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Metabolomics-based translational Metabolomics-based translational biomarkers for Alzheimer’s Diseasebiomarkers for Alzheimer’s DiseaseEugenia Trushina, PhDEugenia Trushina, PhD
Mayo Clinic RochesterMayo Clinic Rochester
June 17, 2013June 17, 2013
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MetabolomicsMetabolomics• The study of low molecular weight The study of low molecular weight molecules (molecules (<1500 Da) or metabolites or metabolites found within cells and biological systems found within cells and biological systems on global level (metabolome)on global level (metabolome)• Measures changes downstream of Measures changes downstream of genomic, transcriptomic and proteomic genomic, transcriptomic and proteomic alterations and, therefore, is consideredalterations and, therefore, is consideredmore representative of the functional more representative of the functional state of a cellstate of a cell• Can measure hundreds to thousands Can measure hundreds to thousands of unique chemical entities providing of unique chemical entities providing an overall understanding of metabolisman overall understanding of metabolism• Metabolites are conserved across Metabolites are conserved across various animal species, facilitating the various animal species, facilitating the extrapolation of research findings in extrapolation of research findings in laboratory animals to humanslaboratory animals to humans• Is an integral part of system biologyIs an integral part of system biology
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1. Sample collection
2. Metabolite extraction
3. Metabolite separation
4. Metabolite identification
5. Data analysis and canonical pathway enrichment analysis (MPP, SIMCA-P, MetacoreTM)
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Identification of Altered Metabolic Pathways in PlasmaIdentification of Altered Metabolic Pathways in Plasmaand 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. Petersen E. 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 andplasma
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PLASMAPLASMA CSFCSF
MC
I vs
CN
MC
I vs
CN
AD
vs
CN
AD
vs
CN
AD
vs
MC
IA
D v
s M
CI
plas
ma
plas
ma
CS
FC
SF
MCI
AD CN
MCI
AD CN
orthogonal two partial least squares-discriminant analysis (O2PLS-DA)Unsupervised Principal Component Analysis (PCA)
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Plasma CSFLysine
Androstenedione and testosterone
TCA cycle
Saturated fatty acid
Mitochondrial ketone bodies
Estrone
Prostaglandin 2
Aminoacyl-tRNA BS in cytoplasm
TryptophanLeucine, isoleucine and valine
Neurophysiological process_ Melatonin signaling
PyruvateSerotonin-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
6/853/41
3/513/69
2/272/353/943/973/1012/422/43
2/492/512/532/54
2/612/632/642/662/662/672/682/76
7/51
7/565/41
5/51
5/56
6/944/43
5/73
3/30
5/95
5/97
5/101
4/702/183/47
4/883/52
3/562/29
3/66
Metabolic changes in MCI vs. CNMetabolic changes in MCI vs. CN
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Plasma CSF
-log(p-value) -log(p-value)
Cholesterol and sphingolipids transportVitamin D2Polyamine
Intracellular cholesterol transport(L)-Arginine
Beta-alanineAspartate and aspargine
CortisoneGalactose
Lipid metabolism
FXR-regulated cholesterol and bile acid transport
Glycolysis and gluconeogenesisCholesterol
Bile acidRegulation of CFTR gating
Role of VDR in regulation of genes involved in osteoporosis
Vitamin D3 metabolic C-23 and C-24 pathwaysTriacylglycerol BS in obesity and diabetes mellitus, type II
Muscle contraction_nNOS signaling in skeletal muscles
Niacin-HDLAminoacyl-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 cholesterolRegulation of lipid MB_FXR-dependent negative-feedback regulation of bile acid concentration
RiboflavinAcetylcholine
Fructose
Tryptophan
Development_Activation of astroglia cell proliferation by ACM3Fatty 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 HPETEFXR-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
8/207/389/689/70
9/908/76
5/357/738/946/566/596/595/41
8/20
7/855/467/887/944/33
4/353/20
4/41 5/56
3/24 6/80
4/476/94
5/66
3/28 3/27
5/745/69
5/66
3/313/31
7/123
2/143/333/34
3/31
5/42
5/565/61
3/24
4/43
3/28
6/97
6/101
3/32
3/34
4/51
13/948/51
9/738/709/908/764/185/33
6/516/565/41
4/327/94
4/42
6/95
6/1014/534/563/35
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Differentiating pathwaysDifferentiating pathways
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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 sameAD: 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
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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