Celia M. Yates

Catecholamines and cholinergic enzymes in pre-senile and senile Alzheimer-type dementia and down's syndrome

Noradrenaline, dopamine, homovanillic acid (HVA), choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) levels were measured in post-mortem brains from 8 cases of pre-senile Alzheimer-type dementia (ATD), 5 cases of senile ATD, 4 cases of Downs syndrome aged 53-57 years, one 27-year-old case of Downs syndrome and 13 controls. In the controls, the concentration of noradrenaline in hypothalamus (P less than 0.05) and mamillary body (P less than 0.02) decreased with age. Compared with age-matched controls, noradrenaline levels in these areas were more markedly reduced in pre-senile ATD (P less than 0.01), the 53-57-year-old cases of Downs syndrome (P less than 0.001) and in the 27-year-old Downs, than in senile ATD (hypothalamus P less than 0.05, mamillary body, n.s.). Dopamine and HVA concentrations in caudate nucleus were unaltered in pre-senile or senile ATD but dopamine was decreased (P less than 0.01) in the older cases, although not in the 27-year-old case, of Downs syndrome. In the olfactory tubercle in ATD the level of HVA was unaltered but the activity of ChAT was decreased (P less than 0.01). ChAT activity was reduced in pre-senile ATD (P less than 0.001), the older Downs cases (P less than 0.01) but not the young Downs case, and senile ATD (P less than 0.001) in the temporal cortex and in pre-senile ATD (P less than 0.001) and the older Downs cases (P less than 0.001) but not senile ATD in the caudate nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)

Enzyme Activities in Relation to pH and Lactate in Postmortem Brain in Alzheimer-Type and Other Dementias

Abstract: Phosphate‐activated glutaminase, glutamic acid decarboxylase, pyruvate dehydrogenase, succinic dehydrogenase, pH, and lactate were measured in frontal cortex and caudate nucleus of postmortem brains from cases of Alzheimer‐type dementia (ATD), Downs syndrome, Huntingtons disease, and one case of Picks disease, as well as from sudden death and agonal controls. Lactate levels were higher and pH, phosphate‐activated glutaminase, and glutamic acid decarboxylase levels were lower in the agonal controls than in the sudden death controls. Phosphate‐activated glutaminase and glutamic acid decarboxylase were correlated with tissue pH and lactate, and also were reduced by in vitro acidification, suggesting that the low activities of these enzymes in agonal controls were related to decreased pH consequent upon lactate accumulation. Compared with control tissues at the same pH, phosphate‐activated glutaminase and glutamic acid decarboxylase were unaltered in ATD and Downs frontal cortex and reduced in Huntingtons caudate nucleus, and glutamic acid decarboxylase was reduced in Huntingtons frontal cortex. These data suggest that GABAergic neurons are not affected in ATD and confirm the GABAergic defect in Huntingtons disease. Pyruvate dehydrogenase and succinic dehydrogenase activities were the same in agonal controls and sudden death controls and were unaffected by acid pH and lactate in vitro, and pyruvate dehydrogenase was not correlated with pH or lactate. Reduced pyruvate dehydrogenase in frontal cortex of individual ATD, Downs, and Picks cases. and in the caudate nucleus of Huntingtons and Downs cases, was accompanied by gliosis/neuron loss. We conclude that decreased pyruvate dehydrogenase reflects neuronal loss.

The treatment of depression in general practice: a comparison of L-tryptophan, amitriptyline, and a combination of L-tryptophan and amitriptyline with placebo

One hundred and fifteen patients from 5 general practices participated in a 12-week, double-blind study comparing L-tryptophan, amitriptyline, L-tryptophan-amitriptyline combination and placebo in the treatment of depression. Analysis of total score on the Hamilton Depression Scale and a global rating of depression showed that all 3 active treatments were more effective than placebo. Significantly more patients were withdrawn as treatment failures in the placebo group compared with the active treatment groups. Side-effects necessitated withdrawal of more patients from the amitriptyline group than from the other active treatment groups, but this difference was not significant. Plasma amitriptyline and nortriptyline levels were similar in the amitriptyline and combined treatment groups. Standard haematological and biochemical profiles did not alter significantly in any group, but mean heart rate was significantly increased in patients receiving amitriptyline. There was no change in free or total plasma tryptophan concentration with treatment or on remission of symptoms.

Distribution of phosphate-activated glutaminase, succinic dehydrogenase, pyruvate dehydrogenase and γ-glutamyl transpeptidase in post-mortem brain from Huntington's disease and agonal cases

The activity of phosphate-activated glutaminase was reduced throughout the brain of cases with longstanding illnesses (agonal controls) compared to cases dying suddenly. The reduction was less marked in cortical than sub-cortical areas, with the caudate nucleus occupying an intermediate position. In control brains succinic dehydrogenase and pyruvate dehydrogenase were little affected by the ante-mortem clinical state. Of 9 brain areas studied, only the caudate nucleus showed a reduction of phosphate-activated glutaminase and succinic dehydrogenase in Huntingtons disease greater than in agonal controls. The levels of succinic dehydrogenase and pyruvate dehydrogenase were highly correlated in frontal cortex and in caudate nucleus of Huntingtons disease and control brains. There was a significant reduction in pyruvate dehydrogenase mean activity and a significant increase in gamma-glutamyl transpeptidase mean activity in Huntingtons disease caudate nucleus. The level of pyruvate dehydrogenase significantly decreased and the level of gamma-glutamyl transpeptidase significantly increased with increasing duration of illness, possibly due to a progressive loss of neurons and increase in the density of glia in Huntingtons disease caudate nucleus.

DISTRIBUTION OF GLUCOCORTICOID AND MINERALOCORTICOID RECEPTOR MESSENGER-RNA EXPRESSION IN HUMAN POSTMORTEM HIPPOCAMPUS

Corticosteroids bind to hippocampal glucocorticoid (GR) and mineralocorticoid (MR) receptors, thereby affecting behaviour and neurochemical transmission. Rat hippocampus has high levels of both receptors and their messenger RNAs (mRNA), but there is little information on receptors in human brain. We used in situ hybridization to determine the distribution of GR and MR mRNA expression in human hippocampus. Frozen sections of human postmortem hippocampus (5 patients, 58-88 years old, without cerebral pathology) were postfixed in paraformaldehyde and hybridized with 35S-UTP-labelled cRNA probes (transcribed in vitro from human cDNA subclones) under stringent conditions. Control included hybridization with sense probes and heterologous cRNA competition studies. GR mRNA was highly expressed in dentate gyrus, CA3 and CA4, but levels were significantly lower in CA1 and CA2. MR mRNA was also very highly expressed in hippocampus, with significantly higher levels in dentate gyrus and CA2, CA3 and CA4 than CA1. Controls confirmed the specificity of hybridization and there was little hybridization of sense probes. High GR and MR mRNA expression is found in both rat and human hippocampus but the subregional distributions clearly differ between the species.

Thyrotropin-releasing hormone, luteinizing hormone-releasing hormone and substance P immuno-reactivity in post-mortem brain from cases of Alzheimer-type dementia and Down's syndrome.

Thyrotropin-releasing hormone (TRH), luteinizing hormone-releasing hormone (LH-RH), substance P immuno-reactivity and choline acetyltransferase activity (CAT) were measured in post-mortem brains from 6 cases of Alzheimer-type dementia (ATD), 3 cases of Downs syndrome and 6 controls and in spinal cords from two cases of ATD and two controls. The activity of CAT was lower in posterior and anterior grey matter of lumbar spinal cord from two cases of ATD than from two controls. No significant differences were observed in the levels of the 3 peptides in the ATD, Downs and control brains and spinal cords, even in areas of ATD and Downs brain in which there were significant reductions in the activity of CAT or concentration of noradrenaline. These results show that TRH, LH-RH and substance P are not affected in ATD and Downs syndrome either as a consequence of a direct effect on the peptidergic neurone or of a secondary effect related to the loss of CAT activity and noradrenaline.

Histological and biochemical studies on the retina of a new strain of dystrophic rat

Abstract A strain of pigmented dystrophic rats has been bred from albino dystrophic rats and pigmented sighted rats. The progress of retinal degeneration has been assessed histologically and biochemically (by estimation of RNA and DNA levels). The onset and progression of the lesion in the pigmented dystrophic rats were delayed by about one week compared with the albino dystrophic rats. It is concluded that the presence of pigment in the eye retards the degenerative process.

Regional brain 5-hydroxytryptamine levels are reduced in senile Down's syndrome as in Alzheimer's disease

5-Hydroxytryptamine (5-HT) and choline acetyltransferase (ChAT) were assayed in amygdala, cingulate cortex and caudate nucleus of post-mortem brains from 7 cases of Downs syndrome (6 with the neuropathological features of Alzheimers disease and one with no such features), 9 cases of Alzheimers disease and 12 controls. 5-HT was markedly reduced in all 3 areas of the pathologically affected Down brains, unaltered in the Down brain with no Alzheimer pathology and reduced in the amygdala and cingulate cortex of the Alzheimer brains. ChAT showed a similar pattern of reduction. These results supply biochemical evidence that 5-hydroxytryptaminergic, as well as cholinergic, neurons are reduced in Downs syndrome with Alzheimer pathology.

Glucocorticoid receptor gene expression is unaltered in hippocampal neurons in Alzheimer's disease

Excessive glucocorticoid levels increase the metabolic vulnerability of hippocampal neurons to a wide variety of insults. Since glucocorticoid hypersecretion occurs in Alzheimers-type dementia it has been proposed that a primary reduction in hippocampal glucocorticoid receptor expression leads to failure of feedback, hypercortisolemia and hence further neuronal loss. However, we have recently found that lesions of the cholinergic innervation of the hippocampus--known to be severely affected in Alzheimers disease--increase corticosteroid receptor gene expression in the rat hippocampus. We have now examined both glucocorticoid (GR) and mineralocorticoid (MR) receptor gene expression in individual neurons in human postmortem hippocampus, using in situ hybridization histochemistry in 5 patients with Alzheimers disease (81 +/- 3 years) and 7 controls (81 +/- 7 years) without neurological disease. The distribution and intensity of MR and GR mRNA expression in the hippocampus of Alzheimers disease were similar to that in control tissue, with high expression in dentate gyrus and CA2-4, but significantly lower expression in CA1. In a separate group of patients with Alzheimers disease we found significantly increased 24 h integrated plasma cortisol levels (59% greater than age-matched controls) and reduced cortisol-binding globulin (21% lower). These data do not suggest a primary deficiency of biosynthesis of hippocampal corticosteroid receptors in Alzheimers disease. The maintenance of hippocampal GR and MR gene expression, in the face of an increased glucocorticoid feedback signal, may reflect loss of the cholinergic innervation.

Neurochemical observations in a case of Pick's disease

Neurochemical markers of the activities of the cholinergic, gabaergic and dopaminergic systems were measured in post-mortem brain from a case of Picks disease. No marked changes were found in the activities of choline acetyltransferase, acetylcholinesterase, L-glutamic acid decarboxylase and the concentration of dopamine. In areas of brain showing no histological changes, muscarinic receptor binding was within the normal range. In the cerebral cortex, which exhibited the neuropathological features of Picks disease, the number of muscarinic cholinergic binding sites was much reduced, suggesting that the cortical neurones which are lost in Picks disease are cholinoceptive.