G. Blessed

Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia.

Necropsy brain tissue from normal (control) patients and patients with depression and dementia was examined for activities of various cholinergic components, and these related to the degree of senile plaque formation and extent of intellectual impairment. Choline acetyltransferase and acetylcholinesterase activities decreased significantly as the mean plaque count rose, and in depressed and demented subjects the reduction in choline acetyltransferase activity correlated with the extent of intellectual impairment as measured by a memory information test; muscarinic cholinergic receptor binding activity remained unchanged with increasing senile plaque formation but butyrylcholinesterase activity increased. The results suggest a close relation between changes in the cholinergic system and Alzheimers dementia, but the precise role of the system in this disease remains to be elucidated.

Cholinergic correlates of cognitive impairment in Parkinson's disease: comparisons with Alzheimer's disease.

Dementia in Parkinsons 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 Parkinsons but not Alzheimers 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 Parkinsons disease.

Pathological changes in the nucleus of meynert in Alzheimer's and Parkinson's diseases ☆

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 Parkinsons 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 Parkinsons disease. These observations, together with major differences in the neuropathology of the nucleus in SDAT and Parkinsons disease (neurofibrillary tangle and Lewy body formation, respectively) suggest that the involvement of the cholinergic system may differ in the two disease processes.

CHANGES IN BRAIN CHOLINESTERASES IN SENILE DEMENTIA OF ALZHEIMER TYPE

Acetyl‐ and butyryl‐cholinesterase activities have been measured biochemically in normal brain tissue, in senile dementia of Alzheimer type and in mental disorders without Alzheimer‐type abnormalities. Acetylcholinesterase was significantly reduced and butyrylcholinesterase significantly increased, compared with the normal, in the hippocampus and temporal cortex of the Alzheimer cases. No significant enzyme changes were seen in the other diseases investigated including multi‐infarct dementia, schizophrenia and depression. There was no correlation between age and acetylcholinesterase activity, but a significant positive correlation between the butyrylcholinesterase activities with increasing age (60–90 years) was found in the hippocampus. The possible connection between cholinergic system pathology and these cholinesterase abnormalities in Alzheimer dementia is discussed.

Aluminosilicates and senile plaque formation in Alzheimer's disease.

Aluminium and silicon were found to be colocalised in the central region of senile plaque cores in studies with energy dispersive X-ray microanalysis. The distribution of these elements was similar in cores isolated from the cerebral cortex of patients with senile dementia of the Alzheimer type and in cores studied in situ from tissue sections from the cerebral cortex of presenile and senile patients with Alzheimers disease, and elderly, mentally normal patients. High-resolution solid-state nuclear magnetic resonance techniques showed aluminium and silicon to be present as aluminosilicates. The presence of aluminosilicates at the centre of senile plaque cores contrasts with the distribution of other inorganic constituents and suggests that they may be involved in the initiation or early stages of senile plaque formation.

Neurochemical activities in human temporal lobe related to aging and Alzheimer-type changes

Activities relating to 3 neurotransmitter and 4 neuropeptide systems have been examined in human temporal lobe (post mortem) for their relationships with age and Alzheimer-type changes (senile plaques and cognitive function). Significant alterations with increasing age (from 61 to 92 years) in a series of non-demented cases included a reduction of the cholinergic enzyme, choline acetyltransferase, and an increase in vasoactive intestinal peptide immunoreactivity. In cases of alzheimers disease the only neurochemical activity investigated which correlated significantly with cognitive impairment (assessed from a Mental Test Score obtained shortly before death) and with the severity of Alzheimer-type abnormalities (senile plaques density) was choline acetyltransferase. Further analyses of the data in relation to the severity of plaque formation suggest that alterations in other neurochemical activities including reductions in dopamine-beta-hydroxylase activity, cholecystokinin octapeptide (aqueous extracted) and somatostatin immunoreactivities and an increase in substance P immunoreactivity, may occur at later stages of the disease process. These comparative data suggest that biochemical changes in this brain area associated with age and earlier stages of Alzheimers disease may be relatively selective.

Nicotinic receptor abnormalities in Alzheimer's and Parkinson's diseases.

The status of cholinergic receptors in dementia is related to the question of potential cholinergic therapy. Whilst muscarinic receptor binding is generally reported to be normal or near normal, findings are reported which indicate substantial reductions of hippocampal nicotinic (high affinity nicotine) binding (occurring in conjunction with decreased choline acetyltransferase) in both Alzheimers and Parkinsons but not Huntingtons disease. A further indication that nicotinic receptor function may be abnormal in Alzheimers disease is the extensive loss of an endogenous compound, detected for the first time in human brain, which inhibits normal nicotinic binding. Both receptor binding and the inhibitor are also substantially decreased with increasing age in the normal hippocampus.

Monoamine metabolism in senile dementia of Alzheimer type

Monoamine metabolism in senile dementia of the Alzheimer-type (SDAT) was assessed by measuring the concentrations of the dopamine metabolite HVA, the noradrenaline metabolite MHPG and serotonin metabolite 5-hydroxy-3-indoleacetic acid (5-HIAA) in post-mortem brains of SDAT patients, a group of control subjects and a group of chronically depressed patients. Concentrations of MHPG and 5-HIAA were significantly reduced in hippocampus and cortical regions of the SDAT group. These changes did not correlate with clinical assessments of the degree of dementia or neuropathological assessment of the degree of Alzheimer-type changes in the SDAT group. It is suggested that changes in monoamine metabolite concentrations are not primarily involved in the pathogenesis of SDAT, and may be secondary to the well established cholinergic deficits.

Studies on neurotransmitter receptor systems in neocortex and hippocampus in senile dementia of the Alzheimer-type

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.

Hippocampal free amino acids in Alzheimer's disease.

The free amino acid content of the hippocampus, obtained at postmortem, has been analysed in cases of Alzheimers disease and compared with normal cases. There were no significant differences in the levels of 23 amino acids including the transmitter candidates γ‐aminobutyric, glutamic or aspartic acids. This finding is interpreted in relation to present knowledge of transmitter pathways in the region of the hippocampus. A tendency for some amino acids to be increased in the Alzheimer group reached statistical significance for arginine. This observation is consistent with increased proteolytic or peptidase activity in Alzheimers disease.