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