Imaging Biomarkers of Osteoarthritis.

Currently no disease-modifying osteoarthritis drug has been approved for the treatment of osteoarthritis (OA) that can reverse, hold, or slow the progression of structural damage of OA-affected joints. The reasons for failure are manifold and include the heterogeneity of structural disease of the OA joint at trial inclusion, and the sensitivity of biomarkers used to measure a potential treatment effect.This article discusses the role and potential of different imaging biomarkers in OA research. We review the current role of radiography, as well as advances in quantitative three-dimensional morphological cartilage assessment and semiquantitative whole-organ assessment of OA. Although magnetic resonance imaging has evolved as the leading imaging method in OA research, recent developments in computed tomography are also discussed briefly. Finally, we address the experience from the Foundation for the National Institutes of Health Biomarker Consortium biomarker qualification study and the future role of artificial intelligence.

Dual energy computed tomography cannot effectively differentiate between calcium pyrophosphate and basic calcium phosphate diseases in the clinical setting.

Background: Recent reports suggested that dual-energy CT (DECT) may help discriminate between different types of calcium phosphate crystals in vivo, which would have important implications for the characterization of crystal deposition occurring in osteoarthritis. Purpose: Our aim was to test the hypothesis that DECT can effectively differentiate basic calcium phosphate (BCP) from calcium pyrophosphate (CPP) deposition diseases. Methods: Discarded tissue after total knee replacement specimens in a 71 year-old patient with knee osteoarthritis and chondrocalcinosis was scanned using DECT at standard clinical parameters. Specimens were then examined on light microscopy which revealed CPP deposition in 4 specimens (medial femoral condyle, lateral tibial plateau and both menisci) without BCP deposition. Regions of interest were placed on post-processed CT images using Rho/Z maps (Syngo.via, Siemens Healthineers, VB10B) in different areas of CPP deposition, trabecular bone BCP (T-BCP) and subchondral bone plate BCP (C-BCP). Results: Dual Energy Index (DEI) of CPP was 0.12 (SD â€‹= â€‹0.02) for reader 1 and 0.09 (SD â€‹= â€‹0.03) for reader 2, The effective atomic number (Zeff) of CPP was 10.83 (SD â€‹= â€‹0.44) for reader 1 and 10.11 (SD â€‹= â€‹0.66) for reader 2. Nearly all DECT parameters of CPP were higher than those of T-BCP, lower than those of C-BCP, and largely overlapping with Aggregate-BCP (aggregate of T-BCP and C-BCP). Conclusion: Differentiation of different types of calcium crystals using DECT is not feasible in a clinical setting.

A perspective on the evolution of semi-quantitative MRI assessment of osteoarthritis: Past, present and future.

OBJECTIVE: This perspective describes the evolution of semi-quantitative (SQ) magnetic resonance imaging (MRI) in characterizing structural tissue pathologies in osteoarthritis (OA) imaging research over the last 30 years. METHODS: Authors selected representative articles from a PubMed search to illustrate key steps in SQ MRI development, validation, and application. Topics include main scoring systems, reading techniques, responsiveness, reliability, technical considerations, and potential impact of artificial intelligence (AI). RESULTS: Based on original research published between 1993 and 2023, this article introduces available scoring systems, including but not limited to Whole-Organ Magnetic Resonance Imaging Score (WORMS) as the first system for whole-organ assessment of the knee and the now commonly used MRI Osteoarthritis Knee Score (MOAKS) instrument. Specific systems for distinct OA subtypes or applications have been developed as well as MRI scoring instruments for other joints such as the hip, the fingers or thumb base. SQ assessment has proven to be valid, reliable, and responsive, aiding OA investigators in understanding the natural history of the disease and helping to detect response to treatment. AI may aid phenotypic characterization in the future. SQ MRI assessment's role is increasing in eligibility and safety evaluation in knee OA clinical trials. CONCLUSIONS: Evidence supports the validity, reliability, and responsiveness of SQ MRI assessment in understanding structural aspects of disease onset and progression. SQ scoring has helped explain associations between structural tissue damage and clinical manifestations, as well as disease progression. While AI may support human readers to more efficiently perform SQ assessment in the future, its current application in clinical trials still requires validation and regulatory approval.

Osteoarthritis year in review 2023: Imaging.

PURPOSE: This narrative review summarizes the original research in the field of in vivo osteoarthritis (OA) imaging between 1 January 2022 and 1 April 2023. METHODS: A PubMed search was conducted using the following several terms pertaining to OA imaging, including but not limited to "Osteoarthritis / OA", "Magnetic resonance imaging / MRI", "X-ray" "Computed tomography / CT", "artificial intelligence /AI", "deep learning", "machine learning". This review is organized by topics including the anatomical structure of interest and modality, AI, challenges of OA imaging in the context of clinical trials, and imaging biomarkers in clinical trials and interventional studies. Ex vivo and animal studies were excluded from this review. RESULTS: Two hundred and forty-nine publications were relevant to in vivo human OA imaging. Among the articles included, the knee joint (61%) and MRI (42%) were the predominant anatomical area and imaging modalities studied. Marked heterogeneity of structural tissue damage in OA knees was reported, a finding of potential relevance to clinical trial inclusion. The use of AI continues to rise rapidly to be applied in various aspect of OA imaging research but a lack of generalizability beyond highly standardized datasets limit interpretation and wide-spread application. No pharmacologic clinical trials using imaging data as outcome measures have been published in the period of interest. CONCLUSIONS: Recent advances in OA imaging continue to heavily weigh on the use of AI. MRI remains the most important modality with a growing role in outcome prediction and classification.

Exploring different models of pain phenotypes and their association with pain worsening in people with early knee osteoarthritis: The MOST cohort study.

OBJECTIVE: To determine i) pain phenotypes (PP) in people with early-stage knee osteoarthritis (EKOA); ii) the longitudinal association between the phenotypes and pain worsening at two years. DESIGN: We studied participants with EKOA from the Multicenter Osteoarthritis Study defined as pain intensity ≤3/10, Kellgren and Lawrence grade ≤2, intermittent pain none to sometimes, and no constant pain. Two models of PP were explored. Model A included pressure pain thresholds, temporal summation, conditioned pain modulation, pain catastrophizing, sleep quality, depression, and widespread pain (WSP). In Model B, gait characteristics, quadriceps strength, comorbidities, and magnetic resonance imaging features were added to Model A. Latent Class Analysis was used to create phenotypes, and logistic regression was used to determine their association with pain worsening. RESULTS: 750 individuals (60% females), mean age [standard deviation (SD)]: 60.3 (9.4) were included in Model A and 333 individuals (60% females), mean age (SD): 59.4 (8.1) in Model B. 3-class and 4-class solutions were chosen for Model A and Model B. In Model A, the most "severe" phenotype was dominated by psychosocial factors, WSP, and measures of nervous system sensitization. Similarly in Model B, the Model A phenotype plus gait variables, quadriceps strength, and comorbidities were dominant. Surprisingly, none of the phenotypes in either model had a significant relationship with pain worsening. CONCLUSION: Phenotypes based upon various factors thought to be important for the pain experience were identified in those with EKOA but were not significantly related to pain worsening. These phenotypes require validation with clinically relevant endpoints.

[11C]-PBR28 positron emission tomography signal as an imaging marker of joint inflammation in knee osteoarthritis.

ABSTRACT: Although inflammation is known to play a role in knee osteoarthritis (KOA), inflammation-specific imaging is not routinely performed. In this article, we evaluate the role of joint inflammation, measured using [11C]-PBR28, a radioligand for the inflammatory marker 18-kDa translocator protein (TSPO), in KOA. Twenty-one KOA patients and 11 healthy controls (HC) underwent positron emission tomography/magnetic resonance imaging (PET/MRI) knee imaging with the TSPO ligand [11C]-PBR28. Standardized uptake values were extracted from regions-of-interest (ROIs) semiautomatically segmented from MRI data, and compared across groups (HC, KOA) and subgroups (unilateral/bilateral KOA symptoms), across knees (most vs least painful), and against clinical variables (eg, pain and Kellgren-Lawrence [KL] grades). Overall, KOA patients demonstrated elevated [11C]-PBR28 binding across all knee ROIs, compared with HC (all P's < 0.005). Specifically, PET signal was significantly elevated in both knees in patients with bilateral KOA symptoms (both P's < 0.01), and in the symptomatic knee (P < 0.05), but not the asymptomatic knee (P = 0.95) of patients with unilateral KOA symptoms. Positron emission tomography signal was higher in the most vs least painful knee (P < 0.001), and the difference in pain ratings across knees was proportional to the difference in PET signal (r = 0.74, P < 0.001). Kellgren-Lawrence grades neither correlated with PET signal (left knee r = 0.32, P = 0.19; right knee r = 0.18, P = 0.45) nor pain (r = 0.39, P = 0.07). The current results support further exploration of [11C]-PBR28 PET signal as an imaging marker candidate for KOA and a link between joint inflammation and osteoarthritis-related pain severity.

Development and qualification of clinical grade decellularized and cryopreserved human esophagi.

Tissue engineering is a promising alternative to current full thickness circumferential esophageal replacement methods. The aim of our study was to develop a clinical grade Decellularized Human Esophagus (DHE) for future clinical applications. After decontamination, human esophagi from deceased donors were placed in a bioreactor and decellularized with sodium dodecyl sulfate (SDS) and ethylendiaminetetraacetic acid (EDTA) for 3 days. The esophagi were then rinsed in sterile water and SDS was eliminated by filtration on an activated charcoal cartridge for 3 days. DNA was removed by a 3-hour incubation with DNase. A cryopreservation protocol was evaluated at the end of the process to create a DHE cryobank. The decellularization was efficient as no cells and nuclei were observed in the DHE. Sterility of the esophagi was obtained at the end of the process. The general structure of the DHE was preserved according to immunohistochemical and scanning electron microscopy images. SDS was efficiently removed, confirmed by a colorimetric dosage, lack of cytotoxicity on Balb/3T3 cells and mesenchymal stromal cell long term culture. Furthermore, DHE did not induce lymphocyte proliferation in-vitro. The cryopreservation protocol was safe and did not affect the tissue, preserving the biomechanical properties of the DHE. Our decellularization protocol allowed to develop the first clinical grade human decellularized and cryopreserved esophagus.

The effect of dynamic versus static visualizations on acquisition of basketball game actions: a diurnal study.

This study aimed to examine the effect of time of day (TOD) on the acquisition of basketball game actions from dynamic and static visualizations in physical education students (novice practitioners). Participants were quasi-randomly assigned to three treatments (static pictures, enriched static-pictures, or video). Morning and late-afternoon sessions were conducted, involving study phases and immediate-recall tests [game comprehension (GC) test and game performance (GP) test]. Oral temperature (OT) and mood states (MS) were also measured. Compared to the morning, the results revealed that afternoon resulted in higher OT, higher negative MS (e.g., anxiety and fatigue), and lower positive MS (i.e., vigor) in all experimental conditions. Moreover, the results showed that: (a) GC and GP decreased throughout the day (regardless of treatments), (b) GC and GP were better with enriched static-pictures (with arrows) than with static pictures, at both TOD, and (c) the video resulted in better GC and GP than the two static presentations, at both TOD. This study (a) highlights the morning's superiority in the acquisition of motor skills from dynamic and static visualizations, due to mood disturbances and lower arousal levels, and (b) encourages basketball teachers to use video modeling by experts, particularly in the morning, for explaining tactical skills.

Emerging Quantitative Imaging Techniques in Sports Medicine.

This article describes recent advances in quantitative imaging of musculoskeletal extremity sports injuries, citing the existing literature evidence and what additional evidence is needed to make such techniques applicable to clinical practice. Compositional and functional MRI techniques including T2 mapping, diffusion tensor imaging, and sodium imaging as well as contrast-enhanced US have been applied to quantify pathophysiologic processes and biochemical compositions of muscles, tendons, ligaments, and cartilage. Dual-energy and/or spectral CT has shown potential, particularly for the evaluation of osseous and ligamentous injury (eg, creation of quantitative bone marrow edema maps), which is not possible with standard single-energy CT. Recent advances in US technology such as shear-wave elastography or US tissue characterization as well as MR elastography enable the quantification of mechanical, elastic, and physical properties of tissues in muscle and tendon injuries. The future role of novel imaging techniques such as photon-counting CT remains to be established. Eventual prediction of return to play (ie, the time needed for the injury to heal sufficiently so that the athlete can get back to playing their sport) and estimation of risk of repeat injury is desirable to help guide sports physicians in the treatment of their patients. Additional values of quantitative analyses, as opposed to routine qualitative analyses, still must be established using prospective longitudinal studies with larger sample sizes.

Relation of Intra-Articular Mineralization to Knee Pain in Knee Osteoarthritis: A Longitudinal Analysis in the MOST Study.

OBJECTIVE: Intra-articular (IA) calcium crystal deposition is common in knee osteoarthritis (OA), but of unclear significance. It is possible that low-grade, crystal-related inflammation may contribute to knee pain. We examined the longitudinal relation of computed tomography (CT)-detected IA mineralization to the development of knee pain. METHODS: We used data from the National Institutes of Health-funded longitudinal Multicenter Osteoarthritis Study. Participants had knee radiographs and bilateral knee CTs at baseline, and pain assessments every 8 months for 2 years. CT images were scored using the Boston University Calcium Knee Score. We longitudinally examined the relation of CT-detected IA mineralization to the risk of frequent knee pain (FKP), intermittent or constant knee pain worsening, and pain severity worsening using generalized linear mixed-effects models. RESULTS: We included 2,093 participants (mean age 61 years, 57% women, mean body mass index 28.8 kg/m2 ). Overall, 10.2% of knees had IA mineralization. The presence of any IA mineralization in the cartilage was associated with 2.0 times higher odds of having FKP (95% confidence interval [CI] 1.38-2.78) and 1.86 times more frequent intermittent or constant pain (95% CI 1.20-2.78), with similar results seen for the presence of any IA mineralization in the meniscus or joint capsule. A higher burden of IA mineralization anywhere within the knee was associated with a higher odds of all pain outcomes (odds ratio ranged from 2.14 to 2.21). CONCLUSION: CT-detected IA mineralization was associated with risk of having more frequent, persistent, and worsening knee pain over 2 years. Targeting IA mineralization may have therapeutic potential for pain improvement in knee OA.

A call for screening MRI as a tool for osteoarthritis clinical trials.

Conventional radiography is the most commonly used imaging modality for the evaluation of osteoarthritis (OA) in clinical trials of disease-modifying OA drugs (DMOADs). Unfortunately, radiography has many shortcomings as an imaging technique to meaningfully assess the pathological features of OA. In this perspective paper, we will describe the reasons why radiography is not an ideal tool for structural OA assessment and why magnetic resonance imaging (MRI) should be preferred for such purposes. These shortcomings include a lack of reproducibility of radiographic joint space measurements (if conducted without using a standardized positioning frame), a lack of sensitivity and specificity, an insufficient definition of disease severity, a weak association of radiographic structural damage and pain, a lack of ability to depict many faces of OA, and incapability to depict diagnoses of exclusion. MRI offers solutions to these limitations of radiography. Several different phenotypes of OA have been recognized and it is important to recruit appropriate patients for specific therapeutic approaches in DMOAD trials. Radiography does not allow such phenotypical stratification. We will explain known hurdles for widespread deployment of MRI at eligibility screening and how they can be overcome by technological advances and the use of simplified image assessment.

Strategic application of imaging in DMOAD clinical trials: focus on eligibility, drug delivery, and semiquantitative assessment of structural progression.

Despite decades of research efforts and multiple clinical trials aimed at discovering efficacious disease-modifying osteoarthritis (OA) drugs (DMOAD), we still do not have a drug that shows convincing scientific evidence to be approved as an effective DMOAD. It has been suggested these DMOAD clinical trials were in part unsuccessful since eligibility criteria and imaging-based outcome evaluation were solely based on conventional radiography. The OA research community has been aware of the limitations of conventional radiography being used as a primary imaging modality for eligibility and efficacy assessment in DMOAD trials. An imaging modality for DMOAD trials should be able to depict soft tissue and osseous pathologies that are relevant to OA disease progression and clinical manifestations of OA. Magnetic resonance imaging (MRI) fulfills these criteria and advances in technology and increasing knowledge regarding imaging outcomes likely should play a more prominent role in DMOAD clinical trials. In this perspective article, we will describe MRI-based tools and analytic methods that can be applied to DMOAD clinical trials with a particular emphasis on knee OA. MRI should be the modality of choice for eligibility screening and outcome assessment. Optimal MRI pulse sequences must be chosen to visualize specific features of OA.

Overuse-Related Injuries of the Knee.

Overuse-related injuries of the knee joint and periarticular soft tissues include a heterogenous group of sports and nonsports-related injuries. These conditions include friction and impingement syndromes, bone stress injuries, bursitis, and tendon-related pathology such as tendinopathy and snapping. Traction apophysitis are also discussed as commonly seen in the pediatric population. Although multiple imaging modalities can be used, this review focuses on MR imaging, which is the most common and, often, the only modality used.

Association Between Structural Change Over Eighteen Months and Subsequent Symptom Change in Middle-Aged Patients Treated for Meniscal Tear.

OBJECTIVE: Middle-aged subjects with meniscal tear treated with arthroscopic partial meniscectomy (APM) experience greater progression of damage to joint structures on imaging than subjects treated nonoperatively. It is unclear whether these changes are clinically relevant. The goal of this study was to assess whether worsening in magnetic resonance imaging (MRI)-assessed tissue damage over 18 months leads to subsequent worsening in knee pain over the subsequent 3.5 years. METHODS: We used data from the Meniscal Tear in Osteoarthritis Research (MeTeOR) trial of APM versus physical therapy for subjects ages ≥45 years with knee pain, cartilage damage, and meniscal tear. We assessed whether change in cartilage surface area damage score (and other structural measures) from baseline to 18 months, assessed on MRI with the MRI Osteoarthritis Knee Score (MOAKS) system, was associated with change in Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score (range 0-100; 100 = worst) from 18 to 60 months. RESULTS: The primary analysis included 168 subjects with complete MRI data at baseline and 18 months and KOOS data at 18 and 60 months. We did not observe clinically important associations between change in cartilage surface area score between baseline and 18 months and change in pain scores from 18 to 60 months. Pain scores in the worst tertile for cartilage surface area damage score progression worsened by 0.45 points more than in the best tertile (95% confidence interval -4.45, 5.35). Similarly, we did not observe clinically important associations between changes in bone marrow lesions, osteophytes, or synovitis and subsequent pain. CONCLUSION: We did not observe clinically important associations between early changes in cartilage damage and other structural measures and worsening in pain over the subsequent 3.5 years. Further follow-up is required to assess this association over a longer follow-up period.

Structural phenotypes of knee osteoarthritis: potential clinical and research relevance.

A joint contains many different tissues that can exhibit pathological changes, providing many potential targets for treatment. Researchers are increasingly suggesting that osteoarthritis (OA) comprises several phenotypes or subpopulations. Consequently, a treatment for OA that targets only one pathophysiologic abnormality is unlikely to be similarly efficacious in preventing or delaying the progression of all the different phenotypes of structural OA. Five structural phenotypes have been proposed, namely the inflammatory, meniscus-cartilage, subchondral bone, and atrophic and hypertrophic phenotypes. The inflammatory phenotype is characterized by marked synovitis and/or joint effusion, while the meniscus-cartilage phenotype exhibits severe meniscal and cartilage damage. Large bone marrow lesions characterize the subchondral bone phenotype. The hypertrophic and atrophic OA phenotype are defined based on the presence large osteophytes or absence of any osteophytes, respectively, in the presence of concomitant cartilage damage. Limitations of the concept of structural phenotyping are that they are not mutually exclusive and that more than one phenotype may be present. It must be acknowledged that a wide range of views exist on how best to operationalize the concept of structural OA phenotypes and that the concept of structural phenotypic characterization is still in its infancy. Structural phenotypic stratification, however, may result in more targeted trial populations with successful outcomes and practitioners need to be aware of the heterogeneity of the disease to personalize their treatment recommendations for an individual patient. Radiologists should be able to define a joint at risk for progression based on the predominant phenotype present at different disease stages.

Update on recent developments in imaging of inflammation in osteoarthritis: a narrative review.

Synovitis is an important component of the osteoarthritis (OA) disease process, particularly regarding the "inflammatory phenotype" of OA. Imaging plays an important role in the assessment of synovitis in OA with MRI and ultrasound being the most deployed imaging modalities. Contrast-enhanced (CE) MRI, particularly dynamic CEMRI (DCEMRI) is the ideal method for synovitis assessment, but for several reasons CEMRI is not commonly performed for OA imaging in general. Effusion-synovitis and Hoffa-synovitis are commonly used as surrogate markers of synovitis on non-contrast-enhanced (NCE) MRI and have been used in many epidemiological observational studies of knee OA. Several semiquantitative MRI scoring systems are available for the evaluation of synovitis in knee OA. Synovitis can be a target tissue for disease-modifying OA drug (DMOAD) clinical trials. Both MRI and ultrasound may be used to determine the eligibility and assess the therapeutic efficacy of DMOAD approaches. Ultrasound is mostly used for evaluation of synovitis in hand OA, while MRI is typically used for larger joints, namely knees and hips. The role of other modalities such as CT (including dual-energy CT) and nuclear medicine imaging (such as positron-emission tomography (PET) and its hybrid imaging) is limited in the context of synovitis assessment in OA. Despite research efforts to develop NCEMRI-based synovitis evaluation methods, these typically underestimate the severity of synovitis compared to CEMRI, and thus more research is needed before we can rely only on NCEMRI.

Crystal arthropathies and osteoarthritis-where is the link?

Osteoarthritis (OA) is one of the leading causes of disability worldwide. As our understanding of OA progressively has moved from a purely mechanical "wear and tear" concept toward a complex multi-tissue condition in which inflammation plays a central role, the possible role of crystal-induced inflammation in OA incidence and progression may be relevant. In addition to gout, which affects 4% of the US population, basic calcium phosphate and calcium pyrophosphate deposition both may induce joint inflammation and may play a role in pain in OA. This narrative review article discusses the possible mechanisms underlying the associations between crystal-induced arthropathies and OA, and the important implications of these for clinical practice and future research.

The effect of web-based Hatha yoga on psychological distress and sleep quality in older adults: A randomized controlled trial.

BACKGROUND: To date, there has been very limited experimental research on the impact of Yoga on older adults' mental health during the COVID-19 crisis. We aimed to explore the effect of a web-based Hatha yoga program on psychological and quality of sleep in older adults who self-isolated at home during the initial stage of the COVID-19 outbreak. METHODS: Two hundred volunteers of both sexes were split into experimental (Yoga group, YG) and control (Control group, CG) groups, in a web-based randomized controlled study. All participants were administered the Depression, Anxiety and Stress Scales (DASS-21) and the Pittsburgh sleep quality index (PSQI); at baseline and following an eight-week online Hatha yoga intervention. RESULTS: The YG showed significant reductions in depression (-56.1%; Z = 5.67, p < 0.01, r = 0.70) anxiety (-64.3%; Z = 5.27, p < 0.01, r = 0.65) and stress (-68.2%; Z = 5.86, r = 0.73) scores, while the CG showed a significant increase in depression. In addition, the total PSQI score of the YG was considerably lower during follow-up (3.38 ± 2.02, p < 0.05) than at baseline (4.8 ± 32, p < 0.05), which indicates an improvement of the quality of sleep. The proportion of individuals experiencing good sleep from the YG increased from 63% to 85% after the Hatha yoga intervention. CONCLUSION: The use of a web-based Hatha Yoga intervention program was associated with a beneficial effect on the mental health and quality of sleep in older adults.

PET Imaging in Osteoarthritis.

Osteoarthritis is a common cause of pain and morbidity resulting in heavy economic burden and large societal costs. Although cross-sectional imaging and in particular MR imaging have largely contributed to a better understanding of the complexity of this complex disease, especially in large joints such as the hip and knee joints, metabolic information of the subchondral bone and periarticular synovial environment has been consistently suggested to provide valuable supplemental information to morphologic and compositional MR imaging. The aim of this narrative review is to provide an overview of the role of the hybrid PET imaging in osteoarthritis with particular focus on PET/MR imaging.