CSF Biomarkers and Its Associations with 18F-AV133 Cerebral VMAT2 Binding in Parkinson's Disease-A Preliminary Report

PLoS One. 2016 Oct 20;11(10):e0164762. doi: 10.1371/journal.pone.0164762. eCollection 2016.

Abstract

Objective: Cerebrospinal fluid (CSF) biomarkers, such as α-synuclein (α-syn), amyloid beta peptide 1-42 (Aβ1-42), phosphorylated tau (181P) (p-tau), and total tau (t-tau), have long been associated with the development of Parkinson disease (PD) and other neurodegenerative diseases. In this investigation, we reported the assessment of CSF biomarkers and their correlations with vesicular monoamine transporter 2 (VMAT2) bindings measured with 18F-9-fluoropropyl-(+)-dihydrotetrabenazine (18F-AV133) that is being developed as a biomarker for PD. We test the hypothesis that monoaminergic degeneration was correlated with CSF biomarker levels in untreated PD patients.

Methods: The available online data from the Parkinson's Progression Markers Initiative study (PPMI) project were collected and analyzed, which include demographic information, clinical evaluations, CSF biomarkers (α-syn, Aβ1-42, p-tau, and t-tau), 18F-AV133 brain PET, and T1 weighted MRIs. Region of interest (ROI) and voxel-wise Pearson correlation between standardized uptake value ratio (SUVR) and CSF biomarkers were calculated.

Results: Our major findings are: 1) Compared with controls, CSF α-syn and tau levels decreased significantly in PD; 2) α-syn was closely correlated with Aβ1-42 and tau in PD, especially in early-onset patients; and 3) hypothesis-driven ROI analysis found a significant negative correlation between CSF Aβ1-42 levels and VMAT2 densities in post cingulate, left caudate, left anterior putamen, and left ventral striatum in PDs. CSF t-tau and p-tau levels were significantly negatively related to VMAT2 SUVRs in substantia nigra and left ventral striatum, respectively. Voxel-wise analysis showed that left caudate, parahippocampal gyrus, insula and temporal lobe were negatively correlated with Aβ1-42. In addition, superior frontal gyrus and transverse temporal gyrus were negatively correlated with CSF p-tau levels.

Conclusion: These results suggest that monoaminergic degeneration in PD is correlated with CSF biomarkers associated with cognitive impairment in neurodegenerative diseases including Alzheimer's disease. The association between loss of dopamine synaptic function and pathologic protein accumulations in PD indicates an important role of CSF biomarkers in PD development.

MeSH terms

  • Aged
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Biomarkers / cerebrospinal fluid*
  • Brain / diagnostic imaging*
  • Brain / metabolism
  • Female
  • Fluorine Radioisotopes / metabolism
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Parkinson Disease / cerebrospinal fluid
  • Parkinson Disease / diagnostic imaging*
  • Parkinson Disease / metabolism
  • Pilot Projects
  • Positron-Emission Tomography
  • Tetrabenazine / analogs & derivatives*
  • Tetrabenazine / metabolism
  • Vesicular Monoamine Transport Proteins / metabolism*
  • alpha-Synuclein / cerebrospinal fluid
  • tau Proteins / cerebrospinal fluid

Substances

  • Amyloid beta-Peptides
  • Biomarkers
  • Fluorine Radioisotopes
  • MAPT protein, human
  • SLC18A2 protein, human
  • Vesicular Monoamine Transport Proteins
  • alpha-Synuclein
  • tau Proteins
  • florbenazine F 18
  • Tetrabenazine

Grant support

As mentioned in the manuscript, data used in the preparation of this article were obtained from the PPMI database (www.ppmi-info.org/data). PPMI is sponsored and partially funded by The Michael J. Fox Foundation for Parkinson’s Research (MJFF). Other funding partners include a consortium of industry players, non-profit organizations and private individuals, including Abbott, Avid, Biogen Idec, Covalence, Elan, GlaxoSmithKline, Lilly, Merck, UCB, F. Hoffman-La Roche Ltd., GE Healthcare, Genentech, and Pfizer Inc. Industry partners are contributing to PPMI through financial and in-kind donations and are playing a lead role in providing feedback on study parameters through the Industry Scientific Advisory Board (ISAB). For up-to-date information on the study, visit www.ppmi-info.org. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work of the author was in part supported by the Project of Natural Science Foundation Research Project of Shaanxi Province (No. 2016JM8056).