This is an application for a Scientist Development Award for Clinicians. The proposed project addresses the problem of agitation and aggression in Alzheimer's disease (AD), symptoms which often lead to the most distress and greatest burden on patients, families and the health care system. Norepinephrine is evidenced to be involved in the mediation and modulation of aggressive behaviors in limbic regions of the brain. The proposed studies examine the pathology of beta-adrenergic receptors in the brains of Alzheimer's disease patients, with particular attention paid to those patients displaying agitated and aggressive behaviors, in order that better treatment strategies can be developed for this debilitating problem. By autoradiographic localization and in situ hybridization, it will be determined which brain regions and cell populations contain beta- adrenergic receptors in the normal, aging human brain. Other specific questions to be addressed include: (i) What changes in distribution or concentration of beta-adrenergic receptor subtypes (beta1 and beta2) are evident in AD? (ii) Are there any changes specific to the subpopulation of AD patients with aggressive behaviors and agitation? (iii) What relation do these receptor changes have to putative neuroanatomical loci of aggression? (iv) To what cell type(s) (neurons, astrocytes, microglia or blood vessels) are beta-adrenergic receptors in these brain areas localized? (v) Which of the known products of beta-adrenergic receptor activation -i.e. nerve growth factor- are present in these brain areas, and altered in AD? These questions will be addressed using the above localization techniques on autopsy tissue from the UCI Alzheimer's Disease Research Center (ADRC) Repository Core.
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