Despite the widespread use of one acetylcholinesterase-inhibitor (AChE- I), donepezil, for treating cognitive deficits of Alzheimer's disease (AD), the efficacy of this and other AChE-I drugs has been modest, and highly variable. As most clinical trials of AChE-I agents have focused on gaining regulatory approval, little is known about what clinical symptoms in AD respond best to AChE-I therapy agents have focused on gaining regulatory approval, little is known about what clinical symptoms in AD respond best to AChE-I therapy. Preliminary work suggests that the primary cognitive effect of AChE-I therapy is on attention, rather than short-term memory, and there is burgeoning evidence that various non- cognitive symptoms in AD patients, particularly apathy, may also benefit from AChE-I therapy. Functions of attention and apathy have been shown to be functionally related to the prefrontal cortex.
The aim of this study is to examine the degree to which cerebral cholinergic deficits, as measured by in vivo AChE binding activity using PET neuroimaging, are associated with clinical responsivity to AChE-I therapy. AChE PET imaging is a novel approach to s to the study of acetylcholine in the living. This study, to be hypothesis that AD patients have lower global cortical AChE binding activity compared to normal control subjects. In addition, we will examine the second hypothesis that specific symptom manifestations (i.e. attentional deficits and apathy) across AC patients may be a robust marker of regional (prefrontal) decreases in AChE activity, and associated with greater responses to donepezil in a 12 week open-label trial. The over-arching goal of this study is to evaluate clinical therapeutic challenge in conjunction with in vivo marker of AChE activity before and after donepezil treatment to identify specific clinical identifications for the use of AChE-I therapy. We will also study cerebral glucose metabolism before and after donepezil treatment in a subset of patients.
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