Probing Tissue Microstructure Using Susceptibility Contrast Magnetic Resonance Imaging

Magnetic resonance imaging is a research and clinical tool that has been applied in a wide variety of sciences. One area of magnetic resonance imaging that has exhibited terrific promise and growth in the past decade is magnetic susceptibility imaging. Imaging tissue susceptibility provides insight into the microstructural organization and chemical properties of biological tissues, but this image contrast is not well understood. The purpose of this work is to develop effective approaches to image, assess, and model the mechanisms that generate both isotropic and anisotropic magnetic susceptibility contrast in biological tissues, including myocardium and central nervous system white matter.

This document contains the first report of MRI-measured susceptibility anisotropy in myocardium. Intact mouse heart specimens were scanned using MRI at 9.4 T to ascertain both the magnetic susceptibility and myofiber orientation of the tissue. The susceptibility anisotropy of myocardium was observed and measured by relating the apparent tissue susceptibility as a function of the myofiber angle with respect to the applied magnetic field. A multi-filament model of myocardial tissue revealed that the diamagnetically anisotropy α-helix peptide bonds in myofilament proteins are capable of producing bulk susceptibility anisotropy on a scale measurable by MRI, and are potentially the chief sources of the experimentally observed anisotropy.

The growing use of paramagnetic contrast agents in magnetic susceptibility imaging motivated a series of investigations regarding the effect of these exogenous agents on susceptibility imaging in the brain, heart, and kidney. In each of these organs, gadolinium increases susceptibility contrast and anisotropy, though the enhancements depend on the tissue type, compartmentalization of contrast agent, and complex multi-pool relaxation. In the brain, the introduction of paramagnetic contrast agents actually makes white matter tissue regions appear more diamagnetic relative to the reference susceptibility. Gadolinium-enhanced MRI yields tensor-valued susceptibility images with eigenvectors that more accurately reflect the underlying tissue orientation.

Despite the boost gadolinium provides, tensor-valued susceptibility image reconstruction is prone to image artifacts. A novel algorithm was developed to mitigate these artifacts by incorporating orientation-dependent tissue relaxation information into susceptibility tensor estimation. The technique was verified using a numerical phantom simulation, and improves susceptibility-based tractography in the brain, kidney, and heart. This work represents the first successful application of susceptibility-based tractography to a whole, intact heart.

The knowledge and tools developed throughout the course of this research were then applied to studying mouse models of Alzheimer’s disease in vivo, and studying hypertrophic human myocardium specimens ex vivo. Though a preliminary study using contrast-enhanced quantitative susceptibility mapping has revealed diamagnetic amyloid plaques associated with Alzheimer’s disease in the mouse brain ex vivo, non-contrast susceptibility imaging was unable to precisely identify these plaques in vivo. Susceptibility tensor imaging of human myocardium specimens at 9.4 T shows that susceptibility anisotropy is larger and mean susceptibility is more diamagnetic in hypertrophic tissue than in normal tissue. These findings support the hypothesis that myofilament proteins are a source of susceptibility contrast and anisotropy in myocardium. This collection of preclinical studies provides new tools and context for analyzing tissue structure, chemistry, and health in a variety of organs throughout the body.

Using a voxel-based krogh cylinder array to simulate microvascular contrast enhancement

The goal of this study is to better simulate microscopic and voxel-based dynamic contrast enhancement in magnetic resonance imaging. Specifically, errors imposed by the traditional two-compartment model are reduced by introducing a novel Krogh cylinder network. The two-compartment model was developed for macroscopic pharmacokinetic analysis of dynamic contrast enhancement and generalizing it to voxel dimensions, due to the significant decrease in scale, imposes physiologically unrealistic assumptions. In the project, a system of microscopic exchange between plasma and extravascular-extracellular space is built while numerically simulating the local contrast agent flow between and inside image elements. To do this, tissue parameter maps were created, contrast agent was introduced to the tissue via a flow lattice, and various data sets were simulated. The effects of sources, tissue heterogeneity, and the contribution of individual tissue parameters to an image are modeled. Further, the study attempts to demonstrate the effects of a priori flow maps on image contrast, indicating that flow data is as important as permeability data when analyzing tumor contrast enhancement. In addition, the simulations indicate that it may be possible to obtain tumor-type diagnostic information by acquiring both flow and permeability data.

Prognostic Significance of Myocardial Fibrosis Quantification by Histopathology and Magnetic Resonance Imaging in Patients With Severe Aortic Valve Disease

Objectives We sought to determine whether the quantitative assessment of myocardial fibrosis (MF), either by histopathology or by contrast-enhanced magnetic resonance imaging (ce-MRI), could help predict long-term survival after aortic valve replacement. Background Severe aortic valve disease is characterized by progressive accumulation of interstitial MF. Methods Fifty-four patients scheduled to undergo aortic valve replacement were examined by ce-MRI. Delayed-enhanced images were used for the quantitative assessment of MF. In addition, interstitial MF was quantified by histological analysis of myocardial samples obtained during open-heart surgery and stained with picrosirius red. The ce-MRI study was repeated 27 +/- 22 months after surgery to assess left ventricular functional improvement, and all patients were followed for 52 +/- 17 months to evaluate long-term survival. Results There was a good correlation between the amount of MF measured by histopathology and by ce-MRI (r = 0.69, p < 0.001). In addition, the amount of MF demonstrated a significant inverse correlation with the degree of left ventricular functional improvement after surgery (r = -0.42, p = 0.04 for histopathology; r = -0.47, p = 0.02 for ce-MRI). Kaplan-Meier analyses revealed that higher degrees of MF accumulation were associated with worse long-term survival (chi-square = 6.32, p = 0.01 for histopathology; chi-square = 5.85, p = 0.02 for ce-MRI). On multivariate Cox regression analyses, patient age and the amount of MF were found to be independent predictors of all-cause mortality. Conclusions The amount of MF, either by histopathology or by ce-MRI, is associated with the degree of left ventricular functional improvement and all-cause mortality late after aortic valve replacement in patients with severe aortic valve disease. (J Am Coll Cardiol 2010; 56: 278-87) (c) 2010 by the American College of Cardiology Foundation

Synchronous adenocarcinoma of the major and minor duodenal papilla

A 50-year-old woman presented with pancreatitis, fluctuant jaundice, weight loss, and abdominal pain. Contrast-enhanced computed tomography and abdominal ultrasound showed slight dilatation of the biliary tree and gallbladder without calculi. Endoscopy demonstrated a tumor protruding from the papilla of Vater. First endoscopically biopsy diagnosed no tumor, and a second biopsy diagnosed as papillary adenocarcinoma. The patient underwent duodenopancreatectomy. The specimen was fixed in formalin (10%). The tissue was processed routinely, and paraffin sections were stained with hematoxylin-eosin and periodic acid Schiff. Gross examination showed two tumors seen as prolapsed nodules growing isolated from the minor and major duodenal papillae measuring 1.5 and 1.0 cm, respectively, both covered by duodenal mucosa and the histologic study of both lesions demonstrated a moderately differentiated tubular adenocarcinoma, which invaded duodenal wall. After surgery, she is alive 24 months without evidence of recurrence.

Magnetic Resonance Angiography in Extracranial Giant Cell Arteritis

Background: Noninvasive diagnosis of giant cell arteritis (GCA) remains challenging, particularly with regard to evaluation of extracranial arterial disease. Objectives: The objective of the study was to retrospectively review extracranial involvement in patients with GCA and/or polymyalgia rheumatica (PMR), evaluated with magnetic resonance imaging (MRI), especially 3-dimensional contrast-enhanced magnetic resonance angiography images of the aortic arch and its branches. Methods: Clinical information, biopsy status, and MRI examinations of 28 patients with GCA/PMR were reviewed. Patient images were mixed randomly with 20 normal control images and were independently reviewed by 2 radiologists. Interobserver agreement for detection of arterial stenosis was determined by the k coefficient. Results: Both readers described vascular alterations in keeping with extracranial GCA in 19 of 28 patients (67%) with good interobserver agreement (k = 0.73) and with even higher agreement on diagnosing nonocclusive versus occlusive disease (k = 1.00). The most common lesions were bilateral axillary stenosis or obstructions, observed by both readers in 8 patients (28%). Among the 19 patients with magnetic resonance angiography lesions in the subclavian/axillary arteries, 12 (75%) had biopsy-proven GCA, but only 5 (41%) of these patients had clinical features of large artery disease. Conclusions: In our series review, MRI could provide accurate information on involvement of the aortic arch and its branches in extracranial GCA, depicting different degrees of stenosis. Our analysis also illustrates that occult large artery vasculitis should be considered in patients without biopsy-proven GCA, patients with classic GCA but without clinical signs of large artery disease, and in patients initially diagnosed as having PMR.

Imaging in osteoarthritis: what have we learned and where are we going?

Osteoarthritis (OA) is a widely prevalent disease of the whole joint including cartilage, bone and soft tissues. Increasing importance of imaging including assessment of all joint structures has been recognized recently. Conventional radiography is still the first and most commonly used imaging technique for evaluation of a patient with a known or suspected diagnosis of OA. However, limitations have been revealed by recent MRI-based knee OA studies. MRI plays a crucial role in understanding the natural history of the disease and in guiding future therapies due to its ability to image the knee as a whole organ and to directly and three-dimensionally assess cartilage morphology and composition. It is crucial to use the appropriate MR pulse sequences to assess various OA features, and thus support from experienced musculoskeletal radiologists should be sought for study design, image acquisition and interpretation. The aim of this article is to describe the roles and limitations of conventional radiography and MRI in imaging of OA, and also to give insight into the use of other modalities such as ultrasound, scintigraphy, computed tomography (CT) and CT arthrography in clinical practice and research in OA, particularly focusing on the assessment of knee OA in the tibiofemoral joint.

Cellular hypomethylation is associated with impaired nitric oxide production by cultured human endothelial cells

Hyperhomocysteinemia (HHcy) is a risk factor for vascular disease, but the underlying mechanisms remain incompletely defined. Reduced bioavailability of nitric oxide (NO) is a principal manifestation of underlying endothelial dysfunction, which is an initial event in vascular disease. Inhibition of cellular methylation reactions by S-adenosylhomocysteine (AdoHcy), which accumulates during HHcy, has been suggested to contribute to vascular dysfunction. However, thus far, the effect of intracellular AdoHcy accumulation on NO bioavailability has not yet been fully substantiated by experimental evidence. The present study was carried out to evaluate whether disturbances in cellular methylation status affect NO production by cultured human endothelial cells. Here, we show that a hypomethylating environment, induced by the accumulation of AdoHcy, impairs NO production. Consistent with this finding, we observed decreased eNOS expression and activity, but, by contrast, enhanced NOS3 transcription. Taken together, our data support the existence of regulatory post-transcriptional mechanisms modulated by cellular methylation potential leading to impaired NO production by cultured human endothelial cells. As such, our conclusions may have implications for the HHcy-mediated reductions in NO bioavailability and endothelial dysfunction.

Análise quantitativa da saturação de gordura em ressonância magnética mamária: comparação das técnicas SPAIR e DIXON

Introdução – A ressonância magnética (RM) mamária com injeção de contraste é uma ferramenta indispensável para a caracterização de lesões mamárias. Para tal, é fulcral uma boa capacidade de saturação de gordura de forma a delimitar as lesões observadas. Este trabalho tem como objetivo analisar quantitativa e qualitativamente as técnicas de saturação de gordura em RM mamária, nomeadamente as técnicas SPAIR e Dixon. Metodologia – Utilizou-se um equipamento de RM de 1,5T com bobina específica para a mama. Aplicou-se, durante o exame, uma sequência adicional em que a técnica de saturação de gordura utilizada foi a Dixon. Posteriormente foram analisadas as imagens obtidas com as técnicas SPAIR e Dixon e colocadas regiões de interesse (ROI) na lesão, na glândula mamária, no tecido adiposo e no ar. Estes valores de sinal obtidos foram registados e calcularam-se as relações sinal-ruído (SNR), contraste-ruído (CNR) e uniformidade de saturação de gordura para as mesmas estruturas a analisar e nas distintas sequências. Resultados – Verificou-se que a técnica de supressão de gordura Dixon apresenta resultados quantitativos e qualitativos superiores à técnica SPAIR. Conclusões – Recomenda-se a utilização da técnica Dixon para saturação de gordura nas sequências de estudo dinâmico com agente de contraste, especificamente nos estudos de RM mamária.

Reproducibility of free-breathing cardiovascular magnetic resonance coronary angiography.

OBJECTIVE: Contemporary free-breathing non contrast enhanced cardiovascular magnetic resonance angiography (CMRA) was qualitatively and quantitatively evaluated to ascertain the reproducibility of the method for coronary artery luminal dimension measurements. SUBJECTS AND METHODS: Twenty-two healthy volunteers (mean age 32 +/- 7 years, 12 males) without coronary artery disease were imaged at 2 centers (1 each in Europe and North America) using navigator-gated and corrected SSFP CMRA on a commercial whole body 1.5T System. Repeat images of right (RCA, n = 21), left anterior descending (LAD, n = 14) and left circumflex (LCX, n = 14) coronary arteries were obtained in separate sessions using identical scan protocol and imaging parameters. True visible vessel length, signal-to-noise (SNR), contrast-to-noise ratios (CNR) and the average luminal diameter over the first 4 cm of the vessel were measured. Intra-observer, inter-observer and inter-scan reproducibility of coronary artery luminal diameter were determined using Pearson's correlation, Bland-Altman analysis and intraclass correlation coefficients (ICC). RESULTS: CNR, SNR and the mean length of the RCA, LAD and LCX imaged for original and repeat scans were not significantly different (all p > 0.30). There was a high degree of intra-observer, inter-observer and inter-scan agreements for RCA, LAD and LCX luminal diameter respectively on Bland-Altman and ICC analysis (ICC's for RCA: 0.98. 0.98 and 0.86; LAD: 0.89, 0.89 and 0.63; LCX: 0.95, 0.94 and 0.79). CONCLUSION: In a 2-center study, we demonstrate that free-breathing 3D SSFP CMRA can visualize long continuous segments of coronary vessels with highly reproducible measurements of luminal diameter.

Sensitivity and specificity of the electrocardiogram to detect chronic myocardial infarction of the anteroseptal wall.

L`electrocardiograma és la primera eina diagnòstica fàcilment disponible per la detecció de l´infart a la práctica clínica. El seu valor va ser donat principalment amb estudis antics anatomopatològics. La ressonància magnètica cardíaca actualment és la tècnica d`elecció per la detecció de l`infart. Aquest estudi investiga el valor de l`electrocardiograma ( sensibilitat i especificitat) per detectar infarts de la zona anteroseptal. Conclusiò: la sensibilitat y la especificitat de quatre patents electrocardiogràfiques de la zona anteroseptal va ser valorada. Així mateix, encara que s`observin extenses ones Q en les derivacions anteriors la necrosis és usualment limitada si VL no está afectat. 3

Hypoxia and vasculature in models of lung cancer: implications for targeted therapeutics

Estudi realitzat a partir d’una estada a la Stanford University School of Medicine. Division of Radiation Oncology, Estats Units, entre 2010 i 2012. Durant els dos anys de beca postdoctoral he estat treballant en dos projectes diferents. En primer lloc, i com a continuació d'estudis previs del grup, volíem estudiar la causa de les diferències en nivells d'hipòxia que havíem observat en models de càncer de pulmó. La nostra hipòtesi es basava en el fet que aquestes diferències es devien a la funcionalitat de la vasculatura. Vam utilitzar dos models preclínics: un en què els tumors es formaven espontàniament als pulmons i l'altre on nosaltres injectàvem les cèl•lules de manera subcutània. Vam utilitzar tècniques com la ressonància magnètica dinàmica amb agent de contrast (DCE-MRI) i l'assaig de perfusió amb el Hoeschst 33342 i ambdues van demostrar que la funcionalitat de la vasculatura dels tumors espontanis era molt més elevada comparada amb la dels tumors subcutanis. D'aquest estudi, en podem concloure que les diferències en els nivells d'hipòxia en els diferents models tumorals de càncer de pulmó podrien ser deguts a la variació en la formació i funcionalitat de la vasculatura. Per tant, la selecció de models preclínics és essencial, tant pels estudi d'hipòxia i angiogènesi, com per a teràpies adreçades a aquests fenòmens. L'altre projecte que he estat desenvolupant es basa en l'estudi de la radioteràpia i els seus possibles efectes a l’hora de potenciar l'autoregeneració del tumor a partir de les cèl•lules tumorals circulants (CTC). Aquest efecte s'ha descrit en alguns models tumorals preclínics. Per tal de dur a terme els nostres estudis, vam utilitzar una línia tumoral de càncer de mama de ratolí, marcada permanentment amb el gen de Photinus pyralis o sense marcar i vam fer estudis in vitro i in vivo. Ambdós estudis han demostrat que la radiació tumoral promou la invasió cel•lular i l'autoregeneració del tumor per CTC. Aquest descobriment s'ha de considerar dins d'un context de radioteràpia clínica per tal d'aconseguir el millor tractament en pacients amb nivells de CTC elevats.

Perfusion and diffusion MRI of glioblastoma progression in a four-year prospective temozolomide clinical trial.

PURPOSE: This study was performed to determine the impact of perfusion and diffusion magnetic resonance imaging (MRI) sequences on patients during treatment of newly diagnosed glioblastoma. Special emphasis has been given to these imaging technologies as tools to potentially anticipate disease progression, as progression-free survival is frequently used as a surrogate endpoint. METHODS AND MATERIALS: Forty-one patients from a phase II temolozomide clinical trial were included. During follow-up, images were integrated 21 to 28 days after radiochemotherapy and every 2 months thereafter. Assessment of scans included measurement of size of lesion on T1 contrast-enhanced, T2, diffusion, and perfusion images, as well as mass effect. Classical criteria on tumor size variation and clinical parameters were used to set disease progression date. RESULTS: A total of 311 MRI examinations were reviewed. At disease progression (32 patients), a multivariate Cox regression determined 2 significant survival parameters: T1 largest diameter (p < 0.02) and T2 size variation (p < 0.05), whereas perfusion and diffusion were not significant. CONCLUSION: Perfusion and diffusion techniques cannot be used to anticipate tumor progression. Decision making at disease progression is critical, and classical T1 and T2 imaging remain the gold standard. Specifically, a T1 contrast enhancement over 3 cm in largest diameter together with an increased T2 hypersignal is a marker of inferior prognosis.

Volume-targeted and whole-heart coronary magnetic resonance angiography using an intravascular contrast agent.

PURPOSE: To compare volume-targeted and whole-heart coronary magnetic resonance angiography (MRA) after the administration of an intravascular contrast agent. MATERIALS AND METHODS: Six healthy adult subjects underwent a navigator-gated and -corrected (NAV) free breathing volume-targeted cardiac-triggered inversion recovery (IR) 3D steady-state free precession (SSFP) coronary MRA sequence (t-CMRA) (spatial resolution = 1 x 1 x 3 mm(3)) and high spatial resolution IR 3D SSFP whole-heart coronary MRA (WH-CMRA) (spatial resolution = 1 x 1 x 2 mm(3)) after the administration of an intravascular contrast agent B-22956. Subjective and objective image quality parameters including maximal visible vessel length, vessel sharpness, and visibility of coronary side branches were evaluated for both t-CMRA and WH-CMRA. RESULTS: No significant differences (P = NS) in image quality were observed between contrast-enhanced t-CMRA and WH-CMRA. However, using an intravascular contrast agent, significantly longer vessel segments were measured on WH-CMRA vs. t-CMRA (right coronary artery [RCA] 13.5 +/- 0.7 cm vs. 12.5 +/- 0.2 cm; P < 0.05; and left circumflex coronary artery [LCX] 11.9 +/- 2.2 cm vs. 6.9 +/- 2.4 cm; P < 0.05). Significantly more side branches (13.3 +/- 1.2 vs. 8.7 +/- 1.2; P < 0.05) were visible for the left anterior descending coronary artery (LAD) on WH-CMRA vs. t-CMRA. Scanning time and navigator efficiency were similar for both techniques (t-CMRA: 6.05 min; 49% vs. WH-CMRA: 5.51 min; 54%, both P = NS). CONCLUSION: Both WH-CMRA and t-CMRA using SSFP are useful techniques for coronary MRA after the injection of an intravascular blood-pool agent. However, the vessel conspicuity for high spatial resolution WH-CMRA is not inferior to t-CMRA, while visible vessel length and the number of visible smaller-diameter vessels and side-branches are improved.

Improved three-dimensional free-breathing coronary magnetic resonance angiography using gadocoletic acid (B-22956) for intravascular contrast enhancement.

PURPOSE: To evaluate gadocoletic acid (B-22956), a gadolinium-based paramagnetic blood pool agent, for contrast-enhanced coronary magnetic resonance angiography (MRA) in a Phase I clinical trial, and to compare the findings with those obtained using a standard noncontrast T2 preparation sequence. MATERIALS AND METHODS: The left coronary system was imaged in 12 healthy volunteers before B-22956 application and 5 (N = 11) and 45 (N = 7) minutes after application of 0.075 mmol/kg of body weight (BW) of B-22956. Additionally, imaging of the right coronary system was performed 23 minutes after B-22956 application (N = 6). A three-dimensional gradient echo sequence with T2 preparation (precontrast) or inversion recovery (IR) pulse (postcontrast) with real-time navigator correction was used. Assessment of the left and right coronary systems was performed qualitatively (a 4-point visual score for image quality) and quantitatively in terms of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), vessel sharpness, visible vessel length, maximal luminal diameter, and the number of visible side branches. RESULTS: Significant (P < 0.01) increases in SNR (+42%) and CNR (+86%) were noted five minutes after B-22956 application, compared to precontrast T2 preparation values. A significant increase in CNR (+40%, P < 0.05) was also noted 45 minutes postcontrast. Vessels (left anterior descending artery (LAD), left coronary circumflex (LCx), and right coronary artery (RCA)) were also significantly (P < 0.05) sharper on postcontrast images. Significant increases in vessel length were noted for the LAD (P < 0.05) and LCx and RCA (both P < 0.01), while significantly more side branches were noted for the LAD and RCA (both P < 0.05) when compared to precontrast T2 preparation values. CONCLUSION: The use of the intravascular contrast agent B-22956 substantially improves both objective and subjective parameters of image quality on high-resolution three-dimensional coronary MRA. The increase in SNR, CNR, and vessel sharpness minimizes current limitations of coronary artery visualization with high-resolution coronary MRA.

Portal Vein Embolization before Right Hepatectomy: Improved Results Using n-Butyl-Cyanoacrylate Compared to Microparticles Plus Coils.

BACKGROUND: There is currently no consensus in the literature on which embolic agent induces the greatest degree of liver hypertrophy after portal vein embolization (PVE). Only experimental results in a pig model have demonstrated an advantage of n-butyl-cyanoacrylate (NBCA) over 3 other embolic materials (hydrophilic gel, small and large polyvinyl alcohol particles) for PVE. Therefore, the aim of this human study was to retrospectively compare the results of PVE using NBCA with those using spherical microparticles plus coils. METHODS: A total of 34 patients underwent PVE using either NBCA (n = 20), or spherical microparticles plus coils (n = 14). PVE was decided according to preoperative volumetry on the basis of contrast-enhanced CT. Groups were compared for age, sex, volume of the left lobe before PVE and future remnant liver ratio (FRL) (volume of the left lobe/total liver volume - tumor volume). The primary end point was the increase in left lobe volume 1 month after PVE. Secondary end points were procedure complications and biological tolerance. RESULTS: Both groups were similar in terms of age, sex ratio, left lobe volume, and FRL before PVE. NBCA induced a greater increase in volume after PVE than did microparticles plus coils (respectively, +74 ± 69 % and +23 ± 14 %, p < 0.05). The amount of contrast medium used for the procedure was significantly larger when microparticles and coils rather than NBCA were used (respectively, 264 ± 43 ml and 162 ± 34 ml, p < 0.01). The rate of PVE complications as well as the biological tolerance was similar in both groups. CONCLUSION: NBCA seems more effective than spherical microparticles plus coils to induce left-lobe hypertrophy.