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Development and Application of Software Tools for Mass Spectrometry Imaging
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Universitet. (Biomolecular Mass Spectrometry Imaging)
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

Mass spectrometry imaging (MSI) has been extensively used to produce qualitative maps of distributions of proteins, peptides, lipids, neurotransmitters, small molecule pharmaceuticals and their metabolites directly in biological tissue sections. Moreover, during the last 10 years, there has been growing demand to quantify target compounds in tissue sections of various organs. This thesis focuses on development and application of a novel instrument- and manufacturer-independent MSI software suite, msIQuant, in the open access format imzML, which has been developed specifically for quantitative analysis of MSI data. The functionality of msIQuant facilitates automatic generation of calibration curves from series of standards that can be used to determine concentrations of specific analytes. In addition, it provides many tools for image visualization, including modules enabling multiple interpolation, low intensity transparency display, and image fusion and sharpening. Moreover, algorithms and advanced data management modules in msIQuant facilitate management of the large datasets generated following rapid recent increases in the mass and spatial resolutions of MSI instruments, by using spectra transposition and data entropy reduction (at four selectable levels: coarse, medium, fine or superfine) before lossless compression of the data. As described in the thesis, implementation of msIQuant has been exemplified in both quantitative (relative or absolute) and qualitative analyses of distributions of neurotransmitters, endogenous substances and pharmaceutical drugs in brain tissue sections. Our laboratory have developed a molecular-specific approach for the simultaneous imaging and quantitation of multiple neurotransmitters, precursors, and metabolites, such as tyrosine, tryptamine, tyramine, phenethylamine, dopamine, 3-methoxytyramine, serotonin, gamma-aminobutyric acid (GABA), and acetylcholine, in histological tissue sections at high spatial resolution by matrix-assisted laser desorption ionization (MALDI) and desorption electrospray ionization (DESI) MSI. Chemical derivatization by charge-tagging primary amines of analytes significantly increased the sensitivity, enabling mapping of neurotransmitters that were not previously detectable by MSI. The two MSI approaches have been used to directly measure changes in neurotransmitter levels in specific brain structures in animal disease models, which facilitates understanding of biochemical mechanisms of drug treatments. In summary, msIQuant software has proven potency (particularly in combination with the reported derivatization technique) for both qualitative and quantitative analyses. Further developments will enable its implementation in multiple operating system platforms and use for statistical analysis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. , 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 234
Keyword [en]
mass spectrometry imaging, MALDI, DESI, msIQuant, quantitation, neurotransmitters, drugs, derivatization, brain, compression, data entropy reduction
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-328016ISBN: 978-91-513-0040-5 (print)OAI: oai:DiVA.org:uu-328016DiVA: diva2:1134457
Public defence
2017-10-06, A1:111a, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-09-13 Created: 2017-08-19 Last updated: 2017-09-13
List of papers
1. Novel mass spectrometry imaging software assisting labeled normalization and quantitation of drugs and neuropeptides directly in tissue sections
Open this publication in new window or tab >>Novel mass spectrometry imaging software assisting labeled normalization and quantitation of drugs and neuropeptides directly in tissue sections
2012 (English)In: Journal of Proteomics, ISSN 1874-3919, Vol. 75, no 16, 4941-4951 p.Article in journal (Refereed) Published
Abstract [en]

MALDI MS imaging has been extensively used to produce qualitative distribution maps of proteins, peptides, lipids, small molecule pharmaceuticals and their metabolites directly in biological tissue sections. There is growing demand to quantify the amount of target compounds in the tissue sections of different organs. We present a novel MS imaging software including protocol for the quantitation of drugs, and for the first time, an endogenous neuropeptide directly in tissue sections. After selecting regions of interest on the tissue section, data is read and processed by the software using several available methods for baseline corrections, subtractions, denoising, smoothing, recalibration and normalization. The concentrations of in vivo administered drugs or endogenous compounds are then determined semi-automatically using either external standard curves, or by using labeled compounds, i.e., isotope labeled analogs as standards. As model systems, we have quantified the distribution of imipramine and tiotropium in the brain and lung of dosed rats. Substance P was quantified in different mouse brain structures, which correlated well with previously reported peptide levels. Our approach facilitates quantitative data processing and labeled standards provide better reproducibility and may be considered as an efficient tool to quantify drugs and endogenous compounds in tissue regions of interest.

Keyword
Brain, Deuterated standard, MALDI, Neuropeptide, Lung, Standard curve
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-182525 (URN)10.1016/j.jprot.2012.07.034 (DOI)000308524400007 ()
Note

This article is part of a Special Issue entitled: Imaging Mass Spectrometry: A User's Guide to a New Technique for Biological and Biomedical Research.

Available from: 2012-10-12 Created: 2012-10-11 Last updated: 2017-08-19Bibliographically approved
2. msIQuant - Quantitation Software for Mass Spectrometry Imaging Enabling Fast Access, Visualization, and Analysis of Large Data Sets
Open this publication in new window or tab >>msIQuant - Quantitation Software for Mass Spectrometry Imaging Enabling Fast Access, Visualization, and Analysis of Large Data Sets
2016 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 88, no 8, 4346-4353 p.Article in journal (Refereed) Published
Abstract [en]

This paper presents msIQuant, a novel instrument- and manufacturer-independent quantitative mass spectrometry imaging software suite that uses the standardized open access data format imzML. Its data processing structure enables rapid image display and the analysis of very large data sets (>50 GB) without any data reduction. In addition, msIQuant provides many tools for image visualization including multiple interpolation methods, low intensity transparency display, and image fusion. It also has a quantitation function that automatically generates calibration standard curves from series of standards that can be used to determine the concentrations of specific analytes. Regions-of-interest in a tissue section can be analyzed based on a number of quantities including the number of pixels, average intensity, standard deviation of intensity, and median and quartile intensities. Moreover, the suite's export functions enable simplified postprocessing of data and report creation. We demonstrate its potential through several applications including the quantitation of small molecules such as drugs and neurotransmitters. The msIQuant suite is a powerful tool for accessing and evaluating very large data sets, quantifying drugs and endogenous compounds in tissue areas of interest, and for processing mass spectra and images.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-297908 (URN)10.1021/acs.analchem.5b04603 (DOI)000374706000026 ()27014927 (PubMedID)
Funder
Swedish Research Council, 2013-3105 2014-6215 2009-6050
Available from: 2016-06-29 Created: 2016-06-28 Last updated: 2017-08-19
3. A Space Efficient Direct Access Data Compression Approach for Mass Spectrometry Imaging
Open this publication in new window or tab >>A Space Efficient Direct Access Data Compression Approach for Mass Spectrometry Imaging
(English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882Article in journal (Refereed) Submitted
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-328051 (URN)
Available from: 2017-08-19 Created: 2017-08-19 Last updated: 2017-08-19
4. Direct targeted quantitative molecular imaging of neurotransmitters in brain tissue sections
Open this publication in new window or tab >>Direct targeted quantitative molecular imaging of neurotransmitters in brain tissue sections
Show others...
2014 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 84, no 4, 697-707 p.Article in journal (Refereed) Published
Abstract [en]

Current neuroimaging techniques have very limited abilities to directly identify and quantify neurotransmitters from brain sections. We have developed a molecular-specific approach for the simultaneous imaging and quantitation of multiple neurotransmitters, precursors, and metabolites, such as tyrosine, tryptamine, tyramine, phenethylamine, dopamine, 3-methoxytyramine, serotonin, GABA, glutamate, acetylcholine, and L-alpha-glycerylphosphorylcholine, in histological tissue sections at high spatial resolutions. The method is employed to directly measure changes in the absolute and relative levels ofneurotransmitters in specific brain structures in animal disease models and in response to drug treatments, demonstrating the power of mass spectrometry imaging in neuroscience.

National Category
Medical Bioscience
Identifiers
urn:nbn:se:uu:diva-239353 (URN)10.1016/j.neuron.2014.10.011 (DOI)000345424900007 ()25453841 (PubMedID)
Available from: 2014-12-29 Created: 2014-12-22 Last updated: 2017-08-19Bibliographically approved
5. Simultaneous imaging of multiple neurotransmitters and neuroactive substances in the brain by desorption electrospray ionization mass spectrometry
Open this publication in new window or tab >>Simultaneous imaging of multiple neurotransmitters and neuroactive substances in the brain by desorption electrospray ionization mass spectrometry
Show others...
2016 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 136, 129-138 p.Article in journal (Refereed) Published
Abstract [en]

With neurological processes involving multiple neurotransmitters and neuromodulators, it is important to have the ability to directly map and quantify multiple signaling molecules simultaneously in a single analysis. By utilizing a molecular-specific approach, namely desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we demonstrated that the technique can be used to image multiple neurotransmitters and their metabolites (dopamine, dihydroxyphenylacetic acid, 3-methoxytyramine, serotonin, glutamate, glutamine, aspartate,gamma-aminobutyric acid, adenosine) as well as neuroactive drugs (amphetamine, sibutramine, fluvoxamine) and drug metabolites in situ directly in brain tissue sections. The use of both positive and negative ionization modes increased the number of identified molecular targets. Chemical derivatization by charge-tagging the primary amines of molecules significantly increased the sensitivity, enabling the detection of low abundant neurotransmitters and other neuroactive substances previously undetectable by MSI. The sensitivity of the imaging approach of neurochemicals has a great potential in many diverse applications in fields such as neuroscience, pharmacology, drug discovery, neurochemistry, and medicine.

Keyword
Neurotransmitter, Dopamine, Imaging, Mass spectrometry, Parkinson's disease, Serotonin
National Category
Neurology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-299698 (URN)10.1016/j.neuroimage.2016.05.004 (DOI)000378048000012 ()27155126 (PubMedID)
Funder
Swedish Research Council, 2013-3105 2014-6215 2009-6050The Swedish Brain FoundationSwedish Foundation for Strategic Research , RIF14-0078EU, FP7, Seventh Framework Programme, 607517
Available from: 2016-07-27 Created: 2016-07-26 Last updated: 2017-08-19Bibliographically approved

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