Biomedical subjects
Publications and source records attributed to B E Tomlinson.
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In a survey to determine the occurrence of Levy bodies in the elderly, the prevalence rate of Lewy body formation was found to be critically dependent on the psychiatric status of control cases. In 131 controls between 51 and 100 years screened to exclude psychiatric and neurological disorders, the Lewy body prevalence rate was 2.3%, but inclusion of cases with psychiatric disorders other than Alzheimer's disease increased the prevalence rate to 9%. An age-related decline in substantia nigra and locus coeruleus neuron numbers was observed in the control group. Brain stem Lewy body formation (found in 3 cases) was not necessarily linked with neuron loss in substantia nigra, though in two of the cases significant locus coeruleus neuron loss was observed. Within the control group, there was no obvious relationship of Lewy body formation to the extent of Alzheimer-type pathology. These findings are compatible with the disease specificity of Lewy bodies and suggest that Lewy body disorders have a relatively short preclinical phase in which Lewy body formation may precede both locus coeruleus and substantia nigra neuron loss. The increase of Lewy body positive cases found when individuals with psychiatric disorders are included in the population surveyed supports the emerging concept of a spectrum of Lewy body diseases ranging from purely psychiatric disorders through combined psychoneurological or neuropsychiatric symptoms, to the classically described neurological disorders of Parkinson's disease.
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The clinical and neuropathological findings of a patient with central neurogenic hyperventilation are described. The patient had an extensive primary central nervous system lymphoma but no lesions below the level of the superior colliculus. The possible mechanism of central neurogenic hyperventilation is discussed with reference to the present case and those previously described.
The major neurochemical abnormality described to date in senile dementia of the Alzheimer type (SDAT) is a central cholinergic deficit. To determine whether this central deficit is reflected by changes in the levels of blood cholinesterases, plasma and erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE), were measured in SDAT and other psychiatric disorders. Plasma AChE, which has only recently been described in human blood, was significantly elevated (P less than 0.01) in the SDAT group compared with the control and other clinical groups investigated. In contrast there were no significant differences in the activities of either erythrocyte AChE or plasma BChE between any of the clinical groups. Although the source of plasma AChE is unknown the possibility that some portion originates from the central nervous system and that the elevated AChE levels in SDAT reflect increased release from degenerating cholinergic neurons is discussed.
Dementia in Parkinson's disease has previously been attributed to the presence in the cerebral cortex of Alzheimer-type neuropathological abnormalities. New evidence suggests, however, that dementia in this disease usually occurs in the absence of substantial Alzheimer-type changes in the cortex and may be related to abnormalities in the cortical cholinergic system. Thus, in Parkinsonian patients with dementia there were extensive reductions of choline acetyltransferase and less extensive reductions of acetylcholinesterase in all four cortical lobes. Choline acetyltransferase reductions in temporal neocortex correlated with the degree of mental impairment assessed by a test of memory and information but not with the extent of plaque or tangle formation. In Parkinson's but not Alzheimer's disease the decrease in neocortical (particularly temporal) choline acetyltransferase correlated with the number of neurons in the nucleus of Meynert suggesting that primary degeneration of these cholinergic neurons may be related, directly or indirectly, to declining cognitive function in Parkinson's disease.
Reductions in the numbers of binding sites for the serotonergic S2-receptor antagonist, ketanserin, are, as previously reported, evident in Alzheimer's disease. New findings indicate that these sites are not affected in the cortex of patients with Parkinson's disease despite the presence of cognitive impairment. In contrast S1-receptor binding sites were reduced to a small but significant extent in both Alzheimer's and Parkinson's disease with cognitive deficit. The S2-receptor binding loss was not related to the cholinergic deficit (decreased choline acetyltransferase) common to both disorders nor to the presence of cortical senile plaques but did relate to the extent of cortical neurofibrillary tangle formation, evident in Alzheimer's but not generally in Parkinson's disease. These observations suggest that S2- but not S1-receptor binding abnormalities may reflect an important intrinsic cortical involvement specifically associated with the Alzheimer disease process.
Ligand binding to alpha 1-, alpha 2- and beta-adrenergic, serotonin, benzodiazepine and GABA receptors was studied in neocortex and hippocampus of controls and patients with senile dementia of the Alzheimer-type. A selective loss of serotonergic binding sites characterised as a loss of both S1 and S2 sites was observed. The reduction in serotonin receptors did not correlate with a clinical assessment of the degree of dementia, or with the extent of Alzheimer-type neuropathological change.
The intralaminar distributions of transmitter and nontransmitter enzyme activities and amino acid levels were determined in the midtemporal cortices from normal individuals and established cases of Alzheimer's disease. In the normal, choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activities were relatively high in the outer cortical layers, particularly, for CAT, in the two granular layers (II and IV). Both activities were reduced in Alzheimer's disease at all, although generally most extensively in the outer and middle layers of the grey matter whereas activities were near normal in the white matter. Further, the enzyme distribution patterns of these cholinergic activities were also disrupted in Alzheimer's disease and the activity of CAT throughout the cortex was generally reduced to that found in the white matter. No such differences in distribution were found for two other enzymes, pseudocholinesterase and lactate dehydrogenase. Assessment of the gamma-aminobutyric acid (GABA) system in the normal revealed a much more extensive intralaminar variation in the enzyme, glutamate decarboxylase, compared with the level of GABA itself. In contrast with the cholinergic enzymes, neither the levels nor intralaminar patterns of GABA were altered in Alzheimer's disease. From an analysis of free amino acids at the different cortical levels, the cortical pattern of glutamic acid in the normal was different from that for GABA, aspartic acid, or nontransmitter amino acids such as alanine. Neither of the putative amino acids, glutamate or aspartate, was altered in Alzheimer's disease. These findings demonstrate the relatively selective nature of microchemical changes occurring in the cortex in Alzheimer's disease and suggest that a functional abnormality in cholinergic input to the outer neocortical layers (I-IV) with predominantly receptive and associative functions may be an important feature of the disease.
A 50-year-old man with a 20-year history of myelofibrosis developed mild impairment of dorsal column sensation and ataxia of gait. A myelogram and subsequent peroperative biopsy demonstrated spinal cord compression due to extramedullary haematopoiesis. There was an excellent clinical response to surgery and radiotherapy. The characteristic clinical features and the pathogenesis of this unusual complication of myelofibrosis and extramedullary haematopoiesis are discussed.
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Using density gradient centrifugation, three molecular forms of acetylcholinesterase have been distinguished in both normal and senile dementia of Alzheimer-type (SDAT) postmortem neocortex. Whilst the levels of the light and heavy forms were unaltered in SDAT there was a selective and extensive loss of the intermediate form. This form is predominantly hydrophobic and its loss from the cerebral cortex in SDAT may reflect degeneration of cholinergic axonal processes. This is the first report of an altered distribution of acetylcholinesterase molecular forms in a disease of the central nervous system.
Combined neuropathological and neurochemical assessment of the nucleus of Meynert in senile dementia of Alzheimer type (SDAT) have demonstrated that the cholinergic biochemical activity, choline acetyltransferase, is more extensively reduced in the nucleus (over 90%) than the loss of putative cholinergic perikarya (35%). Acetylcholinesterase histochemical activity was however substantially retained in individual neurones in the nucleus although virtually absent from the neocortex in SDAT. These abnormalities are consistent with a primary degeneration of cholinergic axons projecting to the cortex and secondary loss of perikarya from the subcortical nucleus. In contrast, preliminary observations on cases of Parkinson's disease suggest that the neuronal loss from the nucleus of Meynert may be greater in this disease than in SDAT, and previous studies have not consistently demonstrated a reduction in cortical choline acetyltransferase activities in Parkinson's disease. These observations, together with major differences in the neuropathology of the nucleus in SDAT and Parkinson's disease (neurofibrillary tangle and Lewy body formation, respectively) suggest that the involvement of the cholinergic system may differ in the two disease processes.
The nature of the ischaemic penumbra, as defined by suppression of electroencephalogram amplitude in the absence of increase in steady state pial surface potassium activity in excess of 13 mM, was examined in the marginal gyrus of cats subjected to middle cerebral artery occlusion. In vitro synaptosomal neurotransmitter uptake, water content (specific gravity), and histopathology at the light and electron microscopic level were studied and the results compared with those obtained at deeper, critical levels of ischaemia (less than 15 ml 100 g-1 min-1). [3H]4-Aminobutyric acid uptake was 104% of control in the marginal gyrus (NS), and 61 and 48% (p less than 0.05) in critical ischaemia. It is concluded that impairment of in vivo synaptosomal uptake is a marker of simultaneous widespread damage to neurones, rather than of a change restricted to the synaptic compartment, although the present findings cannot exclude reversible, substrate-limited impairment of uptake in vivo. Reductions in specific gravity were seen only with critical ischaemia. In 5 of 6 experiments, early or classical ischaemic neuronal cell changes and reactive glia were seen on light microscopy in restricted areas in the marginal gyrus, either in microfoci or scattered more diffusely. Ultrastructural changes were more frequent but were considered to affect only a minority of neurones. Hypotheses for selective electrophysiological suppression in penumbra are discussed.
The binding of tritiated imipramine was significantly reduced in the hippocampus and occipital cortex from a series of patients with depressive illness compared with age-matched patients with no psychiatric disorder. In contrast there was no change in imipramine binding in established cases of senile dementia of Alzheimer-type. Scatchard analysis indicated normal binding affinity but a reduction in the number of imipramine binding sites in depression. These observations parallel previous findings of decreased binding sites in platelets from depressed patients and suggest there may be an abnormality in the uptake mechanism for serotonin in depression.
Choline acetyltransferase activity in discrete tissue punches from the nucleus of Meynert and in tissue from the temporal cortex was reduced by at least 90% and 75%, respectively, in 5 out of 6 elderly cases of Alzheimer's disease compared with 5 normal cases. In contrast, estimates of neurone density in these same cases revealed that there was only, on average, a 33% neurone loss in the nucleus of Meynert in Alzheimer's disease. These observations suggest that a key pathological change in Alzheimer's disease may be the 'down regulation' of transmitter-specific enzyme production in cholinergic neurones, and that neurone loss itself may be a secondary feature of the disease.
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