title: Identification of candidate cerebrospinal fluid biomarkers in parkinsonism using quantitative proteomics.
abstract: Neurodegenerative parkinsonian syndromes have significant clinical and pathological overlap, making early diagnosis difficult. Cerebrospinal fluid (CSF) biomarkers may aid the differentiation of these disorders, but other than α-synuclein and neurofilament light chain protein, which have limited diagnostic power, specific protein biomarkers remain elusive.
  
  
  
  To study disease mechanisms and identify possible CSF diagnostic biomarkers through discovery proteomics, which discriminate parkinsonian syndromes from healthy controls.
  
  
  
  CSF was collected consecutively from 134 participants; Parkinson's disease (n = 26), atypical parkinsonian syndromes (n = 78, including progressive supranuclear palsy (n = 36), multiple system atrophy (n = 28), corticobasal syndrome (n = 14)), and elderly healthy controls (n = 30). Participants were divided into a discovery and a validation set for analysis. The samples were subjected to tryptic digestion, followed by liquid chromatography-mass spectrometry analysis for identification and relative quantification by isobaric labelling. Candidate protein biomarkers were identified based on the relative abundances of the identified tryptic peptides. Their predictive performance was evaluated by analysis of the validation set.
  
  
  
  79 tryptic peptides, derived from 26 proteins were found to differ significantly between atypical parkinsonism patients and controls. They included acute phase/inflammatory markers and neuronal/synaptic markers, which were respectively increased or decreased in atypical parkinsonism, while their levels in PD subjects were intermediate between controls and atypical parkinsonism.
  
  
  
  Using an unbiased proteomic approach, proteins were identified that were able to differentiate atypical parkinsonian syndrome patients from healthy controls. Our study indicates that markers that may reflect neuronal function and/or plasticity, such as the amyloid precursor protein, and inflammatory markers may hold future promise as candidate biomarkers in parkinsonism.
authors.affiliation: Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, Queen Square, London, UK. Electronic address: n.magdalinou@ucl.ac.uk.
authors.forename: N K
authors.initials: NK
authors.lastname: Magdalinou
authors.affiliation: Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Noyce
authors.affiliation: Institute of Chemistry University of Umeå, Umeå, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Pinto
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Lindstrom
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Holmén-Larsson
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Holtta
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, Royal Free Hospital, London, UK.
authors.forename: H R
authors.initials: HR
authors.lastname: Morris
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Skillbäck
authors.affiliation: Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: T T
authors.initials: TT
authors.lastname: Warner
authors.affiliation: Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Lees
authors.affiliation: Proteome Sciences Plc, London, UK.
authors.forename: I
authors.initials: I
authors.lastname: Pike
authors.affiliation: Proteome Sciences Plc, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Ward
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Gobom
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016900:Neurofilament Proteins / Q000134:cerebrospinal fluid*; D020734:Parkinsonian Disorders / Q000134:cerebrospinal fluid* / Q000145:classification / Q000175:diagnosis; D040901:Proteomics / Q000379:methods*; D051844:alpha-Synuclein / Q000134:cerebrospinal fluid*
chemical_list: D015415:Biomarkers; D016900:Neurofilament Proteins; D051844:alpha-Synuclein; C044882:neurofilament protein L
keywords: Biomarker; Cerebrospinal fluid; Corticobasal syndrome; Isobaric labelling; Multiple system atrophy; Parkinson's disease; Parkinsonian disorders; Progressive supranuclear palsy; Proteomics