| 1. |
- Lundberg, Peter, et al.
(författare)
-
Kvantifiering av leversteatos: diagnostisk utvärdering av protonmagnetresonansspektroskopi jämfört med histologiska metoder
- 2016
-
Konferensbidrag (refereegranskat)abstract
- BakgrundLeversteatos är den vanligaste manifestationen av leversjukdom i västvärlden. Leverbiopsi med semikvantitativ histologisk gradering är referensmetod vid gradering av leversteatos. Med protonmagnetsresonansspektroskopi (1H-MRS), en metod som föreslagits ersätta leverbiopsi för värdering av steatos, kan leverns innehåll av triglycerider mätas icke-invasivt. Triglyceridinnehåll >5,00 % används ofta som ett diagnostiskt kriterium för leversteatos vid undersökning med 1H-MRS. Syftet med studien var att jämföra 1H-MRS med semikvantitativ histologisk steatosgradering och kvantitativ histologisk steatosmätning.MetodPatienter remitterade för utredning av förhöjda leverenzymer in-kluderades i studien. Samtliga patienter genomgick klinisk undersökning, laboratorieprovtagning samt 1H-MRS direkt följd av leverbiopsi. För konventionell histologisk semikvantitativ gradering av steatos användes kriterierna utarbetade av Brunt och medarbetare. Kvantitativ mätning av fett i biopsierna utfördes genom att med hjälp av stereologisk punkträkning (SPC) mäta andelen av ytan som innehöll fettvakuoler.ResultatI studien inkluderades 94 patienter, varav 37 hade icke-alkoholor-sakad fettleversjukdom (NAFLD), 49 hade andra leversjukdomar och 8 hade normal leverbiopsi. En stark korrelation noterades mel-lan 1H-MRS och SPC (r=0,92, p<0,0001; к=0.82). Korrelationen mellan 1H-MRS och Brunts kriterier (к=0.26) samt mellan SPC och Brunts kriterier (к=0.38) var betydligt sämre. När patologens gradering (Brunts kriterier) användes som referensmetod för diag-nos av leversteatos så hade alla patienter med triglyceridinnehåll >5,00 % mätt med 1H-MRS steatos (specificitet 100 %). Emellertid hade 22 av 69 patienter med triglyceridinnehåll ≤5,00 % också le-versteatos enligt Brunts kriterier (sensitivitet 53 %). Motsvarande siffror när man använde gränsvärdet 3,02 % var sensitivitet 79 % och specificitet 100 %. Vid ytterligare reduktion av gränsvärdet för triglyceridinnehåll till 2,00 % ökade sensitiviteten till 87 % med upprätthållande av hög specificitet (94 %).Slutsats1H-MRS och SPC uppvisade en mycket hög korrelation vid kvantifiering av leversteatos. SPC borde därför föredras framför Brunts kriterier när noggrann histologisk kvantifiering av leversteatos är önskvärd. Många patienter kan ha histologisk leversteatos trots triglyceridinnehåll ≤5,00 % mätt med 1H-MRS. Gränsvärdet för diagnostisering av leversteatos med 1H-MRS bör därför reduceras.
|
|
| 2. |
- Karlsson, Markus, et al.
(författare)
-
Increased bile excretion of Gd-EOB-DTPA in diffuse liver disease : mechanistic modeling of qDCE-MRI in patients with severe fibro-sis
- 2016
-
Ingår i: Magnetic Resonance Materials in Physics, Biology and Medicine. - : Springer. - 0968-5243 .- 1352-8661. ; 29:1, s. S272-S273
-
Tidskriftsartikel (refereegranskat)abstract
- IntroductionOver the past decades, several different non-invasive methods for staging hepatic fibrosis have been proposed. One such method is dynamic contrast enhanced MRI (DCE-MRI) using the contrast agent (CA) Gd-EOB-DTPA. Gd-EOB-DTPA is liver specific, which means that it is taken up specifically by the hepatocytes via the OATP3B1/B3 transporters and excreted into the bile via the MRP2 transporter. Several studies have shown that DCE-MRI and Gd-EOBDTPA can separate patients with advanced (F3-F4) from mild (F0-F2) hepatic fibrosis by measuring the signal intensity, where patients with advanced fibrosis have a lower signal intensity than the mild fibrosis cases.1 However, none of the studies up to date have been able to differentiate if the reduced signal intensity in the liver is because of an decreased uptake of CA or an increased excretion. Analyzing the DCE-MRI data with mechanistic mathematical modelling has the possibility of investigating such a differentiation.Subjects and methods88 patients with diffuse liver disease were examined using DCE-MRI (1.5 T Philips Achieva, two-point Dixon, TR=6.5 ms, TE=2.3/4.6 ms, FA=13) after a bolus injection of Gd-EOB-DTPA, followed by a liver biopsy. Regions of interest were placed within the liver, spleen and veins and a whole-body mechanistic pharmacokinetic model2 was fitted to the data. The fitted parameters in the model correspond to the rate of CA transport between different compartments, e.g. hepatocytes, blood plasma, and bile (Fig. 1).ResultsAs can be seen in Fig. 2, the parameter corresponding to the transport of CA from the blood plasma to the hepatocytes, kph, is lower for patients with advanced fibrosis (p=0.01). Fig. 3 shows that the parameter corresponding to the CA excretion into the bile, khb, is higher for patients with advanced fibrosis (p<0.01).Discussion/ConclusionThis work shows that the decreased signal intensity in DCE-MRI images in patients with advanced fibrosis depends on both a decreased uptake of CA in the hepatocytes and an increased excretion into the bile. Similar results have also been observed in a rat study3. In that study, rats with induced cirrhosis had a higher MRP2-activity than the healthy control rats.References1Norén et al: Eur. Radiol, 23(1), 174-181, 2013.2Forsgren et al: PloS One, 9(4): e95700, 2014.3Tsuda & Matsui: Radiol, 256(3): 767-773, 2010.
|
|
| 3. |
- Forsgren, Mikael
(författare)
-
The Non-Invasive Liver Biopsy : Determining Hepatic Function in Diffuse and Focal LiverDisease
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The liver is one of the largest organs within the human body and it handles many vital tasks such as nutrient processing, toxin removal, and synthesis of important proteins. The number of people suffering from chronic liver disease is on the rise, likely due to the present ‘western’ lifestyle. As disease develops in the liver there are pathophysiological manifestations within the liver parenchyma that are both common and important to monitor. These manifestations include inflammation, fatty infiltration (steatosis), excessive scar tissue formation (fibrosis and cirrhosis), and iron loading. Importantly, as the disease progresses there is concurrent loss of liver function. Furthermore, postoperative liver function insufficiency is an important concern when planning surgical treatment of the liver, because it is associated with both morbidity and mortality. Liver function can also be hampered due to drug-induced injuries, an important aspect to consider in drug-development.Currently, an invasive liver needle biopsy is required to determine the aetiology and to stage or grade the pathophysiological manifestations. There are important limitations with the biopsy, which include, risk of serious complications, mortality, morbidity, inter- and intra-observer variability, sampling error, and sampling variability. Cleary, it would be beneficial to be able investigate the pathophysiological manifestations accurately, non-invasively, and on regional level.Current available laboratory liver function blood panels are typically insufficient and often only indicate damage at a late stage. Thus, it would be beneficial to have access to biomarkers that are both sensitive and responds to early changes in liver function in both clinical settings and for the pharmaceutical industry and regulatory agencies.The main aim of this thesis was to develop and evaluate methods that can be used for a ‘non-invasive liver biopsy’ using magnetic resonance (MR). We also aimed to develop sensitive methods for measure liver function based on gadoxetate-enhanced MR imaging (MRI).The presented work is primarily based on a prospective study on c. 100 patients suffering from chronic liver disease of varying aetiologies recruited due to elevated liver enzyme levels, without clear signs of decompensated cirrhosis. Our results show that the commonly used liver fat cut-off for diagnosing steatosis should be lowered from 5% to 3% when using MR proton-density fat fraction (PDFF). We also show that MR elastography (MRE) is superior in staging fibrosis.Finally we presented a framework for quantifying liver function based on gadoxetate-enhanced MRI. The method is based on clinical images and a clinical approved contrast agent (gadoxetate). The framework consists of; state-of the-art image reconstruction and correction methods, a mathematical model, and a precise model parametrization method. The model was developed and validated on healthy subjects. Thereafter the model was found applicable on the chronic liver disease cohort as well as validated using gadoxetate levels in biopsy samples and blood samples. The liver function parameters correlated with clinical markers for liver function and liver fibrosis (used as a surrogate marker for liver function).In summary, it should be possible to perform a non-invasive liver biopsy using: MRI-PDFF for liver fat and iron loading, MRE for liver fibrosis and possibly also inflammation, and measure liver function using the presented framework for analysing gadoxetate-enhanced MRI. With the exception of an MREtransducer no additional hardware is required on the MR scanner. The liver function method is likely to be useful both in a clinical setting and in pharmaceutical trials.
|
|
| 4. |
|
|
| 5. |
- Blystad, Ida, et al.
(författare)
-
Quantitative MRI for Analysis of Active Multiple Sclerosis Lesions without Gadolinium-Based Contrast Agent
- 2016
-
Ingår i: American Journal of Neuroradiology. - : American Society of Neuroradiology (ASNR). - 0195-6108 .- 1936-959X. ; 37:1, s. 94-100
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Contrast-enhancing MS lesions are important markers of active inflammation in the diagnostic work-up of MS and in disease monitoring with MR imaging. Because intravenous contrast agents involve an expense and a potential risk of adverse events, it would be desirable to identify active lesions without using a contrast agent. The purpose of this study was to evaluate whether pre-contrast injection tissue-relaxation rates and proton density of MS lesions, by using a new quantitative MR imaging sequence, can identify active lesions.MATERIALS AND METHODS: Forty-four patients with a clinical suspicion of MS were studied. MR imaging with a standard clinical MS protocol and a quantitative MR imaging sequence was performed at inclusion (baseline) and after 1 year. ROIs were placed in MS lesions, classified as nonenhancing or enhancing. Longitudinal and transverse relaxation rates, as well as proton density were obtained from the quantitative MR imaging sequence. Statistical analyses of ROI values were performed by using a mixed linear model, logistic regression, and receiver operating characteristic analysis.RESULTS: Enhancing lesions had a significantly (P < .001) higher mean longitudinal relaxation rate (1.22 ± 0.36 versus 0.89 ± 0.24), a higher mean transverse relaxation rate (9.8 ± 2.6 versus 7.4 ± 1.9), and a lower mean proton density (77 ± 11.2 versus 90 ± 8.4) than nonenhancing lesions. An area under the receiver operating characteristic curve value of 0.832 was obtained.CONCLUSIONS: Contrast-enhancing MS lesions often have proton density and relaxation times that differ from those in nonenhancing lesions, with lower proton density and shorter relaxation times in enhancing lesions compared with nonenhancing lesions.
|
|
| 6. |
- West, Janne, et al.
(författare)
-
Normal Appearing and Diffusely Abnormal White Matter in Patients with Multiple Sclerosis, Assessed with Quantitative MR : Optimization for clinical usage
- 2014
-
Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:4, s. e95161-
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Magnetic Resonance Imaging is a sensitive technique for detecting white matter (WM) MS lesions, but the relation with clinical disability is low. Because of this, changes in both ‘normal appearing white matter’ (NAWM) and ‘diffusely abnormal white matter’ (DAWM) have been of interest in recent years. MR techniques, including quantitative magnetic resonance imaging (qMRI) and quantitative magnetic resonance spectroscopy (qMRS), have been developed in order to detect and quantify such changes.In this study, a combination of qMRI and qMRS was used to investigate NAWM and DAWM in typical MS patients and in MS patients with low number of WM lesions. Patient data were compared to ‘normal white matter’ (NWM) in healthy controls.Methods: QMRI and qMRS measurements were performed on a 1.5T Philips MR-scanner. 35 patients with clinically definite MS and 20 healthy controls were included. Fifteen of the patients showed few WM lesions (‘MRIneg‘) and 20 showed radiologically typical findings (‘MRIpos’). QMRI properties were determined in ROIs of NAWM, DAWM and WM lesions in the MS groups and of NWM in controls. Descriptive statistical analysis and comparisons were performed. Correlations were calculated between qMRI measurements and (1) clinical parameters and (2) WM metabolite concentrations. Regression analyses were performed with brain parenchyma fraction and MSSS.Results: NAWM in the MRIneg group was significantly different from NAWM in the MRIpos group and NWM. In addition, R1 and R2 of NAWM in the MRIpos group correlated negatively with EDSS and MSSS. DAWM was significantly different from NWM, but similar in the two MS groups. N-acetyl aspartate correlated negatively with R1 and R2 in MRIneg. Finally, R2 of DAWM was associated with BPF.Conclusions: Changes in NAWM and DAWM are independent pathological entities in the disease. Combined qMRI and qMRS measurements of NAWM and DAWM provide important markers for disease status.
|
|
| 7. |
- Witt, Suzanne T., et al.
(författare)
-
Evidence for cognitive resource imbalance in adolescents with narcolepsy
- 2018
-
Ingår i: Brain Imaging and Behavior. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 12:2, s. 411-424
-
Tidskriftsartikel (refereegranskat)abstract
- The study investigated brain activity changes during performance of a verbal working memory task in a population of adolescents with narcolepsy. Seventeen narcolepsy patients and twenty healthy controls performed a verbal working memory task during simultaneous fMRI and EEG acquisition. All subjects also underwent MRS to measure GABA and Glutamate concentrations in the medial prefrontal cortex. Activation levels in the default mode network and left middle frontal gyrus were examined to investigate whether narcolepsy is characterized by an imbalance in cognitive resources. Significantly increased deactivation within the default mode network during task performance was observed for the narcolepsy patients for both the encoding and recognition phases of the task. No evidence for task performance deficits or reduced activation within the left middle frontal gyrus was noted for the narcolepsy patients. Correlation analyses between the spectroscopy and fMRI data indicated that deactivation of the anterior aspect of the default mode in narcolepsy patients correlated more with increased concentrations of Glutamate and decreased concentrations of GABA. In contrast, deactivation in the default mode was correlated with increased concentrations of GABA and decreased concentrations of Glutamate in controls. The results suggested that narcolepsy is not characterized by a deficit in working memory but rather an imbalance of cognitive resources in favor of monitoring and maintaining attention over actual task performance. This points towards dysregulation within the sustained attention system being the origin behind self-reported cognitive difficulties in narcolepsy.
|
|
| 8. |
- Stenman, Katarina, 1963-
(författare)
-
Prostate Cancer Diagnosis : experimental and Clinical Studies With HRMAS NMR Spectroscopy
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A few abnormal cells found in a small piece of prostate tissue are most consequential for a man’s future. The prevalence of prostate cancer (PCa) is increasing globally. The main instigating factor for this cancer is not yet known, but it appears to be the consequence of many variables such as an increasingly older population, more frequent PSA-testing, and factors involving lifestyle. Prostate cancer screening, as an equivalent for breast cancer screening, has been suggested but unfortunately there are no accurate diagnostic tools available for this type of screening. The reason for this is simply that the prostate is one of the most difficult organs to diagnose and, consequently, PCa screening would generate far too many false-positive and false-negative results. The prostate is not easily accessible as it is deeply-seated in the male pelvic area, wrapped around the urethra and surrounded by sensitive vital organs. Furthermore, PCa is frequently multi-focal, and the cancer cells have a tendency of assimilating among normal cells and, thus, do not always form solid lumps. Therefore, prostate tumors are often not felt by digital rectal examination (DRE) or identified by imaging. The PSA-test is not reliable as it is more prostate-specific than cancer-specific. Due to increasing prostate awareness, more early-stage and locally confined PCa are being detected. This is saving lives, although there is a high risk of over treatment and unnecessary side-effects. The increased detection of PCa requires sophisticated diagnostic methods and highly skilled clinicians who can discern between indolent and aggressive cancers. The current “gold-standard” for PCa diagnosis is biopsy grading by pathologists using the Gleason score system, which is a difficult task. Therefore, innovative methods to improve the precision of prostate diagnosis, by increased biopsy sensitivity and tumor localization, are of essence. In light of these difficulties, the metabolomic approach using 1D and 2D high-resolution magic angle spinning (HRMAS) NMR spectroscopy combined with histopathology on intact prostatectomy specimens was evaluated in this research project. The non-destructive nature of HRMAS NMR enables spectroscopic analysis of intact tissue samples with consecutive histological examinations under light microscope. Metabolomics aids in the unraveling and the discovery of organ-specific endogenous metabolites that have the potential to be reliable indicators of organ function and viability, extrinsic and intrinsic perturbations, as well as valuable markers for treatment response. The results may, therefore, be applied clinically to characterize an organ by utilizing biomarkers that have the capacity to distinguish between disease and health. The aim was to characterize the human and the rat prostate in terms of its intermediary metabolism, which I show here to differ between species and anatomical regions. Furthermore, the aim is to seek the verification of HRMAS NMR derived metabolites which are known to be a part of the prostate metabolome such as, citrate, choline, and the polyamines which were performed, but also the identification of metabolites not previously identified as part of the local prostate metabolism, such as Omega-6, which was detected in tumors. The extended aim was to elucidate novel bio-markers with clinical potential. In this study, the common phyto-nutrient, inositol, which appears to possess protective properties, was identified as being a potentially important PCa bio-marker for the distinction between the more indolent Gleason score 6 and the more aggressive Gleason score 7 in non-malignant prostate tissues with tumors elsewhere in the organ. Further studies in this area of PCa research are therefore warranted.
|
|
| 9. |
- Karlsson, Markus, 1990-, et al.
(författare)
-
Mathematical models for biomarker calculation of drug-induced liver injury in humans and experimental models based on gadoxetate enhanced magnetic resonance imaging
- 2023
-
Ingår i: PLOS ONE. - San Francisco, CA, United States : Public Library of Science. - 1932-6203. ; 18:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Drug induced liver injury (DILI) is a major concern when developing new drugs. A promising biomarker for DILI is the hepatic uptake rate of the contrast agent gadoxetate. This rate can be estimated using a novel approach combining magnetic resonance imaging and mathematical modeling. However, previous work has used different mathematical models to describe liver function in humans or rats, and no comparative study has assessed which model is most optimal to use, or focused on possible translatability between the two species.AIMS: Our aim was therefore to do a comparison and assessment of models for DILI biomarker assessment, and to develop a conceptual basis for a translational framework between the species.METHODS AND RESULTS: We first established which of the available pharmacokinetic models to use by identifying the most simple and identifiable model that can describe data from both human and rats. We then developed an extension of this model for how to estimate the effects of a hepatotoxic drug in rats. Finally, we illustrated how such a framework could be useful for drug dosage selection, and how it potentially can be applied in personalized treatments designed to avoid DILI.CONCLUSION: Our analysis provides clear guidelines of which mathematical model to use for model-based assessment of biomarkers for liver function, and it also suggests a hypothetical path to a translational framework for DILI.
|
|
| 10. |
- Karlsson, Markus, et al.
(författare)
-
Diffuse Liver Disease: Measurements of Liver Trace Metal Concentrations and R2* Relaxation Rates
- 2016
-
Ingår i: Magnetic Resonance Materials in Physics, Biology and Medicine. - : Springer. - 0968-5243 .- 1352-8661. ; 29:1, s. S395-S395
-
Tidskriftsartikel (refereegranskat)abstract
- IntroductionOver the past decade, several methods for measuring of liver iron content (LIC) non-invasively with MRI have been developed and verified. The most promising methods uses relaxometry, measuring either R2- or R2* relaxation rate in the liver1,2. For instance, several studies have shown that there seems to be a linear relationship between R2* and LIC1. However, few of these studies have measured the liver content of other metals, which could also affect the relaxation rates. The goal of this study was to investigate if any trace metals, other than iron could affect the R2* relaxation rate in liver tissue in a patients with diffuse liver disease.Subjects and methods75 patients with suspected diffuse liver disease underwent an MRI examination followed by a liver biopsy the same day. The R2* relaxation rate of the water protons in the liver was measured using an axial 3D multi-slice fat-saturated multi-echo turbo field echo sequence (TE=4.60/9.20/13.80/18.40/23.00ms). Regions of interest (ROI) were drawn and R2* was estimated by fitting the mean signal intensity from the ROIs to a mono-exponential decay model. The biopsies were freeze dried and the concentrations of iron, manganese, copper, cobalt and gadolinium were measured using Inductively Coupled Plasma Sector Field Mass Spectrometry (ICP-SFMS). A multiple linear regression analysis was applied to determine which of the measured metals significantly affected the relaxation rate.ResultsA linear regression with the LIC and R2* showed a reasonable fit (Figure 1). The multiple linear regression analysis (Table 1) showed that iron as well as manganese had a significant affect on R2*. Unlike iron however, the regression coefficient of manganese was negative, meaning that an increasing manganese concentration gave a shorter R2* relaxation rate. The same trend can be seen when plotting the manganese concentration against R2* (Figure 2).
|
|
