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Bone Metabolic-Morphologic relation is Mediated by Gait; Cartilage Compositional-Morphologic relation isn’t: PET/MRI in Isolated PFJOA1Department of Radiology & Biomedical Imaging, University of California, San Francisco (UCSF), San Francisco, CA, United States, 2Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco (UCSF), San Francisco, CA, United States, 33. Department of Epidemiology and Biostatistics, University of California, San Francisco (UCSF), San Francisco, CA, United States, 4Altos Labs, San Francisco, CA, United States
Synopsis
Keywords: Cartilage, PET/MR
Motivation: Whether the compositional, metabolic, and biomechanical relationships have a mediated effect on one another is the next crucial step toward decoding the isolated PFJOA mechanism.
Goal(s): To investigate whether the relationship of morphological-joint-degradation with SUV-values from 18NaF-PET and cartilage-T2 in isolated-PFJOA are mediated by gait-biomechanics.
Approach: Linear regression was performed between (i)WORMSBME(predictor) vs. Medial-SUVmax, Lateral-SUVmax (outcomes), and (ii) WORMSCartilage(predictor) vs. Mean-T2-Deep-Medial, T2-Superficial-Medial, T2-Deep-Lateral, T2-Superficial-Lateral (outcomes) patellar and trochlear. For significant correlations, mediation analyses were done to examine the role of Normalized-Mean-Peak vGRFIP as a mediator.
Results: WORMSBME vs. Medial-SUVmax, Lateral-SUVmax relationships are mediated by gait; WORMSCartilage vs. Mean-T2-Deep-Medial, T2-Superficial-Medial, T2-Deep-Lateral, T2-Superficial-Lateral aren’t mediated.
Impact: This is the first step towards understanding the flow of causalities and mediated interrelationships of bone remodeling (SUV), morphological degradation (WORMS), cartilage loss (T2), and gait biomechanics in a complex joint developing isolated PFJOA
Introduction
Patellofemoral-joint(PFJ) symptoms often are seen as precursors(1) of the gradual development of knee Osteoarthritis (OA). Adults suffering from isolated PFJOA often experience strong pain(2) which adversely affects their quality of life. Unlike tibiofemoral joint (TFJ) or mixed-OA, the risk factors and mechanisms contributing to progression trajectory could be substantially different in PFJOA(3). Previously, decreased knee flexion and extension strength were reportedly correlated with accelerated bone remodeling in the medial regions of the trochlea and patella in isolated PFJOA(4). Additionally, moderate positive bone-cartilage crosstalk was also noted(4). In this preliminary work, we investigated whether the relationship of morphological-joint-degradation with bone-remodeling biomarker(5) standardized-uptake-values (SUV) from Positron-Emission-Tomography (PET) and cartilage biomarker (6) T2 relaxation properties in isolated PFJOA are mediated by gait factor, i.e., Normalized-Mean-Peak Vertical ground reaction force (vGRF)(7) at impact peak (IP) during the fixed walk.Methods
In this IRB-approved ongoing study, twenty-five patients (age: 51.92±13.01 years; sex: fifteen females, one gender nonbinary; BMI: 24.86±4.19) with isolated PFJOA in one or both knees, with no history of traumatic knee injury or presence of tibiofemoral involvement, were included. Patients underwent simultaneous 18NaF PET-MRI scanning in a 3.0T whole-body, hybrid, GE-Signa PET-MRI scanner (GE Healthcare, Waukesha, WI) for bilateral morphological, compositional, and metabolic knee imaging(Figure-1,Table-1). An automated image analysis pipeline reported previously(4), was employed to compute Medial-SUVmax, Lateral-SUVmax of the patella and trochlea. Average T2 relaxation values for deep-medial (DM), deep-lateral (DL), superficial-medial (SM), and superficial-lateral (SL) compartments of the patellar and trochlear cartilages were computed. Whole-Organ-MRI-Scores (WORMS)(8) for patellar and trochlear compartments were marked for each patient. 3D-skin-marker trajectory data for all the subjects were acquired at 250 Hz using a camera near‐infrared system (Vicon Nexus, Oxford Metrics Ltd). GRF was simultaneously acquired at 1000 Hz from two in‐ground force plates (AMTI). The subjects performed a standing calibration trial and walked across two in‐ground force plates along a 10‐m walkway at 1.35 m/s. Participants completed a minimum of five successful walking trials for each leg. A successful trial was defined as a trial in which the entire foot strike fell entirely on one force plate. Norm-Mean-Peak vGRFIP, (N/Kg) was computed and normalized for patient weight11. Direct correlation analyses were performed using linear regression (R-Studio-Core, 2022.07.2) between (i) WORMSBME (predictor) vs. Medial-SUVmax, Lateral-SUVmax (outcomes), and (ii) WORMSCartilage (predictor) vs. Mean T2-DM, T2-SM, T2-DL, T2-SL (outcomes, ms) across both patellar and trochlear regions of bilateral limbs. For significant correlations, mediation analyses were done to examine the role of Norm-Mean-Peak vGRFIP as a mediator (Figure-2 and 3, Part-a). To determine significance, 95% confidence intervals for direct and mediated effects were derived from experimental data using bootstrap repeated 5000 times. Statistical significance was set at p<0.05.Results and Discussion
Results are summarized in Figures 2 and 3. Strong total-direct-effects(TDE) (p<0.05) were observed between WORMSBME vs. Medial-SUVmax and Lateral-SUVmax (Figure-2, Part-b, and c) indicating a higher extent of morphological-BME presence related to elevated Medial-SUVmax and Lateral-SUVmax, i.e., ongoing bone remodeling on both aspects of the bone. Both the direct effects were partially mediated by Norm-Mean-Peak vGRFIP. The presence of mediated gait effects suggests the morphological-BME vs. bone remodeling relationship to be partially mechanistic driven, by increased magnitude/pattern of mechanical loading in the vertical foot direction. Strong TDEs (p<0.05) were also observed between WORMSCartilage vs. mean T2-DM, T2-SM values (Figure-3, Part-b, and c) indicating a higher extent of morphological-cartilage-degradation related to elevated Mean T2-DM, T2-SM values. However, both the direct effects were not mediated by Norm-Mean-Peak vGRFIP. Cartilage score did not have a significant relation with Mean T2-DL, and T2-SL values directly or when mediated by Norm-Mean-Peak vGRFIP. The direct effects of morphological degradation of cartilage were hence colocalized only on the medial aspects of the patellar and trochlear cartilage in the form of elevated T2 and not on the lateral aspects. Early degeneration seen in the form of elevated T2 only on the medial aspects, has been previously reported in the literature(9). With the absence of mediated gait effects, morphological-cartilage degeneration vs. elevated medial cartilage T2 relationship is suggested to be solely systemic. However, the small sample size limits us from such conclusions.Conclusion
In this study, we report the degree of presence of morphological bone-marrow-edema is directly related to increased peak SUV values, i.e., ongoing bone remodeling, and this relationship is mediated by Normalized-Mean-Peak vGRFIP. The extent of morphological degradation of cartilage had direct effects on elevated T2 colocalized on the medial cartilage, both deep and superficial, but not lateral. The cartilage relationships were not mediated by the Normalized-Mean-Peak vGRFIP.Acknowledgements
This study was supported byR01AR079647 (NIH-NIAMS).References
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Figures
Figure 4: Example case of an adult male of 51 years of age, 1.8 meters height and 81.66 kgs of weight falling in an almost healthy BMI range. The left knee has isolated patellofemoral OA (Top row). Accelerated bone-remodelling in lateral patella is observed. Colocalized changes in T1rho and T2 values of trochlear and patellar cartilages, point to cartilage damage. The right knee, on the contrary, appears normal and no anomalies are noted. (Bottom row). No traces of ongoing bone remodelling or cartilage damage observed.