The topography of nerve cell loss from the locus caeruleus in elderly persons.

A topographical analysis of nerve cell loss from the locus caeruleus in "mentally normal" old people shows cell loss to be uniformly diffuse throughout the whole nucleus with no preferential involvement of any one particular area. Such findings contrast with those of ours on Alzheimer's disease and suggest differing mechanisms underlying the cell loss of old age and Alzheimer's disease. Cell loss in Alzheimer's disease is thought to relate to primary pathogenetic events in terminal fields of cerebral cortex. In "normal" old age, cell loss may be determined by changes occurring at perikaryal level possibly in respect of the cytotoxic effects of noradrenaline degradation and neuromelanin accumulation.

Quantitative changes in cerebral cortical microvasculature in ageing and dementia.

Brains were obtained postmortem from 25 mentally normal patients aged 26 to 96 years and from 3 patients with Alzheimer's disease. Although the number of pyramidal nerve cells within frontal and temporal cortex decreased significantly with age, measures of capillary density correlated only weakly with age. Stronger correlations, however, were noted between measures of capillary density and number of pyramidal cells, irrespective of age or disease. Capillary measures did not differ in 6 of the mentally normal patients who showed a few plaques and tangles in their cortex from those of 6 other patients of similar age who did not show such changes. It is concluded that the extent of the capillary network in the cerebral cortex alters to match the number and activity of functioning nerve cells; changes in quantity of capillary occurring with age or Alzheimer's disease may, therefore, secondarily reflect a primary loss of nerve cells and do not form, per se, part of the degenerative process.

Changes in nerve cells of the nucleus basalis of Meynert in Alzheimer's disease and their relationship to ageing and to the accumulation of lipofuscin pigment.

The number of nerve cells in the nucleus basalis of Meynert in normally aged persons is reduced by 30% by 90 years of age and cytoplasmic RNA content and nucleolar volume by about 20%. In Alzheimer's disease the changes are greatly exacerbated, with the cell number being depleted by a further 60% and cytoplasmic RNA content and nucleolar volume by an extra 35%. Moreover, younger patients with Alzheimer's disease show a much greater difference from controls of the same age than do older patients; indeed, by 90 years of age the levels of these changes are similar in Alzheimer's disease and in old age alone. Lipofuscin content is increased to a similar extent with age in both Alzheimer's disease and control patients and was associated with loss of cytoplasmic RNA content and nucleolar volume in both groups. It is suggested that mechanisms which result in the accumulation of this pigment during life also lower the capability of cells of the nucleus basalis of Meynert to withstand disease pathogens, leading to a certain degree of change in old age alone and one which in other persons may be compounded by secondary factors giving the extreme degeneration of Alzheimer's disease.

Cell surface-associated keratan sulfate on normal and migrating corneal endothelium.

PURPOSE: To investigate cell surface-associated keratan sulfate on the corneal endothelium. METHODS: Immunolabeling techniques were used at the light, scanning, and transmission electron microscopic level to localize keratan sulfate on the corneal endothelium. The investigation included human, bovine, and rabbit corneal endothelia. A quantitative study of the relationship between cell size and keratan sulfate levels was conducted on normal bovine corneal endothelium. Changes in the distribution of keratan sulfate and chondroitin sulfate on endothelial cell surfaces were investigated on organ cultured bovine corneas during endothelial wound healing. Changes in the levels of keratan sulfate during endothelial wound healing were investigated in organ cultured human corneas and in vivo in rabbit corneas. Inhibition-enzyme-linked immunosorbent assay also was used to detect keratan sulfate in the aqueous humor. RESULTS: A variegated distribution of keratan sulfate was revealed on normal human, bovine, and rabbit corneal endothelia. Some cells had high levels of keratan sulfate on their surfaces whereas others, sometimes immediately adjacent, had little or none. Wound healing experiments resulted in changes of keratan sulfate levels on the migrating endothelial cells in bovine, human, and rabbit. In wounded organ cultured bovine corneas, there was a decrease in keratan sulfate levels and an increase in chondroitin sulfate levels on migrating endothelial cells. Keratan sulfate was detected in bovine aqueous humor. CONCLUSIONS: The pattern of occurrence of keratan sulfate and chondroitin sulfate on the corneal endothelial cells in normal and wounded cornea suggests that these glycosaminoglycans have differing roles in endothelial adhesion and migration.

Correlation between senile plaque and neurofibrillary tangle counts in cerebral cortex and neuronal counts in cortex and subcortical structures in Alzheimer's disease.

The quantitative relationship between the numbers of senile plaques and neurofibrillary tangles in the temporal cortex and the degree of atrophy and loss of nerve cells from this region and from cortically projecting areas such as the nucleus basalis of Meynert, locus coeruleus and raphe nucleus was investigated in 32 patients with Alzheimer's disease. Strong correlations were noted between cortical plaque and tangle counts and nerve cell atrophy and loss in all 4 areas, suggesting that the formation of plaques and tangles may be of primary pathogenic importance to the cortical and subcortical cell loss.

Loss of nerve cells from locus coeruleus in Alzheimer's disease is topographically arranged.

Serial sectioning of the locus coeruleus (LC) was employed to determine a topographic loss of nerve cells in patients with Alzheimer's disease (AD). Heaviest loss of nerve cells occurred in the central part of the LC which is thought to project to the temporal cortex and hippocampus, whereas least loss of cells occurred in the most rostral and caudal parts, thought to project to frontal and occipital regions of cortex, respectively. Such changes suggest that the primary damage to these nerve cells in AD occurs within their terminal fields and that perikaryal loss follows as a secondary retrograde change.

Saccharides of senile plaques and neurofibrillary tangles in Alzheimer's disease.

The contribution that oligosaccharides might make to the structure of the senile plaque and the neurofibrillary tangle was investigated using lectin histochemistry in 9 patients with Alzheimer's disease. One group of 4 lectins diffusely stained the neurites of senile plaques whereas two groups of 6 different lectins stained neurofibrillary tangles within neuronal perikarya and plaque neurites. Neuraminidase pretreatment abolished staining of tangles by one of these latter groups, but did not affect staining by the other group. Senile plaque core amyloid failed to stain with any lectin. It is concluded that oligosaccharides may contribute, but in different ways, to glycoprotein or glycolipid residues that form an integral part of the structure of the senile plaque and the neurofibrillary tangle.

The topography of cell loss from locus caeruleus in Alzheimer's disease.

A topographical analysis of nerve cell loss from locus caeruleus in Alzheimer's disease has shown that cell loss is confined to the dorsal areas and occurs uniformly throughout the rostrocaudal length of the locus. By contrast there is no significant cell loss from ventral parts of the locus, at any point along its rostrocaudal length. Dorsally located neurones of the locus project to cerebral cortex; ventrally located neurones to non-cortical areas such as basal ganglia, cerebellum and spinal cord. These data suggest that damage to nerve cells of locus caeruleus in Alzheimer's disease relates primarily to pathological events within their terminal fields, with perikaryal loss following as a secondary retrograde change. The senile plaque may represent the actual site of the damage to nerve terminals.

Some morphometric observations on the cerebral cortex and hippocampus in presenile Alzheimer's disease, senile dementia of Alzheimer type and Down's syndrome in middle age.

The frequency of senile plaques and neurofibrillary tangles and the number of pyramidal neurones and the volume of their nucleolus were measured in temporal cortex (middle temporal gyrus) and hippocampus (area h1) of 32 patients with Alzheimer's disease. Plaques and tangles were greatly increased in frequency in these patients while the pyramidal cell number was reduced (due to the effects of ageing plus disease) by a total of 78% in temporal cortex and 60% in hippocampus with nucleolar volume in surviving cells being reduced in total by 56% and 63%, respectively. These total losses did not correlate with patient age. However, when corrections for the effects of ageing alone were made on these total losses, the extent of pyramidal cell loss and decrease in nucleolar volume due solely to disease as well as the frequency of plaques and tangles were all found to correlate inversely with patient age for temporal cortex; in hippocampus only cell loss so related. The extent of nerve cell loss correlated with the reduction in nucleolar volume in temporal cortex but not in hippocampus. Correlations involving nerve cell loss and decreased nucleolar volume with plaque and tangle frequency were either weak or non-significant in both regions. The number of nerve cells and the volume of their nucleolus were less (when compared with age-matched control patients) in both temporal cortex and hippocampus, in the 6 middle aged patients with Down's syndrome, and match the corresponding values seen in 8 patients of similar age with Alzheimer's disease.

Topography of nerve cell loss from the locus caeruleus in middle aged persons with Down's syndrome.

A topographical analysis of nerve cell loss from the locus caeruleus in middle aged patients with Down's syndrome (whose brains show the pathological changes of Alzheimer's disease), has shown that cell loss is confined to dorsal areas, being least most rostrally and greatest caudally. By contrast, there is no significant cell loss from ventral parts of the locus, at any point along its rostrocaudal length. Dorsally located neurones of the locus project to cerebral cortex; ventrally located neurones to non-cortical areas such as basal ganglia, cerebellum and spinal cord. These data suggest that the damage to nerve cells of the locus caeruleus in Down's syndrome at middle age, like that seen in Alzheimer's disease itself, relates to primary pathological events within the cortical projection fields of affected cells with perikaryal loss following on as a later change.

Loss of neurones from cortical and subcortical areas in Down's syndrome patients at middle age. Quantitative comparisons with younger Down's patients and patients with Alzheimer's disease.

Brains were examined after autopsy from 12 patients over 53 years of age with Down's syndrome (in whose brains plaques and tangles were numerous in many areas of cortex and subcortex), 3 patients under 53 years of age with Down's syndrome (in whose brains plaques and tangles were minimal or absent), 10 patients, of age range similar to the older Down's group but with Alzheimer's disease and 5 control patients of age range similar to the younger Down's group. The number of plaques and tangles in the hippocampus and their density within the temporal cortex, the thickness of the temporal cortex, the cross-sectional area of the hippocampus and the relative number and mean nucleolar volume of nerve cells in these cortical and in some subcortical areas were estimated and compared in each of the 4 groups. The relative loss of nerve cells and the decrease in mean nucleolar volume were calculated in percentage terms for the older Down's syndrome patients by reference to data from the younger Down's syndrome patients, whereas such losses in Alzheimer's disease were calculated by reference to the younger control patients. While in qualitative terms, all areas of brain found to be damaged in Alzheimer's disease were also damaged in Down's syndrome at middle age, quantitative differences emerged with the reductions in relative nerve cell number and mean nucleolar volume being significantly less in many areas in Down's syndrome. Conversely plaques and tangles were more numerous in the hippocampus in Down's syndrome though in the temporal cortex plaques were less numerous. It seems, therefore, that although the same pathological process is likely to operate in the two conditions, additional biological and mortality differences between Down's syndrome and the general population may account for the observed quantitative variations.

Regional variation and age-related changes of lysosomal enzymes in the human retinal pigment epithelium.

In this study the activities of two lysosomal enzymes in retinal pigment epithelial (RPE) cells isolated from three regions of the human fundus were examined: the macula, the nasal midzone, and the periphery. The results obtained showed that the activities of acid phosphatase and cathepsin D were significantly higher in the RPE cells derived from the macular region when compared with those in the periphery. The values for the midzone appeared to be intermediate between the other two regions. Furthermore, the overall activity of both enzymes increased as a function of age.

Detection of herpes simplex virus DNA in donor cornea culture medium by polymerase chain reaction.

AIMS/BACKGROUND: Herpes simplex virus (HSV) may establish latent infection in the cornea and therefore be transmissible by corneal transplantation. Monitoring of donor cornea culture medium was evaluated for HSV infection. METHODS: HSV was sought using virus isolation in cell culture, and its DNA was amplified to detectable levels using the polymerase chain reaction (PCR). RESULTS: Virus isolation in cell culture was negative on neat, cell pellet, and cell free supernatant prepared from the spent culture media of 80 corneas. Three cell pellets (3.8%) were positive for HSV DNA. The PCR positive culture negative results might have reflected latent rather than active HSV infection of the cornea. Post transplant follow up of the three recipients of corneas with HSV PCR positive organ culture media revealed no evidence of HSV induced eye disease or primary graft failure. CONCLUSION: Screening of corneal culture medium for HSV by virus culture or for HSV DNA by PCR could not be recommended.

Diurnal variations in human corneal thickness.

AIM: To elucidate the diurnal variation in human corneal thickness over a 48 hour period. METHOD: Changes in central corneal thickness were monitored in eight healthy subjects (four male, four female) aged between 10 and 63 years using an ultrasonic pachymeter. Measurements were made over a 48 hour period-immediately before sleep, immediately upon waking and at 15, 30, 45 minutes, 1, 1.5, 2, 2.5, 3 hours, and at 2 hour intervals thereafter throughout the remainder of each day. RESULTS: The mean corneal thickness for the group (SD) was 546 (14) microns, with a mean overnight increase of 5.5% (2.9%) (range 1.9-12.6%) and a maximum diurnal increase of 7.2% (2.8%) (range 2.1-14.3%). Individual differences in the extent of diurnal and overnight variation occurred within the group. For three subjects, the first reading taken on waking was not the highest and corneal thickness continued to increase. CONCLUSION: These data confirm an increase of corneal thickness during sleep, but also reveal considerable variation during waking hours. Thus, the overnight changes in corneal thickness are not truly representative of diurnal variations in human corneal thickness and, in fact, much greater diurnal variation occurs than the 3.0-4.4% previously reported.

Prediction of refractive outcome in penetrating keratoplasty for keratoconus.

We carried out a retrospective study to evaluate the relationship between vitreous cavity length, graft size, and final spherical equivalent refraction after penetrating keratoplasty (PK) for keratoconus. We found a straight-line relationship between vitreous cavity length and spherical equivalent for a one-surgeon series using the same technique throughout. The use of 0.25-mm undersized grafts shifted the results an average of 2.2 Dioptres in a more hypermetropic direction (p = 0.07 for the whole group, p < 0.01 for paired eyes). Hence the final spherical equivalent following PK for keratoconus can be predicted. Also, by altering the size of the donor graft button, the final refraction can be manipulated to some extent towards acceptable ametropia or to match the refraction of the fellow eye.

Corneal donor infection by herpes simplex virus: herpes simplex virus DNA in donor corneas.

Three corneoscleral discs (from two donors) underwent subtotal endothelial loss during routine "long-term" organ culture storage. Laboratory studies of these corneas revealed evidence of herpes simplex virus (HSV) infection. The fellow cornea from one of the donors had been issued for transplant to a patient with keratoconus. Deterioration of the graft was noted 5 days after surgery; the disc was removed at 2 months and was shown to be infected with HSV. In an experiment designed to simulate initial "cleansing" of donor globes, 0.1% polyvinylpyrolidone-iodine protected cells from infection with HSV. It was concluded that the detection of HSV in these corneas could not be explained by external contamination of the ocular surface. Furthermore, culture of conjunctival and pharangeal swabs taken from 47 consecutive donors confirmed that HSV is rarely isolated at or around the time of death. Five pairs of donor corneas destined for use in transplantation were selected at random and investigated for the presence of HSV. HSV DNA was detected by polymerase chain reaction (PCR) in tissue from two of the corneal donors. Sequential stepwise sectioning suggested that HSV DNA when present was distributed in discrete foci within the cornea. These observations suggest that HSV infection may be a cause of severe endothelial loss during corneal organ culture and possibly provide an explanation for some "failures" of corneal grafting.

An ultrastructural investigation into proteoglycan distribution in human corneas.

PURPOSE: We report an investigation into the distribution of proteoglycans (PGs) in normal, organ-cultured and dextran-treated human corneas. METHODS: Immunogold labeling was carried out at the electron microscope level to localize keratan sulphate (KS), chondroitin sulphate (CS), and heparan sulphate (HS) PGs. RESULTS: High levels of labeling for CS was found in the epithelium, endothelium, and keratocytes, with light labelling present in the basement membranes and the corneal stroma. Labeling for HS was present in the epithelium, endothelium, and keratocytes, with intense labeling present at the endothelium/Descemet's membrane interface and the epithelium/Bowman's layer interface. Large filaments were also observed in these regions in cuprolinic blue-stained specimens. Keratan sulphate was present at high levels in the stroma and the basement membranes with low levels present within the keratocytes, epithelium, and endothelium. The pattern of KS labeling along the collagen fibrils in the stroma sometimes showed evidence of periodicity. Organ-cultured corneas had extensive collagen-free "lakes," the interior of which immunolabeled positively for KS and showed staining with cuprolinic blue. The lakes were greatly reduced in the dextran-treated samples. CONCLUSION: This investigation determined the ultrastructural distribution of KS, CS, and HS PGs in human cornea and showed that organ culture is associated with a change in distribution of stromal PGs.

Keratan sulphate in the trabecular meshwork and cornea.

PURPOSE: A study was made of the distribution of keratan sulphate in the human anterior chamber. METHODS: The monoclonal antibody, 5-D-4, was used in immuno-electron microscopy to visualise keratan sulphate distribution in the anterior chamber of 16 normal eyes, 7 Fuchs' dystrophy corneas, and a macular dystrophy cornea. RESULTS: Keratan sulphate was detected in normal human aqueous humour and also on the surface of trabecular cells in the uveal meshwork. Normal corneal stroma showed an increase in keratan sulphate labelling from anterior to posterior, with marked labelling in the posterior region of Descemet's membrane. The apical surface of the corneal endothelium labelled positively, but showed considerable variation in the level of labelling from cell to cell. The macular dystrophy cornea had the classic histopathological features of a type I case, including a highly abnormal Descemet's membrane. No keratan sulphate was detected in the macular dystrophy patient's corneal stroma or serum. The Fuchs' endothelial dystrophy corneas showed a normal distribution of keratan sulphate labelling in the stroma. The Fuchs' endothelial cells labelled for keratan sulphate but were highly abnormal in appearance, often exhibiting long filopodia and appearing to be actively migrating. CONCLUSIONS: This work has shown that keratan sulphate has a much wider distribution than was previously believed. The detection of keratan sulphate on the trabecular and endothelial cell surfaces also suggests a possible role for this molecule in cell adhesion and/or migration.

Changes in Alzheimer's disease in the magnocellular neurones of the supraoptic and paraventricular nuclei of the hypothalamus and their relationship to the noradrenergic deficit.

When compared with those of age-matched control patients the number of nerve cells in the locus caeruleus in 30 patients with Alzheimer's disease is reduced by 65% while nucleolar volume in surviving cells of the locus caeruleus and in those of the paraventricular and supraoptic nuclei of the hypothalamus is reduced by 25%, 48% and 26% respectively. Furthermore the reduction in cell number and nucleolar volume in these 3 cell types are all interrelated, emphasizing the close functional linkage of these cell groups. Similar changes (for age) were seen in a group of 10 patients with a mixed Alzheimer/vascular type dementia and in 6 patients over 50 years of age with Down's syndrome whose brains also showed extensive senile plaque and neurofibrillary tangle formation. This damage to the locus caeruleus and hypothalamic systems is probably responsible for losses of noradrenaline and vasopressin reported in cerebral cortex and hypothalamus; the importance of these changes to the pathogenesis of Alzheimer's disease is emphasized.

Monoaminergic neurotransmitter systems in presenile Alzheimer's disease and in senile dementia of Alzheimer type.

The number of nerve cells was counted in locus caeruleus, dorsal motor vagus, dorsal tegmental nucleus and substantia nigra and the volume of their nucleolus measured in 30 patients with Alzheimer's disease ranging from 48-92 years of age and in 67 control patients without neurological disease. Loss of nerve cells and reduction in nucleolar volume was greatest in the locus caeruleus and these changes were most severely expressed in the younger patients, falling with age such that by 90 years of age the level of damage approached that of old age alone. Less extensive changes were present in the dorsal tegmental nucleus and these were also age dependent in their severity. Moderate damage to the dorsal motor vagus was not age related. Nucleolar volume alone was altered in substantia nigra and then only significantly so in the younger patients.