| The thesis was designed to address two major questions about the pathogenesis of Alzheimer's disease. These are: one, does Alzheimer's disease "spread" throughout the brain along neuroanatomical pathways? And two, can the histopathological lesions of Alzheimer's disease be the result of degeneration of a single neuronal system? The investigation began by comparing the pattern of cerebral gliosis in Alzheimer's disease (AD) with that seen in normal aging. This was done using an immunoperoxidase stain for glial fibrillary acidic protein (GFAP) to reveal astrocytic gliosis within whole-hemisphere sections. Gliosis was most severe, and most consistently seen, in the cerebral cortex and hippocampus. Subcortical nuclei were inconsistently affected. Within the cortex, the laminae which are most severely affected are II, III and V. Distinct bands of gliosis were present in these laminae in at least some cortical areas in every AD brain. The pattern of gliosis within area 17, the primary visual area, was anomalous in that there was a thin band of gliosis at the border between layers IVc and V. This was matched by a line of senile plaques at the same site, revealed using an enhanced Bielschowsky stain. Such a precise disposition implies a neuronal origin for these plaques, but there is no known afferent system which is concentrated along this line. Specific afferent systems to layers IVc and V of area 17 were then examined histologically for evidence of morphological relationships to senile plaques. Only cholinergic elements were in obvious relation to senile plaques; in addition, only cholinergic elements showed evidence of depletion and morphological abnormality. In the last part of the thesis, the distribution of amyloid {dollar}beta{dollar}-protein (A{dollar}beta{dollar}P) in area 17 was studied using an immunoperoxidase method. This was found to differ substantially from the distribution of senile plaques, with obvious bands of dense staining in layers I and IVc, layers that did not possess significantly larger numbers of plaques as seen with the enhanced Bielschowsky method. Acetylcholinesterase-positive fibres within area 17 were co-distributed with A{dollar}beta{dollar}P to layers I and IVc, providing further evidence that amyloid may be formed at cholinergic fibres. The results of this thesis are most compatible with the hypothesis that Alzheimer's disease represents a primary degeneration of the cholinergic system of the nucleus basalis of Meynert. A review of the literature suggests that current opinion relegating the cholinergic degeneration to a secondary role is not adequately substantiated. |
