Synopsis

Keywords: Cross-organ: Inflammation, Physics & Engineering: Preclinical MRI, Contrast mechanisms: Molecular Imaging

Inflammation is a key constituent of most neurological conditions including multiple sclerosis. Concerns related to gadolinium-based contrasts agents is limiting their use to monitor inflammation in patients. Preclinical efforts to quantify inflammation includes the development of fluorine-containing materials that can be detected with high specificity with fluorine (¹⁹F) MRI. This talk will go into the basics of ¹⁹F MRI, its strengths and weaknesses, as well as the approaches that strive to overcome those weaknesses. The idea of quantifying inflammation and anti-inflammatory treatment simultaneously will be introduced. Novel ¹⁹F reporter molecules and methods that improve ¹⁹F signal detection will be discussed.

Inflammation is a key constituent of most human diseases. Apart from autoimmune conditions of the central nervous system (CNS) such as multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM), inflammation is also key to other neurological and neurodegenerative conditions such as Alzheimer’s disease [1]. For several decades radiologists have administered gadolinium-based contrasts agents (GBCA) to monitor inflammatory activity in MS patients in the form of contrast-enhanced lesions. However, safety considerations regarding potential gadolinium accumulation in the brain following repeated intravenous applications have questioned this until now effective tool. In recent years MS consortia in Europe and North America have recommended against repeated gadolinium administrations in the absence of clinical consequence [2]. While standardized MS imaging techniques with highest sensitivity and specificity are a great challenge, intensive research on contrast agents continues, including research on novel contrast agents that can be identified by fluorine (¹⁹F) MRI. The development of fluorine-containing materials and compounds that can be detected with high specificity have enriched the field of quantitative inflammation imaging with MRI. This talk will go into the basics of ¹⁹F MRI, especially into its strengths, weaknesses and the approaches that are being studied to overcome its weaknesses. Research in ¹⁹F MRI is progressing at an impressive pace and is yielding tangible results at the forefront of biomedical research. Several decades after its first documented application, the unprecedented opportunities of ¹⁹F MRI in medical research remain intense, and it is an area of increasing clinical interest. The challenges associated with fluorine MRI are also equally recognized, most notably the restrictively low detection limits and sensitivity boundaries. This will also be discussed. New developments from various research domains such as chemistry, physics, engineering and material sciences have been necessary to overcome the challenges and technical barriers. This talk will go into some of the commonly used materials that are employed to study inflammation in preclinical scenarios, with a focus on organofluorine-based emulsions (>100nm) [3] as well as the recently developed ultrasmall fluoride-based nanocrystals (<10 nm) [4]. The motivation in the design and synthesis of new fluorine-rich molecular probes is to improve signal strength. The MR properties of these probes, such as spin-lattice relaxation is manipulated to favor ideal conditions for signal acquisition and detection. Progress in ¹⁹F MRI spans a very broad range of disciplines, beyond chemistry, into physics and information technology for image acquisition and processing. Methods that have been implemented to improve the MR signal from the data acquisition and processing side to lower the detection levels and boost sensitivity will be mentioned. Several innovative developments such as compressed sensing (CS) will ultimately be required to provide the high signal-to noise ratio efficiency especially in situations of signal sparsity that is common in inflammatory lesion signal distribution [5]. Mention of method fidelity will be made as this will be essential for in vivo measurements. Another important issue of ¹⁹F MRI is signal quantification. The necessary technologies such as B₁ mapping to correct for non-uniform radiofrequency fields [6] or development of new radio frequency coil technologies to make quantification feasible and accurate will be discussed. Combating inflammation in autoimmune disease such as MS typically involves the administration of disease modifying drugs (DMDs). Some of these drugs are also fluorinated, thereby opening up a window of opportunity, that is to study inflammation and its treatment simultaneously. In this presentation, mention will be made on the importance of studying relaxation properties of fluorinated anti-inflammatory drugs under different environmental conditions such as temperature to study them in in vivo [7-9]. This presentation will center around the research efforts and goals that can promote the sensitivity for ¹⁹F MRI and the dynamic vision of implementing this invaluable resource within clinical protocols to ultimately answer crucial questions in the pathophysiology and treatment of inflammation.

Acknowledgements

The following agencies and donating institutions are acknowledged for research and travel funding: Novartis, the German-Israeli Foundation for Scientific Research and Development (GIF) and the Gemeinnuetzige Hertie Stiftung (GHS)