The knee connectome: A novel tool for studying spatiotemporal change in cartilage thickness.

Cartilage thickness change is a well-documented biomarker of osteoarthritis pathogenesis. However, there is still much to learn about the spatial and temporal patterns of cartilage thickness change in health and disease. In this study, we develop a novel analysis method for elucidating such patterns using a functional connectivity approach. Descriptive statistics are reported for 1186 knees that did not develop osteoarthritis during the 8 years of observation, which we present as a model of cartilage thickness change related to healthy aging. Within the control population, patterns vary greatly between male and female subjects, while body mass index (BMI) has a more moderate impact. Finally, several differences are shown between knees that did and did not develop osteoarthritis. Some but not all significance appears to be accounted for by differences in sex, BMI, and knee alignment. With this work, we present the connectome as a novel tool for studying spatiotemporal dynamics of tissue change.

Large-Scale Analysis of Meniscus Morphology as Risk Factor for Knee Osteoarthritis.

OBJECTIVE: Although it is established that structural damage of the meniscus is linked to knee osteoarthritis (OA) progression, the predisposition to future development of OA because of geometric meniscal shapes is plausible and unexplored. This study aims to identify common variations in meniscal shape and determine their relationships to tissue morphology, OA onset, and longitudinal changes in cartilage thickness. METHODS: A total of 4,790 participants from the Osteoarthritis Initiative data set were studied. A statistical shape model was developed for the meniscus, and shape scores were evaluated between a control group and an OA incidence group. Shape features were then associated with cartilage thickness changes over 8 years to localize the relationship between meniscus shape and cartilage degeneration. RESULTS: Seven shape features between the medial and lateral menisci were identified to be different between knees that remain normal and those that develop OA. These include length-width ratios, horn lengths, root attachment angles, and concavity. These "at-risk" shapes were linked to unique cartilage thickness changes that suggest a relationship between meniscus geometry and decreased tibial coverage and rotational imbalances. Additionally, strong associations were found between meniscal shape and demographic subpopulations, future tibial extrusion, and meniscal and ligamentous tears. CONCLUSION: This automatic method expanded upon known meniscus characteristics that are associated with the onset of OA and discovered novel shape features that have yet to be investigated in the context of OA risk.

The contributions of cartilage endplate composition and vertebral bone marrow fat to intervertebral disc degeneration in patients with chronic low back pain.

PURPOSE: The composition of the subchondral bone marrow and cartilage endplate (CEP) could affect intervertebral disc health by influencing vertebral perfusion and nutrient diffusion. However, the relative contributions of these factors to disc degeneration in patients with chronic low back pain (cLBP) have not been quantified. The goal of this study was to use compositional biomarkers derived from quantitative MRI to establish how CEP composition (surrogate for permeability) and vertebral bone marrow fat fraction (BMFF, surrogate for perfusion) relate to disc degeneration. METHODS: MRI data from 60 patients with cLBP were included in this prospective observational study (28 female, 32 male; age = 40.0 ± 11.9 years, 19-65 [mean ± SD, min-max]). Ultra-short echo-time MRI was used to calculate CEP T2* relaxation times (reflecting biochemical composition), water-fat MRI was used to calculate vertebral BMFF, and T1ρ MRI was used to calculate T1ρ relaxation times in the nucleus pulposus (NP T1ρ, reflecting proteoglycan content and degenerative grade). Univariate linear regression was used to assess the independent effects of CEP T2* and vertebral BMFF on NP T1ρ. Mixed effects multivariable linear regression accounting for age, sex, and BMI was used to assess the combined relationship between variables. RESULTS: CEP T2* and vertebral BMFF were independently associated with NP T1ρ (p = 0.003 and 0.0001, respectively). After adjusting for age, sex, and BMI, NP T1ρ remained significantly associated with CEP T2* (p = 0.0001) but not vertebral BMFF (p = 0.43). CONCLUSION: Poor CEP composition plays a significant role in disc degeneration severity and can affect disc health both with and without deficits in vertebral perfusion.

Institution-wide shape analysis of 3D spinal curvature and global alignment parameters.

The spine is an articulated, 3D structure with 6 degrees of translational and rotational freedom. Clinical studies have shown spinal deformities are associated with pain and functional disability in both adult and pediatric populations. Clinical decision making relies on accurate characterization of the spinal deformity and monitoring of its progression over time. However, Cobb angle measurements are time-consuming, are limited by interobserver variability, and represent a simplified 2D view of a 3D structure. Instead, spine deformities can be described by 3D shape parameters, addressing the limitations of current measurement methods. To this end, we develop and validate a deep learning algorithm to automatically extract the vertebral midline (from the upper endplate of S1 to the lower endplate of C7) for frontal and lateral radiographs. Our results demonstrate robust performance across datasets and patient populations. Approximations of 3D spines are reconstructed from the unit normalized midline curves of 20,118 pairs of full spine radiographs belonging to 15,378 patients acquired at our institution between 2008 and 2020. The resulting 3D dataset is used to describe global imbalance parameters in the patient population and to build a statistical shape model to describe global spine shape variations in preoperative deformity patients via eight interpretable shape parameters. The developed method can identify patient subgroups with similar shape characteristics without relying on an existing shape classification system.

Uncovering associations between data-driven learned qMRI biomarkers and chronic pain.

Knee pain is the most common and debilitating symptom of knee osteoarthritis (OA). While there is a perceived association between OA imaging biomarkers and pain, there are weak or conflicting findings for this relationship. This study uses Deep Learning (DL) models to elucidate associations between bone shape, cartilage thickness and T2 relaxation times extracted from Magnetic Resonance Images (MRI) and chronic knee pain. Class Activation Maps (Grad-CAM) applied on the trained chronic pain DL models are used to evaluate the locations of features associated with presence and absence of pain. For the cartilage thickness biomarker, the presence of features sensitive for pain presence were generally located in the medial side, while the features specific for pain absence were generally located in the anterior lateral side. This suggests that the association of cartilage thickness and pain varies, requiring a more personalized averaging strategy. We propose a novel DL-guided definition for cartilage thickness spatial averaging based on Grad-CAM weights. We showed a significant improvement modeling chronic knee pain with the inclusion of the novel biomarker definition: likelihood ratio test p-values of 7.01 × 10-33 and 1.93 × 10-14 for DL-guided cartilage thickness averaging for the femur and tibia, respectively, compared to the cartilage thickness compartment averaging.

The International Workshop on Osteoarthritis Imaging Knee MRI Segmentation Challenge: A Multi-Institute Evaluation and Analysis Framework on a Standardized Dataset.

PURPOSE: To organize a multi-institute knee MRI segmentation challenge for characterizing the semantic and clinical efficacy of automatic segmentation methods relevant for monitoring osteoarthritis progression. MATERIALS AND METHODS: A dataset partition consisting of three-dimensional knee MRI from 88 retrospective patients at two time points (baseline and 1-year follow-up) with ground truth articular (femoral, tibial, and patellar) cartilage and meniscus segmentations was standardized. Challenge submissions and a majority-vote ensemble were evaluated against ground truth segmentations using Dice score, average symmetric surface distance, volumetric overlap error, and coefficient of variation on a holdout test set. Similarities in automated segmentations were measured using pairwise Dice coefficient correlations. Articular cartilage thickness was computed longitudinally and with scans. Correlation between thickness error and segmentation metrics was measured using the Pearson correlation coefficient. Two empirical upper bounds for ensemble performance were computed using combinations of model outputs that consolidated true positives and true negatives. RESULTS: Six teams (T 1-T 6) submitted entries for the challenge. No differences were observed across any segmentation metrics for any tissues (P = .99) among the four top-performing networks (T 2, T 3, T 4, T 6). Dice coefficient correlations between network pairs were high (> 0.85). Per-scan thickness errors were negligible among networks T 1-T 4 (P = .99), and longitudinal changes showed minimal bias (< 0.03 mm). Low correlations (ρ < 0.41) were observed between segmentation metrics and thickness error. The majority-vote ensemble was comparable to top-performing networks (P = .99). Empirical upper-bound performances were similar for both combinations (P = .99). CONCLUSION: Diverse networks learned to segment the knee similarly, where high segmentation accuracy did not correlate with cartilage thickness accuracy and voting ensembles did not exceed individual network performance.See also the commentary by Elhalawani and Mak in this issue.Keywords: Cartilage, Knee, MR-Imaging, Segmentation © RSNA, 2020Supplemental material is available for this article.

Towards understanding mechanistic subgroups of osteoarthritis: 8-year cartilage thickness trajectory analysis.

Many studies have validated cartilage thickness as a biomarker for knee osteoarthritis (OA); however, few studies investigate beyond cross-sectional observations or comparisons across two timepoints. By characterizing the trajectory of cartilage thickness changes over 8 years in healthy individuals from the OA initiative data set, this study discovers associations between the dynamics of cartilage changes and OA incidence. A fully automated cartilage segmentation and thickness measurement method were developed and validated against manual measurements: mean absolute error = 0.11-0.14 mm (n = 4129 knees) and automatic reproducibility = 0.04-0.07 mm (n = 316 knees). The mean thickness for the medial and lateral tibia (MT, LT), central weight-bearing medial and lateral femur (cMF, cLF), and patella (P) cartilage compartments were quantified for 1453 knees at seven timepoints. Trajectory subgroups were defined per cartilage compartment such as stable, thinning to thickening, accelerated thickening, plateaued thickening, thickening to thinning, accelerated thinning, or plateaued thinning. For tibiofemoral compartments, the stable (22%-36%) and plateaued thinning (22%-37%) trajectories were the most common, with an average initial velocity (µm/month), acceleration (µm/month2 ) for the plateaued thinning trajectories LT: -2.66, 0.0326; MT: -2.49, 0.0365; cMF: -3.51, 0.0509; and cLF: -2.68, 0.041. In the patella compartment, the plateaued thinning (35%) and thickening to thinning (24%) trajectories were the most common, with an average initial velocity, acceleration for each -4.17, 0.0424; 1.95, -0.0835. Knees with nonstable trajectories had higher adjusted odds of OA incidence than stable trajectories: accelerated thickening, accelerated thinning, and plateaued thinning trajectories of the MT had adjusted odds ratio (OR) of 18.9, 5.48, and 1.47, respectively; in the cMF, adjusted OR of 8.55, 10.1, and 2.61, respectively.

Lumbar intervertebral disc characterization through quantitative MRI analysis: An automatic voxel-based relaxometry approach.

PURPOSE: To develop an automated pipeline based on convolutional neural networks to segment lumbar intervertebral discs and characterize their biochemical composition using voxel-based relaxometry, and establish local associations with clinical measures of disability, muscle changes, and other symptoms of lower back pain. METHODS: This work proposes a new methodology using MRI (n = 31, across the spectrum of disc degeneration) that combines deep learning-based segmentation, atlas-based registration, and statistical parametric mapping for voxel-based analysis of T1ρ and T2 relaxation time maps to characterize disc degeneration and its associated disability. RESULTS: Across degenerative grades, the segmentation algorithm produced accurate, high-confidence segmentations of the lumbar discs in two independent data sets. Manually and automatically extracted mean disc T1ρ and T2 relaxation times were in high agreement for all discs with minimal bias. On a voxel-by-voxel basis, imaging-based degenerative grades were strongly negatively correlated with T1ρ and T2 , particularly in the nucleus. Stratifying patients by disability grades revealed significant differences in the relaxation maps between minimal/moderate versus severe disability: The average T1ρ relaxation maps from the minimal/moderate disability group showed clear annulus nucleus distinction with a visible midline, whereas the severe disability group had lower average T1ρ values with a homogeneous distribution. CONCLUSION: This work presented a scalable pipeline for fast, automated assessment of disc relaxation times, and voxel-based relaxometry that overcomes limitations of current region of interest-based analysis methods and may enable greater insights and associations between disc degeneration, disability, and lower back pain.

Quantitative [18F]-Naf-PET-MRI Analysis for the Evaluation of Dynamic Bone Turnover in a Patient with Facetogenic Low Back Pain.

Imaging techniques that reflect dynamic bone turnover may aid in characterizing a wide range of bone pathologies. Bone is a dynamic tissue undergoing continuous remodeling with the competing activity of osteoblasts, which produce the new bone matrix, and osteoclasts, whose function is to eliminate mineralized bone. [18F]-NaF is a positron emission tomography (PET) radiotracer that enables visualization of bone metabolism. [18F]-NaF is chemically absorbed into hydroxyapatite in the bone matrix by osteoblasts and can thus noninvasively detect osteoblastic activity, which is occult to conventional imaging techniques. Kinetic modeling of dynamic [18F]-NaF-PET data provides detailed quantitative measures of bone metabolism. Conventional semi-quantitative PET data, which utilizes standardized uptake values (SUVs) as a measure of radiotracer activity, is referred to as a static technique due to its snapshot of tracer uptake in time.  Kinetic modeling, however, utilizes dynamic image data where tracer levels are continuously acquired providing tracer uptake temporal resolution. From the kinetic modeling of dynamic data, quantitative values like blood flow and metabolic rate (i.e., potentially informative metrics of tracer dynamics) can be extracted, all with respect to the measured activity in the image data. When combined with dual modality PET-MRI, region-specific kinetic data can be correlated with anatomically registered high-resolution structural and pathologic information afforded by MRI. The goal of this methodological manuscript is to outline detailed techniques for performing and analyzing dynamic [18F]-NaF-PET-MRI data. The lumbar facet joint is a common site of degenerative arthritis disease and a common cause for axial low back pain.  Recent studies suggest [18F]-NaF-PET may serve as a useful biomarker of painful facetogenic disease.  The human lumbar facet joint will, therefore, be used as a prototypical region of interest for dynamic [18F]-NaF-PET-MRI analysis in this manuscript.

Valve Interstitial Cells Act in a Pericyte Manner Promoting Angiogensis and Invasion by Valve Endothelial Cells.

Neovascularization is an understudied aspect of calcific aortic valve disease (CAVD). Within diseased valves, cells along the neovessels' periphery stain for pericyte markers, but it is unclear whether valvular interstitial cells (VICs) can demonstrate a pericyte-like phenotype. This investigation examined the perivascular potential of VICs to regulate valve endothelial cell (VEC) organization and explored the role of Angiopoeitin1-Tie2 signaling in this process. Porcine VECs and VICs were fluorescently tracked and co-cultured in Matrigel over 7 days. VICs regulated early VEC network organization in a ROCK-dependent manner, then guided later VEC network contraction through chemoattraction. Unlike vascular control cells, the valve cell cultures ultimately formed invasive spheroids with 3D angiogenic-like sprouts. VECs co-cultured with VICs displayed significantly more invasion than VECs alone; with VICs generally leading and wrapping around VEC invasive sprouts. Lastly, Angiopoietin1-Tie2 signaling was found to regulate valve cell organization during VEC/VIC spheroid formation and invasion. VICs demonstrated pericyte-like behaviors toward VECs throughout sustained co-culture. The change from a vasculogenic network to an invasive sprouting spheroid suggests that both cell types undergo phenotypic changes during long-term culture in the model angiogenic environment. Valve cells organizing into spheroids and undergoing 3D invasion of Matrigel demonstrated several typical angiogenic-like phenotypes dependent on basal levels of Angiopoeitin1-Tie2 signaling and ROCK activation. These results suggest that the ectopic sustained angiogenic environment during the early stages of valve disease promotes organized activity by both VECs and VICs, contributing to neovessel formation and the progression of CAVD.