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. Although alterations in the serotonergic system have been broadly demonstrated in Alzheimer's disease (AD), changes in the 5-HT1A receptor has never been properly studied. The recent emergence of 5-HT1A antagonists that can be safely used in humans now makes this possible. The 5-HT1A receptor is known to be involved with cognition and behaviour, both of which are disrupted in AD. Furthermore, animal studies suggest that 5-HT1A antagonists may play a therapeutic role in AD via modulation of the gluatmatergic system. As a result, it is important to ascertain whether or not 5-HT1A receptors are disrupted in AD and the magnitude and time course of these changes. Therefore, we aimed to determine if 5-HT1A receptors are decreased in early AD using positron emission tomography (PET). Ten patients who meet NINCDS-ADRDA criteria for probable AD with mild to moderate symptomatology were recruited. All patients will had a full neuropsychiatric assessment that includes measures of general functional capacity, cognitive function and noncognitive function. An equal number of age- and sex-matched controls with intact cognition were also recruited from the community. Patients and controls were free from 5-HT1A-specific medications prior to initiation of the study. After screening for inclusion, each group was administered a 10mCi intravenous injection of the 5-HT1A antagonist, [11C] WAY100635, followed by a PET scan 75 minutes post-injection. Both subjects and controls also underwent an MRI scan that was co-registered with the PET scan. The MRI was be used to determine the location of the regions of interest and to adjust for brain atrophy in the participants. In addition to using a broad region of interest analysis between groups (i.e., comparison of bilateral frontal, temporal, parietal and occipital cortices) smaller areas, such as the hipppocampus, was be compared through a pixel-by-pixel analysis to determine whether local differences exist. Identifying 5-HT1A dysfunction in AD is the first step in elucidating the role of this system in AD and determining its potential as a therapeutic target.
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