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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Bartha, Robert

2nd Supervisor

Duggal, Neil

Co-Supervisor

Abstract

Degenerative cervical myelopathy (DCM) is a degenerative disease of the spinal cord that can lead to neurological dysfunction. It has been hypothesized that ischemia and hypoxia in the spinal cord at the site of compression could impact functional recovery after decompression surgery. Unfortunately, direct in-vivo quantification of hypoxia and ischemia in the spine has been limited in humans. Magnetic resonance imaging (MRI) can be utilized to measure hypoxia indirectly in soft tissue. Specifically, chemical exchange saturation transfer (CEST) is an MRI contrast that can be derived from the transfer of magnetization from selectively excited endogenous protons to bulk water protons. This exchange process is pH-dependent and can be exploited to produce a pH-weighted CEST contrast called amine/amide concentration independent detection (AACID). Hypoxia can decrease the pH of tissue.

For the first time in DCM patients, the severity of spinal cord compression was correlated with functional brain activity changes, suggesting that hypoxic injury in the spinal cord may contribute to cortical reorganization in the motor areas of the brain. The results from this study provided the motivation for this thesis to develop three-dimensional (3D) AACID CEST pH-weighted MRI at the clinically relevant field strength of 3.0T in the healthy brain and spinal cord and then to demonstrate the feasibility of pH-weighted imaging in the spinal cord of DCM patients. Furthermore, the reproducibility of spinal cord AACID CEST MRI was quantified and found to have the greatest reproducibility at the center of the 3D volume when incorporating a B1-inhomogeneity correction.

In conclusion, this dissertation demonstrates the process of developing a 3D pH-weighted CEST MRI contrast at the clinically relevant field strength of 3.0T in the cervical spinal cord. This work includes initially exploring how the severity of cord compression affects brain functional activity, optimizing the CEST sequence at 3.0T, evaluating the reproducibility of the AACID measurement in both the healthy brain and cervical spinal cord and initial utilization in the spinal cord of people with DCM. This dissertation lays the groundwork to determine if hypoxia is occurring in the spinal cord of DCM patients and if it is a measure of neurological outcome.

Summary for Lay Audience

Degenerative cervical myelopathy (DCM) is a progressive disease of the spine that leads to compression, causing disruptions in hand function and walking and may lead to paralysis. Surgery is often the treatment recommended for DCM patients. Unfortunately, some patients continue to decline after surgery, and it is difficult to predict who. A new measure of outcome is needed to identify which patients will improve from decompression surgery and to determine when surgery should be performed. Compression of the spine might reduce the blood supply and oxygen available to the tissue, and this might affect how patients respond to decompression surgery. This thesis investigates and develops a way to non-invasively create images of the spine using magnetic resonance imaging (MRI) that is sensitive to changes in the tissue caused by a lack of oxygen. Specifically, such tissue becomes acidic, decreasing the tissue pH.

In DCM patients, a spinal cord compression measure was developed and compared to changes in brain activity observed when performing a hand-based task. The study found that patients who had more severely compressed spinal cords also tended to show more brain activation, suggesting that injury to the spinal cord caused by a lack of oxygen could cause adaptations to occur in the brain to compensate for the injury.

This study motivated the development of a specialized MRI measurement that is sensitive to tissue acidity using clinically available MRI scanners. This technique has been previously utilized to detect changes in tissue acidity in animal models of stroke and cancer but has never been implemented in humans. Before assessing changes in tissue acidity in the spinal cord of DCM patients, the technique was fine-tuned and tested in the healthy human brain and cervical spinal cord. Measurement reproducibility was evaluated in the healthy brain and cervical spinal cord, demonstrating the feasibility of the method. Preliminary testing also demonstrated that the spinal cord of DCM patients may be acidic at the site of spinal cord compression.

The research in this thesis lays the groundwork for future research in DCM patients to determine if tissue acidity can be used to predict functional outcome after surgery.

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