title: CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study.
abstract: The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ1-42, or highest t-tau/Aβ1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 7.103 Founders Pavilion 3400 Spruce Street, Philadelphia, PA, 19104, USA.|Department of Pharmacology, Hypoxia-related Disease Research Center, Inha University School of Medicine, Incheon, Republic of Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Paracelsus-Elena Klinik, Kassel, Germany.|Department of Neuropathology and Neurosurgery, University Medical Center Goettingen, Göttingen, Germany.
authors.forename: Brit
authors.initials: B
authors.lastname: Mollenhauer
authors.affiliation: Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Coffey
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 7.103 Founders Pavilion 3400 Spruce Street, Philadelphia, PA, 19104, USA.|Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.affiliation: Department of Neurology, Morris K. Udall Center of Excellence for Parkinson's Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Veterans Affairs, Philadelphia, PA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weintraub
authors.affiliation: Department of Neurosciences, University of California, San Diego, CA, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Galasko
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 7.103 Founders Pavilion 3400 Spruce Street, Philadelphia, PA, 19104, USA.|Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Neurology, Morris K. Udall Center of Excellence for Parkinson's Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Irwin
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 7.103 Founders Pavilion 3400 Spruce Street, Philadelphia, PA, 19104, USA.|Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Vivianna
authors.initials: V
authors.lastname: Van Deerlin
authors.affiliation: Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Neurology, Morris K. Udall Center of Excellence for Parkinson's Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Chen-Plotkin
authors.affiliation: Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Caspell-Garcia
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 7.103 Founders Pavilion 3400 Spruce Street, Philadelphia, PA, 19104, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Waligórska
authors.affiliation: BioLegend Inc., Dedham, MA, USA.
authors.forename: Peggy
authors.initials: P
authors.lastname: Taylor
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 7.103 Founders Pavilion 3400 Spruce Street, Philadelphia, PA, 19104, USA.
authors.forename: Nirali
authors.initials: N
authors.lastname: Shah
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 7.103 Founders Pavilion 3400 Spruce Street, Philadelphia, PA, 19104, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pan
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 7.103 Founders Pavilion 3400 Spruce Street, Philadelphia, PA, 19104, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Zero
authors.affiliation: The Michael J. Fox Foundation for Parkinson's Research, New York, NY, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Frasier
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, CT, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Marek
authors.affiliation: Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Kieburtz
authors.affiliation: Institute for Neurodegenerative Disorders, New Haven, CT, USA.
authors.forename: Danna
authors.initials: D
authors.lastname: Jennings
authors.affiliation: University of California-San Francisco and San Francisco Veteran's Affairs Medical Center, San Francisco, CA, USA.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Tanner
authors.affiliation: Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Simuni
authors.affiliation: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: Laboratory of Neuro Imaging, The Institute for Neuroimaging and Informatics, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Toga
authors.affiliation: The Michael J. Fox Foundation for Parkinson's Research, New York, NY, USA.
authors.forename: Sohini
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 7.103 Founders Pavilion 3400 Spruce Street, Philadelphia, PA, 19104, USA.|Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.|Department of Neurology, Morris K. Udall Center of Excellence for Parkinson's Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 7.103 Founders Pavilion 3400 Spruce Street, Philadelphia, PA, 19104, USA. Les.Shaw@uphs.upenn.edu.|Center for Neurodegenerative Disease Research, Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Les.Shaw@uphs.upenn.edu.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid* / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000134:cerebrospinal fluid / Q000150:complications / Q000175:diagnosis; D018450:Disease Progression; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000134:cerebrospinal fluid / Q000150:complications / Q000175:diagnosis*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010641:Phenotype; D011446:Prospective Studies
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments
keywords: Alpha-synuclein; Aβ1-42; Cerebrospinal fluid biomarker; Parkinson’s Progression Markers Initiative; Parkinson’s disease; Tau