Abstract

Preeclampsia (PE), a life threatening pregnancy-related disorder, is characterized mainly by new onset of hypertension and proteinuria after 20 weeks of gestation. Currently, PE cannot be predicted prior to onset of symptoms and there is no cure for the disease. There is a clear value in having biomarkers able, early in a pregnancy, to identify women at risk for PE so that proper treatment therapies could be developed. Although a number of serum candidate markers have been proposed to be altered in PE patients, their use is limited due to poor sensitivity and specificity. Therefore, there is ongoing need for better set of novel biomarkers predicting PE. Consequently, for my first project, we used a serum proteomic approach involving reversed phase capillary-liquid chromatography-electrospray ionization-quadrupole-time of flight mass spectrometry (cLC-ESI-QTOF). Our approach focuses on the less abundant (nM or lower), lower molecular weight peptides and lipids predicting PE. We got previously collected sera from pregnant women at 12–14 weeks gestation. There were 24 controls, having term uncomplicated pregnancies and 24 cases, which developed PE later in the same pregnancy. Many statistically significant serum PE biomarker candidates were found comparing cases and controls. In addition, multimarker combinations having high detection sensitivity and specificity (AUC >0.9) were developed using logistic regression analysis. For my second project, serum lipidomic analysis of sera from pregnant women was undertaken to determine if useful PE lipid biomarkers exist. A discovery study involving a shotgun lipidomic approach was performed using sera collected at 12-14 weeks of pregnancy from 27 controls with uncomplicated pregnancies and 29 cases that later developed PE. Lipids were extracted using organic solvent and analyzed by direct infusion into a time-of-flight mass spectrometer. Statistically significant lipid markers were found and reevaluated in a second confirmatory study having 43 controls and 37 PE cases. The initial study detected 45 potential PE markers. Of these, 23 markers continued to be statistically significant in the second confirmatory set. Several multi-marker panels with AUC >0.85 and high predictive values were developed from these markers. My third project also involved the above mentioned approach for detection of novel lipid biomarkers for Alzheimer's disease. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of age-related dementia. Currently, there are no methods to detect Alzheimer's at an early stage when treatment therapies could be applied. Therefore, there is need for detection of panel of biomarkers for detecting patients at risk to AD at an early stage. In the initial discovery set, sera from 29 different stage AD cases and 32 controls were analyzed using direct infusion mass spectrometry (ESI-TOF). This study yielded 89 potential lipid biomarkers which were evaluated in another confirmation study. Of these, 35 markers continued to be statistically significant in the second confirmatory set. Using the confirmed markers, several multi-marker panels with AUC > 0.87 were developed for any stage AD cases vs controls. Multi-marker panels with AUCs > 0.90 were developed for each specific CDR vs controls, including the earliest stage of AD. These lipidomic biomarkers are likely to distinguish AD cases regardless of the stage from controls. In conclusion, we successfully detected, validated and identified low molecular weight novel biomarkers for PE and lipid biomarkers for AD.

Degree

PhD

College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry

Rights

http://lib.byu.edu/about/copyright/

Date Submitted

2016-03-01

Document Type

Dissertation

Handle

http://hdl.lib.byu.edu/1877/etd8364

Keywords

Preeclampsia, Alzheimer's disease, Proteomics, Lipidomics, Mass spectrometry, diagnosis, biomarkers

Language

english

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Chemistry Commons

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