= Emerging. More than 5 years before clinical availability. (26.62%)
= Expected to be clinically available in 1 to 4 years. (38.91%)
= Clinically available now. (34.47%)
MSACL 2020 US : Jones

MSACL 2020 US Abstract

Topic: Imaging

Podium Presentation in Room 4 on Thursday at 11:40 (Chair: David Muddiman)

MALDI FTICR MS Imaging and Quantitative Lipidyzer Approach to Investigate Total Parkinson Disease Lipidome and Circulating Lipidomic Biomarkers of PD

E. Ellen Jones (Presenter)
NCTR / FDA

Presenter Bio(s): Dr. E. Ellen Jones is a Staff Fellow at the National Center for Toxicological Research, which is part of the Food and Drug Administration, in Jefferson, AR. At NCTR Dr. Jones leads the MALDI Imaging team located within the Biomarkers and Alternative Models Branch (BAMB) in the Division of Systems Biology with the overall goal of utilizing this approach to better understand drug toxicities. The implementation of cutting-edge technologies such as high resolution MALDI IMS within the Food and Drug Administration (FDA) is critical as it corresponds to efforts ongoing in pharmaceutical companies whom are using it both in preclinical and clinical studies to identify biomarkers of drug efficacy and toxicity; data which is beginning to be included within FDA drug filings. Thus, the MALDI IMS team at NCTR recently acquired a state-of-the-art high resolution FTICR mass spectrometer (scimaX MRMS 7T FTICR MS) capable of the mass accuracy and resolution required for small molecule and metabolomic imaging.

Authors: E. Ellen Jones, Syed Imam, Jinchin Susan Lantz, Jinchun Sun, Richard Beger
National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR

Abstract

Introduction

Parkinson's disease is a progressive neurological disease estimated to effect between 7 -10 million people worldwide. With no known cure and little known about the mechanisms leading to the disease it represents a significant and increasing threat to public health, warranting further research. Although preliminary studies suggest a connection between fatty brain and Parkinson disease onset, this hypothesis has not been fully interrogated, and comprehensive lipidomic studies are warranted.

Objective

To perform a comprehensive analysis of lipids and neurotransmitters in post-mortem brain samples obtained from PD patients and age-matched controls using a combination imaging and quantitative lipidomics approach. The overall goal is to identify circulating biomarkers indicative of PD onset and progression.

Methods

Post-mortem brain tissues (Frontal Cortex, Striatum, and Substantia Nigra, N=15 each region) from sporadic PD patients and their age-matched controls were analyzed by both MALDI Fourier-transform ion cyclotron resonance (FTICR) MS imaging and the SelexION lipidyzer. Samples were sectioned for imaging mass spectrometry with serial sections taken for immunohistochemical analysis of tyrosine hydroxylase and synuclein expression to validate the pathological correlation of PD with distribution of lipids and lipid metabolites in PD brain tissues. Following sectioning for imaging, tissues were prepared for quantitative analysis and run on the lipidyzer. In addition to tissues, plasma samples from current PD patients who carry Parkin mutation (n=6), LRRK2 mutation (N=6) and the GBA mutation (N=15) and their age matched controls were also analyzed on the lipidyzer and then correlated with the expression of a-synuclein, UCH-L1 and GFAP in brain homogenates and plasma.

Results

A comprehensive lipidomic analysis using imaging mass spectrometry and the SeleXION Lipidyzer was performed on human PD brain and plasma samples. Using the lipidyzer over 1200 lipids and metabolites were evaluated in PD samples versus control. Differential lipids were then correlated to the spatial distributions of lipid classes from the imaging results, and matched with the IHC data. Statistical analysis from both imaging results and the lipidyzer successfully identified numerous lipids differentially expressed between PD and control samples, including common abundant lipids such as phosphatidylcholines, as well as less abundant and previously hard to detect lipids including glycosphingolipids. A comprehensive analysis of these findings will be presented, along with the immunohistochemical analysis, some of which is ongoing.

Conclusions

Altered lipid metabolism is prevalent in GD patient brain tissues and plasma, suggesting that lipids may not only serve as biomarkers of PD disease, but also offer clues into disease onset, progression and further serve as critical targets for future therapeutics.


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