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P4‐352: AREA UNDER THE CURVE (AUC) POOLED ANALYSIS OF FOUR RANDOMIZED CLINICAL TRIALS SHOWS CUMULATIVE BENEFITS OF MEMANTINE‐DONEPEZIL COMBINATION OVER COMPONENT MONOTHERAPIES ACROSS CLINICAL DOMAINS IN ALZHEIMER'S DEMENTIA
Author(s) -
Atri Alireza,
Hendrix Suzanne,
Pejovic Vojislav,
Hofbauer Robert K.,
Edwards John,
Graham Stephen M.
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.07.122
Subject(s) - donepezil , memantine , medicine , placebo , area under the curve , clinical trial , randomized controlled trial , cholinesterase , dementia , disease , pathology , alternative medicine
Background: Synapse loss and dysfunction characteristic of Alzheimer’s disease (AD) have been linked to the degeneration of neuronal membranes and increased breakdown of membrane phospholipids. Recent studies have demonstrated lower plasma levels of several phospholipid species in AD and/or mild cognitive impairment (MCI) subjects compared with those in healthy individuals. Most interestingly, Mapstone (2014, Nat Med) validated a prognostic biomarker panel of 10 plasma lipids that could predict conversion to MCI/AD within 2-3 years with >90% accuracy. The lower levels of these lipids, particularly phosphatidylcholine species, could reflect altered phospholipid metabolism in the brain and periphery. Methods: We tested in drug-na€ıve patients with very mild to mild AD, a nutritional intervention (Souvenaid , 125mL, taken once daily) containing a specific nutrient combination in a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial. Baseline and 24-week plasma samples of patients taking either the investigational or control product were analyzed for lipid profiles at the Kansas Lipidomics Research Center using ESI-MS/ MS.Results: Five of the 7 measured phosphatidylcholine species described by Mapstone, were significantly increased following the 24-week treatment with the nutrient combination. Plasma concentration (mM; mean (s.d.)) among patients taking the investigational product increased as follows: phosphatidylcholine diacyl (PCaa)-C36:6: +0.66 (0.79); PCaa-C38:0: +1.42 (2.00); PCaa-C38:6: +81.14 (36.74); PCaa-C40:6: +33.58 (16.95); phosphatidylcholine acyl-alkyl (PCae)-C40:6: +3.27 (1.88); (all P<0.001, change from baseline using paired t-test; and all P<0.0001, investigational vs. control product using ANCOVA). Conclusions: These results indicate that a biomarker profile reflecting disturbed phospholipid metabolism and perhaps indicative of early neurodegeneration can be modified in AD by providing nutrients which rate-limit phospholipid biosynthesis. These nutrients are substrates in the Kennedy pathway which synthesizes the phospholipids present in synaptic membranes and could thus ameliorate synaptic degeneration in AD. Previous observations from the same study indicate that this nutritional intervention improves memory performance (Scheltens, 2012, JAD), and preserves brain network organization in AD patients (de Waal, 2014, PLoS One), which both may result from enhanced formation of synaptic membranes. Our findings suggest that the nutritional intervention may also be useful in asymptomatic subjects with a plasma lipid profile prognostic of AD. Souvenaid is a registered trademark of N.V. Nutricia.