of the disease.

Biological correlates of deliberate self-harm behaviour: a study of electroencephalographic, biochemical and psychological variables in parasuicide.

Clinical, electroencephalographic and biochemical variables were measured in 40 patients who attempted suicide and 27 age-matched controls. Patients had significantly higher scores for depression, hopelessness, neuroticism and psychoticism and lower scores for extraversion than controls. They also had significantly lower contingent negative variation (CNV), higher postimperative negative variation and lower whole blood serotonin values than controls. Within the patient group, vulnerability to parasuicide, as determined by previous or repeated acts of deliberate self-harm, was associated with higher scores for hopelessness and suicide intent, lower scores for extraversion and decreased CNV. Factor analysis revealed significant correlations between psychological variables and auditory evoked potential amplitudes for the vulnerable group. A profile of variables associated with increased risk of self-harm in patients presenting with attempted suicide is proposed from our data.

Effects of paroxetine on 5-HT-induced head twitches and phosphatidylinositol hydrolysis in mice.

Head-twitch response and phosphatidylinositol (PIP) hydrolysis in cortex and spinal cord were measured after single or chronic (21 days) administration of paroxetine to normal mice or to mice neonatally treated with 5,7-dihydroxytryptamine, a serotonergic neurotoxin. In normal animals, a down-regulation of 5-HT-receptor numbers after chronic paroxetine was suggested by the attenuation of head-twitch responses compared with a single dose. There was a concomitant decrease in PIP hydrolysis. In DHT-treated animals, although changes in behavioural responses were comparable to those in normals, PIP hydrolysis in cortex and spinal cord after chronic paroxetine increased significantly. These results demonstrate that head-twitch responses and PIP hydrolysis may not be mediated by the same receptor and that the effects of chronic administration of paroxetine depend on the functional state of the serotonergic pathways.

Measures of serotonin metabolism in anorexia nervosa.

Thirty-five consecutive attenders at a clinic specializing in anorexia nervosa were studied. All conformed to a DSM-III-R diagnosis for anorexia nervosa. In addition, 3 cases suffered from major depressive disorder and 9 from dysthymia. Blood from all patients was analysed for monoamine oxidase, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), tryptophan and platelet paroxetine binding. Findings showed that blood 5-HT was higher than normal in all patient groups, and was highest in those having affective disorder with anorexia nervosa. However, of the patients with anorexia nervosa alone, a subgroup having greatest weight loss had blood 5-HT levels significantly below all other groups. Lack of significant changes in other parameters compared with normal subjects points to the possibility of abnormal 5-HT storage or release.

Estimation of human blood plasma 5-hydroxyindoleacetic acid and homovanillic acid.

A method for simultaneous quantification of plasma homovanillic acid and 5-hydroxyindoleacetic acid has been developed, permitting more efficient neurochemical examinations of these often interrelated biogenic amine systems. Zinc sulphate and sodium hydroxide solutions were used for precipitating the protein in plasma prior to injection on the column. This technique allows for cleaner chromatography, greater sensitivity and high precision. The method uses high performance liquid chromatographic separations of these compounds on C18 reversed phase columns with electrochemical detection. The detailed results from controls and untreated parasuicide patients are given.

The relationship between response to fluoxetine, plasma drug levels, imipramine binding to platelet membranes and whole-blood 5-HT.

1) Thirty-four (34) out-patients with major depressive disorder as defined by Research Diagnostic Criteria were treated with fluoxetine in an open study. 2) All patients received 60 mg daily of the drug for between 18 and 21 days. 3) Of the 28 patients who completed the trial 21 showed improvement and 7 of these showed a marked change. 4) The 7 good responders had a higher fluoxetine:norfluoxetine ratio after three weeks treatment than the remaining patients; 6 of these patients were males. 5) All patients, irrespective of response, showed a decrease in imipramine binding and decrease in whole blood 5-hydroxytryptamine (5-HT) during the period of the study. 6) The response to the drug may be related to metabolism of fluoxetine.

5-HT receptor binding in post-mortem brain from patients with affective disorder.

Post-mortem brain tissue was obtained from a group of patients with well documented clinical histories of affective disorder. 5-Hydroxytryptamine-1 (5-HT1) and 5-HT2 receptor binding to homogenates of frontal cortex (Brodmann area 10) was measured using tritiated 5-HT and tritiated ketanserin respectively. 5-Hydroxyindoleacetic acid (5-HIAA) levels from the same brain samples were measured by reverse-phase high performance liquid chromatography with electrochemical detection. A tendency towards increased 5-HT receptor binding density in patients with major affective disorder was found compared to dysthymic disorder patients and normal controls. No relationship was found between receptor binding densities and metabolite values, nor were the differences in 5-HT binding correlated with time to autopsy, storage time prior to assay, or to clinical variables including DSM-III psychoticism/non-psychoticism and melancholia. Previous antidepressant drug histories were similar in the two patient groups and are unlikely to account for the findings. An increase in postsynaptic 5-HT2 receptor binding in major affective disorder is a possible pathophysiological mechanism which is compatible with the observed down-regulatory effect of antidepressant drugs (although not electroconvulsive therapy) on 5-HT2 sites. The methodological problems inherent in post-mortem studies in affective disorder are discussed.

Whole blood serotonin and plasma tryptophan using high-pressure liquid chromatography with electrochemical detection.

Methods are detailed for whole blood serotonin (5-HT), equivalent to platelet 5-HT, and plasma tryptophan. These assays may be carried out on the same blood sample which need be no more than 1 ml, are rapid, and avoid the difficulties, such as protein precipitation and fluorophor formation, encountered in other methods. The linearity of the methods is extensive and allows for accurate measurement of low concentrations. Data are given for normal humans and for patients receiving psychiatric treatment for depression.

Alaproclate--an open clinical study in depressive illness.

This open study of alaproclate points towards an antidepressant effect in a a relatively chronic and drug-resistant group of depressives. Five patients had an average improvement of more than 21 points on the Hamilton Rating Scale for Depression and six had an average improvement of seven points. Several patients had anticholinergic side effects, abnormal results in liver functional tests and faecal occult blood, but none were bad enough to require being taken off the drug and most side effects improved before the end of the trial. The biochemical results suggested that the responders and non-responders constituted two distinct biological groups. In the patients who responded well to treatment there were increases in Km values consistent with treatment. The Km and 5-HT values correlated strongly with plasma drug values. There was a strong correlation between Hamilton Rating scores in the 4th week and Km values in the 4th week, although there were only five cases. However, there were no significant relationships between improvement and any pretreatment value. These results are sufficiently promising to suggest that a controlled clinical trial would yield information on alaproclate as a therapeutic aid.

Decreased imipramine binding in the brains of patients with depressive illness.

The binding of tritiated imipramine was significantly reduced in the hippocampus and occipital cortex from a series of patients with depressive illness compared with age-matched patients with no psychiatric disorder. In contrast there was no change in imipramine binding in established cases of senile dementia of Alzheimer-type. Scatchard analysis indicated normal binding affinity but a reduction in the number of imipramine binding sites in depression. These observations parallel previous findings of decreased binding sites in platelets from depressed patients and suggest there may be an abnormality in the uptake mechanism for serotonin in depression.

Monoamine oxidase inhibitors and whole blood, platelet and plasma monoamine oxidase.

1. Whole lysed blood monoamine oxidase activity using benzylamine as substrate, represents an addition of platelet and plasma activity. 2. Enzyme activity measured in whole lysed blood in the presence of 10(-4)M pargyline gave a value equivalent to plasma monoamine oxidase, and by subtraction gives a value for platelet enzyme activity. 3. This method of measuring platelet and plasma monoamine oxidase activities from a single whole blood sample, has the advantage of not requiring physical separation of the blood fraction.