Cell loss in the nucleus basalis is related to regional cortical atrophy in Alzheimer's disease
Section snippets
Case selection
The brains from eight patients with a clinical diagnosis of probable AD (brain donors) and 12 controls were collected (with consent) at autopsy from Royal Prince Alfred Hospital, the NSW Institute of Forensic Medicine and Concord Repatriation General Hospital (Table 1). The Alzheimer cases had been enrolled in a case-control study at Concord Hospital and studied prospectively.[6]All AD cases were diagnosed with probable AD during life.
Several guidelines governed the inclusion of patients in the
Cholinergic nucleus basalis pathology
In all AD cases, there was an obvious reduction in calbindin-positive neuropil. Calbindin-positive neurons in AD cases were generally very darkly stained compared to controls, often obscuring the normally well-defined, nucleus (Fig. 1d,f,h). Frequently, calbindin-positive neurons resembled the morphology of globose tangles, with a single stubbed tail-like process and a densely stained focus within the cell body (Fig. 1h). The calbindin-stained fibres in the Ch4 were often of thicker calibre
Discussion
The most significant finding of the present study is that residual Ch4 cell number is positively correlated with cortical volume in controls and AD, suggesting a link between cortical cholinergic innervation and cortical volume. No previous studies of AD have analysed cholinergic cell loss and cortical atrophy in concert. Although a correspondence between Ch4 cell number and cortical volumes cannot be assumed to be causal, it strongly suggests a link between cortical atrophy and basal forebrain
Conclusions
The strong correlation between Ch4 cell number and cortical volume in AD and normal ageing noted in the present study was an was an unexpected finding. Cortical atrophy and cell loss in the Ch4 are accepted features of AD pathology; however, it is surprising that the two changes should occur so closely in parallel. An analogous change was not found for cortical histopathology (present analysis) or for the number of brainstem serotonin neurons.[20]As the latter neurons project to similar
Acknowledgements
We are very grateful for the technical assistance from Dale Brown, Heidi Cartwright, Michelle Svoboda, James Pearse and Stephen Kum-Jew. We thank Prof. Clive Harper and Dr Roger Pamphlett, Neuropathology Unit, Department of Pathology, University of Sydney, for neuropathological diagnosis. This work was funded by grants from the National Health and Medical Research Council of Australia, the Medical Foundation of the University of Sydney and the Rebecca Cooper Foundation. K. M. Cullen is an NH
References (51)
- et al.
Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer's disease
Neuroscience
(1985) - et al.
Topography of brain atrophy during normal aging and Alzheimer's disease
Neurobiol. Aging
(1996) - et al.
Reproducible sampling regime for specific cortical regions: application to speech-associated areas
J. Neurosci. Meth.
(1996) - et al.
Localization of nerve growth factor receptors in cholinergic neurons of the human basal forebrain
Neurosci. Lett.
(1986) - et al.
Cell loss and nuclear hypertrophy in topographical subdivisions of the nucleus basalis of Meynert in Alzheimer's disease
Neuroscience
(1991) - et al.
Fiber pathways of basal forebrain cholinergic neurons in monkeys
Brain Res.
(1987) - et al.
Basal forebrain control of cortical cerebral blood flow is independent of local cortical neurons
Brain Res.
(1993) - et al.
Thalamic nuclei in Alzheimer disease: evidence against the cholinergic hypothesis of plaque formation
Brain Res.
(1989) - et al.
No global neocortical nerve cell loss in brains from patients with senile dementia of the Alzheimer type
Neurobiol. Aging
(1994) - et al.
Cell loss and shrinkage in the nucleus basalis of Meynert complex in Alzheimer's disease
Neurobiol. Aging
(1990)
The pharmacotherapy of Alzheimer's disease based on the cholinergic hypothesis: an update
Neurodegeneration
Über eigenartige Krankheitsfaelle des spaeteren Alterns
Z. Neurol. Psychiat.
Loss of neurons in the nucleus basalis of Meynert in Alzheimer's disease, paralysis agitans and Korsakoff's disease
Acta neuropath.
Senile plaques, amyloid β-protein, and acetylcholinesterase fibres: laminar distributions in Alzheimer's disease striate cortex
Acta neuropath.
Neuropathological staging of Alzheimer-related changes
Acta neuropath.
A case control study of Alzheimer's disease in Australia
Neurology
Pathological correlates of the cerebral microvasculature in Alzheimer's disease and related dementing disorders
Acta neuropath.
Nucleus basalis of Meynert neurons contain vitamin D induced calcium binding protein
Anat. Embryol.
Improved specificity in the visualization of neurofibrillary tangles, senile plaques and neuropil threads
Neurodegeneration
Tacrine in Alzheimer's disease: a double blind placebo controlled, multicentre study
New Engl. J. Med.
The CERAD experience, Part VIII: neuroimaging–neuropathology correlates of temporal lobe changes in Alzheimer's disease
Neurology
A controlled clinical trial of tacrine in Alzheimer's disease
J. Am. med. Ass.
Rapid, reliable and economical silver stain for neurofibrillary tangles and senile plaques
J. Histotech.
Systematic regional variations in the loss of cholinergic fibers in Alzheimer's disease
Cerebral Cortex
Hippocampal atrophy in normal human aging. An association with recent memory impairment
Arch. Neurol.
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