Introduction: Magnetic resonance (MR) imaging is one of the most important diagnostic tools in modern medicine. Compared to other imaging modalities, it provides superior soft tissue contrast of all parts of the body and it is considered to be safe for patients. Today almost all MR is performed in a nonquantitative manner, only comparing neighboring tissue in the search for pathology. It is possible to quantify MR-signals and relate them to their physical entities, but time consuming and complicated calibration procedures have prevented this being used in a practical manner for clinical routines. The aim of this work is to develop and improve quantification methods in MRspectroscopy (MRS) and MR-imaging (MRI). The techniques are intended to be applied to diffuse diseases, where conventional imaging methods are unable to perform accurate staging or to reveal metabolic changes associated with disease development.

Methods: Proton (1H) MRS was used to characterize the white matter in the brain of multiple sclerosis (MS) patients. Phosphorus (31P) MRS was used to evaluate the energy metabolism in patients with diffuse liver disease. A new quantitative MRI (qMRI) method was invented for accurate, rapid and simultaneous quantification of B1, T1, T2, and proton density. A method for automatic assessment of visceral adipose tissue volume based on an in- and out-ofphase imaging protocol was developed. Finally, a method for quantification of the hepatobiliary uptake of liver specific T1 enhancing contrast agents was demonstrated on healthy subjects.

Results: The 1H MRS investigations of white matter in MS-patients revealed a significant correlation between tissue concentrations of Glutamate and Creatine on the one hand and the disease progression rate on the other, as measured using the MSSS. High accuracy, both in vitro and in vivo, of the measured MR-parameters from the qMRI method was observed. 31P MRS showed lower concentrations of phosphodiesters, and a higher metabolic charge in patients with cirrhosis, compared to patients with mild fibrosis and to controls. The adipose tissue quantification method agreed with estimates obtained using manual segmentation, and enabled measurements which were insensitive to partial volume effects. The hepatobiliary uptake of Gd-EOB-DTPA and Gd-BOPTA was significantly correlated in healthy subjects.

Conclusion: In this work, new methods for accurate quantification of MR parameters in diffuse diseases in the liver and the brain were demonstrated. Several applications were shown where quantitative MR improves the interpretation of observed signal changes in MRI and MRS in relation to underlying differences in physiology and pathophysiology.

The studies in this thesis were delineated to evaluate the diagnostic possibilities in patients with diffuse liver disease by using phosphorus-31 MR spectroscopy and comparing the results with clinical, laboratory and histopathological findings. For this purpose in all 38 patients and 25 controls without evidence of liver disease were examined.

In the first study ³¹P-MRS using slice selection (DRESS) was implemented to investigate the absolute concentrations of metabolites in human liver. The metabolite concentration quantification procedures included: 1. Determination of optimal depth for the in vivo measurements, 2. Mapping the detection coil characteristics, 3. Calculation of selected slice and liver volume ratios using simple segmentation procedures, and 4. Spectral analysis in the time domain. Patients with histopathologically proven diffuse liver disease (n = 9) and healthy individuals (n = 12) were examined. The patients had significantly lower concentrations of phosphodiesters (PDE) and ATP-ß compared with the control group. Constructing an anabolic charge (AC) based on absolute concentrations, [PME] / ([PME] + [PDE]), the patients had a significant larger AC than the control subjects, 0.29 vs. 0.16 (p < 0.005).

In the second study the MRS technique was applied on two distinct groups of patients with diffuse chronic liver disorders, one group with steatosis and none-to-moderate inflammation (n = 13) and one group with severe fibrosis or cirrhosis (n = 16). All patients underwent liver biopsy and extensive biochemical evaluation. A control group (n = 13) was also included. Lower concentrations of PDE (p = 0.025) and a higher AC (p = 0.001) were found in the cirrhosis group compared to the control group.

Using a PDE concentration of 10.5 mM as a cut-off value to discriminate between mild (stage 0-2) and advanced (stage 3-4) fibrosis the sensitivity and specificity were 81% and 69% respectively. An AC cut-off value of 0.27 showed a sensitivity of 93% and a specificity of 54%.

In conclusion the results indicates that a decrease in PDE concentration is a marker of liver fibrosis and that AC is a potentially clinically useful parameter indiscriminating mild fibrosis from advanced. No significant relationship between the MRS data and the degree of steatosis or inflammation was found.

Magnetic resonance (MR) has become one of the most important diagnostic tools in modern medicine. It provides superior soft tissue contrast compared to other imaging modalities, it is extremely flexible as it can be used to image all parts of the body, and it is considered to be safe for patients.

Today almost all MR is performed in a non-quantitative manner, only by comparing neighbouring tissue in the search for pathology. It is possible to quantify the MR-signals to its physical entities, but time consuming and complicated calibration procedures have prevented this in clinical routine.

In this work two different applications of quantitative MR-spectroscopy in diffuse liver and neurological disease, and a new rapid method for simultaneous quantification of proton density, T1 relaxation and T2* relaxation in MR-imaging are presented.

In Paper I, absolutely quantified phosphorus MR-spectroscopy was tested as a predictive tool in order to determine the degree of fibrosis on patients with diffuse liver disease. One group with steatosis and none to moderate inflammation (n=13), one group with severe fibrosis or cirrhosis (n=16), and one group of healthy volunteers (n=13) were included in the study.

Lower concentrations of PDE (p = 0.025), and a higher metabolic charge (AC) [42] (p < 0.001) were found in the cirrhosis group. A sensitivity and specificity of 81% and 69% respectively, were found for the discrimination between mild and advanced fibrosis using PDE concentrations, and 93% and 54% using AC. The results suggest PDE as a marker of liver fibrosis and AC as a potential clinically useful parameter in discriminating mild from advanced fibrosis.

In Paper II proton MR-spectroscopy was used to investigate if there were differences in the concentrations of the observable metabolites in normal appearing white matter in patients with clinically definite multiple sclerosis (MS), and with normal MR-images compared to healthy volunteers. This 'MRI-negative' group consisted of fourteen patients which were compared with fourteen healthy controls. Absolutely quantified proton MR-spectra were acquired from four different voxels in NAWM.

Significant differences in absolute metabolite concentrations were observed between the two groups. The MS-patients had lower total N-acetyl compounds (tNA) (p=0.002) compared to the healthy controls and lower concentration of choline-containing compounds (Cho) compared to the healthy controls (p<0.001). EDSS showed a slightly positive correlation to myolns concentrations (0.14mM/EDSS,r² = 0.06) and a slightly negative correlation to tNA concentrations (-0.41 mM/EDSS,r² = 0.22). The finding of lower Cho concentrations has not been reported previously and was unexpected.

In Paper III a new rapid imaging method was presented for determination of proton density, B1, T2* relaxation and T1 relaxation. The method was based on a modified Look-Locker pulse sequence with two main differences. (1) The exchange of the inversion pulse in the Lock-Looker sequence to a saturation pulse in order to enable detection of the B1 field, and (2) the introduction of a multi-echo read-out to enable the detection of T2*. The signal intensity was then scaled to proton density using the estimated B1, T1, and T2* value.

The method was validated in vitro, using phantoms filled with solution of different T1 and T2* water relaxation values, and by comparing the results of the measurements to reference metcyods. In vivo the method was compared with literature values.

The validation showed that the method was highly accurate, both in vitro and in vivo, and that this method enabled quantitative imaging of MR-parameters within a clinically feasible examination time. Potential applications of the method are, among a great range of possibilities, to rapidly provide all the necessary quantification parameters in MR-spectroscopy, and to simultaneously provide fast quantitative diagnostic imaging.

The present study aims at demonstrating phosphorus metabolite concentration changes and alterations in uptake/excretion of a hepatocyte specific contrast agent in patients with diffuse - or suspected diffuse - liver disease by applying two non-invasive quantitative MR techniques and to compare the results with histo-pathological findings, with focus on liver fibrosis.

In the first study phosphorus-31 MR spectroscopy using slice selection (DRESS) was implemented. Patients with histopathologically proven diffuse liver disease (n = 9) and healthy individuals (n = 12) were examined. The patients had significantly lower concentrations of phosphodiesters (PDE) and ATP compared with controls. Constructing an ‘anabolic charge’ (AC) based on absolute concentrations, [PME] / ([PME] + [PDE]), the patients had a significant larger AC than the control subjects.

The MRS technique was then, in a second study, applied on two distinct groups of patients, one group with steatosis and none-to-moderate inflammation (n = 13) and one group with severe fibrosis or cirrhosis (n = 16). A control group (n = 13) was also included. Lower concentrations of PDE and a higher AC were found in the cirrhosis group compared to the control group. Also compared to the steatosis group, the cirrhosis group had lower concentrations of PDE and a higher AC.  A significant correlation between fibrosis stage and PDE and fibrosis stage and AC was found. Using an AC cut-off value of 0.27 to discriminate between mild (stage 0-2) and advanced (stage 3-4) fibrosis yielded an AUROC value of 0.78, similar as for discriminating between F0-1 vs. F2-4.

Dynamic contrast enhanced MRI (DCE-MRI) was performed prospectively in a third study on 38 patients referred for evaluation of elevated serum alanine aminotransferase (ALT) and/or alkaline phosphatase (ALP) levels. Data were acquired from regions of interest in the liver and spleen by using single-breath-hold symmetrically sampled two-point Dixon 3D images time-series (non-enhanced, arterial and venous portal phase; 3, 10, 20 and 30 min) following a bolus injection of Gd-EOB-DTPA (0.025 mmol/kg). A new quantification procedure for calculation of the ‘hepatocyte specific uptake rate’, KHep, was applied on a two-compartment pharmacokinetic model. Liver-to-spleen contrast ratios (LSC_N) were also calculated. AUROC values of 0.71, 0.80 and 0.78, respectively, were found for KHep, LSC_N10 and LSC_N20 with regard to severe versus mild fibrosis. Significant group differences were found for KHep (borderline), LSC_N10 and LSC_N20.

In study four no significant correlation between visual assessments of bile ducts excretion of Gd-EOB-DTPA and histo-pathological grading of fibrosis or the quantified uptake of Gd-EOB-DTPA defined as KHep and LSC_N.

In conclusion ³¹P-MRS and DCE-MRI show promising results for achieving a non-invasive approach in discriminating different levels of fibrosis from each other.