MRI and X-ray in axial spondyloarthritis: the relationship between inflammatory and structural changes

Demonstration of an association between inflammation and spinal ankylosis has been challenging. Until the advent of MRI, prospective study was not possible due to inaccessibility of tissue. Recent studies using MRI have described an association between the presence of bone edema at vertebral corners on MRI and the subsequent development of syndesmophytes at the corresponding vertebral corners on radiography. Although reports have also highlighted the development of new syndesmophytes where the baseline MRI shows no inflammation, MRI has limited sensitivity for detection of spinal inflammation that is clearly evident on histopathology. There are also crucial methodological challenges because radiographic assessment is limited to the anterior corners of the cervical and lumbar spine while MRI lesions in the cervical spine are often small while spurious inflammatory signal is common in the lumbar spine. Follow-up MRI evaluation in two independent studies has also shown that inflammatory lesions that resolve after anti-TNF therapy are more prone to develop into syndesmophytes. It may be possible that very early inflammatory lesions resolve completely without sequelae if anti-TNF therapy is introduced before new bone formation becomes largely autonomous. For an individual patient the overall development of new bone during anti-TNF therapy may therefore depend on the balance between the number of early and more mature inflammatory lesions. Clinical trials of anti-TNF agents in early spondyloarthritis together with prospective MRI studies will allow more detailed testing of this hypothesis as a major priority for the research agenda in spondyloarthritis.     

Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features

Demonstration of an association between inflammation and spinal ankylosis has been challenging. Until the advent of MRI, prospective study was not possible due to inaccessibility of tissue. Recent studies using MRI have described an association between the presence of bone edema at vertebral corners on MRI and the subsequent development of syndesmophytes at the corresponding vertebral corners on radiography. Although reports have also highlighted the development of new syndesmophytes where the baseline MRI shows no inflammation, MRI has limited sensitivity for detection of spinal inflammation that is clearly evident on histopathology. There are also crucial methodological challenges because radiographic assessment is limited to the anterior corners of the cervical and lumbar spine while MRI lesions in the cervical spine are often small while spurious inflammatory signal is common in the lumbar spine. Follow-up MRI evaluation in two independent studies has also shown that inflammatory lesions that resolve after anti-TNF therapy are more prone to develop into syndesmophytes. It may be possible that very early inflammatory lesions resolve completely without sequelae if anti-TNF therapy is introduced before new bone formation becomes largely autonomous. For an individual patient the overall development of new bone during anti-TNF therapy may therefore depend on the balance between the number of early and more mature inflammatory lesions. Clinical trials of anti-TNF agents in early spondyloarthritis together with prospective MRI studies will allow more detailed testing of this hypothesis as a major priority for the research agenda in spondyloarthritis.     

The window of opportunity: a relevant concept for axial spondyloarthritis

The window of opportunity is a concept critical to rheumatoid arthritis treatment. Early treatment changes the outcome of rheumatoid arthritis treatment, in that response rates are higher with earlier disease-modifying anti-rheumatic drug treatment and damage is substantially reduced. Axial spondyloarthritis is an inflammatory axial disease encompassing both nonradiographic axial spondyloarthritis and established ankylosing spondylitis. In axial spondyloarthritis, studies of magnetic resonance imaging as well as tumor necrosis factor inhibitor treatment and withdrawal studies all suggest that early effective suppression of inflammation has the potential to reduce radiographic damage. This potential would suggest that the concept of a window of opportunity is relevant not only to rheumatoid arthritis but also to axial spondyloarthritis. The challenge now remains to identify high-risk patients early and to commence treatment without delay. Developments in risk stratification include new classification criteria, identification of clinical risk factors, biomarkers, genetic associations, potential antibody associations and an ankylosing spondylitis-specific microbiome signature. Further research needs to focus on the evidence for early intervention and the early identification of high-risk individuals.     

Progress in spondylarthritis. Mechanisms of new bone formation in spondyloarthritis

Targeted therapies that neutralize tumour necrosis factor are often able to control the signs and symptoms of spondyloarthritis. However, recent animal model data and clinical observations indicate that control of inflammation may not be sufficient to impede disease progression toward ankylosis in these patients. Bone morphogenetic proteins and WNTs (wingless-type like) are likely to play an important role in ankylosis and could be therapeutic targets. The relationship between inflammation and new bone formation is still unclear. This review summarizes progress made in our understanding of ankylosis and offers an alternative view of the relationship between inflammation and ankylosis.     

Molecular imaging: Bridging the gap between neuroradiology and neurohistology

Historically, in vivo imaging methods have largely relied on imaging gross anatomy. More recently it has become possible to depict biological processes at the cellular and molecular level. These new research methods use magnetic resonance imaging (MRI), positron emission tomography (PET), near-infrared optical imaging, scintigraphy, and autoradiography in vivo and in vitro. Of primary interest is the development of methods using MRI and PET with which the progress of gene therapy in glioblastoma (herpes simplex virus-thymidine kinase) and Parkinson's disease can be monitored and graphically displayed. The distribution of serotonin receptors in the human brain and the duration of serotonin-receptor antagonist binding can be assessed by PET. With PET, it is possible to localize neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. MR tracking of transplanted oligodendrocyte progenitors is feasible for determining the extent of remyelinization in myelin-deficient rats. Stroke therapy in adult rats with subventricular zone cells can be monitored by MRI. Transgene expression (beta-galactosidase, tyrosinase, engineered transferrin receptor) can also be visualized using MRI. Macrophages can be marked with certain iron-containing contrast agents which, through accumulation at the margins of glioblastomas, ameliorate the visual demarcation in MRI. The use of near-infrared optical imaging techniques to visualize matrix-metalloproteinases and cathepsin B can improve the assessment of tumor aggressiveness and angiogenesis-inhibitory therapy. Apoptosis could be detected using near-infrared optical imaging representation of caspase 3 activity and annexin B. This review demonstrates the need for neurohistological research if further progress is to be made in the emerging but burgeoning field of molecular imaging.     

Imaging of cell trafficking in Crohn's disease

Inflammatory bowel diseases are represented by ulcerative colitis and Crohn's disease, both consisting of a chronic, uncontrolled inflammation of the intestinal mucosa of any part of the gastrointestinal tract with patchy or continuous inflammation. Ileo‐colonoscopy is considered the current gold standard imaging technique for the diagnosis. However, as the majority of patients need a long‐term follow‐up it would be ideal to rely on a non‐invasive technique with good compliance. This review focuses on nuclear medicine imaging techniques in Crohn's disease. Different scintigraphic methods of imaging cells involved in the pathogenesis are described. The radiopharmaceuticals can be divided into non‐specific radiopharmaceuticals for inflammation and specific radiopharmaceuticals that directly image lymphocytes involved in the process. This non‐invasive molecular imaging approach can be useful also because it images the small bowel or other areas––where colonoscopy is not useful—and that it may play a role for constant follow‐up, because relapses are frequent. Finally, an update on other imaging modalities, and particularly MRI, in the evaluation of Crohn's disease activity, is provided. Although MRI cannot directly detect inflammatory cells, it has shown a high sensitivity in detecting the macroscopic signs of inflammation at the level of the intestinal wall affected by Crohn's disease and Ulcerative colitis. The current diagnostic value of MRI in the detection of inflamed bowel segment and in the assessment of CD activity, as well the potentials MR spectroscopy, MR diffusion imaging and MR molecular imaging, is briefly discussed. J. Cell. Physiol. 223:562–571, 2010. © 2010 Wiley‐Liss, Inc.     

Magnetic resonance imaging of Klebsiella pneumoniae-induced pneumonia in mice

In vivo imaging of small animals is a rapidly developing field. However, the potential of global imaging of infectious processes in animal models remains poorly explored. We used magnetic resonance imaging (MRI) to follow the development and regression of inflammatory lesions caused by infection by Klebsiella pneumoniae in mouse lungs. A virulent strain caused an intense inflammation within 2 days in the whole lungs, while an avirulent strain did not show significant changes. Mice infected with the virulent strain and subsequently treated with antibiotics presented a severe inflammation localized mainly in the left lung that disappeared after a week. The lesions observed by MRI correlated with the damage seen by histological analysis and a 3D representation of the tissue allowed better visualization of the development and healing of inflammatory lesions. MRI thus represents a powerful technique to study in vivo the interactions between a pathogen and its host in real time.     

Progress in spondylarthritis. Immunopathogenesis of spondyloarthritis: which cells drive disease?

Spondyloarthritides, or SpA, form a cluster of chronic inflammatory diseases with the axial skeleton as the most typical disease localisation, although extra-articular manifestations such as intestinal inflammation may frequently occur during the course of the disease. This review summarises recent progress in our understanding of the immunopathogenesis of SpA with special emphasis on the cellular constituents considered to be responsible for the initiation and/or perpetuation of inflammation. There are several arguments favouring a role for haematopoietic cells in the pathophysiology of spondyloarthritis, including HLA-B27-associated dendritic cell disturbances, HLA-B27 misfolding properties and T helper 17 cells. In addition, recent studies have pointed toward a pivotal role for stromal cells. A major challenge, however, remains to determine how recently identified genetic associations such as interleukin-23 receptor polymorphisms may influence cellular targets in spondyloarthritis.     

New concepts in characterization of ischemically injured myocardium by MRI

New concepts regarding the assessment of ischemic myocardial injuries have been addressed in this Minireview using magnetic resonance imaging (MRI). MRI, with its different techniques, brings not only anatomic, but also physiologic, information on ischemic heart disease. It has the ability to measure identical parameters in preclinical and clinical studies. MRI techniques provide the ideal package for repeated and noninvasive assessment of myocardial anatomy, viability, perfusion, and function. MR contrast agents can be applied in a variety of ways to improve MRI sensitivity for detecting and assessing ischemically injured myocardium. With MR contrast agents protocol, it becomes possible to identify ischemic, acutely infarcted, and peri-infarcted myocardium in occlusive and reperfused infarctions. Necrosis specific and nonspecific extracellular contrast-enhanced MRI has been used to assess myocardial viability. Contrast-enhanced perfusion MRI can explore the disturbances in large (angiography) and small coronary arteries (myocardial perfusion) as the underlying cause of myocardial dysfunction. Perfusion MRI has been used to measure myocardial perfusion (ml/min/g) and to demonstrate the difference in transmural myocardial blood flow. Information on no-reflow phenomenon is derived from dynamic changes in regional signal intensity after bolus injection of MR contrast agents. Another development is the near future availability of blood pool MR contrast agents. These agents are able to assess microvascular permeability and integrity and are advantageous in MR angiography (MRA) due to their persistence in the blood. Noncontrast-enhanced MRI such as cine MRI at rest/stress, sodium MRI, and MR spectroscopy also have the potential to noninvasively assess myocardial viability in patients. Futuristic applications for MRI in the heart will focus on identifying coronary artery disease at an early stage and the beneficial effects of new therapeutic agents such as intra-arterial gene therapy. MR techniques will have great future in the drug discovery process and in testing the effects of drugs on myocardial biochemistry, physiology, and morphology. Molecular imaging is going to bloom in this decade.     

Comparative characteristics of radiation imaging methods in the diagnosis of sacroiliitis

Patients with sacroiliac joint, injuries, ankylosing spondyloarthritis, or spondyloarthropathy of various genesis were examined. Pelvis x-ray, spiral computed tomography (CT), and magnetic resonance imaging (MRI) were performed. MRI was found to have advantages in the detection and evaluation of the pattern of detectable bone changes. It is inexpedient to use traditional x-ray study and CT for the detection of edematous-infiltrative changes in both osseous and fibrous and soft tissue elements of the joint since the sensitivity of these techniques is insufficient to detect. To analyze detectable changes, it is expedient to use a unified MRI protocol that involves the characteristics of osseous, fibrous, and soft tissue structures of the joint.     

High-throughput magnetic resonance imaging in murine colonic inflammation

The aim of this study was to investigate if a rapid magnetic resonance imaging (MRI) screening protocol (<5min/mouse) could characterize colonic inflammation in a chronic experimental colitis model. No respiratory triggering or spasmolytic agent was used during MRI-acquisition. Biomarkers assessed in vivo were colon wall thickness and T2w signal intensity (reflecting oedema) and ex vivo inflammatory score, colon weight, and plasma haptoglobin. The inflammation was characterised by significantly higher local and systemic inflammatory markers in the colitic mice compared to healthy mice. MRI-colon wall thickness and T2w signal intensity correlated well with inflammatory score (r=0.95 and 0.94), colon weight (r=0.92 and 0.93) and plasma haptoglobin (r=0.89 and 0.95). Thus, the data showed that in vivo MRI screening could be used to assess colon wall inflammation, suggesting that high-throughput MRI can be used to follow the potential efficacy of new IBD therapies in individual animal in longitudinal studies.     

The Applicability of Amide Proton Transfer Imaging in the Nervous System: Focus on Hypoxic-Ischemic Encephalopathy in the Neonate

In recent years, magnetic resonance imaging (MRI) has become more widely used in neonatal hypoxic-ischemic encephalopathy (HIE), involving, for example, evaluation of cerebral edema, white matter fiber bundle tracking, cerebral perfusion status, and assessment of brain metabolites. MRI has many imaging modalities. However, its application for assessing changes in the internal environment at the tissue and cellular level after hypoxia–ischemia remains a challenge and is currently the focus of intense research. Based on the exchange between amide protons of proteins and polypeptides and free water protons, amide proton transfer (APT) imaging can display changes in pH and protein concentrations in vivo. This paper is a review of the principles of APT imaging, with a focus on the potential application of APT imaging for neonatal HIE.     

Imaging modalities to assess structural birth defects in mutant mouse models

Assessment of structural birth defects (SBDs) in animal models usually entails conducting detailed necropsy for anatomical defects followed by histological analysis for tissue defects. Recent advances in new imaging technologies have provided the means for rapid phenotyping of SBDs, such as using ultra‐high frequency ultrasound biomicroscopy, optical coherence tomography, micro‐CT, and micro‐MRI. These imaging modalities allow the detailed assessment of organ/tissue structure, and with ultrasound biomicroscopy, structure and function of the cardiovascular system also can be assessed noninvasively, allowing the longitudinal tracking of the fetus in utero. In this review, we briefly discuss the application of these state‐of‐the‐art imaging technologies for phenotyping of SBDs in rodent embryos and fetuses, showing how these imaging modalities may be used for the detection of a wide variety of SBDs. Birth Defects Research (Part C) 90:176–184, 2010. © 2010 Wiley‐Liss, Inc.     

Rôle de la TEP FDG dans l’évaluation de l’extension locorégionale et à distance du mélanome

FDG PET/CT is a relevant examination for patients with high-risk melanoma. For early stages with thickness ≥ 1 mm, lymph node ultrasound, and when negative, lymphoscintigraphy for determination of sentinel lymph node, remain necessary. For more advanced stages, FDG PET can map the lesions and guide the therapeutic strategy, either with surgical management, or systemic therapy (or sometimes both). In patients with high-risk melanoma, it allows to detect relapses early, including in asymptomatic patients, with a potential impact on therapeutic decisions. Beside the detection of classical secondary localizations, FDG PET has the advantage of allowing whole-body imaging, the identification of soft tissue lesions, frequent in melanomas, as well as rarer sites of involvement, such as those of the gastro-intestinal tract. For the assessment of cerebral and leptomeningeal involvement, MRI remains mandatory. Evolutions in the therapeutic management of advanced melanomas, and the search for biomarkers to guide the therapeutic strategy, ask for more refined analyses of PET, with metabolic tumour volume analysis and radiomics. The combination of metabolic imaging data with biological and molecular data, and the development of new PET tracers may improve the assessment of prognosis and the prediction of response to therapies, in order to tailor the therapeutic strategy to each patient. Further studies are needed to consolidate the role of PET/CT in this disease for which numerous therapeutic innovations are emerging.     

La tomoscintigraphie myocardique

In the last years, cardiac imaging has dramatically developed, with the generalization of ECG-gated myocardial tomoscintigraphy (MTS) for nuclear cardiology, but also with the precise assessments of cardiac function and of infarction sequels, which are now provided by cardiac MRI, and with the development of coronary angiography by multi-slices CT. In this setting, MTS remains, however, the reference imaging technique for assessing myocardial ischemia, especially at exercise, the sole stress method which is physiologic and which results may be extrapolated to daily-life conditions. Because of this specific property, MTS should remain a major investigation for assessing and following patients with chronic coronary artery disease in the future. The assessment of myocardial ischemia at stress remains unanimously recommended before any invasive therapeutic or diagnostic intervention, when patients are not or only poorly symptomatic. However, it is also likely that this technique will markedly change in the future. Considerable efforts are indeed dedicated to research and development for hybrid recording systems, PET tracers and PET cameras, and gamma detectors systems using semi-conductors.     

Might axial myofascial properties and biomechanical mechanisms be relevant to ankylosing spondylitis and axial spondyloarthritis?

Ankylosing spondylitis and axial spondyloarthropathy have characteristic age- and sex-specific onset patterns, typical entheseal lesions, and marked heritability, but the integrative mechanisms causing the pathophysiological and structural alterations remain largely undefined. Myofascial tissues are integrated in the body into webs and networks which permit transmission of passive and active tensional forces that provide stabilizing support and help to control movements. Axial myofascial hypertonicity was hypothesized as a potential excessive polymorphic trait which could contribute to chronic biomechanical overloading and exaggerated stresses at entheseal sites. Such a mechanism may help to integrate many of the characteristic host, pathological, and structural features of ankylosing spondylitis and axial spondyloarthritis. Biomechanical stress and strain were recently documented to correlate with peripheral entheseal inflammation and new bone formation in a murine model of spondyloarthritis. Ankylosing spondylitis has traditionally been classified by the modified New York criteria, which require the presence of definite radiographic sacroiliac joint lesions. New classification criteria for axial spondyloarthritis now include patients who do not fulfill the modified New York criteria. The male-to-female sex ratios clearly differed between the two patient categories - 2:1 or 3:1 in ankylosing spondylitis and 1:1 in non-radiographic axial spondyloarthritis - and this suggests a spectral concept of disease and, among females, milder structural alterations. Magnetic resonance imaging of active and chronic lesions in ankylosing spondylitis and axial spondyloarthritis reveals complex patterns, usually interpreted as inflammatory reactions, but shows similarities to acute degenerative disc disease, which attributed to edema formation following mechanical stresses and micro-damage. A basic question is whether mechanically induced microinjury and immunologically mediated inflammatory mechanisms operate in both ankylosing spondylitis and degenerative disc disease but differ in relative degrees. The hypothesized biomechanical properties raised in this commentary require documentation of their association with the onset risk and course of ankylosing spondylitis and axial spondyloarthritis. If particular subsets of ankylosing spondylitis and axial spondyloarthritis patients are confirmed to have altered axial myofascial properties, their biological basis and underlying biomechanical mechanisms promise to become clarified. Understanding how biomechanical and physical properties can affect symptomatic and structural manifestations of these disorders could also improve their management.     

Vessel Wall Inflammation of Takayasu Arteritis Detected by Contrast-Enhanced Magnetic Resonance Imaging: Association with Disease Distribution and Activity

Aims

The assessment of the distribution and activity of vessel wall inflammation is clinically important in patients with Takayasu arteritis. Magnetic resonance imaging (MRI) is a useful tool, but the clinical utility of late gadolinium enhancement (LGE) in Takayasu arteritis has yet to be determined. The aim of the present study was to evaluate the utility of LGE in assessing vessel wall inflammation and disease activity in Takayasu arteritis.

Methods and Results

We enrolled 49 patients with Takayasu arteritis who had undergone 1.5 T MRI. Patients were divided into Active (n = 19) and Inactive disease (n = 30) groups. The distribution of vessel wall inflammation using angiography and LGE was assessed by qualitative analysis. In 79% and 63% of patients in Active and Inactive groups, respectively, greater distribution of vessel wall inflammation was observed with LGE than with conventional angiography. MRI values of pre- and post-contrast signal-to-noise ratios (SNR), SNR increment (post-SNR minus pre-SNR), pre- and post-contrast contrast-to-noise ratios (CNR), and CNR increment (post-CNR minus pre-CNR) were evaluated at arterial wall sites with the highest signal intensity using quantitative analysis of post-contrast LGE images. No statistically significant differences in MRI parameters were observed between Active and Inactive groups. Contrast-enhanced MRI was unable to accurately detect active disease.

Conclusion

Contrast-enhanced MRI has utility in detecting the distribution of vessel wall inflammation but has less utility in assessing disease activity in Takayasu arteritis.     

Streptococcus pneumoniae induced c-Jun-N-terminal kinase- and AP-1 -dependent IL-8 release by lung epithelial BEAS-2B cells

Background

Chronic lung diseases are a major issue in public health. A serial pulmonary assessment using imaging techniques free of ionizing radiation and which provides early information on local function impairment would therefore be a considerably important development. Magnetic resonance imaging (MRI) is a powerful tool for the static and dynamic imaging of many organs. Its application in lung imaging however, has been limited due to the low water content of the lung and the artefacts evident at air-tissue interfaces. Many attempts have been made to visualize local ventilation using the inhalation of hyperpolarized gases or gadolinium aerosol responding to MRI. None of these methods are applicable for broad clinical use as they require specific equipment.

Methods

We have shown previously that low-field MRI can be used for static imaging of the lung. Here we show that mathematical processing of data derived from serial MRI scans during the respiratory cycle produces good quality images of local ventilation without any contrast agent. A phantom study and investigations in 85 patients were performed.

Results

The phantom study proved our theoretical considerations. In 99 patient investigations good correlation (r = 0.8; p ≤ 0.001) was seen for pulmonary function tests and MR ventilation measurements. Small ventilation defects were visualized.

Conclusion

With this method, ventilation defects can be diagnosed long before any imaging or pulmonary function test will indicate disease. This surprisingly simple approach could easily be incorporated in clinical routine and may be a breakthrough for lung imaging and functional assessment.     

Longitudinal Assessment of Amyloid Pathology in Transgenic ArcAβ Mice Using Multi-Parametric Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) can be used to monitor pathological changes in Alzheimer''s disease (AD). The objective of this longitudinal study was to assess the effects of progressive amyloid-related pathology on multiple MRI parameters in transgenic arcAβ mice, a mouse model of cerebral amyloidosis. Diffusion-weighted imaging (DWI), T₁-mapping and quantitative susceptibility mapping (QSM), a novel MRI based technique, were applied to monitor structural alterations and changes in tissue composition imposed by the pathology over time. Vascular function and integrity was studied by assessing blood-brain barrier integrity with dynamic contrast-enhanced MRI and cerebral microbleed (CMB) load with susceptibility weighted imaging and QSM. A linear mixed effects model was built for each MRI parameter to incorporate effects within and between groups (i.e. genotype) and to account for changes unrelated to the disease pathology. Linear mixed effects modelling revealed a strong association of all investigated MRI parameters with age. DWI and QSM in addition revealed differences between arcAβ and wt mice over time. CMBs became apparent in arcAβ mice with 9 month of age; and the CMB load reflected disease stage. This study demonstrates the benefits of linear mixed effects modelling of longitudinal imaging data. Moreover, the diagnostic utility of QSM and assessment of CMB load should be exploited further in studies of AD.     

Synthesis and biological evaluation of water-soluble progesterone-conjugated probes for magnetic resonance imaging of hormone related cancers

Progesterone receptor (PR) is strongly associated with disease prognosis and therapeutic efficacy in hormone-related diseases such as endometriosis and breast, ovarian, and uterine cancers. Receptor status is currently determined by immunohistochemistry assays. However, noninvasive PR imaging agents could improve disease detection and help elucidate pathological molecular pathways, leading to new therapies and animal disease models. A series of water-soluble PR-targeted magnetic resonance imaging (MRI) probes were synthesized using Cu(I)-catalyzed click chemistry and evaluated in vitro and in vivo. These agents demonstrated activation of PR in vitro and preferential accumulation in PR(+) compared to PR(-) human breast cancer cells with low toxicity. In xenograft tumor models, the agents demonstrated enhanced signal intensity in PR(+) tumors compared to PR(-) tumors. The results suggest that these agents may be promising MRI probes for PR(+) diseases.