J.M. Candy

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.

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.

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.

Cholinergic Receptors in Cognitive Disorders

Cholinergic receptors (muscarinic subtypes M1 and M2, and putative nicotinic binding) have been examined in the hippocampus obtained at autopsy from a variety of patients with cognitive disorders (Alzheimers, Parkinsons, and Huntingtons diseases, Downs Syndrome and alcoholic dementia) and compared with neurologically normal controls and cases of Motor Neuron disease. In all of the disorders associated with a pre-synaptic cortical cholinergic deficit reflected by an extensive loss of choline acetyltransferase (Alzheimers disease, Parkinsons disease and Downs Syndrome) there was a substantial reduction in the binding of (3H) nicotine to the nicotinic receptor. By contrast reductions in both muscarinic subtypes (M1 and M2) were apparent to only a moderate extent in Alzheimers disease, whereas in Parkinsons disease binding was significantly increased (apparently not in relation to anti-cholinergic drug treatment) in the non-demented but not demented cases. A further abnormality detected in Alzheimers disease but not the other disorders investigated was a decrease in an endogenous inhibitor of nicotinic binding, the identity of which is as yet unknown but which may be a candidate for a possible endogenous modulator of the nicotinic receptor. These observations suggest that in Alzheimers disease not only muscarinic but also nicotinic receptor function should be considered in relation both to future therapeutic strategies and, in the search for a clinical marker which might be of diagnostic value, to potential probes of the cortical cholinergic system.

Cortical serotonin-S2 receptor binding abnormalities in patients with Alzheimer's disease: Comparisons with Parkinson's disease

Reductions in the numbers of binding sites for the serotonergic S2-receptor antagonist, ketanserin, are, as previously reported, evident in Alzheimers disease. New findings indicate that these sites are not affected in the cortex of patients with Parkinsons disease despite the presence of cognitive impairment. In contrast S1-receptor binding sites were reduced to a small but significant extent in both Alzheimers and Parkinsons 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 Alzheimers but not generally in Parkinsons 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.

Comparison of the regional distribution of transferrin receptors and aluminium in the forebrain of chronic renal dialysis patients

Recent studies have emphasised the potential neurotoxicity of aluminium in dialysis encephalopathy and it has also been suggested that this element may have a role in the pathogenesis of Alzheimers disease. Aluminium is known to be transported by the iron transport protein transferrin. In this study using receptor autoradiography we have demonstrated the presence of transferrin binding sites in the human forebrain and shown a pattern similar to that found in other species. Imaging secondary ion mass spectrometry has demonstrated the distribution of aluminium-containing cell-like profiles in the brains of chronic renal dialysis patients who have raised levels of brain aluminium (greater than 4 micrograms/g dry weight) and even in dialysis patients where the gross level of aluminium was within the normal range. The density of these profiles corresponded to the regions of high transferrin receptor density. In contrast, the distribution of iron in the brain showed an inverse correlation with transferrin receptor density with highest iron levels present in the globus pallidus, an area of low transferrin receptor density. These results suggest that the regional distribution of neuropathological changes seen in dialysis encephalopathy patients and also Alzheimers disease may reflect the distribution of transferrin receptors. The discrepancy between iron distribution and transferrin receptor distribution suggests that further, as yet uncharacterized mechanisms, govern the distribution of brain iron.

Parameters of cholinergic neurotransmission in the thalamus in Parkinson's disease and Alzheimer's disease

Loss of cholinergic cells in the basal forebrain is associated with commensurate reductions in cortical acetylcholine-related enzyme activities in both Alzheimers disease (AD) and Parkinsons disease (PD). Nerve cell loss from the cholinergic pontine tegmental nuclei also occurs. As the latter nuclei project to the diencephalon, we used frozen tissue from 5 controls, 5 PD and 5 AD cases to study the distribution of ChAT, AChE and [3H]nicotine binding in the thalamus and subthalamic nucleus. The anterior nuclear group and the mediodorsal nucleus showed high activities of ChAT and AChE together with relatively high levels of [3H]nicotine binding. The centromedian nucleus and subthalamic nucleus contained equally high levels of ChAT but negligible levels of [3H]nicotine binding. There were no significant changes in the levels of ChAT, AChE and nicotine binding in the PD and AD groups indicating that involvement of the pedunculopontine tegmental nucleus is likely to be a secondary retrograde phenomenon rather than part of a systematic cholinergic fibre degeneration.

Evidence for the early prenatal development of cortical cholinergic afferents from the nucleus of Meynert in the human foetus.

A combined histochemical and biochemical approach has shown that the cholinergic system in the nucleus of Meynert region of the substantia innominata is well defined both histochemically and neurochemically within the first 3 months of gestation in the human foetus. Thus, at between 12 and 22 weeks of development the most intense acetylcholinesterase (AChE) histochemical reactivity was observed in the neuropil, cell bodies and processes in the nucleus of Meynert. AChE-stained fibres were observed which coursed from the nucleus of Meynert towards the cortical mantle and within the mantle AChE-stained fibres were also present. Micropunch samples from within the nucleus of Meynert contained higher levels of choline acetyltransferase (ChAT) activity than any other area examined including the striatum, while in the cortical mantle the level of ChAT activity was comparable to that found in the adult cerebral cortex. These observations suggest that the cholinergic innervation from the nucleus of Meynert--considered to be the major source of cholinergic afferents in the adult cerebral cortex--may play a key role in the early development of the human neocortex.

Glutamate deficits in Alzheimer's disease

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