EXCEED THE SPACE PROVIDED. Several large epidemiological studies have associated a profound reduction in the incidence of Alzheimer's Disease (AD) in older individuals who took non-steroidal anti-inflammatory drugs (NSAIDs) for longer than 2 years. However, clinical trials of NSAIDs in patients with established AD failed to show efficacy. This has led to the hypothesis that NSAIDs suppress pathologic processes critical to the initiation of AD and that these processes may be related to inhibition of the cyclooxygenase enzymes and subsequent prostaglandin (PG) production. We propose to test this hypothesis by quantifying endogenous eicosanoid production in subjects enrolled in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), an NIA-sponsored study of NSAIDs in the prevention of AD. Specifically, we will 1) determine the efficacy of selective and non- selective NSAIDs t o suppress 1 evels o f quantitative b iomarkers o f P G p reduction systemically and in t he central nervous system of ADAPT participants; 2) determine the efficacy of NSAIDs to suppress levels of quantitative biomarkers of oxidative damage systemically and in the central nervous system of ADAPT participants; and 3) correlate changes in the levels of biomarkers of PG production and oxidative damage with rates of cognitive decline as determined in ADAPT. We have developed highly accurate and precise mass spectrometric assays to quantify PGs, PG metabolites, and lipid peroxidation products and are routinely performing these assays in our laboratory. These studies will provide important insights into the mechanisms by which NSAIDs prevent AD. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024010-03
Application #
6933146
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (J2))
Program Officer
Molchan, Susan
Project Start
2003-09-30
Project End
2008-08-31
Budget Start
2005-09-15
Budget End
2006-08-31
Support Year
3
Fiscal Year
2005
Total Cost
$310,381
Indirect Cost
Name
University of Washington
Department
Psychiatry
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Reckess, Gila Z; Brandt, Jason; Luis, Cheryl A et al. (2013) Screening by telephone in the Alzheimer's disease anti-inflammatory prevention trial. J Alzheimers Dis 36:433-43
Breitner, John C; Baker, Laura D; Montine, Thomas J et al. (2011) Extended results of the Alzheimer's disease anti-inflammatory prevention trial. Alzheimers Dement 7:402-11
Montine, Thomas J; Sonnen, Joshua A; Milne, Ginger et al. (2010) Elevated ratio of urinary metabolites of thromboxane and prostacyclin is associated with adverse cardiovascular events in ADAPT. PLoS One 5:e9340
Breitner, J C S; Haneuse, S J P A; Walker, R et al. (2009) Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology 72:1899-905
Sonnen, Joshua A; Montine, Kathleen S; Quinn, Joseph F et al. (2008) Biomarkers for cognitive impairment and dementia in elderly people. Lancet Neurol 7:704-14
Sonnen, Joshua A; Breitner, John C; Lovell, Mark A et al. (2008) Free radical-mediated damage to brain in Alzheimer's disease and its transgenic mouse models. Free Radic Biol Med 45:219-30