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The article by Shiozaki et al 1 demonstrating significantly less muscarinic acetylcholine receptor binding sites in the temporal cortex in dementia with Lewy bodies than in Alzheimer's disease and different upregulation of the m1 and m2 receptor subtypes suggests differences in the manner of degeneration of the cholinergicsystem between both dementing disorders that may be of basic and practical therapeutic relevance. The more severe reduction of ChAT activity in the neocortex in dementia with Lewy bodies than in Alzheimer's disease, the higher upregulation of the postsynaptic m1 receptor in dementia with Lewy bodies, and the higher level of the presynaptic m 2 receptor subtype in Alzheimer's disease suggest a severe depletion of presynaptic projection neurons in dementia with Lewy bodies but their relative preservation or upregulation in Alzheimer's disease.1These data are in line with previous—including personal— findings on cell loss and shrinkage in the cholinergic magnocellular posterior part of the nucleus basalis of Meynert in dementing neurodegenerative disorders2: In Parkinson's disease (brain stem type of dementia with Lewy bodies), cell depletion in the nucleus basalis of Meynert averages 30% to 40% without correlation with age or duration of the illness. It is much higher in demented patients with Parkinson's disease (similar to Alzheimer's disease range 50% to 70%) than in non-demented patients (0% to 40%), who show neuronal loss similar to or only slightly higher than age matched controls. Cell loss in the nucleus basalis of Meynert in non-demented patients with Parkinson's disease is usually associated with little or no cortical Alzheimer's disease pathology, whereas in severely demented patients with Parkinson's disease, heavy cell depletion in the nucleus basalis of Meynert is often, but inconsistently, accompanied by severe cortical neuritic Alzheimer's disease pathology suggesting threshold levels of cholinergic forebrain impairment and deficit for the development of dementia.2 Even more severe depletion of the nucleus basalis of Meynert with 75% to 80% loss of large cholinergic neurons is found in dementia with Lewy bodies (figure). There were no major differences in cell loss in the nucleus basalis of Meynert between dementia with Lewy bodies with “plaque only” Alzheimer's disease (two cases) and with “true” Alzheimer's disease (eight cases with Braak stages V or VI). Lewy bodies and neurofibrillary tangles in the nucleus basalis of Meynert neurons were seen in eight brains of patients with Lewy body disease.3
These changes are associated with a decrease in cholinergic innervation of the cortex and hippocampus that may or may not correlate with the severity of cell loss in the nucleus basalis of Meynert and mental status. Neocortical cholinergic activity (choline acetyl transferase) is far more severely depleted in dementia with Lewy bodies than in Alzheimer's disease and Parkinson's disease, and correlates well with dementia and nucleus basalis of Meynert pathology (neuron loss, tangles, and Lewy bodies), but not with local cortical pathology.4 The heterogeneity of degeneration of cholinergic neurons in the basal forebrain and its relative independence from cortical pathology suggests primary involvement of the basal forebrain in Parkinson's disease, by contrast with probable retrograde damage in Alzheimer's disease and dementia with Lewy bodies confirmed by defective retrograde transport of nerve growth factor to the nucleus basalis of Meynert in Alzheimer's disease.5
These morphological differences in the degeneration of the cholinergic forebrain system between various dementing neurodegenerating disorders are, at least in part, supported by the data presented by Shiozakiet al 1 indicating differences between Alzheimer's disease and dementia with Lewy bodies as are also to be suggested between Alzheimer's disease and Parkinson's disease. These and other genetic, morphological, and biochemical differences between the three disorders may strengthen the hypothesis that they represent different nosological entities. This, however, needs further confirmation.
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