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This document discusses using metabolomics to identify biomarkers for Alzheimer's disease (AD). Metabolomics analyzes low molecular weight molecules found within biological systems and can measure hundreds to thousands of metabolites to understand metabolism. The study found metabolic signatures in cerebrospinal fluid and plasma that correlate with AD severity. Signatures in plasma accurately reflected changes in CSF for both mild cognitive impairment and AD. Metabolomics may increase early AD diagnosis when used with other tests and could be conducted on blood, making it attractive for clinical use. Further validation studies in larger cohorts are still needed.
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- 1. 3077463- Metabolomics-based translationalMetabolomics-based translational biomarkers for Alzheimer’s Diseasebiomarkers for Alzheimer’s Disease Eugenia Trushina, PhDEugenia Trushina, PhD Mayo Clinic RochesterMayo Clinic Rochester June 17, 2013June 17, 2013
- 2. 3077463- MetabolomicsMetabolomics • The study of low molecular weightThe study of low molecular weight molecules (molecules (<1500 Da) or metabolitesor metabolites found within cells and biological systemsfound within cells and biological systems on global level (metabolome)on global level (metabolome) • Measures changes downstream ofMeasures changes downstream of genomic, transcriptomic and proteomicgenomic, transcriptomic and proteomic alterations and, therefore, is consideredalterations and, therefore, is considered more representative of the functionalmore representative of the functional state of a cellstate of a cell • Can measure hundreds to thousandsCan measure hundreds to thousands of unique chemical entities providingof unique chemical entities providing an overall understanding of metabolisman overall understanding of metabolism • Metabolites are conserved acrossMetabolites are conserved across various animal species, facilitating thevarious animal species, facilitating the extrapolation of research findings inextrapolation of research findings in laboratory animals to humanslaboratory animals to humans • Is an integral part of system biologyIs an integral part of system biology
- 3. 3077463- 1. Sample collection 2. Metabolite extraction 3. Metabolite separation 4. Metabolite identification 5. Data analysis and canonical pathway enrichment analysis (MPP, SIMCA-P, MetacoreTM )
- 4. 3077463- Identification of Altered Metabolic Pathways in PlasmaIdentification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer’sand CSF in Mild Cognitive Impairment and Alzheimer’s Disease Using MetabolomicsDisease Using Metabolomics E. Trushina, T. Dutta, X-M. T. Persson, M. M. Mielke, R. C. PetersenE. Trushina, T. Dutta, X-M. T. Persson, M. M. Mielke, R. C. Petersen PLoS ONE 8(5): e63644.PLoS ONE 8(5): e63644. Mayo Clinic Study of Aging and ADRC CSF and plasma
- 5. 3077463- PLASMAPLASMA CSFCSF MCIvsCNMCIvsCNADvsCNADvsCNADvsMCIADvsMCI plasmaplasmaCSFCSF MCI AD CN MCI AD CN orthogonal two partial least squares-discriminant analysis (O2PLS-DA) Unsupervised Principal Component Analysis (PCA)
- 6. 3077463- Plasma CSF Lysine Androstenedione and testosterone TCA cycle Saturated fatty acid Mitochondrial ketone bodies Estrone Prostaglandin 2 Aminoacyl-tRNA BS in cytoplasm Tryptophan Leucine, isoleucine and valine Neurophysiological process_ Melatonin signaling Pyruvate Serotonin-melatonin GABA Cholesterol Phospholipid p. 1 Butanoate Plasmalogen Propionate Pyruvate/rodent version Phenylalanine Polyamine (L)-Arginine TCA cycle Nicotine MB in liver Aldosterone Seratonin-melatonin Cortisone Prostaglandin 2 Methionine-cysteine-glutamate Aspartate and asparagine Vitamin B6 Histidine-glutamate-glutamine Arginine/rodent version Tryptophan Urea cycle Ascorbate Vitamin B7 (biotin) Cholesterol Sulfur Alanine, (L)-cysteine, (L)-methionine Pyruvate/rodent version -log(p-value) -log(p-value) Role of Diethylhexyl Phthalate and Tributyltin in fat differentiation 6/85 3/41 3/51 3/69 2/27 2/35 3/94 3/97 3/101 2/42 2/43 2/49 2/51 2/53 2/54 2/61 2/63 2/64 2/66 2/66 2/67 2/68 2/76 7/51 7/56 5/41 5/51 5/56 6/94 4/43 5/73 3/30 5/95 5/97 5/101 4/70 2/18 3/47 4/88 3/52 3/56 2/29 3/66 Metabolic changes in MCI vs. CNMetabolic changes in MCI vs. CN
- 7. 3077463- Plasma CSF -log(p-value) -log(p-value) Cholesterol and sphingolipids transport Vitamin D2 Polyamine Intracellular cholesterol transport (L)-Arginine Beta-alanine Aspartate and aspargine Cortisone Galactose Lipid metabolism FXR-regulated cholesterol and bile acid transport Glycolysis and gluconeogenesis Cholesterol Bile acid Regulation of CFTR gating Role of VDR in regulation of genes involved in osteoporosis Vitamin D3 metabolic C-23 and C-24 pathways Triacylglycerol BS in obesity and diabetes mellitus, type II Muscle contraction_nNOS signaling in skeletal muscles Niacin-HDL Aminoacyl-tRNA biosynthesis in mitochondria Triacylglycerol metabolism p.2 Urea cycle Lysine TCA cycle Prostaglandin 2 Aminoacyl-tRNA BS in cytoplasm Androstenedione and testosterone Alanine, (L)-cysteine, (L)-methionine Mechanism of action of DGAT1 in obesity and diabetes mellitus, type II Methionine-cysteine-glutamate Cortisol BS from cholesterol Regulation of lipid MB_FXR-dependent negative-feedback regulation of bile acid concentration Riboflavin Acetylcholine Fructose Tryptophan Development_Activation of astroglia cell proliferation by ACM3 Fatty Acid Omega Oxidation Methionine Cholesterol and sphingolipids transport Intracellular cholesterol transport (L)-Arginine Histidine-glutamate-glutamine Aspartate and aspargine Cortisone Ascorbate Mitochondrial ketone bodies Nicotine metabolism in liver Glycolysis and gluconeogenesis Cholesterol and sphingolipids transport/transport from Golgi Bile acid Regulation of CFTR gating HETE and HPETE FXR-regulated cholesterol and bile acid cellular transport Pyruvate Propionate Urea cycle Estrone TCA cycle Prostaglandin 2 Saturated fatty acids Serotonin-melatonin UMP (L)-Alanine, (L)-cysteine, (L)-methionine Cortisol BS from cholesterol GABA Glycine, serine, cysteine and threonine Beta-Alanine Tryptophan 8/20 7/38 9/68 9/70 9/90 8/76 5/35 7/73 8/94 6/56 6/59 6/59 5/41 8/20 7/85 5/46 7/88 7/94 4/33 4/35 3/20 4/41 5/56 3/24 6/80 4/47 6/94 5/66 3/28 3/27 5/74 5/69 5/66 3/31 3/31 7/123 2/14 3/33 3/34 3/31 5/42 5/56 5/61 3/24 4/43 3/28 6/97 6/101 3/32 3/34 4/51 13/94 8/51 9/73 8/70 9/90 8/76 4/18 5/33 6/51 6/56 5/41 4/32 7/94 4/42 6/95 6/101 4/53 4/56 3/35
- 9. 3077463- ConclusionsConclusions • Metabolomics offers novel approach to identify alterations in multiple biochemical networks over the course of AD • It allows identification of both expected and non-expected changes in biochemical pathways in animal models of AD and in human samples • Metabolic signatures in CSF and plasma correlate with AD severity • Metabolic signatures in plasma accurately reflect changes in CSF: MCI: 30% of the pathways altered in CSF and plasma were the same AD: 60% of the pathways affected in CSF and plasma were the same • Application of metabolomics in conjunction with other currently available tests could increase early AD diagnosis • Metabolomics could be conducted in readily available fluids such as blood making it attractive for clinical application
- 10. 3077463-1 Future DirectionsFuture Directions • Studies in larger patient cohorts are needed • Test and sample validation studies need to be included in every project • Acquisition of the data using multiple analytical platforms should increase the accuracy and reproducibility • Additional research is needed to reveal the role of metabolites linked to AD pathology in the mechanisms of normal aging
Notas do Editor
- 15 cognitively normal (CN), 15 amnestic mild cognitive impairment (MCI), 15 AD UPLC – TOF-MS – based non-targeted metabolomics approach Patients were enrolled and followed in the Mayo Clinic population-based epidemiologic study of normal aging, MCSA, and Mayo Clinic Alzheimer’s Disease Research Center (ADRC).
- Acetylcholine, noradrenalin, dopamine and serotonin neurotransmitter systems are primarily affected in AD with subsequent loss of associated neurons ( 42 ). Consistent with that, we have found prominent, early changes in tryptophan biosynthesis in both CSF and plasma of MCI and AD patients (Fig. 3-5). Tryptophan is a precursor for serotonin, melatonin, and niacin synthesis ( 43-45 ). We also found alterations in the serotonin/melatonin pathway in CSF of both MCI and AD patients, and in plasma of MCI individuals (Fig. 3,4). These data are in agreement with recent studies indicating that loss of serotonergic neurons correlates with AD severity, memory impairment, and neuropsychiatric symptoms
- Disorder in the hypothalamic-pituitary-adrenal (HPA) axis with increased cortisol levels in CSF and plasma is also well established for AD patients; and increased cortisol levels in CSF from AD patients have been recently demonstrated using metabolomic profiling [30]. Our data confirmed that the pathway related to the cortisol biosynthesis from cholesterol was significantly affected in both CSF and plasma from AD patients (Fig. 5). However, we also found that cortisone biosynthesis and metabolism was among the pathways that, along with PGE2, most accurately separated the clinical groups in CSF (Fig. 6). Among pathways that were uniquely affected in plasma of AD patients were those related to obesity and type II diabetes mellitus (Fig. 5). This is an important observation taking in consideration the data demonstrating that type II diabetes mellitus is associated with an increased risk of cognitive dysfunction and dementia, and needs to be explored in future studies [71] Moreover, our study identified CSF PGE2 biosynthesis and metabolism as one of the key pathways that varied with AD severity (Fig. 7). Implication of PGE2 in neural injury in AD is well documented, and includes modulation of protein-lipid interactions, trans-membrane and trans-synaptic signaling [69]. It was shown that levels of PGE2 measured in the CSF of control, MCI and AD patients enrolled in the longitudinal study inversely correlate with AD severity: PGE2 was higher in patients with mild memory impairment, but lower in those with more advanced AD [70].