Oxylipin Profiling of Alzheimer’s Disease in Nondiabetic and Type 2 Diabetic Elderly
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Metabolic and Cognitive Characterization
4.2. Measurement of Serum Non-Esterified Oxylipins
4.3. Statistical Analyses
4.3.1. Pre-Processing of Data.
4.3.2. Univariate and Multivariate Assessments.
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Metabolites 1 | Cognitively Healthy (n = 39) 2 | Alzheimer’s Disease (n = 39) 2 | P 3 | FDR 4 | Sub-Class | Fatty Acid Precursor |
---|---|---|---|---|---|---|
Total Fatty Acid Alcohol | 209 (110, 490) | 267 (140, 500) | 0.295 | 0.965 | Fatty Acid Alcohol | - |
14-HDoHE | 22.9 (8.3, 52) | 25.9 (14, 53) | 0.376 | 0.965 | Fatty Acid Alcohol | C22:6n3 |
12S-HETE | 93.8 (39, 220) | 119 (46, 250) | 0.386 | 0.965 | Fatty Acid Alcohol | C20:4n6 |
9-HOTE | 1.21 (0.82, 2.1) | 1.13 (0.81, 1.7) | 0.470 | 0.965 | Fatty Acid Alcohol | C18:3n3 |
17-HDoHE | 1.72 (1.1, 3.1) | 1.91 (1.4, 3.1) | 0.471 | 0.965 | Fatty Acid Alcohol | C22:6n3 |
5S-HEPE | 0.553 (0.37, 0.93) | 0.563 (0.35, 0.75) | 0.486 | 0.965 | Fatty Acid Alcohol | C20:5n3 |
11-HETE | 1.53 (0.92, 2.2) | 1.41 (0.89, 2.1) | 0.580 | 0.965 | Fatty Acid Alcohol | C20:4n6 |
13-HOTE | 1.96 (1.3, 3) | 1.88 (1.4, 2.6) | 0.580 | 0.965 | Fatty Acid Alcohol | C18:3n3 |
9-HODE | 17.8 (14, 35) | 19 (15, 24) | 0.643 | 0.965 | Fatty Acid Alcohol | C18:2n6 |
5-HETE | 3.72 (2.7, 4.8) | 3.75 (3.3, 4.5) | 0.668 | 0.965 | Fatty Acid Alcohol | C20:4n6 |
15-HETE | 3.1 (2.2, 5.4) | 3.68 (2.4, 5) | 0.681 | 0.965 | Fatty Acid Alcohol | C20:4n6 |
12S-HEPE | 5.72 (2, 12) | 5 (2.3, 13) | 0.695 | 0.965 | Fatty Acid Alcohol | C20:5n3 |
15-HEPE | 0.313 (0.21, 0.65) | 0.369 (0.21, 0.56) | 0.762 | 0.965 | Fatty Acid Alcohol | C20:5n3 |
9-HEPE | 0.235 (0.17, 0.46) | 0.268 (0.16, 0.41) | 0.824 | 0.972 | Fatty Acid Alcohol | C20:5n3 |
8S-HETE | 0.907 (0.62, 1.3) | 0.876 (0.68, 1.3) | 0.908 | 0.972 | Fatty Acid Alcohol | C20:4n6 |
9-HETE | 0.879 (0.61, 1.2) | 0.864 (0.61, 1.3) | 0.915 | 0.972 | Fatty Acid Alcohol | C20:4n6 |
13S-HODE | 26.7 (19, 46) | 27.6 (20, 36) | 0.957 | 0.972 | Fatty Acid Alcohol | C18:2n6 |
4-HDoHE | 0.596 (0.32, 1.1) | 0.592 (0.4, 0.89) | 0.965 | 0.972 | Fatty Acid Alcohol | C22:6n3 |
14,15-DiHETrE | 0.633 (0.51, 0.77) | 0.738 (0.64, 0.89) | 0.021 | 0.510 | Fatty Acid Diol | C18:3n3 |
11,12-DiHETrE | 0.509 (0.41, 0.62) | 0.599 (0.46, 0.75) | 0.027 | 0.510 | Fatty Acid Diol | C20:4n6 |
5,6-DiHETrE | 0.332 (0.23, 0.43) | 0.38 (0.3, 0.45) | 0.044 | 0.514 | Fatty Acid Diol | C20:4n6 |
8,9-DiHETrE | 0.296 (0.23, 0.38) | 0.367 (0.29, 0.42) | 0.045 | 0.514 | Fatty Acid Diol | C20:4n6 |
LTB4 | 0.763 (0.49, 1.4) | 1.02 (0.68, 1.6) | 0.059 | 0.564 | Fatty Acid Diol | C20:4n6 |
19,20-DiHDPE | 1.55 (1.3, 2) | 1.74 (1.3, 2.6) | 0.155 | 0.930 | Fatty Acid Diol | - |
9,10-DiHODE | 0.182 (0.11, 0.27) | 0.26 (0.14, 0.34) | 0.163 | 0.930 | Fatty Acid Diol | C18:3n3 |
9,10-e-DiHO | 5.02 (4.2, 6) | 4.92 (4.2, 5.5) | 0.437 | 0.965 | Fatty Acid Diol | C18:0 |
17,18-DiHETE | 4.97 (2.9, 7.2) | 5.41 (3.2, 8.6) | 0.448 | 0.965 | Fatty Acid Diol | C20:5n3 |
6-trans-LTB4 | 0.209 (0.11, 0.29) | 0.214 (0.14, 0.35) | 0.596 | 0.965 | Fatty Acid Diol | C20:4n6 |
15,16-DiHODE | 6.52 (5.2, 9.6) | 7.43 (5.5, 11) | 0.646 | 0.965 | Fatty Acid Diol | C18:3n3 |
9,10-DiHOME | 3.08 (2.5, 4.2) | 3.2 (2.5, 4.4) | 0.701 | 0.965 | Fatty Acid Diol | C18:2n6 |
Total Fatty Acid Diol | 30 (27, 32) | 28.3 (24, 36) | 0.872 | 0.972 | Fatty Acid Diol | - |
14,15-DiHETE | 0.605 (0.35, 0.92) | 0.548 (0.41, 0.81) | 0.931 | 0.972 | Fatty Acid Diol | C20:5n3 |
12(13)Ep-9-KODE | 5.35 (2, 11) | 4.22 (1.6, 9.4) | 0.471 | 0.965 | Fatty Acid Epoxide | C18:3n3 |
12(13)-EpOME | 2.04 (1.5, 3.1) | 2.38 (1.6, 3.2) | 0.580 | 0.965 | Fatty Acid Epoxide | C18:2n6 |
Total Fatty Acid Epoxide | 15.4 (9.9, 23) | 12.5 (8.9, 23) | 0.580 | 0.965 | Fatty Acid Epoxide | - |
9,10-EpO | 1.35 (1.1, 1.7) | 1.31 (1.1, 1.6) | 0.621 | 0.965 | Fatty Acid Epoxide | C18:0 |
19(20)-EpDPE | 0.179 (0.14, 0.24) | 0.197 (0.14, 0.29) | 0.794 | 0.972 | Fatty Acid Epoxide | C22:6n3 |
9(10)-EpOME | 0.829 (0.57, 1.2) | 0.924 (0.65, 1.4) | 0.858 | 0.972 | Fatty Acid Epoxide | C18:2n6 |
15,16-EpODE | 1.33 (0.86, 1.9) | 1.39 (0.87, 2.2) | 0.922 | 0.972 | Fatty Acid Epoxide | C18:3n3 |
Total Fatty Acid Ketone | 24.6 (20, 54) | 22.8 (14, 31) | 0.150 | 0.930 | Fatty Acid Ketone | - |
9-KODE | 14.5 (9.6, 28) | 13 (6.9, 20) | 0.168 | 0.930 | Fatty Acid Ketone | C18:2n6 |
15-KETE | 0.287 (0.18, 0.48) | 0.221 (0.15, 0.37) | 0.179 | 0.930 | Fatty Acid Ketone | C20:4n6 |
13-KODE | 5.87 (3.3, 12) | 4.26 (2.2, 8.5) | 0.252 | 0.965 | Fatty Acid Ketone | C18:2n6 |
5-KETE | 0.342 (0.25, 0.55) | 0.36 (0.24, 0.45) | 0.574 | 0.965 | Fatty Acid Ketone | C20:4n6 |
9,12,13-TriHOME | 3.68 (2.7, 4.3) | 3.54 (2.3, 4.7) | 0.735 | 0.965 | Fatty Acid Triol | C18:2n6 |
10-Nitrooleate | 1.46 (1.1, 2.3) | 1.2 (0.88, 1.6) | 0.026 | 0.510 | Nitro-fatty Acid | C18:1n9 |
6-keto-PGF1alpha | 0.22 (0.2, 0.24) | 0.213 (0.19, 0.23) | 0.315 | 0.965 | Prostanoid | C20:4n6 |
PGF2alpha | 0.422 (0.25, 0.71) | 0.518 (0.29, 0.88) | 0.507 | 0.965 | Prostanoid | C20:4n6 |
Total Prostanoid | 0.745 (0.62, 1.1) | 0.816 (0.6, 1.2) | 0.714 | 0.965 | Prostanoid | - |
15-deoxy PGJ2 | 0.115 (0.11, 0.12) | 0.114 (0.11, 0.12) | 0.727 | 0.965 | Prostanoid | C20:4n6 |
TXB2 | 3.24 (0.16, 20) | 0.839 (0.2, 14) | 0.534 | 0.965 | Thromboid | C20:4n6 |
Total C18:0 species | 6.49 (5.3, 7.1) | 6.14 (5.6, 6.9) | 0.456 | 0.965 | - | C18:0 |
Total C18:2n6 species | 73.6 (58, 140) | 76.8 (56, 100) | 0.574 | 0.965 | - | C18:2n6 |
Total C22:6n3 species | 45.3 (26, 98) | 37.8 (19, 83) | 0.723 | 0.965 | - | C22:6n3 |
Total C20:5n3 species | 14.3 (8.9, 26) | 13.9 (9, 20) | 0.747 | 0.965 | - | C20:5n3 |
Total C20:4n6 species | 184 (78, 390) | 138 (96, 290) | 0.888 | 0.972 | - | C20:4n6 |
Total C18:3n3 species | 20.5 (13, 31) | 19.3 (14, 28) | 0.972 | 0.972 | - | C18:3n3 |
Metabolites 1 | Cognitive Healthy (n = 22) 2 | Alzheimer’s Disease (n = 19) 2 | P 3 | FDR 4 | Sub-Class | Fatty Acid Precursor |
---|---|---|---|---|---|---|
17-HDoHE | 1.57 (1.1, 2.2) | 3.22 (2.1, 4.5) | 0.014 | 0.523 | Fatty Acid Alcohol | C22:6n3 |
Total Fatty Acid Alcohol | 228 (120, 290) | 421 (250, 690) | 0.041 | 0.523 | Fatty Acid Alcohol | - |
12S-HEPE | 4.06 (3.4, 8) | 6.94 (3.5, 27) | 0.156 | 0.697 | Fatty Acid Alcohol | C20:5n3 |
9-HODE | 20.1 (17, 26) | 18.2 (15, 24) | 0.237 | 0.697 | Fatty Acid Alcohol | C18:2n6 |
12S-HETE | 125 (49, 190) | 146 (86, 320) | 0.259 | 0.697 | Fatty Acid Alcohol | C20:4n6 |
15-HEPE | 0.242 (0.19, 0.55) | 0.357 (0.21, 0.83) | 0.270 | 0.697 | Fatty Acid Alcohol | C20:5n3 |
15-HETE | 3.67 (2.6, 4.4) | 3.78 (2.7, 6.5) | 0.281 | 0.697 | Fatty Acid Alcohol | C20:4n6 |
9-HEPE | 0.206 (0.14, 0.37) | 0.275 (0.14, 0.47) | 0.318 | 0.697 | Fatty Acid Alcohol | C20:5n3 |
14-HDoHE | 27.5 (16, 42) | 37.5 (19, 110) | 0.344 | 0.697 | Fatty Acid Alcohol | C22:6n3 |
9-HOTE | 1.2 (0.94, 1.6) | 1.06 (0.71, 1.6) | 0.445 | 0.724 | Fatty Acid Alcohol | C18:3n3 |
5S-HEPE | 0.473 (0.33, 0.65) | 0.553 (0.38, 0.85) | 0.460 | 0.729 | Fatty Acid Alcohol | C20:5n3 |
13S-HODE | 26.3 (22, 37) | 25.8 (22, 42) | 0.727 | 0.958 | Fatty Acid Alcohol | C18:2n6 |
4-HDoHE | 0.577 (0.44, 0.76) | 0.491 (0.37, 1.1) | 0.791 | 0.958 | Fatty Acid Alcohol | C22:6n3 |
5-HETE | 3.75 (3, 4.9) | 3.69 (3, 4.9) | 0.846 | 0.958 | Fatty Acid Alcohol | C20:4n6 |
8S-HETE | 0.832 (0.69, 1) | 0.85 (0.71, 1.1) | 0.846 | 0.958 | Fatty Acid Alcohol | C20:4n6 |
13-HOTE | 1.51 (1.3, 2.2) | 1.64 (1.2, 2.8) | 0.867 | 0.958 | Fatty Acid Alcohol | C18:3n3 |
11-HETE | 1.17 (1, 1.8) | 1.35 (0.92, 1.8) | 0.907 | 0.958 | Fatty Acid Alcohol | C20:4n6 |
9-HETE | 0.794 (0.69, 0.99) | 0.789 (0.69, 0.96) | 0.969 | 0.986 | Fatty Acid Alcohol | C20:4n6 |
17,18-DiHETE | 3.86 (2.9, 4.1) | 4.98 (4.2, 8) | 0.024 | 0.523 | Fatty Acid Diol | C20:5n3 |
14,15-DiHETE | 0.42 (0.36, 0.6) | 0.7 (0.61, 0.81) | 0.044 | 0.523 | Fatty Acid Diol | C20:5n3 |
9,10-DiHODE | 0.208 (0.084, 0.29) | 0.341 (0.18, 0.59) | 0.062 | 0.523 | Fatty Acid Diol | C18:3n3 |
15,16-DiHODE | 7.26 (6.1, 10) | 5.19 (4, 8.1) | 0.065 | 0.523 | Fatty Acid Diol | C18:3n3 |
6-trans-LTB4 | 0.211 (0.14, 0.27) | 0.318 (0.17, 0.41) | 0.134 | 0.697 | Fatty Acid Diol | C20:4n6 |
19,20-DiHDPE | 1.46 (1.4, 1.8) | 2.02 (1.4, 2.3) | 0.198 | 0.697 | Fatty Acid Diol | - |
5,6-DiHETrE | 0.39 (0.26, 0.42) | 0.401 (0.31, 0.52) | 0.293 | 0.697 | Fatty Acid Diol | C20:4n6 |
9,10-e-DiHO | 5.04 (4.5, 5.7) | 5.45 (4.3, 9.2) | 0.305 | 0.697 | Fatty Acid Diol | C18:0 |
8,9-DiHETrE | 0.341 (0.27, 0.39) | 0.38 (0.29, 0.46) | 0.357 | 0.697 | Fatty Acid Diol | C20:4n6 |
Total Fatty Acid Diol | 27.4 (22, 31) | 31.3 (26, 33) | 0.426 | 0.724 | Fatty Acid Diol | - |
14,15-DiHETrE | 0.692 (0.53, 0.83) | 0.71 (0.56, 0.93) | 0.578 | 0.876 | Fatty Acid Diol | C18:3n3 |
9,10-DiHOME | 2.71 (2.3, 3.9) | 2.98 (2.1, 4.2) | 0.697 | 0.958 | Fatty Acid Diol | C18:2n6 |
11,12-DiHETrE | 0.567 (0.43, 0.7) | 0.548 (0.44, 0.82) | 0.867 | 0.958 | Fatty Acid Diol | C20:4n6 |
LTB4 | 0.758 (0.43, 1.1) | 0.783 (0.3, 1.5) | 0.990 | 0.990 | Fatty Acid Diol | C20:4n6 |
15,16-EpODE | 1.56 (1.2, 2.3) | 0.887 (0.69, 1.9) | 0.073 | 0.523 | Fatty Acid Epoxide | C18:3n3 |
9,10-EpO | 1.55 (1.2, 2) | 1.19 (1, 1.7) | 0.164 | 0.697 | Fatty Acid Epoxide | C18:0 |
12(13)Ep-9-KODE | 2.08 (0.87, 6.7) | 3.38 (2, 10) | 0.232 | 0.697 | Fatty Acid Epoxide | C18:3n3 |
Total Fatty Acid Epoxide | 15.1 (8.6, 18) | 18.4 (15, 21) | 0.379 | 0.697 | Fatty Acid Epoxide | - |
19(20)-EpDPE | 0.205 (0.15, 0.24) | 0.218 (0.15, 0.29) | 0.600 | 0.876 | Fatty Acid Epoxide | C22:6n3 |
12(13)-EpOME | 1.85 (1.2, 3.1) | 2.07 (1.2, 3) | 0.826 | 0.958 | Fatty Acid Epoxide | C18:2n6 |
9(10)-EpOME | 0.778 (0.61, 1.4) | 0.781 (0.68, 1.2) | 0.887 | 0.958 | Fatty Acid Epoxide | C18:2n6 |
9-KODE | 12.6 (11, 20) | 10.2 (7.4, 15) | 0.141 | 0.697 | Fatty Acid Ketone | C18:2n6 |
13-KODE | 4.79 (3.9, 7.5) | 4.04 (2.3, 7.3) | 0.371 | 0.697 | Fatty Acid Ketone | C18:2n6 |
5-KETE | 0.287 (0.24, 0.54) | 0.284 (0.23, 0.34) | 0.688 | 0.958 | Fatty Acid Ketone | C20:4n6 |
15-KETE | 0.218 (0.15, 0.42) | 0.198 (0.17, 0.26) | 0.905 | 0.958 | Fatty Acid Ketone | C20:4n6 |
Total Fatty Acid Ketone | 19.9 (18, 35) | 21.2 (17, 34) | 0.905 | 0.958 | Fatty Acid Ketone | - |
9,12,13-TriHOME | 3.8 (2.3, 5.4) | 3.25 (2.2, 4.1) | 0.259 | 0.697 | Fatty Acid Triol | C18:2n6 |
10-Nitrooleate | 1.23 (0.86, 2.2) | 1.09 (0.75, 1.4) | 0.254 | 0.697 | Nitro-fatty Acid | C18:1n9 |
6-keto-PGF1alpha | 0.213 (0.19, 0.23) | 0.223 (0.21, 0.24) | 0.189 | 0.697 | Prostanoid | C20:4n6 |
Total Prostanoid | 0.71 (0.58, 0.88) | 0.953 (0.68, 1.1) | 0.314 | 0.697 | Prostanoid | - |
15-deoxy PGJ2 | 0.115 (0.11, 0.12) | 0.121 (0.11, 0.13) | 0.337 | 0.697 | Prostanoid | C20:4n6 |
PGF2alpha | 0.375 (0.26, 0.53) | 0.494 (0.35, 0.75) | 0.404 | 0.719 | Prostanoid | C20:4n6 |
TXB2 | 0.779 (0.49, 9.9) | 0.876 (0.25, 5.8) | 0.940 | 0.974 | Thromboid | C20:4n6 |
Total C22:6n3 species | 19.2 (11, 40) | 118 (75, 140) | 0.073 | 0.523 | - | C22:6n3 |
Total C18:2n6 species | 76 (64, 93) | 64.7 (57, 90) | 0.190 | 0.697 | - | C18:2n6 |
Total C20:5n3 species | 10 (7.7, 23) | 14.9 (7.9, 27) | 0.440 | 0.724 | - | C20:5n3 |
Total C18:0 species | 6.2 (5.7, 7.4) | 6.77 (5.7, 11) | 0.596 | 0.876 | - | C18:0 |
Total C20:4n6 species | 167 (130, 210) | 182 (130, 330) | 0.734 | 0.958 | - | C20:4n6 |
Total C18:3n3 species | 19.6 (16, 24) | 19.2 (13, 24) | 0.778 | 0.958 | - | C18:3n3 |
Nondiabetic Group (n = 84) | T2D Group (n = 42) | Notable Roles | |
---|---|---|---|
10-nitrooleate | Lower in AD | - | Nitric oxide synthase regulation [15] Inhibition of neutrophil chemotaxis via PPARγ activation [16,17] Damage mediation after reperfusion in cardiac ischemia [18] |
14,15-DiHETrE | Higher in AD | - | Promotes vasodilation in preclinical models [19,20] Elevated in pregnancy-related hypertension [21] |
11,12-DiHETrE | Higher in AD | - | Increased odds of vascular events* [22] Potential marker of ventricular arrhythmia [23] Promotes vasodilation in preclinical models [19,20] |
8,9-DiHETrE | Higher in AD | - | Increased odds of vascular events* [22] Potential marker of ventricular arrhythmia [23] Promotes vasodilation in preclinical models [19] Elevated after treatment of ibuprofen in humans [24] |
5,6-DiHETrE | Higher in AD | - | Potential marker of ventricular arrhythmia [23] Vasodilation in mouse due to increased nitric oxide availability [19] Elevated after treatment of ibuprofen in healthy males [24] Promotes vasodilation in preclinical models [20] |
14,15-DiHETE | - | Higher in AD | Inhibition of platelet aggregation [25] |
17,18-DiHETE | - | Higher in AD | Potential marker of ventricular arrhythmia [23] Inhibition of platelet aggregation [25] |
17-HDoHE | - | Higher in AD | Anti-inflammatory action in preclinical models [26] PPARγ agonist in cell models [27] |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Morris, J.K.; Piccolo, B.D.; John, C.S.; Green, Z.D.; Thyfault, J.P.; Adams, S.H. Oxylipin Profiling of Alzheimer’s Disease in Nondiabetic and Type 2 Diabetic Elderly. Metabolites 2019, 9, 177. https://doi.org/10.3390/metabo9090177
Morris JK, Piccolo BD, John CS, Green ZD, Thyfault JP, Adams SH. Oxylipin Profiling of Alzheimer’s Disease in Nondiabetic and Type 2 Diabetic Elderly. Metabolites. 2019; 9(9):177. https://doi.org/10.3390/metabo9090177
Chicago/Turabian StyleMorris, Jill K., Brian D. Piccolo, Casey S. John, Zachary D. Green, John P. Thyfault, and Sean H. Adams. 2019. "Oxylipin Profiling of Alzheimer’s Disease in Nondiabetic and Type 2 Diabetic Elderly" Metabolites 9, no. 9: 177. https://doi.org/10.3390/metabo9090177