POSITRON EMISSION TOMOGRAPHY (PET) STUDIES OF CHOLINERGIC MODULATION IN ALZHEIME

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Previous investigations of neurochemical deficits in Alzheimer's disease (AD) have evaluated individual neurotransmitter systems in post-mortem brain tissue at the end stage of the disease or in plasma or cerebrospinal fluid (CSF). These studies have most consistently implicated a presynaptic cholinergic deficit and the strength of these findings led to a cholinergic hypothesis of memory dysfunction and AD. Several lines of evidence indicate that the neurochemical pathology in AD involves more than a cholinergic deficit: (1) attempts to reverse the cholinergic deficit by treatment with cholinergic agents have not been consistently efficacious and have not stopped disease progression, (2) animal models of AD involving lesions of the cholinergic system have only mimicked some aspects of AD, and, (3) neuropathologic studies have reported deficits in other neurotransmitter systems (e.g. serotonin, dopamine, glutamate). While it is likely that the symptomatology in AD is produced by multiple neurotransmitter deficits, based on the consistency and severity of the cholinergic deficit in AD, the cholinergic system must still be central to the pathophysiology of AD. To integrate the present knowledge concerning the neurochemistry of AD and the consistent neuroanatomic and neurophysiologic observations that neurotransmitter systems function synergistically, not in isolation, the proposed study will test the novel hypotheses that AD represents a failure of acetylcholine to modulate other functionally-linked neurotransmitters and that the mechanism of action of cholinergic therapies involves the modulation of other neurotransmitters. The study will evaluate whether chronic treatment with cholinesterase inhibitors affects serotonin function in mild AD patients and whether these secondary effects relate to clinical improvement. The cholinesterase inhibitor selected for use in this study (galantamine) increases concentrations of acetylcholine and allosterically modulates the nicotinic receptor, which should result in a greater net effect on dopamine and serotonin systems as compared to the other available cholinesterase inhibitors. Neuroanatomic and neurophysiologic studies have demonstrated the role of presynaptic nicotinic receptors in modulating the release of dopamine and serotonin.