In normal human aging the remaining neurons of two areas of the hippocampal region have been found to compensate for age-related neuronal loss by proliferating new dendrites. In Alzheimer's disease (AD) the layer II pyramidal neurons of the parahippocampal gyrus fail to show this compensatory response, in spite of a probable, exaggerated disease-related loss of neurons. In AD the dentate gyrus granule cells of the hippocampus also show a reduced amount of the compensatory response. This failure of the AD brain to show the normal compensatory plastic response, seen in normal aging as dendritic growth, may be viewed as one of the pathophysiological processes of the disease.

This paper describes the comparability of counts in the locus coeruleus made from serial sections and those made from a single section at the point of greatest density of neurons. Samples of the locus coeruleus neuronal population derived from single section counts though not exactly comparable, are of comparable utility to those obtained from more laborious total neuronal counts. The simpler method was used to examine the hypothesis that there are subtypes of senile dementia of the Alzheimer type. Separation into two groups was achieved when independent variables of cortical neuronal counts and tangle estimates were used. This finding adds to the growing evidence that Alzheimer's disease of the senile type is not a unitary disorder.

The brains of most demented patients show at autopsy the lesions of Alzheimer's disease (AD). However, the brains of other demented patients show either no morphological changes or lesions distinct from those of AD. We report clinicopathological studies on two diseases in this latter group. The study of these diseases can improve our understanding of AD.

Pick's disease is characterized by dementia, lobar cerebral atrophy, and neuronal cytoplasmic inclusions. Most cases, which we have called “classical”, show inclusions made up of straight fibrils that are immunologically cross-reactive with the paired helical filaments of AD. In other “generalized” cases, similar fibrils are coated by granular material and are less reactive with anticytoskeletal antibodies.

In contrast to the cytoplasmic localization of the lesions in Pick's disease, it is the cell nucleus that shows abnormalities in neuronal intranuclear hyaline inclusion disease. This disease can present clinically as dementia of adult onset. Thus, either nuclear or cytoplasmic lesions can produce a pattern of neuronal dysfunction resulting in dementia.

Three patients with clinical Alzheimer's disease were found at postmortem examination to have Lewy-bodies and Lewy-like bodies in the cerebral cortex and the pigmented brainstem nuclei. Neuritic plaques were found in neocortical areas but no neurofibrillary tangles. The distribution of cortical neuronal inclusions correlated with the proposed projection of dopamine terminals. Neuronal cell loss was marked in the ventral tegmental area (paranigral nucleus) and the basal nucleus of Meynert, suggesting a defect in dopaminergic and cholinergic innervation of the cerebral cortex. Immunohistochemical investigations revealed positive staining of cortical Lewy- and Lewy-like bodies for monoclonal antibodies to phosphorylated neurofilaments (03-44, 06-17, 04-7). Also cerebral neurons containing no inclusions showed positivity, suggesting an early neurofilament abnormality, preceding the formation of Lewy-type inclusions.

The effects of bilateral ibotenic acid-induced lesions of the nucleus basalis magnocellularis (nBM) on the acquisition and retention of several spatial memory tasks were studied in the rat. Maintenance of spatial memory in a food search task was impaired following nBM lesions. Acquisition of spontaneous alternation and reinforced alternation in a T-maze was also significantly impaired in animals with these lesions. In contrast, the animals with nBM lesions were not impaired in the acquisition of a position habit in a T-maze. In several of the tasks there was evidence of some learning in the lesioned animals after substantial training, although they were significantly deficient when compared with the controls. Administration of the cholinergic agonists physostigmine sulfate or pilocarpine nitrate prior to behavioral testing resulted in a rapid and significant improvement in the performance of the lesion animals. The ibotenate-induced lesions significantly reduced the activity of choline acetyltransferase (CAT) in the anterior and the posterior neocortex. Hippocampal CAT activity was not changed. The results indicate that the cholinergic projections originating in the nBM are involved in the learning and memory of spatial tasks. They also suggest that degeneration of cholinergic neurons in the basal forebrain contributes significantly to the learning and memory deficits observed in Alzheimer's disease.