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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

McKenzie, Charles A.

Abstract

Fetal life is a significant period of human development because organ systems that sustain life outside the uterus begin to develop during this time. A necessary process that begins during fetal life is myelination, which is the process by which myelin, a lipid-rich substance, is wrapped around neurons in the brain to increase the speed of action potential transmission. Since myelination is critical for the normal function of the central nervous system, fetal myelin assessment is important for understanding neurodevelopment and neurodegeneration, such as intrauterine growth restriction (IUGR).

Magnetic resonance imaging (MRI) is an excellent tool for visualizing fetal anatomy and identifying pathology. Relaxometry quantifies T1, T2, and T2* relaxation times, which are MR parameters that reflect fundamental tissue properties sensitive to the tissue microenvironment, providing an interpretation of images in absolute units. For the first time, fetal tissue T1 and T2* relaxation times were successfully quantified in uncomplicated pregnancies as a function of gestational age (GA) in the third trimester.

A tissue microenvironment that can be investigated by MR relaxometry is myelin water. Myelin water imaging (MWI) uses MR relaxometry to visualize the aqueous components associated with myelin sheath to quantify myelin water fraction (MWF), a validated myelin marker. Moving to a guinea pig model of pregnancy, MWI was successfully conducted in the fetal environment as MWF was quantified in various fetal brain regions late in gestation.

To investigate the effects of IUGR on myelination in utero, MWI was applied in a guinea pig model of natural IUGR late in gestation. MWF was significantly reduced in different brain regions of guinea pigs with IUGR compared to those without IUGR. Furthermore, the study highlighted the utility of MWF as a functional marker for IUGR.

In conclusion, this dissertation demonstrates using MR relaxometry to quantify T1 and T2* relaxation times of fetal tissues throughout pregnancy and assess fetal brain myelin content in both a normal and IUGR environment. The findings demonstrate MR relaxometry's utility in assessing fetal tissue development in utero.

Summary for Lay Audience

Fetal life is an important period of human development because organs and tissues, which help us survive outside the womb, undergo significant development. Furthermore, pathologies, such as intrauterine growth restriction (IUGR), developed during this developmental period can lead to life-long consequences, such as a reduction in brain myelin content; myelin is a fatty substance found in the brain that is necessary for normal cerebral functioning. This thesis investigates fetal tissue development and the effect of IUGR on fetal brain myelin using magnetic resonance imaging (MRI).

Human fetal tissue development was first investigated by measuring various tissues' MR tissue relaxation times in normal pregnancies in the third trimester. The study found that the parameters of most analyzed tissues did not change because these tissues are well-differentiated before the third trimester.

A specialized MRI technique that quantifies relaxation times has been used previously to assess myelin in adults, children, and neonates but never in fetuses. Before assessing the effects of IUGR on fetal brain myelin, the feasibility of the specialized technique was determined in a guinea pig model of pregnancy late in gestation. Myelin content was successfully measured in different brain regions, with initial data showing the myelin content to be less in fetuses with IUGR.

Moving to a guinea pig model of natural IUGR, it was found that myelin content in all analyzed brain regions was significantly less in fetuses with IUGR than those without IUGR. This was the first time that the IUGR-related reduction in myelin was visualized non -invasively with MRI.

The research in this thesis is important because it demonstrates MRI's utility in assessing fetal tissue development by measuring tissue relaxation times and the impact of pathologies on biological processes, such as the IUGR-related reduction in myelin. These results promote the use of MRI to assess fetal tissue development as well as the possibility of myelin as a biomarker for IUGR.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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