Metabolomics tools for identifying biomarkers for neuropsychiatric diseases

The repertoire of biochemicals (or small molecules) present in cells, tissue, and body fluids is known as the metabolome. Today, clinicians utilize only a very small part of the information contained in the metabolome, as revealed by the quantification of a limited set of analytes to gain information on human health. Examples include measuring glucose or cholesterol to monitor diabetes and cardiovascular health, respectively. With a focus on comprehensively studying the metabolome, the rapidly growing field of metabolomics captures the metabolic state of organisms at the global or "-omics" level. Given that the overall health status of an individual is captured by his or her metabolic state, which is a reflection of what has been encoded by the genome and modified by environmental factors, metabolomics has the potential to have a great impact upon medical practice by providing a wealth of relevant biochemical data. Metabolomics promises to improve current, single metabolites-based clinical assessments by identifying metabolic signatures (biomarkers) that embody global biochemical changes in disease, predict responses to treatment or medication side effects (pharmachometabolomics). State of the art metabolomic analytical platforms and informatics tools are being used to map potential biomarkers for a multitude of disorders including those of the central nervous system (CNS). Indeed, CNS disorders are linked to disturbances in metabolic pathways related to neurotransmitter systems (dopamine, serotonin, GABA and glutamate); fatty acids such as arachidonic acid-cascade; oxidative stress and mitochondrial function. Metabolomics tools are enabling us to map in greater detail perturbations in many biochemical pathways and links among these pathways this information is key for development of biomarkers that are disease-specific. In this review, we elaborate on some of the concepts and technologies used in metabolomics and its promise for biomarker discovery. We also highlight early findings from metabolomic studies in CNS disorders such as schizophrenia, Major Depressive Disorder (MDD), Bipolar Disorder (BD), Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD).

[1]  Matej Orešič,et al.  The role of metabolomics in systems biology : a new vision for drug discovery and development , 2003 .

[2]  I. Wilson,et al.  A multi-analytical platform approach to the metabonomic analysis of plasma from normal and Zucker (fa/fa) obese rats. , 2006, Molecular bioSystems.

[3]  S. Rozen,et al.  Metabolomic analysis and signatures in motor neuron disease , 2005, Metabolomics.

[4]  Qing Yang,et al.  Diagnosis of liver cancer using HPLC-based metabonomics avoiding false-positive result from hepatitis and hepatocirrhosis diseases. , 2004, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[5]  D. Kell.  Metabolomics and systems biology: making sense of the soup. , 2004, Current opinion in microbiology.

[6]  Erin E. Carlson,et al.  Chemoselective probes for metabolite enrichment and profiling , 2007, Nature Methods.

[7]  R. Yolken,et al.  Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress , 2004, Molecular Psychiatry.

[8]  M. Wenk.  The emerging field of lipidomics , 2005, Nature Reviews Drug Discovery.

[9]  G. Harrigan.  Metabolic profiling: pathways in drug discovery. , 2002, Drug discovery today.

[10]  Douglas B. Kell,et al.  A metabolome pipeline: from concept to data to knowledge , 2005, Metabolomics.

[11]  C. Schmidt.  Metabolomics takes its place as latest up-and-coming "omic" science. , 2004, Journal of the National Cancer Institute.

[12]  I. Björkhem,et al.  Side chain oxidized oxysterols in cerebrospinal fluid and the integrity of blood-brain and blood-cerebrospinal fluid barriers Published, JLR Papers in Press, February 1, 2003. DOI 10.1194/jlr.M200434-JLR200 , 2003, Journal of Lipid Research.

[13]  M. Phillips,et al.  Identifying functional neuroimaging biomarkers of bipolar disorder: toward DSM-V. , 2007, Schizophrenia bulletin.

[14]  K. Krishnan,et al.  Metabolomic mapping of atypical antipsychotic effects in schizophrenia , 2007, Molecular Psychiatry.

[15]  John C Lindon,et al.  Integrated application of transcriptomics and metabonomics yields new insight into the toxicity due to paracetamol in the mouse. , 2004, Journal of pharmaceutical and biomedical analysis.

[16]  M. Mimmack,et al.  Further evidence for altered myelin biosynthesis and glutamatergic dysfunction in schizophrenia. , 2007, The international journal of neuropsychopharmacology.

[17]  J. van der Greef,et al.  The role of analytical sciences in medical systems biology. , 2004, Current opinion in chemical biology.

[18]  B. Maier,et al.  Physiological levels of pro- and anti-inflammatory mediators in cerebrospinal fluid and plasma: a normative study. , 2005, Journal of neurotrauma.

[19]  S. DeKosky.  Taking the Next Steps in the Diagnosis of Alzheimer's Disease: The Use of Biomarkers , 2008, CNS Spectrums.

[20]  R. Weinshilboum,et al.  Metabolomics: a global biochemical approach to drug response and disease. , 2008, Annual review of pharmacology and toxicology.

[21]  W. Willett,et al.  Biological variability dominates and influences analytical variance in HPLC-ECD studies of the human plasma metabolome , 2006, BMC clinical pathology.

[22]  W. Weckwerth,et al.  Metabolomics: from pattern recognition to biological interpretation. , 2005, Drug discovery today.

[23]  John E. Duda,et al.  Olfactory Dysfunction in Parkinson’s Disease , 2007, Neurosignals.

[24]  Oliver Fiehn,et al.  Extending the breadth of metabolite profiling by gas chromatography coupled to mass spectrometry. , 2008, Trends in analytical chemistry : TRAC.

[25]  Bruce S Kristal,et al.  Metabolomics: opening another window into aging. , 2005, Science of aging knowledge environment : SAGE KE.

[26]  Marco Oldiges,et al.  Metabolomics: current state and evolving methodologies and tools , 2007, Applied Microbiology and Biotechnology.

[27]  Burkhard Morgenstern,et al.  Metabolite-based clustering and visualization of mass spectrometry data using one-dimensional self-organizing maps , 2008, Algorithms for Molecular Biology.

[28]  J. Lindon,et al.  NMR-based metabolic profiling and metabonomic approaches to problems in molecular toxicology. , 2008, Chemical research in toxicology.

[29]  S. DeKosky,et al.  Looking Backward to Move Forward: Early Detection of Neurodegenerative Disorders , 2003, Science.

[30]  Xiaohui Fan,et al.  Diagnosis of breast cancer using HPLC metabonomics fingerprints coupled with computational methods. , 2005, Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference.

[31]  G. Curzon.  Relationships between plasma, CSF and brain tryptophan. , 1979, Journal of neural transmission. Supplementum.

[32]  Sunia A Trauger,et al.  Correlating the Transcriptome, Proteome, and Metabolome in the Environmental Adaptation of a Hyperthermophile , 2022 .

[33]  J. Soares,et al.  Metabolomics: A Global Biochemical Approach to the Discovery of Biomarkers for Psychiatric Disorders , 2008 .

[34]  L. Bren.  Metabolomics: working toward personalized medicine. , 2005, FDA consumer.

[35]  Frederick P Roth,et al.  Metabolomic Identification of Novel Biomarkers of Myocardial Ischemia , 2005, Circulation.

[36]  J. Klosterkötter,et al.  CSF Metabolic and Proteomic Profiles in Patients Prodromal for Psychosis , 2007, PloS one.

[37]  Mark R Viant,et al.  An NMR metabolomic investigation of early metabolic disturbances following traumatic brain injury in a mammalian model , 2005, NMR in biomedicine.

[38]  Mark R. Trusheim,et al.  Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers , 2007, Nature Reviews Drug Discovery.

[39]  J. Nicholson.  Global systems biology, personalized medicine and molecular epidemiology , 2006, Molecular systems biology.

[40]  T. Ebbels,et al.  Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts , 2007, Nature Protocols.

[41]  B. Hammock,et al.  Mass spectrometry-based metabolomics. , 2007, Mass spectrometry reviews.

[42]  B. Puri,et al.  The use of artificial neural networks to study fatty acids in neuropsychiatric disorders , 2008, BMC psychiatry.

[43]  Pedro Mendes,et al.  Emerging bioinformatics for the metabolome , 2002, Briefings Bioinform..

[44]  H. D. Rosas,et al.  Using advances in neuroimaging to detect, understand, and monitor disease progression in Huntington’s disease , 2004, NeuroRX.

[45]  David Borsook,et al.  A role for fMRI in optimizing CNS drug development , 2006, Nature Reviews Drug Discovery.

[46]  Mia K. Markey,et al.  A machine learning perspective on the development of clinical decision support systems utilizing mass spectra of blood samples , 2006, J. Biomed. Informatics.

[47]  Ian D. Wilson,et al.  Metabolic Phenotyping in Health and Disease , 2008, Cell.

[48]  H. Reichmann,et al.  A longitudinal study of olfactory function in patients with idiopathic Parkinson's disease , 2008, Journal of Neurology.

[49]  A. Nobel,et al.  Concordance among Gene-Expression – Based Predictors for Breast Cancer , 2011 .

[50]  T. Raedler,et al.  CSF-studies in neuropsychiatric disorders. , 2006, Neuro endocrinology letters.

[51]  D. Brooks.  Neuroimaging in Parkinson’s disease , 2004, NeuroRX.

[52]  W. R. Wikoff,et al.  Metabolomic analysis of the cerebrospinal fluid reveals changes in phospholipase expression in the CNS of SIV-infected macaques. , 2008, The Journal of clinical investigation.

[53]  Nigel W. Hardy,et al.  The Metabolomics Standards Initiative , 2007, Nature Biotechnology.

[54]  Elaine Holmes,et al.  Metabolic changes in schizophrenia and human brain evolution , 2008, Genome Biology.

[55]  Alan Hutson,et al.  Detection of epithelial ovarian cancer using 1H‐NMR‐based metabonomics , 2005, International journal of cancer.

[56]  R. Vasan,et al.  Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations , 2006, Circulation.

[57]  Daniela Berg,et al.  Biomarkers for the Early Detection of Parkinson’s and Alzheimer’s Disease , 2008, Neurodegenerative Diseases.

[58]  J. Lindon,et al.  Spectroscopic and statistical techniques for information recovery in metabonomics and metabolomics. , 2008, Annual review of analytical chemistry.

[59]  D. Wishart.  Applications of Metabolomics in Drug Discovery and Development , 2008, Drugs in R&D.

[60]  V. Tolstikov,et al.  Probing genetic algorithms for feature selection in comprehensive metabolic profiling approach. , 2008, Rapid communications in mass spectrometry : RCM.

[61]  D. DeMets,et al.  Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework , 2001, Clinical pharmacology and therapeutics.

[62]  Dominique Gauguier,et al.  Direct quantitative trait locus mapping of mammalian metabolic phenotypes in diabetic and normoglycemic rat models , 2007, Nature Genetics.

[63]  J. Lindon,et al.  Metabonomics and its role in drug development and disease diagnosis , 2004, Expert review of molecular diagnostics.

[64]  Rima Kaddurah-Daouk,et al.  A preliminary metabolomic analysis of older adults with and without depression , 2007, International journal of geriatric psychiatry.

[65]  Nigel W. Hardy,et al.  Summary recommendations for standardization and reporting of metabolic analyses , 2005, Nature Biotechnology.

[66]  J. van der Greef,et al.  Evaluation of metabolite profiles as biomarkers for the pharmacological effects of thiazolidinediones in Type 2 diabetes mellitus patients and healthy volunteers. , 2007, British journal of clinical pharmacology.

[67]  Michael E Phelps,et al.  Systems Biology and New Technologies Enable Predictive and Preventative Medicine , 2004, Science.

[68]  William Jagust,et al.  Molecular neuroimaging in Alzheimer’s disease , 2004, NeuroRX.

[69]  P. Quinn,et al.  Lipidomics: practical aspects and applications. , 2008, Progress in lipid research.

[70]  Vladimir Shulaev,et al.  Metabolomics technology and bioinformatics , 2006, Briefings Bioinform..

[71]  D. Leibfritz,et al.  Visualizing metabolic changes in breast‐cancer tissue using 1H‐NMR spectroscopy and self‐organizing maps , 2003, NMR in biomedicine.

[72]  J. van der Greef,et al.  The art and practice of systems biology in medicine: mapping patterns of relationships. , 2007, Journal of proteome research.

[73]  Elaine Holmes,et al.  Metabolic profiling of plasma from discordant schizophrenia twins: correlation between lipid signals and global functioning in female schizophrenia patients. , 2006, Journal of proteome research.

[74]  C. Champagne,et al.  Nutritional effects on blood pressure. , 2007, Current opinion in lipidology.

[75]  R. Kaddurah-Daouk,et al.  High-Performance Liquid Chromatography Separations Coupled With Coulometric Electrode Array Detectors , 2007 .

[76]  Warwick B Dunn,et al.  Current trends and future requirements for the mass spectrometric investigation of microbial, mammalian and plant metabolomes , 2008, Physical biology.

[77]  Douglas B. Kell,et al.  Novel biomarkers for pre-eclampsia detected using metabolomics and machine learning , 2005, Metabolomics.

[78]  K. Fassbender,et al.  Biomarkers of folate and vitamin B12 are related in blood and cerebrospinal fluid. , 2007, Clinical chemistry.

[79]  Hans-Werner Mewes,et al.  Bioinformatics analysis of targeted metabolomics--uncovering old and new tales of diabetic mice under medication. , 2008, Endocrinology.

[80]  David S. Wishart,et al.  HMDB: a knowledgebase for the human metabolome , 2008, Nucleic Acids Res..

[81]  Elaine Holmes,et al.  Metabolic characterization of the R6/2 transgenic mouse model of Huntington's disease by high-resolution MAS 1H NMR spectroscopy. , 2006, Journal of proteome research.

[82]  Julian L Griffin,et al.  Metabolites from cerebrospinal fluid in aneurysmal subarachnoid haemorrhage correlate with vasospasm and clinical outcome: a pattern‐recognition 1H NMR study , 2005, NMR in biomedicine.

[83]  T. Hankemeier,et al.  Metabolomics-based systems biology and personalized medicine: moving towards n = 1 clinical trials? , 2006, Pharmacogenomics.

[84]  W. Matson,et al.  Metabolomic profiling to develop blood biomarkers for Parkinson's disease. , 2008, Brain : a journal of neurology.

[85]  Ian J. Brown,et al.  Human metabolic phenotype diversity and its association with diet and blood pressure , 2008, Nature.

[86]  M. Tewari,et al.  The Limits of Reductionism in Medicine: Could Systems Biology Offer an Alternative? , 2006, PLoS medicine.

[87]  D. Kell.  Systems biology, metabolic modelling and metabolomics in drug discovery and development. , 2006, Drug discovery today.

[88]  E. Wolters,et al.  Variability in the clinical expression of Parkinson's disease , 2008, Journal of the Neurological Sciences.

[89]  M. Tewari,et al.  The Clinical Applications of a Systems Approach , 2006, PLoS medicine.

[90]  Ivano Bertini,et al.  Evidence of different metabolic phenotypes in humans , 2008, Proceedings of the National Academy of Sciences.

[91]  Yi-Zeng Liang,et al.  Plasma fatty acid metabolic profiling and biomarkers of type 2 diabetes mellitus based on GC/MS and PLS‐LDA , 2006, FEBS letters.

[92]  R. Goodacre,et al.  Metabolic Profiling: Its Role in Biomarker Discovery and Gene Function Analysis , 2003, Springer US.

[93]  Elaine Holmes,et al.  Metabolic Profiling of CSF: Evidence That Early Intervention May Impact on Disease Progression and Outcome in Schizophrenia , 2006, PLoS medicine.

[94]  Thomas Hummel,et al.  Olfactory loss may be a first sign of idiopathic Parkinson's disease , 2007, Movement disorders : official journal of the Movement Disorder Society.

[95]  Paul Sajda,et al.  Machine learning for detection and diagnosis of disease. , 2006, Annual review of biomedical engineering.

[96]  D. Morvan,et al.  Metabolomics by proton nuclear magnetic resonance spectroscopy of the response to chloroethylnitrosourea reveals drug efficacy and tumor adaptive metabolic pathways. , 2007, Cancer research.

[97]  Royston Goodacre,et al.  Metabolomics: Current technologies and future trends , 2006, Proteomics.

[98]  David Broadhurst,et al.  Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles. , 2006, Brain : a journal of neurology.

[99]  Andrew Hayes,et al.  Integrative investigation of metabolic and transcriptomic data , 2006, BMC Bioinformatics.

[100]  J. Nicholson,et al.  Application of chemometrics to 1H NMR spectroscopic data to investigate a relationship between human serum metabolic profiles and hypertension. , 2003, The Analyst.