PET and MRI: The Odd Couple or a Match Made in Heaven?

Abstract

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are imaging modalities routinely used for clinical and research applications. Integrated scanners capable of acquiring PET and MRI data in the same imaging session, sequentially or simultaneously, have recently become available for human use. In this manuscript, we describe some of the technical advances that allowed the development of human PET/MR scanners, briefly discuss methodological challenges and opportunities provided by this novel technology and present potential oncologic, cardiac, and neuro-psychiatric applications. These examples range from studies that might immediately benefit from PET/MR to more advanced applications where future development might have an even broader impact.

PET is a quantitative technique that provides exceptionally sensitive assays of a wide range of biological processes, allowing the detection of very low concentrations of molecules of interest labeled with positron emitters. However it suffers from lesser spatial resolution, in many cases limited anatomical information, and it involves ionizing radiation. MR provides high-resolution anatomical information with excellent soft tissue contrast, and the ability to measure a variety of physiological, metabolic and biochemical parameters. On the other hand, the molar sensitivity of MR for different metabolites and probes is many orders of magnitude lower than that of PET, imposing significant restrictions on the kinds of targets that can be visualized. Furthermore absolute quantification of substrate concentration with MR remains challenging. Given the complementary nature of each modality’s strengths and weaknesses, integrating PET and MRI offers the opportunity to gain in a single examination many of the positive attributes of both, and mitigate some of their limitations. The wealth of information provided by MR enables PET/MR to go far beyond simple anatomical registration of PET molecular imaging, while the simultaneous acquisition of PET and MR data opens up opportunities impossible to realize using sequentially acquired data.

This manuscript paraphrases the Wagner Lecture delivered by B.R. at the 2011 Society of Nuclear Medicine Annual Meeting and summarizes the technical aspects of the novel technology PET/MRI in addition to emphasizing the areas where PET/MRI may make a significant impact. Although these areas include oncologic, neurologic, cardiac and psychiatric applications, PET/MRI has the potential to impact dramatically the burgeoning field of molecular imaging.

WHY NOW – TECHNICAL ASPECTS

While PET/CT scanners have quickly become well established clinical tools (1), development of combined PET and MRI has been much slower because of numerous technical challenges on both sides.

The major obstacle to PET in or near an MRI is the presence of the magnetic field, which cause gain changes and spatial distortion in photomultiplier tubes (PMTs), the scintillation light detector of choice for PET scanners. The fundamental technical advance that has made simultaneous PET/MR possible for clinical use was the emergence of a new type of solid-state photon detector (i.e. avalanche photodiode (APD)), which maintains PMT’s light sensitivity while insensitive to magnetic fields (2). More recently, another type of magnetic-field insensitive silicon-based photon-detector – called silicon-photomultiplier (SiPMT) – has been proposed for developing an integrated PET/MR system (3, 4). Based on APD technology but operated in Geiger mode (allowing high timing resolution) these devices holds great promise for becoming the photon detector of choice in the PET/MR field.

PET in turn can be problematic for MRI: image artifacts or decreased signal-to-noise can be caused by electromagnetic interference, eddy currents can be induced in the PET shielding materials, B₀ field homogeneity can be disrupted by susceptibility effects due to PET components, etc. Though all issues are important, perhaps the most significant challenge until recently has been the limited space available inside the bore of standard MR systems. Gradient systems in particular pay a steep price/performance penalty from increased size, as power requirements go steeply with radius, and manufacturing tolerances for gradient shielding become much more demanding. For many years, the widest bore MRI systems were no larger than 60 cm in diameter, providing no additional space for integrating key PET components. However, recently new gradient designs have been designed that allow peak performance with larger 70 cm bore diameters, providing (just) enough space for the PET camera, as described below.

Beyond these two technical advances (i.e. development magnetic field insensitive PET photon detectors and larger bore magnets), another major factor setting the stage for clinical PET/MR was the success of PET/CT, which has proven the value and clinical relevance of combining anatomical and molecular information during a single scanning session.

Integrated Scanners for Human Use

For the first decade after simultaneous PET and MR data acquisition was first demonstrated in vivo in small animals (5), most of the progress in the field was made in the preclinical arena.

Fortunately, the major medical equipment manufacturers have realized the potential of this emerging field and the first integrated scanner for human brain imaging was installed in 2007. This prototype PET insert into an MR scanner, called BrainPET (Siemens Healthcare, Inc.) (Fig. 1A), was integrated with a standard 3-Tesla MR scanner (Magnetom TIM Trio, Siemens Healthcare, Inc.) and proof-of-principle simultaneous data acquisition was demonstrated (6–8). When not in use, the BrainPET can be docked at the back of the magnet, without obstructing the bore so that the MR scanner can be used in stand-alone mode.

Fig. 1.

Integrated PET/MR scanners currently available for human use: (A) Siemens MR-BrainPET prototype, (B) Philips sequential PET/MR whole-body scanner and (C) Siemens Biograph mMR whole-body scanner.

Quickly on the heals of this development, Philips developed a whole-body sequential PET/MRI scanner (Philips Ingenuity TF PET/MRI) (Fig. 1B), addressing the challenges of MRI’s magnetic field and space limitations by placing the PET adjacent to an MR scanner (the two scanners are eight feet apart) to acquire data sequentially using a common patient table, similarly to PET/CT scanners (9). One advantage of this approach is that the state-of-the-art time-of-flight (TF) PET (Philips Gemini TF PET) modified so that the PET detectors work in the vicinity of the MR scanner and the MRI (Philips Achieva 3T X-series) systems are used. However, simultaneous data acquisition is not possible using this approach. This scanner received the CE Mark in Europe and FDA 510(k) clearance in US.

General Electric has also begun to explore the sequential approach and designed a new patient table designed to shuttle patients between the two scanners – the table is both MR and PET compatible. In this approach they use their own state of the art TF PET/CT scanner (Discovery PET/CT 690, GE Healthcare) and a 3-Tesla MR scanner (Discovery MR750, GE Healthcare), located in adjacent rooms.

Very recently, Siemens introduced a fully integrated whole-body MR-PET scanner, the Biograph mMR (Fig. 1C). Similar to the BrainPET prototype, the Biograph mMR uses APD-technology, but now the PET detectors have been placed in the space between the gradient coils and the RF body coil, utilizing the additional bore space of a more advanced gradient design. In this way, the two scanners have been fully integrated and the resulting 60 cm diameter bore size allows for whole-body simultaneous MR-PET imaging (10). This scanner also received the CE Mark in Europe and 510(k) clearance from the FDA in US.

From here on, we will use “PET/MR” to refer to both sequential and simultaneous PET/MR, especially when describing common challenges or applications that would benefit from both approaches. The word “simultaneous” will be used when the distinct advantages offered by the temporal correlation of the measured signals are highlighted.

Technical Challenges and Opportunities

PET/MRI provides distinct challenges, and opportunities, when compared to PET/CT. One, attenuation correction, immediately presents itself as a problem for any system without an ionizing radiation source or CT scanner. A second, the capability for dynamic motion correction, presents as a unique opportunity in simultaneous PET/MR systems. Indeed, sometimes tackling one set of challenges leads to other opportunities – solving the problem of attenuation and motion correction would potentially allow for improved attenuation correction in simultaneous PET/MR relative to PET/CT since misregistration of attenuation maps with the PET emission data can be fully mitigated. There are of course other relevant technical and practical issues (e.g. setting up a PET/MR facility (11), designing combined data acquisition protocols (12), etc.) that will not be discussed in this review.

MR-based Attenuation Correction

Due to technical difficulties in placing/operating a rotating transmission source inside the MR scanner bore/room and the limited space available, the MR data have to be used for deriving the attenuation maps in the integrated scanners developed to date. Several factors have to be considered in order to implement an accurate MR-based method to account for the photon attenuation caused by the subject and the hardware located in the PET field of view (FOV) (e.g. RF coils).

While the MR soft tissue contrast offers many ways to infer tissue type, one particularly challenging task consists of differentiating bone tissue from air-filled spaces – they both appear as signal voids on the MR images obtained using conventional pulse sequences. This of course is the worst possible outcome, as bone is especially relevant as a photon-attenuating medium, being the tissue with the highest linear attenuation coefficient. Atlas-based methods have been implemented for deriving the attenuation map from the MR data (13–15), and these have proven quite useful, although they can potentially lead to errors in patients with modified anatomy. One interesting alternative is the use of so-called “Ultra-short Echo Time” (UTE) sequences, previously developed for imaging cortical bone and other connective tissues (16, 17). These sequences are used to image solid phase tissues with very short T2 relaxation times such as bone (T2’s in bone typically range from 0.05–2 ms, compared to most other soft tissues whose relaxation times are between 50–100 ms). Methods for generating the head attenuation maps from UTE data have been implemented recently (7, 18, 19). Extending these methods to the whole-body remains challenging, but is an area of active research. As initial solutions, the major manufactures have proposed methods in which linear attenuation coefficients corresponding to soft tissue were assigned to bone voxels (20, 21). Good quality images were obtained using these methods though the quantitative properties of these data still need to be evaluated.

MR-assisted Motion Correction. PET studies are usually long and subject motion is difficult to avoid, leading to degradation (blurring) of PET images and to severe artifacts when motion has large amplitude, offsetting the benefit of using high-resolution scanners. While other methods for minimizing or tracking the subject’s motion have been proposed with variable success, in a simultaneous PET/MRI scanner, high temporal resolution motion estimates can be derived from the MR data and used for rigid- (22) and non-ridig (23–25) body PET motion correction.

Although many challenges still remain, MR-assisted PET motion correction could dramatically reduce the spatial blurring and artifacts associated with PET movement of solid organs. If techniques to track the motion in the background of the sequences used for acquiring standard MR data are successfully developed, this unique opportunity enabled by simultaneous PET/MR could completely revolutionize the way PET is performed for certain applications (e.g. neurological, lung, liver, cardiac imaging).

WHY NOW – POTENTIAL APPLICATIONS

Although PET/CT and stand-alone MR are independently useful imaging modalities, there are numerous unmet medical needs that may benefit from this new hybrid technology. In the sections below we highlight some of these, starting with clinical situations where the benefits of PET/MR systems are most apparent, and moving to applications where future development might have even broader impact.

Low Hanging Fruit – Studies where PET/MR May Have Immediate Impact

Patients where Radiation Exposure is a Concern

FDG-PET/CT has improved the diagnostic accuracy in the majority of pediatric malignancies (26–28). Furthermore, studies have suggested that FDG uptake is a compelling and early surrogate marker of treatment efficacy in various pediatric malignancies (29, 30). Yet, to date, these studies are limited, and prospective trials although needed, may be driven by the increasing consideration of radiation risk to the pediatric population (28, 31, 32). This is because whenever a PET scan is needed in these patients, a CT scan is also required for attenuation correction or for anatomical correlation. However, the radiation dose being delivered to the patient is of special concern in this population for at least two reasons. First, the effective dose from CT is several times higher in newborns and children than in adults for the same acquisition settings (33). Second, pediatric patients have a higher lifetime risk of developing cancer relative to adults (34). MR in PET/MR devices could replace CT for attenuation correction in these patients, reducing the radiation dose by at least 50% compared to a PET/CT study. Furthermore, collecting the data simultaneously limits anesthetic times for the pediatric populations who benefit from both examinations.

Similarly, radiation exposure is of concern in patient populations in need for multiple PET/CT scans such as lymphoma patients that require repeated PET/CT scans at the time of diagnosis, interim restaging during therapy and end of treatment staging. However, this comes with significant exposure to ionizing radiation, on the order of 23–26 mSv, with the PET component contributing just 5–7 mSv of this dose. Thus, there is interest in an alternative imaging modality, such as MRI, that provides accurate anatomic localization and functional imaging without the associated excess radiation exposure of CT scanning.

Areas of the Body where CT Anatomy is Suboptimal

In the head and neck area, MRI is superior to CT in terms of accurate staging of tumor extent, involvement of vital soft tissue structures, and nodal involvement (35, 36). Because of the added soft tissue discrimination capability of MRI, PET/MRI will likely improve the assessment of tumor extent, involvement of bony structures and bone marrow. Post-treatment surveillance presents many challenges because tissue distortion, scarring and fibrosis from radiation and surgery can obscure early detection of recurrence by conventional follow up. At our institution ~20% of patients with malignancies of the head and neck require both FDG PET/CT and MRI in order to marry the soft tissue discrimination of MRI with the metabolic specificity of FDG PET.

MRI is the method of choice for evaluating pelvic malignancies (i.e. gynecological, rectal (Fig. 2), prostate cancers), because of its improved soft tissue discrimination compared to CT. For example, in cervical (Fig. 3) and edometrial cancers, MRI plays a principal role in staging in terms of parametrial invasion (T-staging). However, loco-regional control (discrimination of lymph node metastases) is not fully achieved in the majority of cases. While ovarian cancers are rare, benign adnexal masses (functional cysts, endometriosis, infectious processes, non-malignant growths) are common, thus it is challenging to identify those lesions that will benefit from surgical resection while sparing patients from the morbidity of an unnecessary surgery. MRI has demonstrated improved potential based on morphology alone and T1 and T2 signal intensity characteristics. In all these cases, combining the MR data with PET will likely improve clinical staging accuracy.

Fig. 2.

Simultaneous PET/MR exam in a colorectal cancer patient. T1-weighted post-contrast MR image demonstrates an enhancing mass within the rectum (white arrow). The PET image shows FDG-avidity of the mass without anatomic correlate. The DWI image at the same level demonstrates a hyperintense lesion. Low signal intensity compatible with restricted diffusion is observed in the ADC map. Data acquired on the Biograph mMR scanner, A.A. Martinos Center, MGH.

Fig. 3.

Sequential PET/MR for staging in a patient with an epidermoidal carcinoma of the cervix after conization and sigmoidectomy. (A) Whole-body PET shows hypermetabolic uptake in lower pelvis. (B–D) MR shows thickening of the colon wall with involvement of the outer fatty tissue corresponding to a hypermetabolic tracer uptake. Follow-up biopsy revealed granulomatosis without residual tumor. Data acquired on the Philips Ingenuity PET/MR scanner, University Hospital of Geneva. Images courtesy of Osman Ratib.

MRI is also preferred for staging prostate cancer because of its accuracy at diagnosing extracapsular extent and neural invasion and its ability to incorporate multiple specific biomarkers that have shown promise in diagnosing prostate cancer (e.g. dynamic contrast enhanced (DCE) MRI, diffusion weighted imaging (DWI), and magnetic resonance spectroscopy (MRS)). Yet, its sensitivity is only approximately 80% for the primary malignancy, and often becomes much lower when considering bony metastases outside of the pelvis as well as lymph node metastases. A recent study showed that the combination of MRI with ¹¹C-acetate PET/CT was superior to the individual methods alone for detecting localized prostate cancer (37). Furthermore, a different study suggested that combining ¹¹C-choline and apparent diffusion coefficient (ADC) measurements improved the tissue-to-background contrast of Gleason ≥3+4 disease (38). Thus morphological and potentially multiparametric MRI may be the modality of choice for providing anatomical and physiological correlation to the PET findings, improving the accuracy of the assesment of the primary tumor (Fig. 4) and distant metastases (39).

Fig. 4.

Multiparametric imaging using [¹¹C]choline PET and DCE-MRI increases diagnostic confidence/accuracy in a patient with prostate-specific antigen recurrence after radical prostatectomy. Only faint anatomical correlate is observed in the contrast-enhanced CT. Similarly, the T2-weighted MR image shows superb anatomical detail but also only small tumor correlate. However, very clear enhancement is observed in the early arterial phase of the DCE-MRI and the parametric map, correlating with the PET signal. The cumulative evidence suggesting local recurrence as opposed to scar tissue/unspecific enhancement increases the diagnostic certainty. Data acquired on the Biograph mMR scanner, TUM/LMU, Munich, Germany. Images courtesy of Ambros Beer.

Areas where MRI Offers Improved Tissue Specificity

In breast cancer, MRI has proven very useful for local staging and treatment monitoring and it has greater sensitivity even than conventional imaging methods (i.e. X-ray mammography, sonography). On the other hand, its specificity is variable and could be improved when combined with spatially fused FDG-PET images (40). Several factors, however, limit the efficacy of spatially registering images acquired from standalone MRI and PET systems and near-perfect spatial co-registration requires simultaneous acquisition. Furthermore, axillary lymph node status, which is the most powerful prognostic indicator in breast cancer patients, can be better assessed using PET/MR using FDG or other radiolabelled targeted agents and MRI lymph node specific agents.

The liver is a common site for distant metastases from many subtypes of cancers. MRI has been shown to be useful and superior in its ability to discriminate small lesions (e.g. <10 mm) (41). FDG-PET remains problematic due to the heterogeneous uptake in the normal liver, its low sensitivity to lesions smaller than 10 mm, and the concomitant decrease in sensitivity in patients with underlying liver disease including cirrhosis and non-alcoholic fatty liver disease (42). PET/MRI will likely play a large role in determining the true sensitivity of FDG-PET as compared to other liver specific reticuloendothelial, or hepatocyte specific agents for determining true extent of disease.

Bone marrow involvement is one of the most important prognostic factors in patients with lymphoma. In a meta-analysis conducted by Wu et al., PET/CT was demonstrated to be superior to MRI or PET alone in the staging of lymphoma (43). However, this study came under scrutiny and it was suggested that prospective studies for comparing the distinct (and complementary) value of each imaging modality in specific settings are required (44). Multiple myeloma (Fig. 5) is the most frequent primary neoplasm of the skeletal system. Whole-body MRI has been proposed for detecting infiltrative focal bone marrow lesions and demonstrated to have higher sensitivity than skeletal survey for this task. As compared to PET/CT, the radiation exposure would be minimized in the case of PET/MRI. Furthermore, as novel agents having demonstrated sensitivity in multiple myeloma or novel therapies are developed (e.g. Bortezomib), PET/MRI may be the perfect tool to test these strategies.

Fig. 5.

Simultaneous PET/MR in a myeloma patient. (A) Plain film of the left knee demonstrating lytic lesions in the medial femoral condyle and proximal tibia (black arrows). (B) Coronal FDG-PET, (C) fat-saturated T2-weighted MR and (D) fused images at the same level demonstrating concordant foci in the right tibia, right femoral condyle, and left medial femoral condyle. Data acquired on the Biograph mMR scanner, A.A. Martinos Center, MGH.

Advanced Physiological Applications – The Next Generation of PET/MR Studies

Treatment Monitoring in Oncology

A growing understanding of the underlying molecular biology of cancer has led to the development of novel therapies targeting various molecular pathways active in cancer. Unlike the conventional cytotoxic chemotherapeutic agents, many of the molecularly targeted agents are cytostatic, causing inhibition of tumor growth rather than tumor regression. In this context, conventional endpoints such as tumor volume reduction may be delayed as compared to other metabolic or physiologic parameters. Combined PET/MR studies may provide important biomarkers to predict and monitor targeted treatment response and to document pharmacodynamic response.

The emerging importance of angiogenesis as a cancer therapy target makes assays of vascularity important to clinical research and future clinical practice related to targeted cancer therapy. DCE-MRI allows the assessment of tumor vascularity and detects changes associated with angiogenesis targeted therapy (45–47). For example, in glioblastoma patients treated with vascular endothelial growth factor inhibitors, evidence of tumor vascular normalization was demonstrated using DCE-MRI (48). However, using only DCE-MRI, the true anti-tumor effects of these agents cannot be completely understood and combining PET parameters (e.g. estimates of tumor glucose metabolism, cellular proliferation, aminoacid transport, etc.) and MRI methods may provide a better approach to this investigation. Furthermore, alternative probing of the microvascular system with magnetic nanoparticles (MNP) has shown promise at interrogating anti-vascular effects in preclinical models (49).

Combined PET/MR measurements could help quantify precisely how tumor vascular properties (assessed by functional MR methods), proliferation and anti-tumor effects (assessed with PET) occur and interact. First, a richer data set is obtained using both imaging modalities (Fig. 6). Second, the quantification of PET could be improved using the simultaneously acquired MR information (e.g. MR-assisted PET motion and partial volume effects correction, MR-based radiotracer arterial input function estimation). Third, the meaning of PET findings could be better understood using MR information. All these tools would enable a more precise understanding of tumor biology and therapeutic response, both for trials of new treatment protocols and perhaps even on an individual basis. The wide range of responses among patients suggests that further studies of individual responses to therapy, correlating structural and functional imaging, metabolic imaging and clinical findings (e.g., survival) will be helpful in understanding the mechanism of action of novel therapeutic agents.

Fig. 6.

Multi-parametric PET/MR imaging in glioblastoma: FDG-PET and morphological MR image after administration of MR contrast agent (middle column). Parameters derived from the MR data (K^trans, cerebral blood volume (CBV) and ADC) and the PET data (metabolic rate of glucose (CMRglu), K1, k3) in the region of interest (red contour) defined on the enhancing part of the tumor are shown in the left and right column, respectively. Data acquired on the MR-BrainPET prototype, A.A. Martinos Center, MGH. Images courtesy of Dan Chonde and Dominique Jennings.

Cardiac Applications

In the clinical assessment of patients with cardiovascular disease, PET allows the quantification of blood flow and it is considered the gold standard method for assessing myocardial tissue viability. MR can inform about ventricle function, structural changes, and using contrast agents, perfusion and tissue viability. It was suggested that the combination of these methods in a simultaneous PET/MR scanner (Fig. 7) allows a more detailed risk assessment to be performed (50). Furthermore, the non-rigid body MR-assisted motion correction methods described above have the potential to significantly improve PET data quantification and reproducibility.

Fig. 7.

Simultaneous cardiac PET/MR study: (A) EKG-gated PET and (B) delayed contrast enhanced cardiac MR images. PET data acquired in list mode and binned. (C) The MR images acquired in diastole are fused with diastolic PET data. Patient has a normal heart. Data acquired on the Biograph mMR scanner, Washington University in St. Loius. Images courtesy of Pamela Woodard and Richard Laforest.

Both PET and MRI are also used for molecular imaging cardiovascular applications. In the context of stem cell therapy monitoring, direct labeling either with FDG or gadolinium and MNP and reporter gene approaches allow the non-invasive imaging of stem cells and some of these methods have already been used in clinical trials (51). PET/MR could improve the short-term assessment of stem cell delivery and the long-term treatment efficacy.

A number of groups have recently started to develop dual-labeled PET-MR probes. For example, MNP coupled to chelated ⁶⁴Cu have been proposed for targeting vascular inflammation (52) and tumor integrin α_vβ₃ expression (53). In our center we have focused on atherosclerotic plaque imaging as a potential first application for bi-modal probes (54).

Future Applications – Potential Domains Where PET/MR May Change How We Practice

Neuropsychiatric Diseases

The burden from neuropsychiatric disorders (expressed as disability-adjusted life years lost) is higher than the burden from any other disease category in the developed world (55), yet despite the amazing advances in brain imaging over the last 30 years, imaging has had little to no impact on todays clinical practice (56). Nevertheless, both PET and MR imaging have had a profound impact on our understanding of neuropsychiatric diseases, from an improved understanding of neurotransmitter imbalances in schizophrenia to an evolving understanding of brain network perturbations in diseases such as depression and autism (57). Indeed, a comprehensive understanding of psychiatric diseases must encompass the integration of neurochemical, genetic, behavioral and circuit based models. Today the dominant tools for these investigations, at the brain level, are PET and MRI, thus their marriage becomes a natural one for the study of mental illnesses. While simultaneous PET/MR systems are thus likely to be profoundly useful for translational investigations, might this tool find its way into clinical practice?

Perhaps the first will be in the study of patients with suspected Alzheimer’s disease (AD). The evolving understanding of AD as a disease encompassing a potentially long prodromal state (58) preceding definitive clinical manifestations, and the forthcoming arrival of disease modifying treatments will likely require both earlier, and more definitive, diagnosis. In this regard PET and MRI provide complementary information (Fig. 8) in the assessment of AD patients (59–61), with PET’s ability to characterize amyloid (and soon tau) buildup regionally, and MR’s ability to see the associated neuronal degeneration and changes in circuit behavior (62). Imaging strategies in the future thus will likely extend beyond todays “rule out” with MRI alone (to exclude other organic causes of dementia like tumor or hydrocephalus) to comprehensive “rule in” studies, assessing amyloid and/or tau burden (through improved PET quantification facilitated by MR-assisted PET motion and partial volume effects correction) and their sequellae in terms of direct observation of ongoing neuronal degeneration and cortical dysfunction. Given the likely expense, and potential morbidity, associated with therapy altering treatments, the combined use of PET/MR may provide a cost effective way to assess who should, and should not, enter into such therapeutic regimens.

Fig. 8.

Simultaneous PET/MR study in an AD patient. Left column: axial FDG-PET, morphological MR and fused images. Upper right column: Surface projections of cerebral metabolism showing the areas with reduced metabolism as compared to controls. Lower right column: Diffusion tensor imaging showing the white matter tracts in the same patient. Data acquired on the MR-BrainPET prototype, A.A. Martinos Center, MGH.

Beyond AD the crystal ball is cloudier, but with no less potential for impact. Today, as novel treatments for disorders such as medically intractable depression are being explored (63), the need for pre-therapeutic diagnoses to match the precision of these treatments will present itself. Indeed Mayberg used both PET and MR for the pre and post-treatment evaluation of her patients, and it is likely that the combination of modalities will emerge alongside these new therapeutic approaches to provide the needed pharmacological and physiological information required to make informed treatment decisions. One tool that may emerge as a key asset in our exploration of therapeutic options for psychiatric diseases is the combination of PET and MR to study the dynamics of neurotransmission. PET investigations for the last 20 years have certainly provided the foundation for these studies, but the simultaneous collection of functional MR data should allow for important advances in these methods, both through the clearer definition of associated networks, and the concurrent collection of neurophysiologic parameters to refine (perhaps redefine) the traditional kinetic models used to analyze such PET data.

Lymph Node Imaging

Surgical assessment is the gold standard for the diagnosis of lymph node metastases. However, surgical lymphadenectomy confers an increased risk of immediate and delayed complications and noninvasive techniques that accurately identify lymph node metastases are needed.

FDG-PET/CT has played a role in evaluating lymph node metastases of multiple oncologic etiologies but has demonstrated mixed sensitivities and specificities. MRI using contrast agents administered interstitially or intravenously has been proposed as an alternative. Ultra-small superparamagnetic iron oxide (USPIO) (a.k.a. MNP) enhanced MRI is the method that has shown the most promise and has been used for N staging of patients with head and neck (64), breast (65), gastric (66) and prostate (67) cancer. Although USPIO agents are not yet approved for clinical use and further trials are needed to demonstrate their utility, recent provocative evidence has been shown with other FDA approved MRI contrast agents (68).

Several studies investigated the relationship between MR and PET measurements for the assessment of metastatic lymph nodes. For example, statistically significant inverse correlation was observed between ADC values and standardized uptake values (SUVs) in metastatic lymph nodes of head and neck squamous cell carcinoma (69). In non-small cell lung cancer, short inversion time inversion recovery turbo spin-echo MRI proved more accurate than DWI-MRI and FDG-PET/CT (70). PET/CT is thought to have a higher sensitivity and specificity to detect retroperitoneal lymph node metastasis compared to current cross-sectional imaging modalities. Although these preliminary results suggest a complementary role for PET and MRI in the evaluation of lymph nodes, these studies would likely benefit from the perfect spatial co-registration and improved PET data quantification (e.g. partial volume effects correction) in a simultaneous PET/MR scanner.

Beyond FDG in Oncology

FDG is currently used with PET for primary staging, assessing treatment response, and follow-up in more than 90% of cancers (71). However, not all tumors show significant increase of metabolic activity on FDG-PET imaging secondary to various factors (e.g. variable expression of hexokinase and glucose transporters in hepatocellular carcinoma (72)) and other tracers have entered clinical trials (73). In the context of drug development, PET allows the characterization of pharmacokinetics and pharmacodynamics of novel agents that can be radiolabeled with positron emitters.

A PET/MR scanner may provide an ideal tool for testing and validating these agents. First, the reduced radiation exposure when compared to CT will facilitate the translation to human studies. Second, MRI provides the anatomical details needed for assessing the whole-body distribution of these tracers. Third, the potential for improved data quantification will allow researchers to go beyond semiquantitative methods (e.g. the SUV). Finally, advanced MR techniques will provide physiological information complementary to the PET data, including basic physiological and biophysical measurements, mapping of endogenous metabolites with MRS, etc.

In-vivo Quantification of “Smart” MR Probes

MR contrast agents induce relaxation of tissue water, and the extent of this relaxation enhancement, termed relaxivity, depends on a number of factors which influence the accessibility of water to the MR active agent (paramagnetic ion or superparamagnetic nanoparticle), as well as the overall concentration of the contrast agent. In a seminal paper, Louie and colleagues demonstrated that the relaxivity of a specifically designed contrast agent could be changed in the presence of the enzyme β-galactosidase (74). Numerous publications have followed that described “smart” agents responsive to other enzymes, pH, pO₂ and temperature, amongst other factors. However, a key limitation of these approaches is that the MR signal depends on both the relaxivity of the contrast agent and the local probe concentration – typically the product of these two factors. In vivo, the probe concentration is in general unknown, will change with time, and may vary in diseased versus normal tissue. Using a bimodal PET-MR probe, it has proven to be possible to use PET for estimating the overall concentration and the MR data to determine the molar relaxivity of the agent, allowing for determination of its specific biochemical or physiological “target” (75).

CONCLUSION

Despite the technical demands underlying the “matchmaking” between PET and MR, the differences between these two partners is the greatest source of strength in their potential marriage. Odd though the underlying technologies may be to each other, finding ways to bring these two pillars of medical imaging together can confer a high degree of synergy. And like any good marriage, the more intimate the connection between them, the stronger the resulting partnership. Many factors will decide the ultimate role of PET/MR systems within our overall health care system, not the least of which is the cost of such systems, and the degree to which the benefits accrued match the resources required to perform and interpret these studies in the clinic. Training the next generation of interpreters in the art and science of both PET and MR is another challenge, which will have to be met if this tool is to have widespread impact outside a small group of academic sites. Nevertheless, if the future of clinical practice is precision medicine, where therapeutic decision are designed around specific molecular pathological events at the earliest possible stage, then PET/MR systems may be the first of the next generation of molecular imaging tools for that future.