This Pilot Project will initiate studies on brain specimens of elderly psychiatric patients who 40+ years ago underwent frontal lobotomy. In conjunction with an ongoing Program to study biologic issues related to schizophrenia we are actively collecting brain specimens derived from patients in a large psychiatric hospital. In this hospital we have identified a large cohort of post-lobotomy patients who are sufficiently old to be at high risk of dying and being autopsied in conjunction with the schizophrenia Program. The lobotomy procedure leaves the rostral prefrontal cortex intact while mechanically severing its efferent and afferent connections to the rest of the brain. The proposed pilot project will examine aspects of the connectivity hypothesis of Alzheimer's disease. This hypothesis suggests that the distribution of the lesions associated with Alzheimer's disease follows consistent patterns which coincide with certain neuroanatomic pathways with selective involvement of neurons having long corticocortical projection pathways. Furthermore, the connectivity hypothesis proposes that the progressive sequence of involvement of brain structures by the lesions of Alzheimer's disease is governed by their neuroanatomic connections. The availability of this unique source of elderly post-lobotomy brain specimens will allow us to investigate whether the rostral prefrontal cortex, effectively deafferented from the remainder of the brain, will develop neuropathologic lesions associated with Alzheimer's disease of long corticocortical neuronal connections for over 40 years. We will specifically investigate the extent and distribution of neurofibrillary tangles, senile plaques and dystrophic neurites in the rostral prefrontal cortex as compared to the involvement in neocortical regions with remaining connections and in non-operated schizophrenia subjects with a comparable degree of neocortical senile changes. This pilot project will allow us to begin to test whether long corticocortical connections re required for the formation of these important features of Alzheimer's disease and thus test crucial aspects of the connectivity hypothesis. Preliminary data are presented to indicate that we have already collected some brain specimens which are appropriate for this study. In these specimens senile plaques, surrounded by dystrophic neurites, do appear in the deafferented prefrontal cortex while neurofibrillary tangles are rare. The results of this pilot project will be used to apply for further support of a more detailed study of these important issues in these unique brain specimens.
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