Investigation of biological tissues by diffusion weighted magnetic resonance spectroscopy

Abstract

Magnetic resonance spectroscopy (MRS) is one of the most powerful methods that allow the in vivo and in situ measurement of molecular concentrations in live tissues. Diffusion weighted MRS (DW-MRS), along with other MRS derived techniques, provides alternative methods to investigate different molecular properties and collect the information that reveals the underlying biochemical mechanisms in the microscopic view. The purposes of my doctoral work were developing, testing and applying DW-MRS and other MRS derived or related MR techniques, to characterize the important molecular properties in the biological tissues that may be the important markers for clinical diagnosis and pre-clinical investigations.

Firstly, DW-MRS was applied on the skeletal muscles. DW-MRS measurement of the creatine apparent diffusion coefficient (ADC) in rat hindlimb muscles in two orthotropic diffusion directions showed that creatine has a highly anisotropic diffusion behavior in the muscle fibers. In muscle ischemia model, the intramyocellular lipid (IMCL) and creatine ADCs had significantly increased during muscle ischemia while the metabolite concentrations remained relatively unchanged. The IMCL ADC carries important information about the alterations of lipid droplet microstructure and as such may reveal the changes in lipid droplet size and lipid metabolism under disease conditions in skeletal muscles.

Secondly, the feasibility of using DW-MRS for the separation of spectrally overlapped lactate and lipid resonances in different tissue types was thoroughly studied and presented. Lactate and lipid are important biomarkers in cancerous and ischemic tissues. Using diffusion weighting, robust separation of lactate and lipid signals at 1.3 ppm was demonstrated in the lactate/lipid phantoms and animal models of glioma and stroke. In practice, this separation method was further implemented by the simple spectral subtraction using two or three diffusion weighted spectra acquired with carefully chosen b-values. Such new method presented a novel approach to separate and quantify spectrally overlapped molecules like lactate and lipid but not limited to them.

Thirdly, DW-MRS was applied in the cartilage tissue and was proved to be able to detect the extracellular matrix (ECM) degradation during intervertebral disc degeneration (IVDD) by measuring the increased mobility of ECM macromolecules, including proteoglycans (PG) and collagens. Macromolecular (especially PG) ADCs are sensitive to the ECM degradation, and they are early markers for ECM degradation than the PG content, PG T2 value, water T2 value and water ADC during early IVDD. The DW-MRS approach could directly monitor the ECM integrity, yielding biophysical insights into the ECM degradation process. Lastly, DW-MRS was compared with other techniques such as T2-weighted MRS and chemical exchange saturation transfer (CEST) imaging in detecting and characterizing the ECM degradation process during the early stage of IVDD. CEST imaging provides the sensitive detection of the distribution changes of PG according to the changes in the ECM integrity. On the other hand, suggested by the preliminary results from the human study, the PG T2 value may be also related to the ECM integrity in different disc levels. Altogether, PG ADC, distribution, and T2 values are important potential markers for detecting the onset of the ECM degradation in IVDD.