The general purpose of the study is to develop and interrogate novel MR imaging biomarkers with histologic and biomechanical reference standards that detect structural alteration in cartilage and meniscus and to apply these techniques for characterization of patterns of degeneration that aid in understanding pathogenesis of knee OA.
Four specific aims (SA) are proposed: 1) validation of novel MR pulse sequences for qualitative meniscal characterization with a histologic reference standard, 2) validation of novel MR pulse sequences that detect meniscal collagen and proteoglycan alteration with histologic, and biomechanical reference standards, 3) exploration of the relationship of cartilage lesions and meniscal pathology in cadaveric specimens, and 4) translation of MR techniques to a patient population with both conservative treatment and meniscectomy in the setting of meniscal tear. This is a prospective study that will use cadaveric knee specimens to carry out specific aims 1 through 3. Knee specimens will be screened with radiographs and those with severe OA as determined by radiographic grading will be excluded from the study.
In specific aim 1, morphologic MR grading of menisci will be performed with standard and novel MR pulse sequences, independently by 3 subspecialized musculoskeletal radiologists. A histologic reference standard will be used to determine whether novel sequences are more sensitive to detection and classification of meniscal lesions. Our null hypothesis will be that novel MR sequences will be more accurate at unmasking normal meniscal infrastructure and structural alteration.
In specific aim 2, we will compare standard quantitative MR techniques (T2 mapping, T1 rho evaluation) to novel quantitative MR techniques (UTE T2* techniques, UTE T1 rho evaluation) to determine whether novel sequences are more sensitive for the detection of altered collagen and proteoglycan respectively, in meniscal tissue.
This aim will be carried out through controlled specific enzymatic digestion of cadaveric meniscal tissue. We will use analysis of bathing digestion fluid, as well as histologic and biomechanical reference standards for the digested tissue. The latter will allow us to determine whether there is the potential for quantitative MR data to reflect tissue function. Our null hypothesis will be that novel MR sequences will be more sensitive to changes in collagen and proteoglycan degradation in meniscus and cartilage.
In specific aim 3, we will establish quantitative MR values for normal and pathologic menisci in cadaveric knee specimens. Further, we will identify patterns of cartilage lesions (morphologic and quantitative MR data) characteristic of each type of meniscal pathology. We will implement histologic and biomechanical reference standards. Our null hypothesis will be that quantitative MR properties will reflect the earliest structural alteration in meniscus and cartilage and that the severity of cartilage damage will correlate with type and severity of meniscal tear.
In specific aim 4, we will implement novel MR imaging sequences in a patient population with meniscal tear. Patterns of meniscal tears will be characterized, and cohorts with conservative therapy and meniscectomy will be followed longitudinally. Correlation with functional clinical, and activity scores will be performed. This project has exciting implications for clinical use. The developed novel pulse sequences allow non- invasive interrogation of earliest tissue structural changes with imaging biomarkers reflecting integrity of proteoglycan and collagen in cartilage and meniscus, and calcified layer cartilage. The potential applications are limitless. While the current study focuses on OA, the leading cause of disability in the nation, second only to cardiovascular disease, these techniques could be applied to any process affecting tissue structure (degeneration, trauma, rheumatologic disease) allowing non-invasive MR evaluation of tissue infrastructure, guidance of clinical therapy, determination of progression of structural alteration, and response to therapy.

Public Health Relevance

This project has exciting implications for clinical use. It will focus on development of novel MR pulse sequences that will allow non-invasive interrogation of the earliest structural alterations in cartilage and meniscus, providing imaging biomarkers that reflect the integrity of collagen and proteoglycan, the building blocks of these tissues. The project will explore the relationship of cartilage degeneration and meniscal pathology, focusing on the concept that the joint as a whole must be considered when identifying factors that affect progression of osteoarthrosis. Further, the project will analyze the effect of meniscectomy on cartilage degeneration. In addition, this work will explore the concept that non- invasive quantitative MRI techniques may reflect tissue function as expressed with biomechanical testing. The information from this study could be instrumental in understanding and monitoring progression of degenerative joint disease, as well as guiding clinical therapy.

Agency
National Institute of Health (NIH)
Type
Non-HHS Research Projects (I01)
Project #
5I01CX000625-03
Application #
8698392
Study Section
Endocrinology B (ENDB)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92161