Association of Blood Metabolomics Biomarkers with Brain Metabolites and Patient-Reported Outcomes as a New Approach in Individualized Diagnosis of Schizophrenia
Abstract
:1. Introduction
2. Results
2.1. Distributions of Clinical Parameters by Groups
2.2. Correlation Analysis of Lactates, Glutamic Acid and Cortisol Concentrations and Questionnaire Results in the Test Group
2.3. Correlation Analysis of Lactates, Glutamic acid and Cortisol Concentrations and Selected Clinical and Brain Parameters
2.4. The Cluster Analysis of the Test Results in the Test Group
3. Discussion
3.1. Distributions of Clinical Parameters by Groups
3.2. Correlation Analysis of Lactates, Glutamic Acid and Cortisol Concentrations and Questionnaire Results in the Studied Group
3.3. Correlation Analysis of Lactates, Glutamic Acid and Cortisol Concentrations and Selected Clinical and Brain Parameters
3.4. The Cluster Analysis of the Test Results in the Studied Group
3.5. Limitations
4. Materials and Methods
4.1. Participants
4.2. Material
Characteristics of the Sample
4.3. Methods
4.3.1. Laboratory Routine Tests
4.3.2. Determination of Metabolites in Peripheral Blood
4.3.3. Magnetic Resonance Techniques
4.3.4. Statistical Methods
Clustering Analysis
Statistical Environment
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Characteristic | N | Group | p 2 | r | |
---|---|---|---|---|---|
Control, n = 45 1 | Test, n = 51 1 | ||||
Serotonin [µg/mL] | 96 | 133.46 (127.63, 138.31) | 130.30 (126.21, 137.87) | 0.301 | 0.11 |
Alanine [µg/mL] | 96 | 1.52 (1.23, 1.83) | 1.52 (1.22, 1.76) | 0.977 | <0.01 |
Glutamic acid [µg/mL] | 95 | 2923.96 (2139.69, 3630.11) | 2367.73 (1411.55, 3246.98) | 0.048 | 0.20 |
missing value | 0 | 1 | |||
Glutamine [µg/mL] | 96 | 334.20 (286.22, 367.14) | 354.35 (307.89, 382.01) | 0.249 | 0.12 |
Cortisol [ng/mL] | 96 | 162.34 (131.19, 184.54) | 120.57 (93.37, 174.50) | 0.031 | 0.22 |
Lactates [µg/mL] | 94 | 156.98 (129.59, 177.59) | 120.92 (88.37, 146.86) | <0.001 | 0.41 |
missing value | 1 | 1 | |||
Lactates [mmol/L] | 94 | 1.74 (1.44, 1.97) | 1.34 (0.98, 1.63) | <0.001 | 0.41 |
missing value | 1 | 1 | |||
Kinurenic acid [ng/mL] | 95 | 54.80 (40.01, 65.52) | 46.81 (35.55, 60.14) | 0.167 | 0.14 |
missing value | 0 | 1 | |||
Acetic acid [nM] | 96 | 9.56 (7.71, 11.15) | 8.86 (6.19, 10.86) | 0.071 | 0.19 |
Propionic acid [nM] | 96 | 0.54 (0.42, 0.64) | 0.50 (0.36, 0.60) | 0.146 | 0.15 |
Butyric acid [nM] | 96 | 0.07 (0.03, 0.10) | 0.06 (0.03, 0.10) | 0.675 | 0.04 |
Isobutyric acid [nM] | 96 | 0.18 (0.14, 0.24) | 0.17 (0.06, 0.24) | 0.215 | 0.13 |
Valerian acid [nM] | 96 | 0.06 (0.04, 0.13) | 0.05 (0.01, 0.12) | 0.145 | 0.15 |
Isovaleric acid [nM] | 96 | 0.31 (0.23, 0.48) | 0.35 (0.18, 0.52) | 0.863 | 0.02 |
Characteristic | Optimal Cutpoint | Accuracy | Sensitivity | Specificity | AUC |
---|---|---|---|---|---|
Cortisol [ng/mL] | 131.19 | 0.69 | 0.76 | 0.63 | 0.63 |
Glutamic acid [µg/mL] | 1671.59 | 0.62 | 0.91 | 0.36 | 0.62 |
Lactates [µg/mL] | 112.15 | 0.70 | 0.95 | 0.48 | 0.74 |
Questionnaire | Lactates [µg/mL] | Glutamic Acid [µg/mL] | Cortisol [ng/mL] | ||||||
---|---|---|---|---|---|---|---|---|---|
npairs | rho | p | npairs | rho | p | npairs | rho | p | |
Positive symptoms | 49 | 0.09 | 0.507 | 49 | 0.24 | 0.093 | 50 | 0.14 | 0.322 |
Negative symptoms | 49 | -0.09 | 0.547 | 49 | 0.13 | 0.360 | 50 | −0.04 | 0.773 |
Disorganized speech | 49 | 0.10 | 0.500 | 49 | 0.18 | 0.205 | 50 | 0.17 | 0.242 |
Uncontrolled hostility excitement | 49 | 0.12 | 0.412 | 49 | 0.34 | 0.016 | 50 | 0.07 | 0.628 |
Anxiety depression | 49 | 0.04 | 0.806 | 49 | 0.15 | 0.290 | 50 | 0.06 | 0.658 |
P1–P7 | 49 | 0.09 | 0.536 | 49 | 0.23 | 0.100 | 50 | 0.07 | 0.614 |
N1–N7 | 49 | −0.06 | 0.701 | 49 | 0.09 | 0.511 | 50 | −0.01 | 0.925 |
G1–G16 | 49 | 0.09 | 0.546 | 49 | 0.30 | 0.030 | 50 | 0.17 | 0.238 |
Total score | 49 | 0.04 | 0.790 | 49 | 0.25 | 0.075 | 50 | 0.13 | 0.353 |
Total score | 49 | −0.06 | 0.699 | 49 | 0.18 | 0.198 | 50 | 0.01 | 0.960 |
Total score | 49 | 0.23 | 0.108 | 49 | 0.26 | 0.062 | 50 | −0.09 | 0.548 |
Total score | 49 | 0.14 | 0.340 | 49 | 0.22 | 0.128 | 50 | −0.06 | 0.674 |
Total score | 49 | −0.15 | 0.288 | 49 | −0.23 | 0.106 | 50 | 0.03 | 0.811 |
Total score | 46 | 0.21 | 0.145 | 46 | 0.17 | 0.224 | 47 | 0.07 | 0.647 |
Total score | 45 | 0.14 | 0.313 | 45 | 0.17 | 0.229 | 46 | 0.08 | 0.581 |
Total score | 45 | 0.29 | 0.038 | 45 | 0.26 | 0.068 | 46 | −0.02 | 0.900 |
SSZ | 38 | 0.07 | 0.609 | 38 | 0.18 | 0.216 | 39 | 0.09 | 0.513 |
SSE | 38 | 0.08 | 0.596 | 38 | 0.17 | 0.234 | 39 | 0.09 | 0.532 |
SSU | 38 | −0.15 | 0.294 | 38 | −0.06 | 0.689 | 39 | −0.07 | 0.649 |
ACZ | 38 | −0.16 | 0.251 | 38 | 0.01 | 0.919 | 39 | −0.13 | 0.349 |
PKT | 38 | −0.03 | 0.852 | 38 | −0.19 | 0.175 | 39 | −0.02 | 0.909 |
Total score | 38 | 0.04 | 0.789 | 38 | 0.17 | 0.225 | 39 | 0.03 | 0.852 |
Total score | 45 | 0.30 | 0.032 | 45 | 0.33 | 0.019 | 46 | 0.09 | 0.552 |
Reexperiencing trauma | 41 | 0.09 | 0.547 | 41 | 0.34 | 0.014 | 42 | 0.16 | 0.263 |
Avoidance | 41 | 0.39 | 0.005 | 41 | 0.36 | 0.009 | 42 | 0.13 | 0.347 |
Threat | 41 | 0.18 | 0.206 | 41 | 0.25 | 0.071 | 42 | 0.17 | 0.231 |
Affective dysregulation | 41 | −0.23 | 0.099 | 41 | 0.00 | 0.974 | 42 | −0.01 | 0.921 |
Negative self-concept | 41 | −0.03 | 0.853 | 41 | 0.06 | 0.700 | 42 | 0.06 | 0.683 |
Disturbance relationships | 41 | 0.04 | 0.779 | 41 | 0.05 | 0.711 | 42 | 0.03 | 0.847 |
PTSDFI | 41 | 0.07 | 0.606 | 41 | −0.03 | 0.814 | 42 | 0.08 | 0.579 |
DSOFI | 41 | −0.01 | 0.929 | 41 | −0.05 | 0.722 | 42 | 0.06 | 0.681 |
PTSD | 41 | 0.26 | 0.069 | 41 | 0.36 | 0.010 | 42 | 0.16 | 0.264 |
DSO | 41 | −0.05 | 0.735 | 41 | 0.07 | 0.601 | 42 | −0.02 | 0.904 |
Total score | 41 | 0.10 | 0.470 | 41 | 0.10 | 0.475 | 42 | 0.05 | 0.739 |
Emotional abuse | 41 | 0.13 | 0.376 | 41 | 0.02 | 0.865 | 42 | 0.01 | 0.924 |
Physical abuse | 41 | −0.20 | 0.168 | 41 | −0.18 | 0.200 | 42 | −0.07 | 0.650 |
sexual abuse | 41 | 0.12 | 0.411 | 41 | 0.03 | 0.832 | 42 | −0.22 | 0.129 |
Emotional neglect | 41 | −0.12 | 0.393 | 41 | −0.09 | 0.525 | 42 | −0.15 | 0.285 |
Physical neglect | 41 | 0.01 | 0.949 | 41 | 0.16 | 0.270 | 42 | −0.28 | 0.045 |
Denial | 41 | 0.01 | 0.938 | 41 | 0.00 | 0.998 | 42 | 0.08 | 0.593 |
Total score | 41 | −0.08 | 0.585 | 41 | −0.05 | 0.731 | 42 | −0.08 | 0.567 |
Total score | 40 | 0.03 | 0.825 | 40 | 0.01 | 0.940 | 41 | −0.06 | 0.680 |
Total score | 40 | 0.02 | 0.866 | 40 | −0.08 | 0.575 | 41 | −0.24 | 0.088 |
Characteristic | Lactates [µg/mL] | Glutamic acid [µg/mL] | Cortisol [ng/mL] | ||||||
---|---|---|---|---|---|---|---|---|---|
npairs | rho | p | npairs | rho | p | npairs | rho | p | |
WBC [×103/µL] | 94 | −0.12 | 0.226 | 95 | −0.07 | 0.522 | 96 | −0.18 | 0.074 |
NEUT [×103/µL] | 94 | −0.21 | 0.044 | 95 | −0.12 | 0.248 | 96 | −0.16 | 0.120 |
Re-Lymph [×103/µL] | 94 | −0.35 | <0.001 | 95 | −0.07 | 0.498 | 96 | −0.24 | 0.020 |
IG [×103/µL] | 94 | −0.11 | 0.284 | 95 | 0.07 | 0.496 | 96 | −0.22 | 0.035 |
NEUT [%] | 94 | −0.29 | 0.005 | 95 | −0.21 | 0.041 | 96 | −0.12 | 0.225 |
Lymph [%] | 94 | 0.26 | 0.012 | 95 | 0.15 | 0.133 | 96 | 0.06 | 0.549 |
Re-Lymph [%] | 94 | −0.33 | 0.001 | 95 | −0.04 | 0.734 | 96 | −0.18 | 0.073 |
EO [%] | 94 | 0.16 | 0.115 | 95 | 0.32 | 0.001 | 96 | −0.01 | 0.951 |
BASO [%] | 94 | 0.12 | 0.244 | 95 | 0.11 | 0.273 | 96 | 0.10 | 0.328 |
RBC [×106/µL] | 94 | −0.06 | 0.585 | 95 | 0.01 | 0.894 | 96 | −0.14 | 0.168 |
Hgb [g/dl] | 94 | −0.08 | 0.448 | 95 | 0.01 | 0.944 | 96 | −0.12 | 0.253 |
Hct [%] | 94 | −0.09 | 0.406 | 95 | −0.05 | 0.596 | 96 | −0.17 | 0.092 |
Macrocytes [%] | 94 | −0.03 | 0.777 | 95 | 0.03 | 0.768 | 96 | −0.08 | 0.435 |
K+ [mmol/L] | 94 | −0.09 | 0.378 | 95 | 0.00 | 0.983 | 96 | −0.13 | 0.200 |
Glucose [mmol/L] | 94 | −0.33 | 0.001 | 95 | −0.40 | <0.001 | 96 | −0.01 | 0.924 |
Uric acid [µmol/L] | 94 | −0.11 | 0.266 | 95 | 0.03 | 0.809 | 96 | −0.11 | 0.271 |
Cholesterol HDL [µmol/L] | 93 | 0.26 | 0.011 | 94 | 0.01 | 0.903 | 95 | 0.21 | 0.037 |
Triglycerides [µmol/L] | 93 | −0.03 | 0.796 | 94 | 0.04 | 0.677 | 95 | −0.10 | 0.337 |
FT4 [pmol/L] | 94 | 0.27 | 0.008 | 95 | 0.11 | 0.295 | 96 | 0.00 | 0.992 |
DHEA-S [µmol/L] | 94 | −0.16 | 0.131 | 95 | −0.04 | 0.681 | 96 | 0.09 | 0.408 |
Insulin [µU/mL] | 94 | 0.00 | 0.993 | 95 | 0.04 | 0.709 | 96 | −0.10 | 0.342 |
HOMA-IR | 92 | −0.04 | 0.674 | 93 | −0.02 | 0.853 | 94 | −0.10 | 0.309 |
Creatine conc [×106] | 91 | 0.24 | 0.019 | 92 | 0.13 | 0.217 | 93 | 0.19 | 0.062 |
Glucose Cr+PCr | 91 | −0.10 | 0.329 | 92 | 0.02 | 0.828 | 93 | −0.09 | 0.404 |
Glucose Cr+PCr | 91 | −0.15 | 0.144 | 92 | 0.05 | 0.630 | 93 | −0.14 | 0.174 |
Glutamine Cr+PCr | 91 | 0.17 | 0.098 | 92 | 0.15 | 0.152 | 93 | 0.28 | 0.005 |
Glutamine Cr+PCr | 91 | 0.09 | 0.364 | 92 | 0.20 | 0.049 | 93 | 0.17 | 0.097 |
Inositol conc [×106] | 91 | 0.06 | 0.586 | 92 | 0.01 | 0.928 | 93 | 0.04 | 0.722 |
N-Acetylaspartate conc [×106] | 91 | 0.15 | 0.148 | 92 | 0.04 | 0.729 | 93 | 0.23 | 0.026 |
Cr+PCr conc [×106] | 91 | 0.27 | 0.008 | 92 | 0.05 | 0.604 | 93 | 0.30 | 0.003 |
Glu+Gln conc [×106] | 91 | 0.33 | 0.001 | 92 | 0.08 | 0.465 | 93 | 0.21 | 0.042 |
Glu+Gln Cr+PCr | 91 | 0.19 | 0.059 | 92 | 0.10 | 0.334 | 93 | 0.02 | 0.869 |
Phosphocreatine conc | 91 | 0.19 | 0.067 | 92 | 0.08 | 0.467 | 93 | 0.10 | 0.344 |
Glutamate conc | 91 | 0.26 | 0.009 | 92 | −0.04 | 0.707 | 93 | 0.13 | 0.193 |
Glu/Cr+PCr | 91 | 0.20 | 0.048 | 92 | −0.09 | 0.403 | 93 | 0.04 | 0.683 |
N-Acetylaspartate conc. | 91 | 0.30 | 0.003 | 92 | 0.03 | 0.787 | 93 | 0.07 | 0.496 |
NAA/Cr+PCr | 91 | 0.21 | 0.039 | 92 | 0.01 | 0.900 | 93 | −0.07 | 0.504 |
N-Acetyaspartate + N-Acetylspartylglutamate conc | 91 | 0.27 | 0.009 | 92 | −0.03 | 0.785 | 93 | 0.15 | 0.150 |
NAA+NAAG/Cr+PCr | 91 | 0.19 | 0.069 | 92 | 0.00 | 0.965 | 93 | 0.04 | 0.713 |
Cr+PCr conc | 91 | 0.23 | 0.026 | 92 | 0.04 | 0.728 | 93 | 0.14 | 0.164 |
Glu+Gln conc | 91 | 0.23 | 0.025 | 92 | 0.00 | 0.965 | 93 | 0.12 | 0.249 |
Glu+GlnCr+PCr | 91 | 0.13 | 0.197 | 92 | 0.00 | 0.999 | 93 | 0.06 | 0.537 |
Phosphocreatine conc [×103] | 91 | −0.01 | 0.960 | 92 | −0.05 | 0.618 | 93 | 0.16 | 0.111 |
N-Acetylaspartate conc [×106] | 91 | 0.04 | 0.727 | 92 | 0.02 | 0.867 | 93 | 0.09 | 0.371 |
Taurine conc [×106] | 91 | −0.18 | 0.087 | 92 | −0.02 | 0.873 | 93 | −0.22 | 0.028 |
Taurine Cr+PCr [×103] | 91 | −0.18 | 0.081 | 92 | −0.01 | 0.896 | 93 | −0.24 | 0.020 |
Cr+PCr conc [×106] | 91 | 0.12 | 0.242 | 92 | 0.02 | 0.833 | 93 | 0.20 | 0.056 |
Lip20 conc [×106] | 91 | 0.13 | 0.222 | 92 | 0.13 | 0.205 | 93 | 0.08 | 0.427 |
Lip20 Cr+PCr [×103] | 91 | 0.11 | 0.265 | 92 | 0.13 | 0.223 | 93 | 0.07 | 0.495 |
L-alanine conc | 91 | 0.07 | 0.528 | 92 | −0.10 | 0.350 | 93 | 0.21 | 0.045 |
Creatine Cr conc. | 91 | −0.06 | 0.539 | 92 | −0.07 | 0.475 | 93 | −0.14 | 0.189 |
Creatine, Cr/(Cr+PCr) | 91 | −0.05 | 0.599 | 92 | −0.10 | 0.354 | 93 | −0.12 | 0.250 |
Phosphocreatine, PCr | 91 | 0.03 | 0.769 | 92 | 0.04 | 0.694 | 93 | 0.11 | 0.283 |
Phosphocreatine, PCr/(Cr+PCr) | 91 | 0.05 | 0.599 | 92 | 0.010 | 0.354 | 93 | 0.12 | 0.250 |
Scylloinositol conc. | 91 | −0.04 | 0.692 | 92 | 0.08 | 0.451 | 93 | −0.10 | 0.321 |
Scylloinositol/(Cr+PCr) | 91 | −0.04 | 0.703 | 92 | 0.09 | 0.387 | 93 | −0.10 | 0.322 |
GPC+PCh/Cr+PCr | 91 | −0.12 | 0.244 | 92 | 0.02 | 0.848 | 93 | 0.02 | 0.860 |
Test | V test | MCluster | Mtest group | SDCluster | SDtest group | p |
---|---|---|---|---|---|---|
Cluster 1 (n = 12) | ||||||
GAF | 4.25 | 68.92 | 52.34 | 10.48 | 15.31 | <0.001 |
Gastrointestinal symptoms | −2.36 | 9.50 | 18.83 | 4.68 | 15.49 | 0.018 |
ITQ | −2.44 | 23.75 | 33.83 | 11.35 | 16.19 | 0.015 |
CTQ | −2.46 | 57.08 | 66.45 | 8.23 | 14.95 | 0.014 |
GHQ-28 | −2.51 | 22.42 | 31.85 | 7.94 | 14.77 | 0.012 |
STAI | −2.57 | 81.83 | 95.83 | 11.98 | 21.34 | 0.010 |
CALGARY | −3.14 | 3.67 | 8.58 | 3.25 | 6.14 | 0.002 |
BDI II | −3.34 | 7.33 | 18.76 | 5.88 | 13.41 | 0.001 |
SAPS | −4.69 | 8.50 | 35.28 | 7.31 | 22.38 | <0.001 |
SANS | −5.06 | 20.25 | 51.28 | 10.10 | 24.05 | <0.001 |
PANSS | −5.08 | 47.83 | 78.20 | 19.58 | 23.46 | <0.001 |
Cluster 2 (n = 23) | ||||||
SANS | 2.88 | 62.10 | 51.28 | 13.78 | 24.05 | 0.004 |
PANSS | 2.60 | 87.70 | 78.20 | 13.39 | 23.46 | 0.009 |
SAPS | 2.50 | 44.01 | 35.28 | 22.25 | 22.38 | 0.012 |
ECR-RS | −2.09 | 47.44 | 52.76 | 12.53 | 16.34 | 0.037 |
CTQ | −2.21 | 61.29 | 66.45 | 9.68 | 14.95 | 0.027 |
STAI | −2.34 | 88.05 | 95.83 | 17.32 | 21.34 | 0.020 |
BDI II | −2.36 | 13.82 | 18.76 | 7.88 | 13.41 | 0.018 |
ITQ | −3.02 | 26.20 | 33.83 | 9.90 | 16.19 | 0.003 |
GAF | −3.03 | 45.10 | 52.34 | 11.55 | 15.31 | 0.002 |
Cluster 3 (n = 16) | ||||||
BDI II | 5.59 | 34.44 | 18.76 | 8.90 | 13.41 | <0.001 |
ITQ | 5.47 | 52.36 | 33.83 | 9.75 | 16.19 | <0.001 |
STAI | 4.86 | 117.50 | 95.83 | 14.45 | 21.34 | <0.001 |
CTQ | 4.62 | 80.90 | 66.45 | 14.62 | 14.95 | <0.001 |
GHQ 28 | 4.34 | 45.25 | 31.85 | 13.13 | 14.77 | <0.001 |
ECR-RS | 3.94 | 66.22 | 52.76 | 15.23 | 16.34 | <0.001 |
Gastrointestinal symptoms | 3.55 | 30.31 | 18.83 | 20.58 | 15.49 | <0.001 |
TEC PL | 2.34 | 28.08 | 21.32 | 16.13 | 13.80 | 0.019 |
CALGARY | 2.23 | 11.44 | 8.58 | 6.22 | 6.14 | 0.026 |
CISS | 2.00 | 149.05 | 141.87 | 19.63 | 17.15 | 0.046 |
Characteristic | N | Distribition 1 |
---|---|---|
Serotonin [µg/mL] | 96 | 131.32 (126.66, 138.05) |
Alanine [µg/mL] | 96 | 1.52 (1.23, 1.83) |
Glutamic acid [µg/mL] | 95 | 2732.44 (1785.60, 3575.55) |
Glutamic acid [µg/mL] | 96 | 341.84 (289.56, 380.60) |
Cortisol [ng/mL] | 96 | 138.96 (106.69, 184.22) |
Lactates [µg/mL] | 94 | 135.33 (111.05, 167.62) |
Lactates [mmol/L] | 94 | 1.50 (1.23, 1.86) |
Kinurenic acid [ng/mL] | 95 | 48.76 (37.05, 64.44) |
Acetic acid [nM] | 96 | 8.96 (6.78, 11.11) |
Propionic acid [nM] | 96 | 0.53 (0.38, 0.62) |
Butyric acid [nM] | 96 | 0.07 (0.03, 0.10) |
Isobutyric acid [nM] | 96 | 0.18 (0.11, 0.24) |
Valerian acid [nM] | 96 | 0.06 (0.02, 0.13) |
Isovaleric acid [nM] | 96 | 0.34 (0.21, 0.49) |
LC-ESI-MS/MS | LCMS-SCFA | LC-ESI-MS/MS Cortisol | |
---|---|---|---|
Sample preparation | 4 µL of internal standard (methanolic solution of the tested compounds with a concentration of 500 µg/mL) was added to 100 µL of sample (serum). Protein was precipitated by adding 100 μL of ice-cold acetonitrile. After mixing, the samples were centrifuged (8000 rpm, 5 min, 15 °C). The supernatant was collected and placed in chromatographic vessels. | 60 µL of a mixture of methanol and water (1:1, v/v) was added to 20 µL of serum, the samples were vortexed, then centrifuged (14000 rpm, 10 min, 4 °C), 40 µL of the supernatant was collected. Derivatization: 40 µL of water was added to 40 µL of the supernatant, then 10 µL of 0.1 M BHA and 10 µL of 0.25 M EDC. After mixing, the samples were incubated for 1 h at 25 °C with constant stirring. The derivatization process was completed by adding 100 µL of 50% methanol and 600 µL of dichloromethane. The samples were then mixed and centrifuged (8000 rpm, 10 min). The organic phase was collected and evaporated to dryness under nitrogen and then dissolved in 30 µL of 50% methanol. | 4 µL of internal standard (methanolic solution containing cortisol with a concentration of 500 µg/mL) was added to 100 µL of sample (serum). Protein was precipitated by adding 100 μL of ice-cold acetonitrile. After mixing, the samples were centrifuged (8000 rpm, 5 min, 15 °C). The supernatant was collected and placed in chromatographic vessels. |
Chromatography column | ZIC®-HILIC (5 µm, 200 Å, 150 × 21.2 mm; Merck, Darmstadt, Germany), thermostated at 40 °C | Kinetex (1.7 µm Biphenyl, 100 Å; 100 × 2.1 mm; Phenomenex Companies Worldwide, Torrance, CA, USA) | Kinetex (2.6 µm Biphenyl 100 Å, 100 × 2.1 mm; Phenomenex Companies Worldwide, Torrance, CA, USA), thermostated at 40 °C |
Mobile phases | Phase A: 0.1% aqueous HCOOH solution; Phase B: 0.1% HCOOH in acetonitrile | Phase A: 0.1% HCOOH + 10 mM NH4COOH; Phase B: 0.1% HCOOH in a mixture of methanol: isopropanol (9: 1 v/v) | Phase A: 0.1% aqueous HCOOH solution; Phase B: methanol |
Phase flow rate | 0.6 mL/min | 0.4 mL/min | 0.4 mL/min |
Separation program | Gradient separation program: 0–0.2 min, isocratic gradient 5.0% of phase A; 0.2–1.5 min, linear gradient 5–55% of phase A; 1.5–3.1 min, isocratic gradient 55% of phase A; 3.1–4.5 min, linear gradient 55.0–5.0% of phase A; 4.5–6 min, isocratic gradient 5.0% of phase A | Gradient separation program: 0–4 min, 68.0–40.0% of phase A, 4–4.8 min, 35% of phase A, 4.8–4.9 min, 2% of phase A; after this time, isocratic conditions were achieved (4.9–5.2 min), and then the initial conditions were returned—68% of phase A (5.2–5.3 min) | Gradient separation program: 0–0.4 min, isocratic gradient 5.0% of phase B; 0.4–0.5 min, linear gradient 5–50% of phase B; 0.5–1.9 min, isocratic gradient 50% of phase B; 1.9–2.0 min, linear gradient 100.0% of phase B; 2.0–2.9 min, isocratic gradient 100.0% of phase B; 2.9–4.0 min, linear gradient 100–5.0% of phase B; 4.0–5.0 min, isocratic gradient 5.0% of phase B |
Injection volume | 4 µL | 4 µL | 2 µL |
Time of single sample analysis | 6 min | 5.3 min | 5 min |
Retention time | ALA, ALA-d4—2.44 min; SER, SER-d4—2.35 min; GLUT, GLUT-C13—2.40 min; LA—0.99 min | acetic acid—1.4 min; propionic acid—1.9 min; isobutyric acid—2.59 min; butyric acid—2.8 min; isovaleric acid—3.2 min; valeric acid—3.5 min | COR, COR-d4—3.39 min |
Ion source parameters | IS: 5500 V; atomizing gas (gas 1): 30 psi; turbo gas (gas 2): 20 psi; TEM: 550 °C; CUR: 30 psi | IS: 5400 V; atomizing gas (gas 1): 30 psi; turbo gas (gas 2): 20 psi; TEM: 550 °C; CUR: 30 psi | IS: 5500 V; atomizing gas (gas 1): 30 psi; turbo gas (gas 2): 20 psi; TEM) 300 °C; CUR: 30 psi |
Ion pairs | ALA: m/z = 90.09/44.9; ALA-d4: m/z = 93.93/47.97; GLUT: m/z = 148.0/84.0; GLUT-C13: m/z = 153.0/89.0; SER: m/z = 177.0/119.0; SER-d4: m/z = 182.83/119.76; LA: m/z = 88.84/43.948 | acetic acid: m/z = 166.1/91.1; propionic acid: m/z = 180.1/91.1; butyric and isobutyric acid: 194.1/91.1; valeric and isovaleric acid: m/z = 208.1/124.1 | COR: m/z = 363.11/120.92; COR-d4: m/z = 367.11/120.95 |
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Krzyściak, W.; Bystrowska, B.; Karcz, P.; Chrzan, R.; Bryll, A.; Turek, A.; Mazur, P.; Śmierciak, N.; Szwajca, M.; Donicz, P.; et al. Association of Blood Metabolomics Biomarkers with Brain Metabolites and Patient-Reported Outcomes as a New Approach in Individualized Diagnosis of Schizophrenia. Int. J. Mol. Sci. 2024, 25, 2294. https://doi.org/10.3390/ijms25042294
Krzyściak W, Bystrowska B, Karcz P, Chrzan R, Bryll A, Turek A, Mazur P, Śmierciak N, Szwajca M, Donicz P, et al. Association of Blood Metabolomics Biomarkers with Brain Metabolites and Patient-Reported Outcomes as a New Approach in Individualized Diagnosis of Schizophrenia. International Journal of Molecular Sciences. 2024; 25(4):2294. https://doi.org/10.3390/ijms25042294
Chicago/Turabian StyleKrzyściak, Wirginia, Beata Bystrowska, Paulina Karcz, Robert Chrzan, Amira Bryll, Aleksander Turek, Paulina Mazur, Natalia Śmierciak, Marta Szwajca, Paulina Donicz, and et al. 2024. "Association of Blood Metabolomics Biomarkers with Brain Metabolites and Patient-Reported Outcomes as a New Approach in Individualized Diagnosis of Schizophrenia" International Journal of Molecular Sciences 25, no. 4: 2294. https://doi.org/10.3390/ijms25042294