Remarks by David F. Cavers to Duke Students Converning the Origin of and Vision for Law and Contemporary Problems

Objectives To present a method for generating reference maps of typical brain characteristics of groups of subjects using a novel combination of rapid quantitative Magnetic Resonance Imaging (qMRI) and brain normalization. The reference maps can be used to detect significant tissue differences in patients, both locally and globally. Materials and Methods A rapid qMRI method was used to obtain the longitudinal relaxation rate (R1), the transverse relaxation rate (R2) and the proton density (PD). These three tissue properties were measured in the brains of 32 healthy subjects and in one patient diagnosed with Multiple Sclerosis (MS). The maps were normalized to a standard brain template using a linear affine registration. The differences of the mean value ofR1, R2 and PD of 31 healthy subjects in comparison to the oldest healthy subject and in comparison to an MS patient were calculated. Larger anatomical structures were characterized using a standard atlas. The vector sum of the normalized differences was used to show significant tissue differences. Results The coefficient of variation of the reference maps was high at the edges of the brain and the ventricles, moderate in the cortical grey matter and low in white matter and the deep grey matter structures. The elderly subject mainly showed significantly lower R1 and R2 and higher PD values along all sulci. The MS patient showed significantly lower R1 and R2 and higher PD values at the edges of the ventricular system as well as throughout the periventricular white matter, at the internal and external capsules and at each of the MS lesions. Conclusion Brain normalization of rapid qMRI is a promising new method to generate reference maps of typical brain characteristics and to automatically detect deviating tissue properties in the brain

Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase

The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin - its interactions with collagen affect collagen cross-linking, packing, and fibril diameter. We investigated the possibility that a specific relationship exists between fibromodulin and lysyl oxidase, potentially imparting a specific collagen matrix phenotype. We mapped the fibromodulin-collagen interaction sites using the Collagen II and III Toolkit peptide libraries. Fibromodulin interacted with the peptides containing the known collagen cross-linking sites and the MMP-1 cleavage site in collagens I and II. Interestingly, the interaction sites are closely aligned within the quarter-staggered collagen fibril, suggesting a multivalent interaction between fibromodulin and several collagen helices. Furthermore, we detected an interaction between fibromodulin and lysyl oxidase - a major collagen cross-linking enzyme - and mapped the interaction site to 12 N-terminal amino acids on fibromodulin. This interaction also increases the activity of lysyl oxidase. Altogether, the data suggest a fibromodulin-modulated collagen cross-linking mechanism, where fibromodulin binds to a specific part of the collagen domain and also forms a complex together with lysyl oxidase, targeting the enzyme towards specific cross-linking sites.SK and KR were supported by grants from the Swedish Cancer Foundation, the Swedish Research Council, the Alfred Österlund Foundation, the Crafoord Foundation, the Magnus Bergvall Foundation, and the Åke Wiberg Foundation; AB, DB and RWF by grants from the Wellcome Trust (094470/Z/10/Z) and British Heart Foundation (RG/15/4/31268).This is the final version of the article. It first appeared from the American Society for Biochemistry and Molecular Biology] via http://dx.doi.org/10.1074/jbc.M115.69340

Increased fMRI Sensitivity at Equal Data Burden Using Averaged Shifted Echo Acquisition

There is growing evidence as to the benefits of collecting BOLD fMRI data with increased sampling rates. However, many of the newly developed acquisition techniques developed to collect BOLD data with ultra-short TRs require hardware, software, and non-standard analytic pipelines that may not be accessible to all researchers. We propose to incorporate the method of shifted echo into a standard multi-slice, gradient echo EPI sequence to achieve a higher sampling rate with a TR of amp;lt; 1 s with acceptable spatial resolution. We further propose to incorporate temporal averaging of consecutively acquired EPI volumes to both ameliorate the reduced temporal signal-to-noise inherent in ultra-fast EPI sequences and reduce the data burden. BOLD data were collected from 11 healthy subjects performing a simple, event-related visual-motor task with four different EPI sequences: (1) reference EP/sequence with TR = 1440 ms, (2) shifted echo EP/sequence with TR = 700 ms, (3) shifted echo EPI sequence with every two consecutively acquired EPI volumes averaged and effective TR = 1400 ms, and (4) shifted echo EPI sequence with every four consecutively acquired EPI volumes averaged and effective TR = 2800 ms. Both the temporally averaged sequences exhibited increased temporal signal-to-noise over the shifted echo EPI sequence. The shifted echo sequence with every two EPI volumes averaged also had significantly increased BOLD signal change compared with the other three sequences, while the shifted echo sequence with every four EPI volumes averaged had significantly decreased BOLD signal change compared with the other three sequences. The results indicated that incorporating the method of shifted echo into a standard multi-slice EPI sequence is a viable method for achieving increased sampling rate for collecting event-related BOLD data. Further, consecutively averaging every two consecutively acquired EPI volumes significantly increased the measured BOLD signal change and the subsequently calculated activation map statistics

Modeling the Presence of Myelin and Edema in the Brain Based on Multi-Parametric Quantitative MRI

The aim of this study was to present a model that uses multi-parametric quantitative MRI to estimate the presence of myelin and edema in the brain. The model relates simultaneous measurement of R-1 and R-2 relaxation rates and proton density to four partial volume compartments, consisting of myelin partial volume, cellular partial volume, free water partial volume, and excess parenchymal water partial volume. The model parameters were obtained using spatially normalized brain images of a group of 20 healthy controls. The pathological brain was modeled in terms of the reduction of myelin content and presence of excess parenchymal water, which indicates the degree of edema. The method was tested on spatially normalized brain images of a group of 20 age-matched multiple sclerosis (MS) patients. Clear differences were observed with respect to the healthy controls: the MS group had a 79 mL smaller brain volume (1069 vs. 1148 mL), a 38 mL smaller myelin volume (119 vs. 157 mL), and a 21 mL larger excess parenchymal water volume (78 vs. 57 mL). Template regions of interest of various brain structures indicated that the myelin partial volume in the MS group was 1.6 +/- 1.5% lower for gray matter (GM) structures and 2.8 +/- 1.0% lower for white matter (WM) structures. The excess parenchymal water partial volume was 9 +/- 10% larger for GM and 5 +/- 2% larger for WM. Manually placed ROls indicated that the results using the template ROls may have suffered from loss of anatomical detail due to the spatial normalization process. Examples of the application of the method on high-resolution images are provided for three individual subjects: a 45-year-old healthy subject, a 72-year-old healthy subject, and a 45-year-old MS patient. The observed results agreed with the expected behavior considering both age and disease. In conclusion, the proposed model may provide clinically important parameters, such as the total brain volume, degree of myelination, and degree of edema, based on a single qMRI acquisition with a clinically acceptable scan time.Funding Agencies|Linkoping University; County Council Ostergotland</p

Brain Characterization Using Normalized Quantitative Magnetic Resonance Imaging

Objectives To present a method for generating reference maps of typical brain characteristics of groups of subjects using a novel combination of rapid quantitative Magnetic Resonance Imaging (qMRI) and brain normalization. The reference maps can be used to detect significant tissue differences in patients, both locally and globally. Materials and Methods A rapid qMRI method was used to obtain the longitudinal relaxation rate (R1), the transverse relaxation rate (R2) and the proton density (PD). These three tissue properties were measured in the brains of 32 healthy subjects and in one patient diagnosed with Multiple Sclerosis (MS). The maps were normalized to a standard brain template using a linear affine registration. The differences of the mean value ofR1, R2 and PD of 31 healthy subjects in comparison to the oldest healthy subject and in comparison to an MS patient were calculated. Larger anatomical structures were characterized using a standard atlas. The vector sum of the normalized differences was used to show significant tissue differences. Results The coefficient of variation of the reference maps was high at the edges of the brain and the ventricles, moderate in the cortical grey matter and low in white matter and the deep grey matter structures. The elderly subject mainly showed significantly lower R1 and R2 and higher PD values along all sulci. The MS patient showed significantly lower R1 and R2 and higher PD values at the edges of the ventricular system as well as throughout the periventricular white matter, at the internal and external capsules and at each of the MS lesions. Conclusion Brain normalization of rapid qMRI is a promising new method to generate reference maps of typical brain characteristics and to automatically detect deviating tissue properties in the brain

Modeling the Presence of Myelin and Edema in the Brain Based on Multi-Parametric Quantitative MRI

The aim of this study was to present a model that uses multi-parametric quantitative MRI to estimate the presence of myelin and edema in the brain. The model relates simultaneous measurement of R-1 and R-2 relaxation rates and proton density to four partial volume compartments, consisting of myelin partial volume, cellular partial volume, free water partial volume, and excess parenchymal water partial volume. The model parameters were obtained using spatially normalized brain images of a group of 20 healthy controls. The pathological brain was modeled in terms of the reduction of myelin content and presence of excess parenchymal water, which indicates the degree of edema. The method was tested on spatially normalized brain images of a group of 20 age-matched multiple sclerosis (MS) patients. Clear differences were observed with respect to the healthy controls: the MS group had a 79 mL smaller brain volume (1069 vs. 1148 mL), a 38 mL smaller myelin volume (119 vs. 157 mL), and a 21 mL larger excess parenchymal water volume (78 vs. 57 mL). Template regions of interest of various brain structures indicated that the myelin partial volume in the MS group was 1.6 +/- 1.5% lower for gray matter (GM) structures and 2.8 +/- 1.0% lower for white matter (WM) structures. The excess parenchymal water partial volume was 9 +/- 10% larger for GM and 5 +/- 2% larger for WM. Manually placed ROls indicated that the results using the template ROls may have suffered from loss of anatomical detail due to the spatial normalization process. Examples of the application of the method on high-resolution images are provided for three individual subjects: a 45-year-old healthy subject, a 72-year-old healthy subject, and a 45-year-old MS patient. The observed results agreed with the expected behavior considering both age and disease. In conclusion, the proposed model may provide clinically important parameters, such as the total brain volume, degree of myelination, and degree of edema, based on a single qMRI acquisition with a clinically acceptable scan time.Funding Agencies|Linkoping University; County Council Ostergotland</p

http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-97964 Brain Characterization Using Normalized Quantitative Magnetic Resonance Imaging

Objectives: To present a method for generating reference maps of typical brain characteristics of groups of subjects using a novel combination of rapid quantitative Magnetic Resonance Imaging (qMRI) and brain normalization. The reference maps can be used to detect significant tissue differences in patients, both locally and globally. Materials and Methods: A rapid qMRI method was used to obtain the longitudinal relaxation rate (R1), the transverse relaxation rate (R 2) and the proton density (PD). These three tissue properties were measured in the brains of 32 healthy subjects and in one patient diagnosed with Multiple Sclerosis (MS). The maps were normalized to a standard brain template using a linear affine registration. The differences of the mean value ofR1, R2 and PD of 31 healthy subjects in comparison to the oldest healthy subject and in comparison to an MS patient were calculated. Larger anatomical structures were characterized using a standard atlas. The vector sum of the normalized differences was used to show significant tissue differences

Clinical feasibility of 3D-QALAS - Single breath-hold 3D myocardial T1 and T2-mapping

Purpose: To investigate the in-vivo precision and clinical feasibility of 3D-QALAS- a novel method for simultaneous three-dimensional myocardial T1- and T2-mapping. Methods: Ten healthy subjects and 23 patients with different cardiac pathologies underwent cardiovascular 3 T MRI examinations including 3D-QALAS, MOLLI and T2-GraSE acquisitions. Precision was investigated in the healthy subjects between independent scans, between dependent scans and as standard deviation of consecutive scans. Clinical feasibility of 3D-QALAS was investigated for native and contrast enhanced myocardium in patients. Data were analyzed using mean value and 95% confidence interval, Pearson correlation, Paired t-tests, intraclass correlation and Bland-Altman analysis. Results: Average myocardial relaxation time values and SD from eight repeated acquisitions within the group of healthy subjects were 1178 +/- 18.5 ms (1.6%) for T1 with 3D-QALAS, 52.7 +/- 1.2 ms (23%) for T2 with 3D-QALAS, 1145 +/- 10.0 ms (0.9%) for Tl with MOLLI and 49.2 +/- 0.8 ms (1.6%) for T2 with GraSE. Myocardial Tl and T2 relaxation times obtained with 3D-QALAS correlated very well with reference methods; MOW for T1 (r = 0.994) and T2-GraSE for T2 (r = 0.818) in the 23 patients. Average native/post-contrast myocardial Tl values from the patients were 1166.2 ms/411.8 ms for 3D-QALAS and 1174.4 ms/438.9 ms for MOW. Average native myocardial T2 values from the patients were 53.2 ms for 3D-QAIAS and 54.4 ms for T2-GraSE. Conclusions: Repeated independent and dependent scans together with the intra-scan repeatability, demonstrated all a very good precision for the 3D-QALAS method in healthy volunteers. This study shows that 3D T1 and T2 mapping in the left ventricle is feasible in one breath hold for patients with different cardiac pathologies using 3D-QALAS. (C) 2016 Elsevier Inc. All rights reserved.Funding Agencies|Swedish Heart-Lung Foundation [20120449, 20140398]; Swedish Research Council [2014-6191]</p

http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-97960 Application of Quantitative MRI for Brain Tissue Segmentation at 1.5 T and 3.0 T Field Strengths

Background: Brain tissue segmentation of white matter (WM), grey matter (GM), and cerebrospinal fluid (CSF) are important in neuroradiological applications. Quantitative Mri (qMRI) allows segmentation based on physical tissue properties, and the dependencies on MR scanner settings are removed. Brain tissue groups into clusters in the three dimensional space formed by the qMRI parameters R 1, R 2 and PD, and partial volume voxels are intermediate in this space. The qMRI parameters, however, depend on the main magnetic field strength. Therefore, longitudinal studies can be seriously limited by system upgrades. The aim of this work was to apply one recently described brain tissue segmentation method, based on qMRI, at both 1.5 T and 3.0 T field strengths, and to investigate similarities and differences. Methods: In vivo qMRI measurements were performed on 10 healthy subjects using both 1.5 T and 3.0 T MR scanners. The brain tissue segmentation method was applied for both 1.5 T and 3.0 T and volumes of WM, GM, CS