Metabolic profiling of Parkinson's disease: evidence of biomarker from gene expression analysis and rapid neural network detection

BackgroundParkinson's disease (PD) is a neurodegenerative disorder. The diagnosis of Parkinsonism is challenging because currently none of the clinical tests have been proven to help in diagnosis. PD may produce characteristic perturbations in the metabolome and such variations can be used as the marker for detection of disease. To test this hypothesis, we used proton NMR and multivariate analysis followed by neural network pattern detection.Methods & Results1H nuclear magnetic resonance spectroscopy analysis was carried out on plasma samples of 37 healthy controls and 43 drug-naive patients with PD. Focus on 22 targeted metabolites, 17 were decreased and 5 were elevated in PD patients (p < 0.05). Partial least squares discriminant analysis (PLS-DA) showed that pyruvate is the key metabolite, which contributes to the separation of PD from control samples. Furthermore, gene expression analysis shows significant (p < 0.05) change in expression of PDHB and NPFF genes leading to increased pyruvate concentration in blood plasma. Moreover, the implementation of 1H- NMR spectral pattern in neural network algorithm shows 97.14% accuracy in the detection of disease progression.ConclusionThe results increase the prospect of a robust molecular definition in detection of PD through the early symptomatic phase of the disease. This is an ultimate opening for therapeutic intervention. If validated in a genuinely prospective fashion in larger samples, the biomarker trajectories described here will go a long way to facilitate the development of useful therapies. Moreover, implementation of neural network will be a breakthrough in clinical screening and rapid detection of PD.

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

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

[3]  K. Becker,et al.  Microarray analysis of oxidative stress regulated genes in mesencephalic dopaminergic neuronal cells: Relevance to oxidative damage in Parkinson's disease , 2007, Neurochemistry International.

[4]  E. Kalso,et al.  Gene for pain modulatory neuropeptide NPFF: induction in spinal cord by noxious stimuli. , 1999, Molecular pharmacology.

[5]  J. O'Brien,et al.  A Comprehensive Review of Proton Magnetic Resonance Spectroscopy Studies in Dementia and Parkinson’s Disease , 2002, Dementia and Geriatric Cognitive Disorders.

[6]  J. Benito-León,et al.  Neurotransmitter amino acids in cerebrospinal fluid of patients with Parkinson's disease , 1996, Journal of the Neurological Sciences.

[7]  B D Ross,et al.  Alzheimer disease: depiction of increased cerebral myo-inositol with proton MR spectroscopy. , 1993, Radiology.

[8]  Bruce D. Hammock,et al.  Metabolomics: building on a century of biochemistry to guide human health , 2005, Metabolomics.

[9]  G. Chazot,et al.  Peripheral Blood Markers of Oxidative Stress in Parkinson’s Disease , 2007, European Neurology.

[10]  N. Hattori,et al.  Role of mitochondria in the etiology and pathogenesis of Parkinson's disease. , 1995, Biochimica et biophysica acta.

[11]  D. Turnbull,et al.  Respiratory chain abnormalities in skeletal muscle from patients with Parkinson's disease , 1991, Journal of the Neurological Sciences.

[12]  K. Ikeda,et al.  Increased plasma concentrations of aspartate, glutamate and glycine in Parkinson's disease , 1992, Neuroscience Letters.

[13]  F. Crews,et al.  Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration , 2007, Glia.

[14]  F. Fouque,et al.  Mutations in PDX1, the human lipoyl-containing component X of the pyruvate dehydrogenase-complex gene on chromosome 11p1, in congenital lactic acidosis. , 1997, American journal of human genetics.

[15]  Jianren Gu,et al.  Plasma phospholipid metabolic profiling and biomarkers of type 2 diabetes mellitus based on high-performance liquid chromatography/electrospray mass spectrometry and multivariate statistical analysis. , 2005, Analytical chemistry.

[16]  C. Marsden,et al.  Platelet mitochondrial function in Parkinson's disease. The Royal Kings and Queens Parkinson Disease Research Group. , 1992, Annals of neurology.

[17]  Masahiko Watanabe,et al.  Calbindin 1, fibroblast growth factor 20, and α-synuclein in sporadic Parkinson’s disease , 2008, Human Genetics.

[18]  Oliver Fiehn,et al.  Metabolite profiling of human colon carcinoma – deregulation of TCA cycle and amino acid turnover , 2008, Molecular Cancer.

[19]  N. Bresolin,et al.  Parkinson's disease, chronic hydrocarbon exposure and striatal neuronal damage: a 1-H MRS study. , 2006, Neurotoxicology.

[20]  Henrik Antti,et al.  Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics , 2003, Nature Medicine.

[21]  I. Biaggioni.  Parkinson's disease: autonomic neuronopathy with impaired cardiovascular regulation. , 2007, Hypertension.

[22]  D. Pozo,et al.  Alzheimer's disease beyond the genomic era: nuclear magnetic resonance (NMR) spectroscopy-based metabolomics , 2008, Journal of cellular and molecular medicine.

[23]  Paul F. Smith.  Inflammation in Parkinson's disease: an update. , 2008, Current opinion in investigational drugs.

[24]  Robert Hill,et al.  Low platelet mitochondrial complex I and complex II/III activity in early untreated parkinson's disease , 1995, Annals of neurology.

[25]  O. Okonkwo,et al.  Brain metabolism differs in Alzheimer's disease and Parkinson's disease dementia , 2008, Alzheimer's & Dementia.

[26]  M. Makley,et al.  Cerebrospinal fluid evidence of increased extra-mitochondrial glucose metabolism implicates mitochondrial dysfunction in multiple sclerosis disease progression , 2008, Journal of the Neurological Sciences.

[27]  Yasuto Itoyama,et al.  Systemic Increase of Oxidative Nucleic Acid Damage in Parkinson's Disease and Multiple System Atrophy , 2002, Neurobiology of Disease.

[28]  M Schulzer,et al.  Cerebral glucose metabolism in Parkinson's disease with and without dementia. , 1992, Archives of neurology.

[29]  J. Poderoso,et al.  Overexpression of neutrophil neuronal nitric oxide synthase in Parkinson's disease. , 2000, Nitric oxide : biology and chemistry.

[30]  R. Clements,et al.  Raised plasma-myoinositol levels in uraemia and experimental neuropathy. , 1973, Lancet.

[31]  P. Hauser,et al.  Elevated sorbitol concentration in the cerebrospinal fluid of patients with mood disorders , 2000, Psychoneuroendocrinology.

[32]  W. Gibb,et al.  The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. , 1988, Journal of neurology, neurosurgery, and psychiatry.

[33]  Maria Speranza Desole,et al.  Hormones Are Key Actors in Gene X Environment Interactions Programming the Vulnerability to Parkinson's Disease: Glia as a Common Final Pathway , 2005, Annals of the New York Academy of Sciences.

[34]  Minjun Chen,et al.  Metabolic profiling reveals therapeutic effects of Herba Cistanches in an animal model of hydrocortisone-induced 'kidney-deficiency syndrome' , 2008, Chinese medicine.

[35]  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.

[36]  G. Siegel,et al.  Neurotrophic factors in Alzheimer’s and Parkinson’s disease brain , 2000, Brain Research Reviews.

[37]  R. Hewer,et al.  Applying biofluid 1H NMR-based metabonomic techniques to distinguish between HIV-1 positive/AIDS patients on antiretroviral treatment and HIV-1 negative individuals. , 2006, Journal of pharmaceutical and biomedical analysis.

[38]  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.

[39]  P. Jenner,et al.  Increased neuropeptide Y mRNA expression in striatum in Parkinson's disease. , 2003, Brain research. Molecular brain research.

[40]  F. Gerstenbrand,et al.  [Correlation between Parkinsonism symptoms and a disorder in the amino acid metabolism in CNS]. , 1970, Wiener klinische Wochenschrift.

[41]  A. Torroni,et al.  Mitochondrial oxidative phosphorylation defects in parkinson's disease , 1991, Annals of neurology.

[42]  I. Obrosova.  Increased sorbitol pathway activity generates oxidative stress in tissue sites for diabetic complications. , 2005, Antioxidants & redox signaling.

[43]  J. Growdon,et al.  Molecular markers of early Parkinson's disease based on gene expression in blood , 2007, Proceedings of the National Academy of Sciences.

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

[45]  M. Farrer,et al.  Phenotypic associations of tau and ApoE in Parkinson's disease , 2007, Neuroscience Letters.

[46]  Hiroshi Kimura,et al.  Insulin receptor mRNA in the substantia nigra in Parkinson's disease , 1996, Neuroscience Letters.

[47]  S. Bluml,et al.  Magnetic resonance spectroscopy of the human brain , 2001, The Anatomical record.

[48]  N. Hattori,et al.  Leucine-Rich Repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population , 2007, Neuroreport.

[49]  Joseph Jankovic,et al.  Pathophysiology and Clinical Assessment of Parkinsonian Symptoms and Signs , 2003 .

[50]  Satoshi Takahashi,et al.  A significant reduction of putative transmitter amino acids in cerebrospinal fluid of patients with Parkinson's disease and spinocerebellar degeneration , 1991, Neuroscience Letters.

[51]  Andrew Lees,et al.  Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease , 2004, Neuron.

[52]  P. Allen,et al.  Generalized mitochondrial dysfunction in Parkinson's disease detected by magnetic resonance spectroscopy of muscle , 1995, Neurology.

[53]  S. Gilman,et al.  Diagnostic criteria for Parkinson disease. , 1999, Archives of neurology.

[54]  L. Parnetti,et al.  Increased cerebrospinal fluid pyruvate levels in Alzheimer's disease , 1995, Neuroscience Letters.

[55]  H. Prokisch,et al.  Clinical and molecular characterisation of a Parkinson family with a novel PINK1 mutation , 2008, Journal of Neurology.

[56]  F. Gerstenbrand,et al.  Über Ergebnisse von Liquoranalysen beim Parkinson-Syndrom , 1964, Acta Neuropathologica.

[57]  Royston Goodacre,et al.  Metabolome analyses : strategies for systems biology , 2005 .

[58]  J. Málly,et al.  Changes in the concentration of amino acids in serum and cerebrospinal fluid of patients with Parkinson's disease , 1997, Journal of the Neurological Sciences.

[59]  E. Sidransky,et al.  Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease. , 2007, Molecular genetics and metabolism.

[60]  L. Parnetti,et al.  INCREASED CSF PYRUVATE LEVELS AS A MARKER OF IMPAIRED ENERGY METABOLISM IN ALZHEIMER'S DISEASE , 1995, Journal of the American Geriatrics Society.

[61]  C. Marsden,et al.  Mitochondrial function in Parkinson's disease , 1992, Annals of neurology.

[62]  Goutham Rao,et al.  Does this patient have Parkinson disease? , 2003, JAMA.

[63]  A. Ergul,et al.  Oxidative stress and the use of antioxidants in diabetes : Linking basic science to clinical practice , 2015 .

[64]  I. Biaggioni.  Autonomic Neuronopathy With Impaired Cardiovascular Regulation , 2006 .

[65]  Ph.D. Margo Panush Cohen M.D..  The Polyol Paradigm and Complications of Diabetes , 1987, Springer New York.

[66]  Eden Martin,et al.  Genomic convergence: identifying candidate genes for Parkinson's disease by combining serial analysis of gene expression and genetic linkage. , 2003, Human molecular genetics.

[67]  Rajesh Pahwa,et al.  Stroke , 1987, Neurology.

[68]  J. Moffett,et al.  Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[69]  J. Parks,et al.  Abnormalities of the electron transport chain in idiopathic parkinson's disease , 1989, Annals of neurology.

[70]  C. Becker,et al.  Differential Metabolic Profiling for Biomarker Discovery , 2005 .