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JNNP Online First, published on March 20, 2015 as 10.1136/jnnp-2014-309676 Movement disorders
RESEARCH PAPER
Identification of novel biomarkers for Parkinson’s disease by metabolomic technologies Taku Hatano,1 Shinji Saiki,1 Ayami Okuzumi,1 Robert P Mohney,2 Nobutaka Hattori1,3 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ jnnp-2014-309676). 1
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan 2 Metabolon Inc., Durham, North Carolina, USA 3 Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan Correspondence to Dr Nobutaka Hattori, Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; [email protected] Received 10 October 2014 Revised 26 January 2015 Accepted 6 March 2015
ABSTRACT Objective The pathogenesis of Parkinson’s disease (PD) involves complex interactions between environmental and genetic factors. Metabolomics can shed light on alterations in metabolic pathways in many diseases, including neurodegenerative diseases. In the present study, we attempted to elucidate the candidate metabolic pathway(s) associated with PD. Methods Serum samples were collected from 35 individuals with idiopathic PD without dementia and 15 healthy age-matched control participants without PD. This analysis used a combination of three independent platforms: ultrahigh-performance liquid chromatography/ tandem mass spectrometry (UPLC/MS/MS) optimised for basic species, UPLC/MS/MS optimised for acidic species and gas chromatography/MS (GC/MS). Results The metabolomic profiles of PD were clearly different from normal controls. PD profiles had significantly lower levels of tryptophan, caffeine and its metabolites, bilirubin and ergothioneine, and significantly higher levels of levodopa metabolites and biliverdin than those of normal controls. Alterations in the bilirubin/biliverdin ratio and ergothioneine can indicate oxidative stress intensity and may suggest elevated oxidative stress and/or insufficient ability for scavenging free radicals, which could contribute to PD pathogenesis. Decreased serum tryptophan level is associated with psychiatric problems in PD. A decrease in serum caffeine levels is consistent with an inverse association of caffeine consumption with development of PD based on past epidemiological studies. Conclusions Metabolomic analysis detected biomarkers associated with PD pathogenesis and disease progression. Since critical metabolic biomarkers need to be identified in PD, future studies should include assay validation and replication in independent cohorts.
INTRODUCTION
To cite: Hatano T, Saiki S, Okuzumi A, et al. J Neurol Neurosurg Psychiatry Published Online First: [please include Day Month Year] doi:10.1136/jnnp2014-309676
The pathological hallmarks of Parkinson’s disease (PD) are the marked loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), causing the depletion of dopamine in the striatum, as well as the presence of intracytoplasmic inclusions known as Lewy bodies. Neuronal loss and the formation of Lewy bodies have been detected not only in the SNc, but also in the locus coeruleus, pedunculopontine nucleus, raphe nucleus, dorsal motor nucleus of the vagal nerve, olfactory bulb, parasympathetic and sympathetic postganglionic neurons, Meynert nucleus, amygdaloid nucleus and cerebral cortex. Thus, PD is recognised as a multicentric disorder. Widespread neurodegeneration is responsible for the various motor and non-motor
symptoms of PD. Although the pathomechanisms underlying neuronal degeneration in PD remain unknown, various PD-related genetic-environmental interactions may contribute to the pathogenesis of this disease.1 2 Previous studies revealed the diagnostic value of measuring α-synuclein3 4 and DJ-15 levels in cerebrospinal fluid; however, useful biomarkers related to environmental factors have not as yet been elucidated. The recent development of several ‘omics’ technologies has allowed for the profiling of biospecimens for ageing and/or disease-specific genetic markers, proteins and small-molecular-weight (
JNNP Online First, published on March 20, 2015 as 10.1136/jnnp-2014-309676 Movement disorders
RESEARCH PAPER
Identification of novel biomarkers for Parkinson’s disease by metabolomic technologies Taku Hatano,1 Shinji Saiki,1 Ayami Okuzumi,1 Robert P Mohney,2 Nobutaka Hattori1,3 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ jnnp-2014-309676). 1
Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan 2 Metabolon Inc., Durham, North Carolina, USA 3 Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan Correspondence to Dr Nobutaka Hattori, Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; [email protected] Received 10 October 2014 Revised 26 January 2015 Accepted 6 March 2015
ABSTRACT Objective The pathogenesis of Parkinson’s disease (PD) involves complex interactions between environmental and genetic factors. Metabolomics can shed light on alterations in metabolic pathways in many diseases, including neurodegenerative diseases. In the present study, we attempted to elucidate the candidate metabolic pathway(s) associated with PD. Methods Serum samples were collected from 35 individuals with idiopathic PD without dementia and 15 healthy age-matched control participants without PD. This analysis used a combination of three independent platforms: ultrahigh-performance liquid chromatography/ tandem mass spectrometry (UPLC/MS/MS) optimised for basic species, UPLC/MS/MS optimised for acidic species and gas chromatography/MS (GC/MS). Results The metabolomic profiles of PD were clearly different from normal controls. PD profiles had significantly lower levels of tryptophan, caffeine and its metabolites, bilirubin and ergothioneine, and significantly higher levels of levodopa metabolites and biliverdin than those of normal controls. Alterations in the bilirubin/biliverdin ratio and ergothioneine can indicate oxidative stress intensity and may suggest elevated oxidative stress and/or insufficient ability for scavenging free radicals, which could contribute to PD pathogenesis. Decreased serum tryptophan level is associated with psychiatric problems in PD. A decrease in serum caffeine levels is consistent with an inverse association of caffeine consumption with development of PD based on past epidemiological studies. Conclusions Metabolomic analysis detected biomarkers associated with PD pathogenesis and disease progression. Since critical metabolic biomarkers need to be identified in PD, future studies should include assay validation and replication in independent cohorts.
INTRODUCTION
To cite: Hatano T, Saiki S, Okuzumi A, et al. J Neurol Neurosurg Psychiatry Published Online First: [please include Day Month Year] doi:10.1136/jnnp2014-309676
The pathological hallmarks of Parkinson’s disease (PD) are the marked loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), causing the depletion of dopamine in the striatum, as well as the presence of intracytoplasmic inclusions known as Lewy bodies. Neuronal loss and the formation of Lewy bodies have been detected not only in the SNc, but also in the locus coeruleus, pedunculopontine nucleus, raphe nucleus, dorsal motor nucleus of the vagal nerve, olfactory bulb, parasympathetic and sympathetic postganglionic neurons, Meynert nucleus, amygdaloid nucleus and cerebral cortex. Thus, PD is recognised as a multicentric disorder. Widespread neurodegeneration is responsible for the various motor and non-motor
symptoms of PD. Although the pathomechanisms underlying neuronal degeneration in PD remain unknown, various PD-related genetic-environmental interactions may contribute to the pathogenesis of this disease.1 2 Previous studies revealed the diagnostic value of measuring α-synuclein3 4 and DJ-15 levels in cerebrospinal fluid; however, useful biomarkers related to environmental factors have not as yet been elucidated. The recent development of several ‘omics’ technologies has allowed for the profiling of biospecimens for ageing and/or disease-specific genetic markers, proteins and small-molecular-weight (
