G. B. Steventon

Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson's and Alzheimer's disease

Elevated plasma cysteine to sulphate ratios were found in patients with Motor neurone disease (MND), Parkinsons disease (PD) and Alzheimers disease (AD). Cysteine and sulphate were measured by colourimetric methods. Following recent discovery of a defect in sulphoxidation and sulphation of xenobiotics in these diseases, this finding confirms that endogenous sulphur metabolism is disturbed. The mean cysteine:sulphate ratios (x 10(3] in fasting early morning plasma were 506, 521 and 477 for MND, PD and AD whereas it was 96 for normal controls (P less than 0.001). This excess of cysteine thiol groups may interfere with neural protein function. The deficiency of sulphate ions may lead to reduced xenobiotic detoxification.

Plasma levels of neuroexcitatory amino acids in patients with migraine or tension headache

Plasma amino acids were analysed in patients with migraine with (9) and without (80) aura, in patients with tension headache (14) and in controls (62). The neuroexcitatory amino acids glutamic acid, glutamine, glycine, cysteic acid and homocysteic acid were elevated in migraine patients while total thiols (cysteine/cystine) were reduced. Patients with tension headache had values which were similar to those of controls. Tryptophan was elevated in migraine patients without aura only. Studies on two patients showed that the raised resting excitatory amino acid levels became still further elevated during a migraine attack. These results show that high concentrations of neurotransmitter amino acids occur normally in migraine patients and suggest that this profile may be a contributory factor in migraine attacks. Tension headache, however, has different biochemical parameters.

S-METHYLATION IN MOTORNEURON DISEASE AND PARKINSON'S DISEASE

Thiolmethyltransferase activity has been measured in newly diagnosed, untreated patients with idiopathic Parkinsons disease and motorneuron disease, and in normal volunteers. In Parkinsonian patients, mean thiolmethyltransferase activity was low (300 U/mg protein [SD 96]) compared with that in controls (947 [409]), whereas activity was high in patients with motorneuron disease (2077 [825]).

Metabolism of low-dose paracetamol in patients with chronic neurological disease

1. Low dose (500 mg) paracetamol (acetaminophen) was administered to patients with Parkinsons disease, motor neurone disease and to age-matched controls. 2. At this low dose level the controls excreted proportionately more sulphate and less glucuronide conjugate than has been reported for administration of 1000 mg of paracetamol. 3. Both groups of patients with chronic neurological disease excreted decreased amounts of paracetamol sulphate (control mean 11.2 +/- 5.4% dose; Parkinsons disease 3.9 +/- 3.7%; motor neurone disease, 5.0 +/ 4.1%). 4. The mean ratio of excretion of paracetamol sulphate/paracetamol glucuronide was 5.6 +/- 11.7 in controls, but 1.1 +/- 1.7 and 1.2 +/- 1.7 in Parkinsons disease and motor neurone disease respectively. These differences are statistically significant (p less than 0.001).

XENOBIOTIC METABOLISM IN MOTORNEURON DISEASE

Debrisoquine, carbocysteine, and paracetamol were selected as safe drugs to investigate the ability of the livers microsomal system to oxidise carbon, oxidise sulphur, and conjugate sulphate in patients with motor neuron disease (MND), other hospital patients, and healthy volunteers. Subjects with poor sulphur-oxidising and sulphur-conjugating activities were heavily over-represented in the MND group.

Platelet monoamine oxidase-B activity in Parkinson's disease

SummaryPlatelet MAO-B levels have been investigated in seventeen consecutively diagnosed and previously untreated patients with idiopathic Parkinsons disease using the non-hydroxylated catecholamine, β-phenylethylamine, as substrate. Patients with Parkinsons disease had MAO-B activity levels that were considerably higher than sex and age matched normal controls or patients with Motor neurone disease or Myasthenia gravis.

Monoamine oxidase substrates in Parkinson's disease

Platelet MAO-B activity was determined in control and Parkinsons disease (PD) patients using dopamine as the substrate and was found to be significantly reduced in PD platelets compared to controls. These results have been discussed in relation to published results using non-hydroxylated, mono-hydroxylated and di-hydroxylated aromatic amines as substrates for platelet MAO-B. They indicate a substrate variation relative activity defect in platelet MAO-B from PD patients

Metabolic biomarkers of Parkinson's disease

Enzymic systems involved with metabolism of foreign chemicals, xenobiotics, have been studied in Parkinsons disease. Enzymes involved with sulphur oxidation and methylation are under‐active. Cysteine levels are high and sulphate levels low. Differences in the activity of the enzyme monoamine oxidase‐B are evident. Pathways involved with N‐methylation of pyridines are different from controls leading to a rise in potentially toxic N‐methylated derivatives.

Pathways of cysteine metabolism in MND/ALS

Analysis of plasma from MND/ALS patients has shown no significant differences in metabolism of cysteine derivatives, although a sub-set of the population has raised glutamate values. Cysteine dioxygenase was found to have reduced activity in vitro, consistent with previous findings of a high plasma cysteine/sulphate ratio.

Hereditary variation of liver enzymes involved with detoxification and neurodegenerative disease

SummaryEnzymes involved with the metabolic transformation of xenobiotics have recently been studied in patients with the neurodegenerative diseases, Alzheimers disease, Parkinsons disease and motor neurone disease. Defects were detected in sulphur pathways and also, in the case of Parkinsons disease, in monoamine oxidase B. The possibility exists that the ability to cope safely with endogenous and exogenous substances which have neurotoxic properties is important in the pathogenesis of these diseases. Potentially such individuals could be identified preclinically and these diseases postponed by reduction in the load of toxin or modification of the relevant enzymic activity.