Metabolite-weighted chemical exchange saturation transfer MRI can be used to indirectly image metabolites such as creatine and glutamate. This study aims to further explore the contrast of CEST at... Show moreMetabolite-weighted chemical exchange saturation transfer MRI can be used to indirectly image metabolites such as creatine and glutamate. This study aims to further explore the contrast of CEST at 2 ppm in the human brain at 7T and investigate the metabolite correlates of CEST at 2 ppm via correlations with magnetic resonance spectroscopy (MRS). Simulations were performed to establish the optimal acquisition parameters, such as total saturation time (tsat) and B1 root mean squared (B1rms) for CEST at 2 ppm in the human brain. Parameters were validated via in vitro phantom studies at 7T using concentrations, pH and temperature comparable to what is found in the human brain. Finally, 10 healthy volunteers were scanned at 7T for comparison with MRS. Our results show that the optimal parameters to acquire CEST at 2 ppm images are: B1rms = 2.14 mu T & tsat = 1500 ms, respectively. Comparison with MRS showed no significant correlation between CEST at 2 ppm and total Creatine measured by MRS (R = 0.19; p-value = 0.273). However, a significant correlation was found between CEST at 2 ppm and Glu (R = 0.39; p-value = 0.033), indicating the broad Glutamate-weighted CEST as the main measurable contributor to CEST at 2 ppm. We identified and confirmed optimal CEST at 2 ppm sequence parameters and validated CEST at 2 ppm measurements in a controlled in vitro environment. Our findings suggest that glutamate is a substantial contributor to the CEST at 2 ppm contrast observed in the human brain, whereas the creatine contribution to CEST at 2 ppm in the brain did not show a measurable contribution.CEST can be used to indirectly image in vivo amine protons, such as those in creatine and glutamate. CEST at 2 ppm was measured in the human gray and white matter (A) and correlated with MRS concentrations of total creatine and glutamate of the same regions (B). A significant correlation was found between CEST at 2 ppm and glutamate (C), suggesting glutamate to substantially contribute to CEST contrast at 2 ppm in the human brainimage Show less
In Becker muscular dystrophy (BMD), muscle weakness progresses relatively slowly, with a highly variable rate among patients. This complicates clinical trials, as clinically relevant changes are... Show moreIn Becker muscular dystrophy (BMD), muscle weakness progresses relatively slowly, with a highly variable rate among patients. This complicates clinical trials, as clinically relevant changes are difficult to capture within the typical duration of a trial. Therefore, predictors for disease progression are needed. We assessed if temporal increase of fat fraction (FF) in BMD follows a sigmoidal trajectory and whether fat fraction at baseline (FFbase) could therefore predict FF increase after 2 years (Delta FF). Thereafter, for two different MR-based parameters, we tested the additional predictive value to FFbase. We used 3-T Dixon data from the upper and lower leg, and multiecho spinecho MRI and 7-T P-31 MRS datasets from the lower leg, acquired in 24 BMD patients (age: 41.4 [SD 12.8] years). We assessed the pattern of increase in FF using mixed-effects modelling. Subsequently, we tested if indicators of muscle damage like standard deviation in water T-2 (stdT(2)) and the phosphodiester (PDE) over ATP ratio at baseline had additional value to FFbase for predicting Delta FF. The association between FFbase and Delta FF was described by the derivative of a sigmoid function and resulted in a peak Delta FF around 0.45 FFbase (fourth-order polynomial term: t = 3.7, p < .001). StdT(2) and PDE/ATP were not significantly associated with Delta FF if FFbase was included in the model. The relationship between FFbase and Delta FF suggests a sigmoidal trajectory of the increase in FF over time in BMD, similar to that described for Duchenne muscular dystrophy. Our results can be used to identify muscles (or patients) that are in the fast progressing stage of the disease, thereby facilitating the conduct of clinical trials. Show less
Ramos, L.A.; Kappelhof, M.; Os, H.J.A. van; Chalos, V.; Kranendonk, K. van; Kruyt, N.D.; ... ; Marquering, H.A. 2020
Background: Although endovascular treatment (EVT) has greatly improved outcomes in acute ischemic stroke, still one third of patients die or remain severely disabled after stroke. If we could... Show moreBackground: Although endovascular treatment (EVT) has greatly improved outcomes in acute ischemic stroke, still one third of patients die or remain severely disabled after stroke. If we could select patients with poor clinical outcome despite EVT, we could prevent futile treatment, avoid treatment complications, and further improve stroke care. We aimed to determine the accuracy of poor functional outcome prediction, defined as 90-day modified Rankin Scale (mRS) score >= 5, despite EVT treatment.Methods: We included 1,526 patients from the MR CLEAN Registry, a prospective, observational, multicenter registry of ischemic stroke patients treated with EVT. We developed machine learning prediction models using all variables available at baseline before treatment. We optimized the models for both maximizing the area under the curve (AUC), reducing the number of false positives.Results: From 1,526 patients included, 480 (31%) of patients showed poor outcome. The highest AUC was 0.81 for random forest. The highest area under the precision recall curve was 0.69 for the support vector machine. The highest achieved specificity was 95% with a sensitivity of 34% for neural networks, indicating that all models contained false positives in their predictions. From 921 mRS 0-4 patients, 27-61 (3-6%) were incorrectly classified as poor outcome. From 480 poor outcome patients in the registry, 99-163 (21-34%) were correctly identified by the models.Conclusions: All prediction models showed a high AUC. The best-performing models correctly identified 34% of the poor outcome patients at a cost of misclassifying 4% of non-poor outcome patients. Further studies are necessary to determine whether these accuracies are reproducible before implementation in clinical practice. Show less
This thesis adresses a variety of early markers of Alzheimer's disease, using MRI, histology and MRS. MRS is found to be promising for early diagnosis of AD. However this study is done on mice... Show moreThis thesis adresses a variety of early markers of Alzheimer's disease, using MRI, histology and MRS. MRS is found to be promising for early diagnosis of AD. However this study is done on mice and should be replicated on AD patients over time. Besides the early markers the thesis descibes a potential difference between male and female in the development of AD in the brain. Show less
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple... Show moreDuchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness caused by DMD gene mutations leading to absence of the full-length dystrophin protein in muscle. Multiple dystrophin isoforms are expressed in brain, but little is known about their function. DMD is associated with specific learning and behavioral disabilities which are more prominent in patients with mutations in the distal part of the DMD gene, predicted to affect expression of shorter protein isoforms. The aim of this thesis was to provide a detailed description of the structural, perfusion and metabolic differences in the brain between patients with DMD and healthy age-matched controls and to assess the role of dystrophin isoforms. Show less
Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) can play a key role in understanding neurobiological mechanisms of diseases that affect the human brain. The specific changes that occur... Show moreDiffusion-weighted magnetic resonance spectroscopy (DW-MRS) can play a key role in understanding neurobiological mechanisms of diseases that affect the human brain. The specific changes that occur within neurons can be reflected as changes in the diffusivity of tNAA, whereas the changes in glial cells can cause pronounced changes in the diffusivities of tCr and tCho. This information combined with that obtained from diffusion tensor imaging (DTI) and other MRI tools can help elucidate various disease processes in the future. The main purposes of this thesis are (i) to investigate neuroanatomy in vivo with DW-MRS, (ii) to develop methodology to enable future clinical applications of the technique in human brain in vivo, and (iii) to characterize the microstructural deficit in neuropsychiatric systemic lupus erythematous (NPSLE) with DW-MRS and other microstructural tools such as DTI and magnetization transfer imaging. The studies presented in this thesis show the robustness and clinical relevance of microstructural information obtained via DW-MRS. The contributions of this thesis such as the optimized acquisition protocols for single volume DW-MRS, the robust DW-CSI and DW-MRS post-processing pipelines that comprise information from DTI, will all facilitate the applications of DW-MRS both for basic neuroscience research and clinical research studies. Show less
In this thesis we evaluated several MRI/S methods as outcome parameters to assess muscle pathology in DMD and BMD patients. We applied 3-point Dixon MRI to compare levels of fatty infiltration in... Show moreIn this thesis we evaluated several MRI/S methods as outcome parameters to assess muscle pathology in DMD and BMD patients. We applied 3-point Dixon MRI to compare levels of fatty infiltration in muscle of DMD patients with a semi-quantitative method. Dixon MRI showed to be more sensitive to subtle changes. Implementation of a multipeak model to account for multiple lipid spectrum peaks in this method allowed even more sensitive measurements. We evaluated non-contractile and contractile cross-sectional areas in leg muscles of DMD patients. Combined with strength measurements we could measure muscle quality and showed muscle hypertrophy and fatty infiltration to be two distinct processes. We explored the relation between dystrophin levels and fat in BMD patients and found no such relation, but did find a relation between strength and age in a subgroup, demonstrating the location of the mutation to be a major determinant of disease severity. Using T2 MRI as inflammatory marker in DMD/BMD patients and healthy controls we showed an increased T2 in DMD patients. Finally we investigated the muscle energy metabolism in BMD patients with MRS and showed increased PDE/ATP ratios prior to onset of fatty infiltration, consequently 31P MRS could be another potential outcome parameter. Show less
Bank, B.L. van de; Emir, U.E.; Boer, V.O.; Asten, J.J.A. van; Maas, M.C.; Wijnen, J.P.; ... ; Scheenen, T.W.J. 2015
The aims of this thesis were to gain insight into specific disease processes in Huntington__s Disease (HD) and to identify biomarkers. To achieve these aims, cognitive functioning, structural brain... Show moreThe aims of this thesis were to gain insight into specific disease processes in Huntington__s Disease (HD) and to identify biomarkers. To achieve these aims, cognitive functioning, structural brain characteristics and intrinstic functional brain connectivity of premanifest and early HD subjects were examined. Cortical, subcortical and the intermediate white matter brain tissue shows evidence of structural and functional decline. We found evidence that disease processes, such as altered metabolism, excessive iron accumulation and cell loss, play a role in the changes. We conclude that changes occur throughout the brain from the earliest disease phase onwards. Hence, both premanifest and manifest HD should not be regarded as a disorder of the basal ganglia, but as a disease affecting the whole brain. Candidate biomarkers that have the potential to objectively reflect the early changes and the progressive nature of the disease are measures of subcortical atrophy, integrity of white matter pathways and of intrinsic functional brain connectivity. Iron, creatine, and N-acetylaspartate concentrations in the caudate nucleus and putamen may prove to be useful as markers of disease state for objectifying transitional disease processes from premanifest to manifest HD. Visuospatial working memory could be applied as a state marker for stage two HD. Show less
The aim of this thesis was to find potential MRI biomarkers for Huntington__s disease (HD). Therefore, after an overview of the current literature on MRI biomarkers, followed by examinations of... Show moreThe aim of this thesis was to find potential MRI biomarkers for Huntington__s disease (HD). Therefore, after an overview of the current literature on MRI biomarkers, followed by examinations of volumetric MRI, magnetization transfer imaging (MTI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) were applied in patients in different disease stages of HD. The main conclusions demonstrate that choosing the optimal biomarker for evaluating therapeutic effects is dependent on the disease stage and therapeutic compound. To evaluate the premanifest stages of the disease volumetric MRI and DTI are most suitable. When the transition period is the desired timeframe for evaluation, also MRS can be very useful, especially if the compound in question has a direct potential influence on certain pathogenic pathways which in turn have an impact on specific metabolites. Future research should focus on combining multiple imaging techniques; __multimodal imaging__. A composite MRI biomarker has the potential to distinguish between disease groups more accurately than a single biomarker and in this way improve the evaluation of therapeutic compounds. Show less
