Helen Wilton-Cox

Alpha-1-acid glycoprotein in major depressive and eating disorders

Plasma alpha 1-acid glycoprotein (AGP) levels were measured in 49 subjects with major depressive disorder, 15 subjects with anorexia nervosa and 18 subjects with bulimia nervosa, together with age- and sex-matched controls. AGP levels were elevated in depression and bulimia compared to controls. They were particularly elevated in depressed subjects who proved unresponsive to treatment with a standard course of antidepressants. In the depressed subjects, elevated AGP levels returned to control levels after treatment whether or not treatment was successful. There was a correlation between AGP and post-dexamethasone plasma cortisol levels in depression but not in bulimia and a correlation with age in depressed subjects only. There was no correlation between AGP values and tritiated imipramine binding parameters. Further studies are suggested to explore the issue of whether variations in AGP level are responsible for the abnormalities in platelet 5HT uptake and tritiated imipramine binding that have been reported in depression or for treatment non-response.

Changes in intraneuronal lipopigment in Alzheimer's disease

Brains were examined from 22 patients with Alzheimers disease (AD) (mean age 80.5, S.D. 11.5) and were compared with brains from 20 nondiseased subjects (mean age 81.1, S.D. 10.2). Intraneuronal lipopigment in all layers of a region of the superior frontal cortex was identified by fluorescence microscopy. The areas enclosed by the outlines of discrete regions of lipopigment autofluorescence were measured and assigned to a range of size categories. AD was associated with significant (p less than 0.05) decreases in the mean number (per neuron) of discrete regions of yellow lipopigment autofluorescence in the three smallest size categories and a significant increase in one of the larger size categories. Also, AD was associated with a significant decrease in the mean number (per neuron) of discrete regions of lipopigment autofluorescence (p less than 0.001). Significant (p less than 0.05) correlations were obtained between the Blessed dementia score (obtained within 2 years of death) and these lipopigment variables. The changes in neuronal lipopigment in AD may reflect an increased rate of lipopigment formation related to membrane and lysosomal abnormalities.

The morphology of lipopigment in rat Purkenje neurons after chronic acetyl-l-carnitine administration: A reduction in aging-related changes

The aging-related accumulation of neuronal lipopigment is considered to be cellular debris from processes of renewal of cellular constituents, but it can also reflect cell damage and certain diseases. Acetyl-L-carnitine (AC) has been reported to reduce some morphological and behavioral associations of brain aging and the present study investigated the effects of 37 weeks of AC administration on lipopigment in rat Purkinje neurons. Lipopigment was identified by fluorescence microscopy and the area enclosed by an outline of each discrete region of lipopigment was measured. Acetyl-L-carnitine was associated with a significant (p = 0.05) reduction in the number of discrete lipopigment regions and there was a significant (p = 0.001) association of AC administration with numbers of lipopigment regions in various size categories. As AC administration was associated with a reduction in some of the aging-related morphological changes in lipopigment, this compound is a candidate for evaluation as a long-term prophylactic agent for the adverse effects of cerebral aging.

Platelet α2-adrenoceptors, defined with agonist and antagonist ligands, in depressed patients, prior to and following treatment

Saturation binding of the alpha 2-adrenoceptor antagonist, 3H-yohimbine, and displacement of 3H-yohimbine with the alpha 2-adrenoceptor agonist, UK-14,304, were performed concurrently in platelet membranes obtained from drug-free depressed patients and healthy volunteers. Where possible platelet binding was repeated in depressed patients following treatment. The number and affinity of 3H-yohimbine binding sites did not differ between controls and depressed patients, or when depressed patients were divided on the basis of endogenicity (Newcastle or RDC criteria) or dexamethasone test result. The proportion of alpha 2-adrenoceptor binding sites with high affinity for UK-14,304 and KD values for the two states of the receptor did not differ in the total sample of depressed patients compared to controls. The KD for both states of the receptor and the proportion of sites with high affinity for UK-14,304 was lower in RDC non-endogenous patients than RDC endogenous patients. Treatment did not alter the total number of alpha 2-adrenoceptors or the proportion of sites with high affinity for UK-14,304, but reduced the KD for 3H-yohimbine and the KD of UK-14,304 for the low affinity state of the alpha 2-adrenoceptor.

Lipopigment in rat hippocampal and Purkinje neurones after chronic phenytoin administration.

The accumulation of lipopigment may indicate ageing, certain diseases and cellular damage, while phenytoin, which has been claimed to cause selective clinical cerebellar dysfunction and degeneration, has been reported to produce increased lipopigment accumulation in rat Purkinje neurones. In the present study, 8 rats received phenytoin, 300 mg/kg/day for 20 weeks, and were compared with a control group of 9 rats in respect of lipopigment in Purkinje and hippocampal neurones. Neuronal lipopigment was identified by fluorescence microscopy. The results did not indicate that phenytoin administration was associated with an increase in the area corresponding to (i.e. within the outlines of) neuronal lipopigment in Purkinje neurones, although the relatively small number of animals limits the power of the study. However, in hippocampal neurones, a two-way analysis of variance for numbers of discrete regions of lipopigment demonstrated a significant interaction (P = 0.003) between, firstly, size categories of discrete regions of lipopigment and, secondly, phenytoin administration or a control procedure. In hippocampal neurones, phenytoin administration was accompanied by a decrease in the numbers of discrete lipopigment regions in the smaller size categories and an increase in the numbers in the larger size categories. This finding indicates the need for further investigation into the effects of phenytoin on brain regions other than the cerebellum, as intellectual deterioration may be related to chronic use of this drug.

The effects of ageing and a vitamin E-deficient diet on the lipopigment content of rat hippocampal and Purkinje neurones.

This study examined associations between a vitamin E-deficient diet, ageing and aspects of the morphology of neuronal lipopigment in rat hippocampal and Purkinje neurones. Groups of rats given a standard diet were killed at 6, 12, 18 and 25 months of age, while a group which had received a vitamin E-deficient diet from 1-18 months were killed at 18 months of age. Lipopigment within a neuronal cell body consists of a number of discrete regions of varying size. These were identified by fluorescence microscopy and a photograph for each individual neurone was projected onto paper, so that the outlines of the discrete regions of lipopigment could be drawn and subjected to morphometric measurements. Both ageing and vitamin E deficiency in relation to hippocampal neurones and vitamin E deficiency in relation to Purkinje neurones (in which ageing effects were not examined), were associated with a significant (< 0.05) increase in the mean total area (per rat) enclosed by the lipopigment outlines. For both vitamin E deficiency and ageing this increase was associated with both an increase in the number of relatively large discrete lipopigment regions and a decrease in the number of relatively small discrete lipopigment regions. The findings in relation to vitamin E deficiency could be explained by an increased rate of lipopigment formation, involving processes which also occur in ageing.

Alzheimers Disease: Distribution of Changes in Intraneuronal Lipopigment in the Frontal Cortex

Brains from 22 patients with Alzheimers disease (AD) and 20 non-diseased subjects were examined. Intraneuronal lipopigment in 2,440 nucleolated neurons throughout the depth of cortex was identified by fluorescence microscopy. In the AD brains, the mean total area per neuron of the outlines of lipopigment was significantly increased in the region adjacent to the brain surface (sixths 1-3), and analysis of variance showed a significant interaction between depth of cortex (in sixths) and AD for this lipopigment variable (p = 0.012). After relating this lipopigment variable to the size of neuronal bodies, the results indicate that this change occurs in pyramidal neurons, although other neuronal types may also be affected. At least one of three AD-related changes in lipopigment was found in each sixth of the depth of cortex.

Characteristics of neuronal lipofuscin in the superior temporal gyrus in Alzheimer's disease do not differ from non-diseased controls: a comparison with disease-related changes in the superior frontal gyrus

Neuronal lipofuscin characteristics in the superior temporal gyrus from 21 patients with Alzheimer’s disease (AD) and from 18 age-matched non-diseased subjects were compared with previously reported findings from the superior frontal gyrus. A discriminant function analysis of lipofuscin characteristics in the superior temporal gyrus did not provide a significant predictive level for cases whose diagnoses were correctly classified (56.4%, P=0.63). In contrast, AD-related decrease in the number of smaller lipofuscin regions in the neurons of the frontal gyrus was confirmed, and the same analysis of lipofuscin characteristics in this region gave a significant predictive level for membership of the AD group of 86.6% (P<0.001). The findings indicate that changes in neuronal lipofuscin related to AD, which may reflect an increased rate of lipofuscin formation, show differences between neocortical regions. This study provides additional information on the distribution of neuropathological characteristics in AD.

Effects of chronic chlorpromazine or lithium administration on ageing-related lipopigment in rat Purkinje neurones

Ageing-related accumulation of neuronal lipopigment is considered to be debris from processes of renewal of cellular constituents, but can also reflect cell damage and certain diseases. Chlorpromazine (an example of a class of drug chronically administered in psychiatric practice) has been reported to reduce neuronal lipopigment accumulation, and the present study investigated the effects of 28 weeks of chlorpromazine administration on lipopigment in rat Purkinje neurones. The effects of 26 weeks of lithium administration (also chronically administered in psychiatric practice) were also studied. Lipopigment was identified by fluorescence microscopy and the area enclosed by an outline of each discrete region of lipopigment was measured. While lithium administration was not associated with significant changes in lipopigment variables, chlorpromazine administration was associated with a significant (p=0.001) reduction in the number of discrete lipopigment regions and with significant (p=0.001) differences in the numbers of discrete lipopigment regions in various size categories. The findings are similar to those associated with the administration of acetyl-L-carnitine (which has been reported to reduce some morphological and behavioural associations of brain ageing) and are compatible with a reduction in the rate of lipopigment formation. This could reflect an adverse effect of chlorpromazine administration (i.e. reduced functional activity of neurones) or a beneficial effect (i.e. a reduction in ageing-related changes).