Lipopigment Changes in Purkinje Cells in Alzheimer's Disease.

Cerebellar tissue was examined from 22 patients with Alzheimer's disease (AD) and from an age-matched group of 20 non-diseased subjects. Intraneuronal lipopigment in the bodies of 1344 Purkinje cells (PCs) (32 per brain) was identified by fluorescence microscopy. The mean total area (per PC) of the outlines of discrete regions of lipopigment in a PC perikaryon for the AD-related group of PCs was significantly greater than the mean for the comparison group (p<0.001). Also, the two groups of PCs showed significant (

Alzheimer's disease: distribution of changes in intraneuronal lipopigment in the frontal cortex.

Brains from 22 patients with Alzheimer's 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.

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).

Changes in intraneuronal lipopigment in Alzheimer's disease.

Brains were examined from 22 patients with Alzheimer's 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 Purkinje 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.

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.

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.

Platelet alpha 2-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.

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.

Platelet [3H]imipramine and alpha 2-adrenoceptor binding in normal subjects during desipramine administration and withdrawal.

The effect of desipramine 150 mg daily on platelet [3H]imipramine and alpha 2-adrenoceptor binding sites was studied over a 6-week period and for 6 weeks after withdrawal. Modest (10%) increases in [3H]imipramine binding site densities during treatment were noted with a decrease between 1 and 4 weeks after withdrawal. No effect was found on alpha 2-adrenoceptors. Time of day appeared to have some effect on the results found. None of the [3H]imipramine binding site effects of desipramine, on treatment or following withdrawal, was comparable in magnitude to trait differences that were also found between subjects.

3H-imipramine binding to previously frozen platelet membranes from depressed patients, before and after treatment.

3H-imipramine binding in 39 drug-free patients with major depression and 44 healthy controls did not differ significantly between the two groups, in male or female subjects or in subgroups of depressed patients divided by endogenicity or dexamethasone suppression test result. 3H-imipramine binding in depressed patients drug-free for less than three weeks did not differ from those drug-free for longer intervals or from controls. A significant seasonal variation of 3H-imipramine Bmax was found, with lower values in summer and autumn. Treatment of depressed patients with imipramine or lofepramine for six weeks increased KD and Bmax. Methodological modification (in preparation and storage of platelets) does not explain the major differences in results between this study (using frozen platelets), a previous one (using freshly prepared platelets) and others in general, although it might contribute to the range of values reported.

Autofluorescence emission spectra of neuronal lipopigment in mucopolysaccharidosis (Sanfilippo's syndrome).

Characteristics of intraneuronal lipopigment in two siblings with Sanfilippo's syndrome are reported. A lipopigment emission spectrum probably reflects its composition and the (uncorrected) autofluorescence emission spectra results are compared with spectra from non-diseased tissue and from previously reported childhood-onset neuronal ceroidlipofuscinoses (ceroidoses), adult-onset ceroidosis (Kufs' disease) and animal ceroidoses. Values derived from the emission spectra from Sanfilippo's syndrome could be distinguished from those obtained from equivalent regions of non-diseased brains and were within the range of abnormal values previously reported from accumulations of pigment in various types of neuronal ceroidosis. Some abnormal lipopigment in Sanfilippo tissue was indistinguishable from some lipopigment in childhood-onset ceroidosis and in Kufs' disease. These results indicate that the intraneuronal lipopigment which accumulates to an abnormal extent in Sanfilippo's syndrome should not be termed "lipofuscin", which is a normal cerebral constituent, but "ceroid" to denote lipopigment with abnormal characteristics.

Pulpal response to a new visible light-cured composite restorative material: Fotofil.

A new visible light-cured composite resin, Fotofil, has been developed for the esthetic restoration of anterior teeth. The pulpal responses elicited by this material in unlined cavities and cavities lined with Dycal were compared with those elicited by a negative control consisting of modified zinc oxide-eugenol cement Notebec and a silicate cement Syntrex. The pulpal responses were evaluated in the permanent maxillary and mandibular incisors in vervet monkeys using labial Claterial in each monkey. Groups of 10 monkeys were killed at intervals of 2 days, and 2 and 8 weeks after restoration of the teeth. The most severe pulpal responses were elicited by the unlined Fotofil and Syntrex restorations at all three time intervals. The Dycal lined Fotofil restorations elicited a milder pulp response than the Nobetec at 2 days and 2 weeks. No pulpal response was elicited by the latter two materials at 8 weeks. These results clearly showed that Fotofil and Syntrex are irritant to the dental pulp up to 8 weeks. The placement of a Dycal liner beneath Fotofil restorations reduced the pulpal irritation elicited by this material to levels which were lower than those elicited by the Nobetec control at 2 days and 2 weeks.