Cerebral vasculopathy in divers.

Brains from 12 amateur and 13 professional divers, all but one of whom died accidentally, were examined neuropathologically. Grossly distended, empty vessels (presumably caused by gas bubbles) were found in the brains of 15 out of 22 divers who died from diving accidents. Perivascular lacuna formation was found in cerebral and/or cerebellar white matter in three amateurs and in five professionals. In addition to lacuna formation, hyalinization of vessel walls was present in the brains of three amateurs and five professionals. Necrotic foci in grey matter occurred in seven cases and perivascular vacuolation of white matter occurred in seven cases. The vascular changes probably arose from intravascular gas bubble formation. In one professional diver, there was also unilateral necrosis of the head of the caudate nucleus.

A monoclonal antibody which discriminates between sub-types of astrocytoma.

A monoclonal antibody, M2, was produced by somatic cell hybridisation of splenocytes, from mice immunised with human fetal brain, with the murine myeloma cell line NS-1. Indirect immuno-peroxidase staining of formalin-fixed, paraffin embedded tissue sections showed that, whilst the monoclonal antibody gave a positive reaction with 32/39 astrocytomas from adult patients and 33/36 of children's astrocytomas of the adult histological type, only 17/39 of juvenile astrocytomas were stained. A Chi-squared test showed that the difference in staining between the two groups (adult versus juvenile) was highly significant (p less than 0.0001). In contrast, using a polyclonal antiserum to GFAP, a significantly larger proportion of juvenile astrocytomas than adult astrocytomas stained positively (p less than 0.05). Thus, whereas the distribution of GFAP accorded with the general finding that the degree of malignancy of a tumour correlates with the loss of cell type specific markers, the distribution of M2 reactivity was similar to that of some oncogene products which increase with malignancy. From the flow cytometry data it is apparent that the antigen recognised by M2 is not cell cycle dependent.

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.

The progression of the pathological changes of Alzheimer's disease in frontal and temporal neocortex examined both at biopsy and at autopsy.

Brains were obtained at autopsy from five patients with Alzheimer's disease, each of whom had undergone diagnostic craniotomy 3-7 years previously. It was possible, therefore, to examine the number (density) and nucleolar volume of pyramidal nerve cells, and the density of senile plaques and neurofibrillary tangles within the cerebral cortex on two occasions during the progression of their illness, and to assess how these measures might have changed during the period between biopsy and death. In all five patients, at biopsy, the density and the nucleolar volume of pyramidal nerve cells was significantly less than controls and, in general, values for both these measures fell significantly further from biopsy to death. By contrast, in none of the five patients did senile plaque density consistently change from biopsy to death; neurofibrillary tangle density either did not change, or indeed sometimes decreased from biopsy to death. These data show that both the clinical and the pathological progression of Alzheimer's disease is marked by a continuing loss of pyramidal cells from frontal and temporal cortex, although the densities of plaques and tangles within the cortex do not, per se, correlate with the stage of the illness. The usefulness of measurement of plaque and tangle densities as pathological criteria by which the clinical and neurochemical deficits of Alzheimer's disease can be compared in different patients is clearly questionable.

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.

Alzheimer's disease: an olfactory connection?

The density and distribution of senile plaques and neurofibrillary tangles were examined in the olfactory bulbs and tracts, amygdala and hippocampus of 28 patients with Alzheimer's disease, 13 with Down's syndrome and 60 non-demented patients of age range 6-84 years. In all three patient groups comparisons of incidence and severity over the three areas showed the amygdala to be the most commonly and most severely affected area by senile plaques, the hippocampus by neurofibrillary tangles, and the olfactory bulbs and tracts to be the least affected by both. These findings are discussed in relationship to the possibility that the olfactory tracts might provide a portal of entry to the brain for any putative pathogenic agent(s) that might be responsible for the induction of senile plaques and/or neurofibrillary tangles.

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.

A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease.

A quantitative morphometric analysis was used to estimate neurone and synapse densities in cerebral cortical biopsy tissues from patients with dementia under 65 years of age and pathologically verified as suffering from Alzheimer's disease. Estimates of the numerical density of neurones and synapses were made in layers II-III and V of both frontal and temporal cortex. A greater loss of synapses than that of neurones was found in Alzheimer's disease, amounting to a minimum (uncorrected for atrophy) of 25% in layers II-III and 36% in layer V of the temporal cortex, and 27% in layer V of the frontal cortex. Values of synapse to neurone ratio also demonstrated this greater loss of synapses, there being on average 38% fewer synapses associated with each surviving neurone in layers II-III of the temporal cortex, 30% fewer in layer V, and a deficit of 14% in layer V of the frontal cortex. It is concluded that a major loss of synapses occurred in this group of patients with Alzheimer's disease, probably at an early stage of the disease, and that the loss is likely to form a fundamental part of the pathological process that underlies the cortical damage of this condition.

The topographic distribution of senile plaques and neurofibrillary tangles in the brains of non-demented persons of different ages.

The incidence and severity of senile plaques (SP) and neurofibrillary tangles (NFT) were examined in six areas of brain in 60 non-demented patients of age range 6-84 years. Thirty-two patients showed neither SP nor NFT in any region (30 of these were under 65 years of age), 15 patients showed both SP and NFT in one or more regions (14 were over 60 years of age), 11 patients aged 21-84 years showed NFT only in one or more areas and two patients showed SP alone and only in the amygdala. Overall comparison of number and severity showed the greatest severity of SP within the amygdala in most instances, whereas NFT were found in most instances and at greatest severity within the hippocampus. The reason for this apparent vulnerability of these areas of brain to SP and NFT formation may lie with their connections with the outside world via the olfactory bulbs and tract. This pathway may thus provide an entry point to the brain for pathogenic agent(s) that may induce, either directly or indirectly, pathological processes that ultimately lead to SP and NFT formation.

Dopaminergic neurotransmitter systems in Alzheimer's disease and in Down's syndrome at middle age.

In 15 patients with Alzheimer's disease and in 10 with Down's syndrome at middle age, there was severe atrophy, neurofibrillary degeneration and loss of pigmented dopaminergic nerve cells from ventral tegmental area (A10) whereas nerve cells in neighbouring substantia nigra (A9) were much less affected in all three respects. It is suggested that these findings may represent different patterns of damage within the two systems in these conditions which may relate to the presence of Alzheimer type changes (senile plaques) within their respective projection fields.

Glycogen accumulations in the cerebral cortex in Alzheimer's disease.

The fine structure of granular glycogen bodies (GGB) within the grey matter of the temporal cortex of 11 patients with Alzheimer's disease is described. GGB measure up to 50 microns in diameter and consist of densely packed alpha or beta glycogen granules (never both), neither of which are membrane bound. They were noted in axons, both myelinated and unmyelinated (sometimes close to the dystrophic neurites of senile plaques), and also in other processes of indeterminate origin. Their appearance may relate to disturbances of axonal transport resulting from damage to terminals within evolving senile plaques.

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.

The topography of plaques and tangles in Down's syndrome patients of different ages.

The topographical distribution of senile plaques and neurofibrillary tangles has been investigated in 12 patients with Down's syndrome ranging from 31 to 65 years of age. No plaques or tangles whatsoever were seen in the brain of the 31-year-old patient. The nine patients over 53 years of age, showed a similar pathological picture in which there were numerous mature plaques in all areas of cerebral cortex, hippocampus and amygdala and numerous tangles in these areas and in subcortical structures such as nucleus basalis, locus caeruleus, dorsal raphe, ventral tegmental area, substantia nigra, olfactory bulb and tracts. In the other two patients aged 37 and 51 years, an intermediate pathological picture was seen in which primitive plaques predominated within the cortex, with numerous mature plaques in hippocampus and amygdala. In the 37-year-old patient, tangles were numerous in the entorhinal cortex, but much less common in hippocampus and amygdala, rare in cerebral cortex and absent in the subcortical areas, olfactory bulbs and tracts. A similar pattern was seen in the 51-year-old patient though here some cells in the subcortex were also affected. These observations suggest that the primary focus of plaque and tangle formation in Down's syndrome may be in amygdala, entorhinal cortex and hippocampus, with a 'spreading out' to subsequently involve all areas of cortex, certain subcortical regions and the olfactory bulbs and tracts. It appears unlikely that the olfactory bulbs and tracts provide a portal of entry for any pathogenic agent that may be responsible for inducing plaque and tangle formation within the rest of the brain.

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.

An ultrastructural analysis of the effects of accumulation of neurofibrillary tangle in pyramidal neurons of the cerebral cortex in Alzheimer's disease.

Quantitative morphometric (stereological) methods have been used to assess the effects of accumulation of neurofibrillary material on the fine structure of pyramidal cells in biopsy specimens of temporal cortex from nine patients with Alzheimer's disease. When compared with non-tangled cells from the same patients, tangled cells show an increase in total area of cytoplasm due to the accumulation of tangle and a reduction in the area of the nucleus; the area proportion of the cell body occupied by total cytoplasm, therefore, increases whereas that of the nucleus decreases. Within the total cytoplasm, nucleolar and mitochondrial areas are maintained, but that of lipofuscin is increased, though all are increased when expressed as a proportion of the useful cytoplasm alone (i.e. total cytoplasmic area minus area occupied by tangle). Measures of the amount of rough endoplasmic reticulum and ribosomes are decreased overall in tangled cells, though when related to useful cytoplasm alone such measures approach non-tangled cell values. Measures of smooth endoplasmic reticulum are unaltered throughout. When related to the amount of tangle within cells it was found that the most heavily tangled cells retain 28% of useful cytoplasm, 72% of the nuclear area, 50% of the rough endoplasmic reticulum and 27% of ribosomes present within least tangled and non-tangled cells. By contrast, mitochondrial area is maintained and that of lipofuscin increased. The capacity for protein synthesis in tangled cells appears, therefore, to be progressively decreased with accumulation of tangle, whereas that for oxidative metabolism is maintained and lysosomal activity, perhaps, increased. Neurofibrillary tangle formation and accumulation may, therefore, lead to the eventual death of neurons and be the major cause of nerve cell loss in Alzheimer's disease.

A quantitative study of the ultrastructure of pyramidal neurons of the cerebral cortex in Alzheimer's disease in relationship to the degree of dementia.

Quantitative morphometric (stereological) methods have been used to measure the number or amount of organelles in pyramidal nerve cells, unaffected by neurofibrillary degeneration, in biopsy specimens of temporal cortex from 11 patients with Alzheimer's disease, and to relate these to the degree of dementia, as measured by psychometric testing. Only areal proportion (AA) and surface area (SA) of rough endoplasmic reticulum were significantly reduced in line with the severity of the degree of dementia. It is suggested that these changes reflect a progressively diminishing requirement for packaging and transport of replacement proteins, particularly in relation to neurotransmitter metabolism in nerve terminals following the loss of synapses which we have shown to occur in these patients.

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.