Imaging of the joint has benefited greatly from new technologies to image morphology and function in many tissues[1, 2]. Conventional radiography has long been used to detect structural changes, including fractures, osseous erosions and joint space narrowing but is only sensitive to established morphologic changes at later disease stages[3]. MRI has become the benchmark for musculoskeletal imaging due to its ability to non-invasively evaluate soft tissue, articular and osseous structures. Additionally, advanced quantitative MRI techniques can provide unique cellular and microstructural information in several musculoskeletal soft tissues[4-7]. While MRI is unmatched in its ability to evaluate soft tissue and bone marrow pathology, it has some limitation for molecular imaging, particularly in osseous structures. Positron Emission Tomography (PET) offers incomparable ability to provide quantitative information about molecular and metabolic activity that often precedes structural and even biochemical changes[8]. In this session, several emerging PET applications for evaluation of numerous degenerative joint processes and features will be discussed. Additionally, the potential of combining this complementary PET information with established quantitative MRI methods with simultaneous PET-MRI will be presented.
Imaging of Bone Metabolism
18F-NaF was first recognized as a bone-seeking agent in 1962[9] and has been approved for PET imaging by the food and drug administration (FDA) since 1972. Uptake of 18F-NaF is a function of osseous blood flow and reflects bone remodeling and has been shown to correlate with bone histomorphometry[10].
PET imaging with 18F-NaF provides a method to assess subchondral bone activity in the joint. Increased bone remodeling has been implicated as a mechanism of OA progression that affects not only bone but also adjacent tissues[11, 12]. Initial results have shown significantly different levels of 18F-NaF uptake in various bone tissue types as well as in subchondral bone pathology (bone marrow lesions, osteophytes, sclerosis) identified on MRI. Furthermore, high 18F-NaF uptake in subchondral bone did not always correspond to structural damage detected on MRI. Additionally, in patients with unilateral anterior cruciate ligament (ACL) tears, who have a known increased risk for developing accelerated OA, significantly increased 18F-NaF PET uptake has been observed in the subchondral bone of ACL-injured knee joints, compared with their uninjured contralateral knees[13]. As molecular changes often precede changes at the tissue level, these findings suggest increased bone activity detected with 18F-NaF PET may serve as a marker for early disease in this population.
18F-NaF PET bone information can be combined with MRI data for comprehensive whole-joint imaging. Increases in cartilage T1ρ relaxation times, which are associated with a loss of cartilage GAG content, have been correlated with increased 18F-NaF uptake in the adjoining bone as well as reduced uptake in the nonadjoining compartments[14]. In a separate study of patients with unilateral ACL tears, a correlation was observed between increased 18F-NaF uptake measures of bone remodeling and increased T2 values in adjacent cartilage, which is indicative of early collagen matrix breakdown[13]. This correlation was particularly pronounced in the deep layers of cartilage adjacent to the subchondral bone. This supports an interdependent relationship between bone and cartilage with early degenerative changes in one tissue having an effect on the neighboring tissue.
Imaging of Inflammation and Immune response
18F-FDG, an analog of glucose, is the most widely used PET radiotracer in clinical practice and can provide information about inflammatory processes occurring in the musculoskeletal system[15, 16]. FDG has been applied to study synovitis and the inflammatory component of bone marrow lesions (BMLs) in OA and RA. A diffuse increase in FDG uptake was seen in OA patients compared to healthy age-matched controls, which the authors attributed to the presence of synovitis in OA[17, 18]. FDG PET is also able to quantitatively image elevated glucose utilization in cells mounting an immune response. FDG uptake has been correlated with disease activity and C-reactive protein levels in Rheumatoid Arthritis (RA) patients[19]. Further, it has been used to evaluate the extent of whole body involvement in RA[20], clinical outcomes, and treatment efficacy in early RA patients undergoing DMARD therapy[21]. In addition to FDG PET, additional PET tracers may offer new molecular targets with greater sensitivity to inflammation. For example, 11C-choline can target cellular proliferation[22] while 11C-(R)-PK11195 targets proteins on activated macrophages and may offer more specific molecular marker of inflammation[23].
Imaging of Pain Generators
FDG PET has shown promising results in diagnosis for neuropathic pain. The main assumption of this approach is that the neuroinflammatory process in the painful nerve lesion may result in hypermetabolic activity, presenting as focally high FDG uptake in the PET image. Co-registration of the PET image with high-resolution MRI facilitates identification and localization of increased FDG uptake within nerve tissues. An animal study validated this assumption with a rat-model experiment and human studies have since shown the sensitivity of FDG to neuroinflammation at the site of impinged spinal nerves.
A more specific radioligand, 18F-FTC-146[24, 25], was recently introduced for PET-MRI with improved specificity to pain. 18F-FTC-146 specifically binds to sigma-1 receptors, a transmembrane protein that becomes increasingly expressed in the nervous system with many neurological diseases that cause neuropathic pain[25, 26]. 18F-FTC-146 PET-MRI of patients with complex regional pain syndrome showed that the imaging findings altered the pain management plan for 7 out of 8 patients, and change of therapy in two patients achieved a considerably improved pain-relief outcome[27].
Multimodality PET Imaging
While PET imaging is unmatched for molecular imaging, it needs the assistance of higher-resolution, anatomic information to localize these physiologic processes. It is most often combined with CT imaging, which is able to provide not only high resolution anatomic detail but also attenuation correction information for acquired PET data[28]. While PET/CT has become essential for evaluation of oncologic disease, its utility as a stand-alone modality for characterization of musculoskeletal disease (including cancers) has been limited, largely due to the unparalleled soft tissue contrast of MRI.
New integrated PET-MRI systems potentially provide a complete imaging modality for musculoskeletal imaging, combining simultaneous molecular and physiologic information from PET with the high spatial resolution and soft tissue contrast information of MRI to provide a superior level of anatomic and functional information. Other comparative advantages of PET-MRI include no additional ionizing radiation for anatomic localization and the ability of MRI to provide supplementary functional information such as DWI. Hybrid PET-MRI offer new opportunities to incorporate the molecular capabilities of nuclear imaging into studies of joint degradation.
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NIH Grant Funding: K99EB022634
ACL tears are a common knee injury and are associated with an elevated risk of developing OA. Bone plays an important role in OA development, and bone mass has been shown in animal models and human studies to decrease immediately following injury before partially recovering. ACL transection models have confirmed this bone loss is driven by trabecular structure degradation, however, this has not been confirmed in humans due to limited in vivo image resolution. The recent development of high-resolution peripheral quantitative computed tomography (HR-pQCT) provides an unprecedented opportunity to longitudinal assess bone microarchitecture in the knee, and magnetic resonance imaging (MRI) complements this technology so that both hard and soft tissues can be simultaneously tracked. This allows, for example, the monitoring of bone marrow lesions, which commonly occur in post-traumatic knee injury, and we are particularly interested in early joint changes that may lead to long-term development of knee osteoarthritis.
The objective of this study was to establish bone microarchitectural changes in the human knee within the first year following a unilateral acute ACL tear, using HR-pQCT and MRI.
METHODS: Participants with unilateral ACL tears (n=15, 22-44 years of age, 10 female and 5 male) were followed with HR-pQCT with up to four time points (baseline, +2 months, +4 months, +8months). The baseline measurement occurred within 6 weeks of injury. Both the ACL deficient and uninjured contralateral knees were imaged at 61μm isotropic voxel size (XtremeCTII, Scanco Medical). Bone microarchitecture was assessed up to 7.5 mm below the weight bearing surfaces of the medial and lateral tibia and femur. The subchondral bone plate (density, thickness), and trabecular bone (density, thickness, number, separation) were quantified. Longitudinal bone changes within each knee were assessed using quadratic temporal mixed effects models, which were compared to linear and intercept-only mixed effects models using chi-squared tests (level of significance: p<0.05). 95% confidence intervals for each model parameter were assessed using bootstrapping (200 samples with replacement). MRI captured regions of bone marrow lesions, and by multimodal image registration between HR-pQCT and MRI it was possible to establish the changes to bone microarchitecture that occur specifically in the BML region.
RESULTS: Bone loss occurred throughout the injured knee (-4.6% to -15.8%; Fig 1). Bone loss occurred in a non-linear manner, with loss occurring within the first 7 to 8 months post-injury before indicating the start of a recovery phase. The loss was driven by trabecular structure degradation as reflected by an increase in trabecular separation (6.4% to 10.6%) and decrease in number (-3.1% to -7.8%) of trabecular elements. The subchondral bone plate of the lateral femur significantly decreased in thickness (-9.0%). Regions of BMLs had accelerated microarchitectural adaptations compared to the rest of the knee. The contralateral knee was mostly unaffected.
CONCLUSION: Bone loss in the injured knee during the first year following ACL tears is driven by loss of trabecular elements. This likely cannot be reversed as for any future ‘recovery’ of bone mass there is no known mechanism to re-establish the original bone structure. Thus, permanent structural changes may persist, which indicates there may be a short window for intervention to reduce the risk of long-term OA development.
This study was funded by The Arthritis Society, SOG-15-226.