PRECURSORS TO ACCELERATED KNEE OA DEVELOPMENT
Knee osteoarthritis (OA) is typically a slowly progressive disorder, but at least 1 in 5 people develop advanced-stage knee OA with dramatic rapidity (i.e., normal to advance-stage disease within 4 years; often within 12 months). Therefore, we urgently need to be able to detect which individuals are at greatest risk of accelerated knee OA prior to the development of this debilitating disease. Our research has quantified structural pathology on magnetic resonance images (MRIs) using data from the Osteoarthritis Initiative. We have determined that ligamentous degeneration, effusion/synovitis, destabilizing meniscal tear, and diffuse cartilage alterations may serve as prognostic biomarkers as they precede the onset of accelerated KOA.
Harkey MS , Davis JE, Price LL, Ward RJ, MacKay JW, Eaton CB, Lo GH, Barbe MF, Zhang M, Pang J, Stout AC, Lu B, McAlindon TE, Driban JB. Composite Quantitative Knee Structure Metrics Predict the Development of Accelerated Knee Osteoarthritis: Data from the Osteoarthritis Initiative. Published in BMC Musculoskeletal Disorders. 2020 May. 21(299):1-10.
Driban JB, Davis JE, Lu B, Price LL, Ward R, MacKay J, Eaton CB, Lo GH, Barbe M, Zhang M, Pang J, Stout AC, Harkey MS , McAlindon TE. Accelerated Knee Osteoarthritis is Characterized by Destabilizing Meniscal Tears and Pre-Radiographic Structural Disease Burden. Published in Arthritis and Rheumatology. 2019 Jul; 71(7): 1089-1100. PMID: 30592385. PMCID: PMC6594896.
Harkey MS , Davis JE, Lu B, Price LL, Ward R, MacKay J, Eaton CB, Lo GH, Barbe MF, Zhang M, Pang J, Stout AC, McAlindon TE, Driban JB. Early pre-radiographic structural pathology precedes the onset of accelerated knee osteoarthritis. Published in BMC Musculoskeletal Disorders. 2019 May; 20(241): 1-10. PMID: 31113401. PMCID: PMC6530034.
Harkey MS , Davis JE, Lu B, Price L, Eaton CB, Lo GH, Barbe MF, Ward R, Zhang M, Liu SH, Lapane KL, MacKay JW, McAlindon TE, Driban JB. Diffuse Tibiofemoral Cartilage Change Prior to the Development of Accelerated Knee Osteoarthritis: Data from the Osteoarthritis Initiative. Published in Clinical Anatomy. 2019 Apr; 32(3): 369-378. PMID: 30521068. PMCID: PMC6414263.
Davis JE, Harkey MS , Ward R, MacKay J, Lu B, Price LL, Eaton CB, Barbe MF, Lo GH, McAlindon TE, Driban JB. Effusion-Synovitis and Infrapatellar Fat Pad Signal Intensity Alteration Differentiate Accelerated Knee Osteoarthritis. Published in Rheumatology. 2019 Mar; 58(3): 418-426. PMID: 30346594. PMCID: PMC6381765.

ASSESSING ARTICULAR CARTILAGE WITH DIAGNOSTIC ULTRASOUND
Decline in cartilage health is a hallmark sign of osteoarthritis, and ultrasound represents a valid, clinically-accessible alternative to MRI to assess cartilage. We have developed methods for assessing femoral cartilage area and average cartilage thickness using novel semi-automated ultrasound processing techniques. Additionally, we developed novel methodology to use ultrasound to sensitively quantify femoral cartilage deformation following an acute bout of physical activity, as well as characterizing how the cartilage recovers throughout the first hour following loading. We have demonstrated that individuals following knee injury present with greater femoral cartilage thickness compared to their contralateral limb, as well as a healthy control limb. Since one in three individuals following knee injury will develop knee OA within a decade, we believe that ultrasound represents a clinically feasible, sensitive technique to detect cartilage swelling in early stages of knee OA.
Lisee C, McGrath ML, Kuenze C, Zhang M, Salzler M, Driban JB, Harkey MS . Novel Semi-Automated Ultrasound Segmentation Technique for Assessing Average Regional Femoral Articular Cartilage Thickness. Accepted for Published in Journal of Sports Rehabilitation. 2020 Mar.
Harkey MS , Blackburn JT, Nissman D, Davis HC, Durrington I, Rizk C, Kuismanen A, Pietrosimone B. Ultrasonographic Assessment of Femoral Cartilage in Individuals with Anterior Cruciate Ligament Reconstruction: A Case-Control Study. Published in Journal of Athletic Training. 2018 Nov; 53(11):1082-1088. PMID: 30615493. PMCID: PMC6333222.
Harkey MS , Blackburn JT, Hackney AC, Lewek M, Schmitz R, Nissman D, Pietrosimone B. Comprehensively Assessing the Acute Femoral Cartilage Response and Recovery After Walking and Drop-Landing: An Ultrasonographic Study. Published in Ultrasound in Medicine & Biology. 2018 Feb, 44(2):311-20. PMID: 29198383.
Harkey MS , Davis H, Sierra-Arévalo L, Blackburn JT, Nissman D, Pietrosimone B. The Association Between Habitual Walking Speed and Medial Femoral Cartilage Deformation Following 30-Minutes of Walking. Published in Gait & Posture. 2018 Jan, 59:128-33. PMID: 29031137.
Harkey MS , Davis H, Sierra-Arévalo L, Blackburn JT, Nissman D, Pietrosimone B. Ultrasonographic Assessment of Medial Femoral Cartilage Deformation Acutely Following Walking and Running. Published in Osteoarthritis and Cartilage. 2017 June, 25(6):907-13. PMID: 28043940.

EFFECTS OF WALKING SPEED ON KNEE JOINT HEALTH
Walking speed is a clinically accessible physical function measure that is predictive of disability in activities of daily living and mortality in older individuals. Additionally, walking speed is a simple clinical outcome measure that has implications for knee biomechanics that occur during gait. We observed that individuals following knee injury who walked slower presented with greater serum concentrations of cartilage breakdown biomarkers, as well as worse femoral cartilage composition. We demonstrated that slower walking speed was associated with greater medial femoral cartilage deformation assessed with ultrasound. Additionally, we have determined that longitudinal declines in walking speed in individuals that develop accelerated knee OA are associated with increasing bone marrow lesion and effusion volume. We have determined that longitudinal declines in walking speed in individuals that develop accelerated knee OA are associated with increasing bone marrow lesion and effusion volume. We also demonstrated a one-year decline in walking speed was associated with twice the risk, while an increase in walking speed was associated with half the risk of receiving a knee replacement in the compared to someone with no change in walking speed. Therefore, walking speed is a clinically relevant physical function outcome that has important implications in declining knee joint health across a continuum of people with and at risk for knee OA.
Harkey MS , Lapane KL, Liu S, Lo GH, McAlindon TE, Driban JB. A Decline in Walking Speed is Associated with Incident Knee Replacement in Adults with and at Risk for Knee Osteoarthritis. Accepted for Publication in the Journal of Rheumatology. 2020 Jun. Epub Ahead of Print. PMID: 32541076.
Harkey MS , Price LL, McAlindon TE, Davis, JE, Lu B, Zhang M, Eaton CB, Barbe M, Lo GH, Driban J. Association Between Declining Walking Speed and Increasing Bone Marrow Lesion and Effusion Volume in Individuals with Accelerated Knee Osteoarthritis. Published in Arthritis Care & Research. 2019 Jan; 71(2):259-270. PMID: 29882630. PMCID: PMC6286681.
Pfeiffer SJ, Harkey MS , Stanley LE, Blackburn JT, Padua DA, Spang JT, Marshall SW, Jordan JM, Schmitz RJ, Nissman DB, Pietrosimone B. Associations between Slower Walking Speed and T1ρ Magnetic Resonance Imaging of Femoral Cartilage following Anterior Cruciate Ligament Reconstruction. Published in Arthritis Care and Research. 2018 Aug, 70(8):1132-1140. PMID: 29193888. PMCID: PMC5972050.
Harkey MS , Davis H, Sierra-Arévalo L, Blackburn JT, Nissman D, Pietrosimone B. The Association Between Habitual Walking Speed and Medial Femoral Cartilage Deformation Following 30-Minutes of Walking. Published in Gait & Posture. 2018 Jan, 59:128-33. PMID: 29031137.
Pietrosimone B, Blackburn JT, Harkey MS , Luc BA, Hackney AC, Padua DA, Driban JB, Spang JT, Jordan JM. Walking Speed as a Potential Indicator of Cartilage Breakdown Following ACL Reconstruction. Published in Arthritis Care and Research. 2016 Jun, 68(6):793-800. PMID: 26502367.

PHYSICAL FUNCTION IN PEOPLE WITH OR AT RISK FOR KNEE OA
One of the primary symptoms of knee OA is a decline in physical function leading to physical disability. Objective measures of physical function quantify functional limitations by testing an individual’s performance on a variety of daily tasks (e.g., short/long walking, standing from a chair). Objective physical function is considered clinically important as worse performance is associated with poor quality of life, a decline in physical activity levels, and mortality in older adults and those with or at risk for knee OA. We created patient-specific reference values for objective physical function tests within subsets across both sexes and a wide spectrum of age, radiographic knee OA severity, and BMI categories. We created a mobile application that is downloadable on all mobile App stores (OAFunction) as a clinically accessible way for clinicians and researchers to use these references values. We have also utilized therapeutic exercise coupled with transcutaneous electrical nerve stimulation as a way to improve physical function in people with knee OA.
Harkey MS, Lapane KL, Liu S, Lo GH, McAlindon TE, Driban JB. A Decline in Walking Speed is Associated with Incident Knee Replacement in Adults with and at Risk for Knee Osteoarthritis. Accepted for Publication in the Journal of Rheumatology. 2020 Jun. Epub Ahead of Print. PMID: 32541076
Driban, JB, Harkey MS, Price LL, Lo GH, McAlindon TE. The inverse OARSI-OMERACT criteria is a valid indicator of the clinical worsening of knee osteoarthritis: data from the Osteoarthritis Initiative. Accepted for Publication in the Journal of Rheumatology. 2020 Jun. Epub Ahead of Print. PMID: 32541081
Harkey MS, Price LL, Reid KF, Lo GH, Liu S, Lapane KL, Dantas LO, McAlindon TE, Driban JB. Patient-Specific Reference Values for Objective Physical Function Tests: Data from the Osteoarthritis Initiative. Published in Clinical Rheumatology. 2020 Feb. Epub Ahead of Print. PMID: 32030634
Pietrosimone B, Luc-Harkey BA, Harkey MS, Davis-Wilson HC, Pfeiffer SJ, Schwartz TA, Nissman D, Padua DA, Blackburn JT, Spang JT. Using TENS to Enhance Therapeutic Exercise in Individuals with Knee Osteoarthritis. Accepted for Publication in Medicine & Science in Sport &; Exercise. 2020 Apr. Epub Ahead of Print. PMID: 32251254
Luc-Harkey BA, Davis HC, Harkey MS, Ryan ED, Gaynor B, Blackburn JT, Nissman DB, Spang JT, Pietrosimone B. Quadriceps Rate of Torque Development and Disability in Persons with Tibiofemoral Osteoarthritis. Published in Journal of Orthopaedic & Sports Physical Therapy. 2018 Sept, 48(9):694-703. PMID: 29787693

OA-RELATED BIOMARKERS
Assessing various biochemical markers in serum allows for the quantification of dynamic physiological processes related to knee OA. We demonstrated that greater body mass index was associated with greater cartilage breakdown biomarkers in people following knee injury, especially women. Maintaining or reducing body mass index following knee injury may be protective for maintaining optimal cartilage health. Additionally, assessing cartilage biomarkers before and after a mechanical stimulus (e.g., walking, drop-landing) provides an estimate of the dynamic cartilage response to functional loading. We demonstrated that walking and drop-landing produced a greater acute cartilage biomarker response when compared to a control condition in healthy individuals. However, the acute cartilage biomarker response was similar between the two physical activity conditions even though the conditions differed in magnitude and frequency of loading. Further work is needed to better understand how to optimize joint loading in people at risk for knee OA to maintain cartilage health.
Harkey MS, Blackburn JT, Hackney AC, Lewek M, Schmitz R, Pietrosimone B. Sex-Specific Associations Between Cartilage Structure and Metabolism at Rest and Acutely Following Walking and Drop-Landing. Accepted for Publication in Cartilage. 2020 Aug
Lane AR, Harkey MS , Davis HC, Luc-Harkey BA, Stanley L, Hackney AC, Blackburn JT, Pietrosimone B. Body Mass Index and Type 2 Collagen Turnover in Individuals after Anterior Cruciate Ligament Reconstruction. Published in Journal of Athletic Training. 2019 Mar; 54(3):270-275. PMID: 30829538. PMCID: PMC6485853.
Harkey MS , Blackburn JT, Hackney AC, Lewek M, Schmitz R, Pietrosimone B. Acute Serum Cartilage Biomarker Response following Walking and Drop Landing. Published in Medicine & Science in Sports & Exercise. 2018 July, 50(7):1465-71. PMID: 29470279.
Harkey MS, Luc B, Golightly Y, Thomas A, Driban J, Hackney A, Pietrosimone B. Osteoarthritis-Related Biomarkers Following Anterior Cruciate Ligament Injury and Reconstruction: A Systematic Review. Published in Osteoarthritis and Cartilage. 2015 Jan, 23(1):1-12. PMID: 25219671.

COMPOSITIONAL MRI TO ASSESS CARTILAGE COMPOSITION
Compositional MRI sequences (e.g., T1rho, T2 mapping) assess cartilage composition by quantifying proteoglycan density or collagen orientation. We have used compositional sequence to determine how cartilage composition is associated with walking biomechanics, patient reported outcomes, and muscle strength in individuals following knee injury. We have identified that specific walking strategies and muscle weakness is associated with poor cartilage composition. Additionally, poor cartilage composition is related to poor patient reported outcomes following knee injury. Therefore, interventions targeting the specific walking strategies and improvement in strength may help improve cartilage composition and patient outcomes following knee injury.
Pietrosimone B, Pfeiffer SJ, Harkey MS , Wallace K, Hunt C, Blackburn JT, Schmitz R, Lalush D, Nissman D, Spang JT. Quadriceps Weakness Associates with Greater T1ρ Relaxation Time in the Medial Femoral Articular Cartilage 6 Months Following Anterior Cruciate Ligament Reconstruction. Published in Knee Surgery, Sports Traumatology, Arthroscopy. 2019 Aug; 27(8):2632-2642. PMID: 30560446.
Pfeiffer S, Spang J, Nissman D, Lalush D, Wallace K, Harkey MS , Stanley L, Schmitz R, Schwartz T, Blackburn JT, Pietrosimone B. Gait Mechanics and T1rho MRI of Tibiofemoral Cartilage 6 Months Post ACL Reconstruction. Published in Medicine & Science in Sports & Exercise. 2019 Apr; 51(4):630-639. PMID: 30444797.
Pietrosimone B, Nissman D, Blackburn JT, Harkey MS , Creighton A, Kamath G, Healy K, Schmitz R, Driban JB, Padua DA, Marshall SW, Jordan JM, Spang JT. Associations between Cartilage Proteoglycan Density and Patient Outcomes 12months Following Anterior Cruciate Ligament Reconstruction. Published in Knee. 2018 Jan, 25(1):118-29, PMID: 29329888.