Neuroimaging: do we really need new contrast agents for MRI?

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Abstract

The use of exogenous contrast media in magnetic resonance imaging of the brain has brought dramatic improvement in the sensitivity of detection and delineation of pathological structures, such as primary and metastatic brain tumors, inflammation and ischemia. Disruption of the blood brain barrier leads to accumulation of the intravenously injected contrast material in the extravascular space, leading to signal enhancement. Magnetic resonance angiography benefits from T1-shortening effects of contrast agent, improving small vessel depiction and providing vascular visualization even in situations of slow flow. High speed dynamic MRI after bolus injection of contrast media allows tracer kinetic modeling of cerebral perfusion. Progressive enhancement over serial post-contrast imaging allows modeling of vascular permeability and thus quantitative estimation of the severity of blood brain barrier disruption. With such an array of capabilities and ever improving technical abilities, it seems that the role of contrast agents in MR neuroimaging is established and the development of new agents may be superfluous. However, new agents are being developed with prolonged intravascular residence times, and with in-vivo binding of ever-increasing specificity. Intravascular, or blood pool, agents are likely to benefit magnetic resonance angiography of the carotid and cerebral vessels; future agents may allow the visualization of therapeutic drug delivery, the monitoring of, for example, gene expression, and the imaging evaluation of treatment efficacy. So while there is a substantial body of work that can be performed with currently available contrast agents, especially in conjunction with optimized image acquisition strategies, post processing, and mathematical analysis, there are still unrealized opportunities for novel contrast agent introduction, particularly those exploiting biological specificity. This article reviews the current use of contrast media in magnetic resonance neuroimaging, discusses some of the developing strategies for new applications of imaging with these agents and finally offers some views and indications for contrast agents currently under development, as well as some speculation on unsolved problems in neuroimaging, and opportunities for novel contrast agents.

Introduction

MRI has emerged as a powerful and robust tool in the identification and study of diseases of the central nervous system (CNS). In many cases, it has surpassed the capabilities of computed tomography (CT), offering physiological sensitivity as well as high spatial resolution and the absence of ionizing radiation. Furthermore, in studies of cerebral neoplasms, ischemic events, inflammations and demyelinating diseases, it offers quantitative assessments of tissue characterization, yielding insights towards both diagnosis and prognosis, as well as potential measures of efficacy of therapeutic interventions. Much of this capability is achieved by exploiting the control over tissue contrast that arises from appropriate pulse sequence choice. Some of the capabilities are additionally ‘enhanced’ by the use of FDA-approved magnetic resonance contrast media, which are typically administered intravenously and used to delineate pathological structures (commonly associated with breakdown of the blood brain barrier, BBB). Thus both native and contrast-enhanced MRI are important and powerful techniques. However, there remain a large number of neurologic disorders and diseases, the diagnosis of which is unclear based on current neuroimaging alone. In the absence of visible structural anomalies, what is the role of neuroimaging, and MRI in particular? Can developments in MR technology and, specifically, in novel contrast agents, broaden the repertoire of MRI to provide improved clinical utility in the diagnosis, prognosis and therapy monitoring of diseases that are not satisfactorily examined with the present imaging technologies, for example, Alzheimer’s disease, Parkinson’s disease, epilepsy or migraine headache?

At the time of writing1, three gadolinium (Gd)-based contrast agents are approved for clinical use in the USA2. These are low molecular weight (≈500 Da) Gd chelates: gadopentetate dimeglumine (Magnevist, Berlex Laboratories), gadoteridol (ProHance, Bracco s.p.a.) and gadodiamide (Omniscan, Nycomed–Amersham). All three agents share similar practical and enhancement properties, being administered at similar doses (≈0.1 mmol Gd/kg BW) and having similarly low rates of adverse reaction. Physical size and relaxivity (relaxation rate enhancement per unit concentration) are similar, while gadoteridol differs from gadopentetate and gadodiamide in that it is non-ionic. All three agents are considered primarily in terms of their ‘positive enhancement’ effect, i.e. as T1-shortening agents. Interestingly, certain applications exploit the potential of these agents as ‘negative enhancing’ or magnetic susceptibility agents, which shorten transverse relaxation time constants, T2 and, particularly, T2*. The focus of this article is to assess the opportunities for MR, enhanced with exogenous contrast media in general, to review the techniques and approaches in clinical use and under development using these FDA-approved contrast media and to speculate on the capabilities not yet realizable, and thus opportunities for novel contrast media development.

The following discussions relate to the use of MR contrast agents in neuroimaging, and specifically, intracerebrally. The brain provides a unique environment for contrast agent use; namely, by virtue of the blood brain barrier, small solutes (e.g. the Gd-based contrast agents) are retained intravascularly. This is in stark contrast to the remainder of the body where such small agents are known as ‘extracellular fluid (ECF)’ markers, and rapidly equilibrate between intravascular and extravascular spaces, with first pass extraction fractions up to 50%. Thus, the physiological environment of the brain compared to the rest of the body gives these contrast agents markedly different behavior and offers considerably different applications, analysis opportunities and physiological inferences. Conversely, many of the exciting developments in novel contrast agent research are focused on delivering macromolecular contrast agents which would have similar intravascular retention throughout the body, offering those applications previously available only in brain to other organs as well. The immediate advantages of such agents for brain imaging is, however, not so apparent.

Section snippets

Intrinsic contrast control of MRI

Magnetic resonance imaging offers a variety of sensitivities to physiological parameters of tissue, allowing tissues and pathologies to be delineated on the basis of differences in the local physico–chemical microenvironment. By appropriate choice of pulse sequence and parameters, it is possible to make image contrast dependent, for example, on intrinsic tissue spin relaxation times (T1 and T2), on local blood flow and perfusion, on water diffusion and on chemical and micro-structural

Static contrast enhanced (CE)-MRI

The role of contrast-enhanced MRI in detecting breakdown of the blood brain barrier has been widely recognized. Static contrast enhancement is a sensitive indicator of BBB disruption. However, the mere presence of BBB disruption is not disease-specific, and may not offer quantitative characterization of tissue status, or indication of prognosis. BBB disruption is known to be associated with malignant tumors, inflammation, demyelinating disease and ischemia, for example. Furthermore the contrast

Novel contrast agents

Currently available contrast agents can be used in a variety of ways to improve sensitivity for the detection and delineation of pathological tissues. Increasing the administered dose (gadoteridol is approved for administration up to 0.3 mmol Gd/kg BW; other agents may be used at higher than recommended doses at physician’s discretion) tends to increase contrast enhancement. Combination with magnetization transfer prepulses may yield improved lesion conspicuity by virtue of synergistic lesion

Conclusion

In summary, the opportunities for advanced, quantitative, physiologically-relevant MR imaging of the brain with currently available contrast media are abundant. Techniques such as perfusion-sensitive imaging are rapidly becoming clinically routine in cases of cerebral ischemia. Application of rCBV mapping to other diseases and disorders is accelerating. Furthermore, our technical and analytic techniques are improving: assessments of microvascular permeability derived from dynamic post-contrast

Acknowledgements

The authors would like to thank Professor Robert C. Brasch and members of the UCSF Contrast Media Laboratory as well as Professor William P. Dillon and members of the UCSF Neuroradiology Section for useful discussions, relating to this work. Paul Ferrari is also thanked for his help in manuscript preparation.

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