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

Rui Gao,Gwenn Smith,Aimin Yang,Yun Zhou,Dean F Wong,Xueqi Chen,Guangjian Zhang,Kewei Chen

doi:10.1371/journal.pone.0164762

Abstract

ObjectiveCerebrospinal 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.MethodsThe 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.ResultsOur 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.ConclusionThese 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.

Highlights

Cerebrospinal fluid (CSF) analyses, reflecting metabolic and pathological states of the central nervous system, are widely used for Parkinson disease (PD) biomarker discovery [1,2,3]
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 Region of interest (ROI) analysis found a significant negative correlation between CSF Aβ1–42 levels and Vesicular monoamine transporter 2 (VMAT2) densities in post cingulate, left caudate, PLOS ONE | DOI:10.1371/journal.pone
The correlation was more greater in the early-onset PDs; (iii) CSF Aβ1–42 and tau levels were inversely correlated with VMAT2 standardized uptake value ratio (SUVR) in cortical brain areas associated with cognitive dysfunction

Summary

Introduction

Cerebrospinal fluid (CSF) analyses, reflecting metabolic and pathological states of the central nervous system, are widely used for Parkinson disease (PD) biomarker discovery [1,2,3]. Though some studies reported a relationship between the biomarkers and PD clincial progression [5, 8,9,10], it remains unclear how these CSF markers relate to striatal dopamine degeneration in PD [4, 11]. VMAT2 imaging has been shown to be a biomarker for the monoaminergic neuron integrity in PD [13,14,15]. 18F-AV133, a positron emission tomography (PET) tracer for VMAT2 imaging that is being developed for commercial distribution, has been shown to be a promising tracer for detecting and monitoring the VMAT2 reduction in PD [13]. The 18F-AV133-PET data is likely to allow us to directly assess the degeneration of monoaminergic neuron in the living PD brain. A correlation between 18F-AV133 uptake and cognitive impairment has been reported in Lewy body dementia patients [15]

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Conclusion