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UTE-T2∗ mapping detects sub-clinical meniscus injury after anterior cruciate ligament tear

Open ArchivePublished:February 23, 2012DOI:https://doi.org/10.1016/j.joca.2012.01.009

      Summary

      Objective

      Meniscus tear is a known risk factor for osteoarthritis (OA). Quantitative assessment of meniscus degeneration, prior to surface break-down, is important to identification of early disease potentially amenable to therapeutic interventions. This work examines the diagnostic potential of ultrashort echo time-enhanced T2∗ (UTE-T2∗) mapping to detect human meniscus degeneration in vitro and in vivo in subjects at risk of developing OA.

      Design

      UTE-T2∗ maps of 16 human cadaver menisci were compared to histological evaluations of meniscal structural integrity and clinical magnetic resonance imaging (MRI) assessment by a musculoskeletal radiologist. In vivo UTE-T2∗ maps were compared in 10 asymptomatic subjects and 25 ACL-injured patients with and without concomitant meniscal tear.

      Results

      In vitro, UTE-T2∗ values tended to be lower in histologically and clinically normal meniscus tissue and higher in torn or degenerate tissue. UTE-T2∗ map heterogeneity reflected collagen disorganization. In vivo, asymptomatic meniscus UTE-T2∗ values were repeatable within 9% (root-mean-square average coefficient of variation). Posteromedial meniscus UTE-T2∗ values in ACL-injured subjects with clinically diagnosed medial meniscus tear (n=10) were 87% higher than asymptomatics (n=10, P<0.001). Posteromedial menisci UTE-T2∗ values of ACL-injured subjects without concomitant medial meniscal tear (n=15) were 33% higher than asymptomatics (P=0.001). Posterolateral menisci UTE-T2∗ values also varied significantly with degree of joint pathology (P=0.001).

      Conclusion

      Significant elevations of UTE-T2∗ values in the menisci of ACL-injured subjects without clinical evidence of subsurface meniscal abnormality suggest that UTE-T2∗ mapping is sensitive to sub-clinical meniscus degeneration. Further study is needed to determine whether elevated subsurface meniscus UTE-T2∗ values predict progression of meniscal degeneration and development of OA.

      Keywords

      Introduction

      Meniscus degeneration and tear are known cofactors in the pathogenesis of both post-traumatic and idiopathic osteoarthritis (OA)
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      have been investigated as tools to assess the biochemical status of the meniscus with the goal of detecting microscopic alterations before gross damage occurs. Quantitative T1rho measurements detect differences between healthy controls and Anterior Cruciate Ligament-injured subjects within 3 months of injury in the posterior lateral meniscus, but the physiologic basis for this difference is not yet understood
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      T1rho relaxation time of the meniscus and its relationship with T1rho of adjacent cartilage in knees with acute ACL injuries at 3 T.
      . Similarly, dGEMRIC values in meniscus have been shown to correlate with dGEMRIC values in articular cartilage, an index of glycosaminoglycan content that is known to vary with OA severity
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      Delayed gadolinium-enhanced magnetic resonance imaging of cartilage in knee osteoarthritis: findings at different radiographic stages of disease and relationship to malalignment.
      . However, the biophysical basis for this observation also needs more investigation. A study by Rausher et al found that meniscus T2, but not T1rho, differentiated healthy controls from subjects with mild or severe OA after adjustment for age
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      • et al.
      Meniscal measurements of T1rho and T2 at MR imaging in healthy subjects and patients with osteoarthritis.
      . Another study by Zarins et al found that while both T2 and T1rho discriminated intact from torn menisci, neither metric discriminated healthy menisci from intact menisci with intra-substance abnormality
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      Cartilage and meniscus assessment using T1rho and T2 measurements in healthy subjects and patients with osteoarthritis.
      .
      T2 is usually measured with spin echo sequences that, in order to satisfy safety restrictions, use long echo times (TE10 ms) and, consequently, only capture long-T2 relaxations. T2∗, the effective T2 shortened by phase dispersion from both main and local magnetic field inhomogeneities, captures fast-T2 relaxations (T2∗<10 ms) that reflect spin–spin interactions of protons bound to collagen and the degree of collagen fibril-alignment
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      Macromolecule and water magnetization exchange modeling in articular cartilage.
      . Ultrashort echo time-enhanced T2∗ (UTE-T2∗) mapping is a novel quantitative technique with the potential to measure short-T2∗ relaxations from joint tissues that are not well captured by standard T2 mapping
      • Williams A.
      • Qian Y.
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      • Chu C.R.
      Assessing degeneration of human articular cartilage with ultra-short echo time (UTE) T2∗ mapping.
      . UTE-T2∗ maps illustrate the spatial distribution of T2∗ relaxation times from protons within the meniscus and provide an estimate of meniscus T2∗ values.
      In articular cartilage in vitro, UTE-T2∗ measurements reflect collagen matrix integrity as determined by polarized light microscopy (PLM)
      • Williams A.
      • Qian Y.
      • Bear D.
      • Chu C.R.
      Assessing degeneration of human articular cartilage with ultra-short echo time (UTE) T2∗ mapping.
      and are sensitive to T2∗ values as short as 1.3 ms
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      Short T2 contrast with three-dimensional ultrashort echo time imaging.
      . Meniscus is a particularly good target tissue for assessment by UTE imaging due to its abundance of type I collagen and short-T2 components
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      The distribution of different molecular species of collagen in fibrous, elastic and hyaline cartilages of the pig.
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      Magnetic resonance imaging of short T2 components in tissue.
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      Contrast enhancement of short T2 tissues using ultrashort TE (UTE) pulse sequences.
      . In vitro UTE imaging of human meniscus has produced stunning high-resolution (∼200 μm) depictions of collagen fiber arrangements
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      Short T2 contrast with three-dimensional ultrashort echo time imaging.
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      • et al.
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      and reveals microcalcifications
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      Short T2 contrast with three-dimensional ultrashort echo time imaging.
      . In vivo, subtraction of meniscus UTE images from longer TE images with contrast enhancement permits visualization of vascularized and non-vascularized zones
      • Gatehouse P.D.
      • He T.
      • Puri B.K.
      • Thomas R.D.
      • Resnick D.
      • Bydder G.M.
      Contrast-enhanced MRI of the menisci of the knee using ultrashort echo time (UTE) pulse sequences: imaging of the red and white zones.
      . UTE-prepared T1rho-quantification has also been explored in meniscus
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      • Carl M.
      • Diaz E.
      • Takahashi A.
      • Han E.
      • Szeverenyi N.M.
      • et al.
      Ultrashort TE T1rho (UTE T1rho) imaging of the Achilles tendon and meniscus.
      .
      The aim of the current work is to examine the diagnostic potential of UTE-T2∗ mapping to detect meniscus degeneration. UTE-T2∗ of meniscus is evaluated in vitro, compared to histology as the gold standard, and in vivo, in ACL-injured human patients with meniscal abnormalities related to ACL tear.

      Patients and methods

      Human meniscus specimens

      Sixteen human meniscus specimens (eight medial, eight lateral) were obtained from six intact cadaver knee joints (LifeLegacy Foundation, Phoenix, AZ, USA) and two tibial plateau explants with menisci attached (Musculoskeletal Transplant Foundation, Edison, NJ, USA). Menisci sourced from intact knee joints varied in health by gross inspection. Menisci sourced from explants were from specimens originally harvested for meniscal allograft transplantation.

      MRI of meniscus specimens

      All MRI images were acquired on a clinical 3T MRI scanner (MAGNETOM Trio Tim, Siemens, Erlangen, Germany) with an eight-channel knee coil (Invivo Inc., Gainesville, FL, USA). Intact cadaver joints (n=6) were scanned with the NIH-sponsored Osteoarthritis Initiative (OAI) sequences and scanner (www.oai.ucsf.edu) described in detail by Peterfy et al
      • Peterfy C.G.
      • Schneider E.
      • Nevitt M.
      The osteoarthritis initiative: report on the design rationale for the magnetic resonance imaging protocol for the knee.
      . The OAI images of intact cadaver joints were reviewed by a musculoskeletal radiologist who assessed each joint for meniscus degeneration and/or tear. Low signal in all pulse sequences indicated normal meniscus. Abnormal signal within the meniscus was considered secondary to degeneration: Grade 1 – minimal, linear signal within the meniscus; Grade 2 – globular signal replacing most of the meniscus; Grade 3 – abnormal signal extending to the femoral, tibial or inner margin of the meniscus. Abnormal signal extending to the meniscus surface in more than two consecutive slices indicated tear. UTE-T2∗ mapping images were acquired on all meniscal specimens.

      Histology methods

      Following MRI, menisci were dissected from intact joints (n=12 menisci from six knees) and from tibial plateaus (n=4 menisci from two explants) and fixed in 10% neutral buffered formalin. Gross sections (1 cm wide) were removed from the posterior medial and lateral horns to coincide with the MRI sections evaluated (Fig. 1). Histologic sections were then processed, paraffin-embedded, vertically sectioned (5 μm thickness) parallel to the sagittally oriented MR images, and stained with hematoxylin/eosin (HE), alcian blue (AB), Safranin-O (Saf-O), and picro-sirius red (PSR) using standard techniques
      • Junqueira L.C.
      • Bignolas G.
      • Brentani R.R.
      Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue sections.
      • Junquiera L.C.
      • Junqueira L.C.
      • Brentani R.R.
      A simple and sensitive method for the quantitative estimation of collagen.
      . PLM analysis of the collagen network was performed using a Nikon Eclipse TE2000-U polarized light microscope (Nikon, Chiyoda-ku, Tokyo) with two orthogonal polarizers. PSR-stained sections were placed between the polarizers and rotated so that the polarizers were aligned 45° against the superior meniscus surface. HE, AL, Saf-O and PSR/PLM images were graded using a simplified version of the scoring system devised by Pauli et al
      • Pauli C.
      • Grogan S.P.
      • Patil S.
      • Otsuki S.
      • Hasegawa A.
      • Koziol J.
      • et al.
      Macroscopic and histopathologic analysis of human knee menisci in aging and osteoarthritis.
      , shown in Table I.
      Figure thumbnail gr1
      Fig. 1(a) Human medial meniscus from a 34-year-old female. Black arrow shows gross section of posterior meniscus removed for histologic assessments. Red-dashed line indicates plane of MRI and histologic sectioning. (b) In vivo AWSOS image from an asymptomatic subject with 7 ms echo time. Segmentation of posterior medial meniscus is demonstrated with the red-dashed line. (c) In vivo regional differences were evaluated by comparing UTE-T2∗ values of the “inner” portion (yellow-dashed line) to the “outer” portion (blue-dashed line) of the posteromedial menisci.
      Table IHistologic scoring system for human menisci specimens
      Meniscus featureCriteriaScore
      Surface and matrix integrityComplete substance tear, loss of tissue, tissue maceration3
      Partial substance tear, fraying, surface fibrillations2
      Fraying at inner borders, minor surface fibrillation/undulation, no tears1
      Intact borders, no surface irregularities0
      CellularityHypocellular3
      Regions of hypo – or a-cellularity2
      Diffuse hypercellularity1
      Normal, homogeneous cellularity0
      Matrix organization, collagen alignmentFibrocartilaginous separation, severe mucoid degeneration, cysts, loss of birefringence3
      Bands of mucoid degeneration, some loss of birefringence2
      Diffuse foci of mucoid matrix, collagen mostly tightly woven1
      Highly organized tightly woven collagen fibrils, birefringent and homogenous staining of ground substance0
      GAG distributionStrong Saf-O staining intensity3
      Moderate Saf-O staining2
      Slight Saf-O staining1
      No Saf-O staining0
      Simplified from macro and histopathic scoring system developed by Pauli et al
      • Pauli C.
      • Grogan S.P.
      • Patil S.
      • Otsuki S.
      • Hasegawa A.
      • Koziol J.
      • et al.
      Macroscopic and histopathologic analysis of human knee menisci in aging and osteoarthritis.
      .

      Human subjects

      Ten asymptomatic human subjects with no known or suspected knee pathology and 25 subjects recruited from the clinical practices of three surgeons for ACL tear participated in these studies. All subjects gave informed consent and all studies were approved by the institutional review board.
      Asymptomatic subjects (n=10) underwent MR imaging for UTE-T2∗ mapping of the left knee, one time daily for three consecutive days. Subjects were scanned at same time (±1 h) each day. One asymptomatic subject was scanned on only two consecutive days. ACL-injured subjects (n=25) underwent imaging of the injured knee one time within 4 weeks prior to ACL-repair surgery. At the time of surgery, meniscus status was assessed with arthroscopic examination and palpation. Status of menisci in ACL-injured subjects (tear/no tear; degree of degeneration) was determined from surgical and/or clinical MRI reports (clinical MRI report was unavailable in five cases).

      UTE-T2∗ imaging and mapping

      UTE-T2∗ mapping images for all tissue specimens and human subjects were acquired with a three-dimensional (3D) sequence acquisition-weighted stack of spirals (AWSOS)
      • Qian Y.
      • Boada F.E.
      Acquisition-weighted stack of spirals for fast high-resolution three-dimensional ultra-short echo time MR imaging.
      as previously described
      • Williams A.
      • Qian Y.
      • Chu C.R.
      UTE-T2∗ mapping of human articular cartilage in vivo: a repeatability assessment.
      . Briefly, the single-echo AWSOS acquisition was repeated 11 times at 11 different echo times (0.6, 1, 2, 3, 4, 5, 7, 10, 20, 30, 40 ms). Other acquisition parameters were: 140 mm field of view (FOV), 2 mm slice thickness, 52–60 slices, 24 in-plane spirals, 11.52 ms spiral readout time, 5 μs data sampling interval. For in vitro imaging (cadaver knee joints and explants), FA/TR was 30/100 ms with 512 matrix and scantime of 5.12 min per TE image, for a total scantime of 56 min. For in vivo imaging, FA/TR was 30/80 ms with 256 matrix and scantime of 1.92 min per TE image for a total scantime of 22 min. UTE-T2∗ acquisitions were sagittally oriented and centered on the femorotibial joint.
      UTE-T2∗ maps were generated with a mono-exponential T2 curve-fit of all 11 echo images using MRIMapper software (©Beth Israel Deaconess and MIT 2006). Prior to T2 curve-fitting, TE images from the AWSOS sequence collected in vivo were linearly interpolated to a matrix size of 512 (or a pixel size of 273 mm) to permit finer image registration. TE images were then registered to reduce spatial offsets between images resulting from patient motion during acquisition. Image registration was performed with rigid, whole-pixel, in-plane-only translations between successive echo acquisitions to maximize mutual information between the images.
      Regions of interest (ROIs) were manually segmented, by one individual with 10 years prior segmenting experience, from a single section from each of the medial and lateral compartments of each knee or explant. In order to reduce variability across subjects with respect to hoop-fiber alignment, a mid-sagittal slice was selected so that the cross-section of meniscus captured in the imaging plane was orthogonal to the hoop fibers [Fig. 1(a)]. The posterior horns were chosen for evaluation because they are in the zone of injury during ACL tear. Menisci were segmented by manually outlining the posterior aspects of the medial or lateral meniscus seen on an AWSOS image collected at TE time of 7 ms in which the contrast between menisci and surrounding tissues was strongest [Fig. 1(b)]. The mean and standard deviations (SDs) of UTE-T2∗ values observed in each meniscus ROI were calculated and recorded. Regional differences were assessed by segmenting smaller sub-regions within the posteromedial meniscus [Fig. 1(c)]. Sub-ROIs included the “inner” portion of the meniscus, consisting of approximately 40% of all pixels seen in the posteromedial meniscus section and the “outer” portion, consisting of approximately 25% of pixels. Inner and outer sub-regions were segmented to roughly correspond to the red and white zones delineated by Gatehouse et al
      • Gatehouse P.D.
      • He T.
      • Puri B.K.
      • Thomas R.D.
      • Resnick D.
      • Bydder G.M.
      Contrast-enhanced MRI of the menisci of the knee using ultrashort echo time (UTE) pulse sequences: imaging of the red and white zones.
      . Regional differences of the posterolateral meniscus were not evaluated because inner/outer segmentation was more difficult laterally preventing consistent segmentation across subjects.

      In vivo UTE-T2∗ mapping repeatability assessment

      Three-day intersession UTE-T2∗ repeatability was evaluated in two ways. First, relative inter-subject intersession reproducibility across all 10 asymptomatic subjects was expressed by the root-mean-square average coefficients of variation (RMSA-CV) for each ROI. RMSA-CV was determined by √((∑CV2)/n) where intra-subject CV was calculated by dividing the SD of a subjects' UTE-T2∗ values from Day 1, Day 2, and Day 3 by the mean of the subjects' UTE-T2∗ values from Day 1, Day 2, and Day 3 for each ROI, where n was the number of subjects. Second, absolute intersession precision was expressed as median of the intra-subject SDs for each ROI.

      Statistical analyses

      In vitro and in vivo, medial and lateral meniscus UTE-T2∗ values were evaluated separately. In vitro, non-parametric Spearman's rho assessed correlations between meniscal specimens' UTE-T2∗ values and histopathic scores. In addition, specimens were binned into two groups by histologic score (‘less degenerate’ scores 0–4 vs ‘more degenerate’ scores 5–9) and average UTE-T2∗ values calculated for each group of medial or lateral menisci, respectively. Non-parametric Mann–Whitney tests assessed pairwise differences between groups. Human subject UTE-T2∗ values were binned into three groups: asymptomatic, ACL-injured without clinical evidence of subsurface meniscal abnormality, and ACL-injured with tear to the meniscus. Non-parametric Kruskal–Wallis statistics examined differences across these groups and Mann–Whitney tests assessed pairwise differences. Regional differences in UTE-T2∗ values were assessed by non-parametric Wilcoxon signed rank tests. All statistical analyses were performed using Excel (Microsoft, Seattle, WA, USA) and SPSS (SPSS Inc., Chicago, IL, USA). Statistical significance was accepted for P<0.05.

      Results

      In vitro histologic and clinical MRI assessments

      Table II summarizes clinical MRI assessment, bulk mean UTE-T2∗ value and histopathic score of each meniscus sample examined. In vitro, mean UTE-T2∗ values ranged 6–13 ms. Areas of histologically confirmed tear showed focally higher values in the region of the tear (Fig. 2). Non-parametric correlation of unbinned UTE-T2∗ values and histopathic scores shows UTE-T2∗ and histology are not significantly correlated in either medial or lateral menisci (Spearman's rho P=0.62, 0.54; P=0.10, 0.16, respectively). UTE-T2∗ values binned by histologic grade (scores 0–4 vs 5–9) were not found to vary significantly with histopathic degeneration in this small sample size (medial n=8, Mann–Whitney P=0.13; lateral n=8, Mann–Whitney P=0.29). Medially, more degenerated samples (scores 5–9, n=6) showed a mean UTE-T2∗ value of 9.7 [95% confidence interval (CI)=8.1–11.3] ms, while less degenerated samples (scores 0–4, n=2) had an average UTE-T2∗ value of 6.5 (95%CI=5.5–7.5) ms. Laterally, the difference was smaller: 8.3 (6.4–10.1) vs 9.8 (7.2–12.3) ms, n=4, 4.
      Table IIUTE-T2∗ values, clinical MRI and histologic evaluations of human menisci specimens
      SpecimenAgeClinical MRI assessment of posterior meniscusMean±SD UTE-T2∗, msHistologic score
      1 – medial77Grade II–III degeneration, complex posterior tear10±39
        lateralGrade I–II degeneration, no tear
      Histology does not support clinical MRI assessment.
      11±43
      2 – medial76Grade II degeneration, no tear8±36
        lateralGrade II–III degeneration, no tear8±49
      3 – medial75Grade II degeneration, no tear13±47
        lateralGrade I–II degeneration, complex posterior tear12±45
      4 – medial77Grade I degeneration, posterior tear to body-junction8±37
        lateralGrade I degeneration12±46
      5 – medial40Grade I degeneration, no tear6±35
        lateralGrade II degeneration, incomplete posterior tear7±45
      6 – medial
      Specimen #6 is from a female donor. All others specimens are from male donors.
      34No degeneration, no tear7±20
        lateralNo degeneration, no tear8±23
      7 – medial
      Meniscal specimens from tibial plateau explants. These specimens were evaluated by gross inspection in place of clinical MRI.
      27Gross defect to superior surface11±55
        lateralPristine meniscus7±21
      8 – medial
      Meniscal specimens from tibial plateau explants. These specimens were evaluated by gross inspection in place of clinical MRI.
      26Pristine meniscus6±22
        lateralPristine meniscus7±21
      Specimen #6 is from a female donor. All others specimens are from male donors.
      Meniscal specimens from tibial plateau explants. These specimens were evaluated by gross inspection in place of clinical MRI.
      Histology does not support clinical MRI assessment.
      Figure thumbnail gr2
      Fig. 2Sample UTE-T2∗ maps of histologically and clinically confirmed tears to the posterior horn of the medial meniscus. UTE-T2∗ maps demonstrate focal regions (red arrows) of relatively high UTE-T2∗ values in (a) a 77-year-old male with a posterior tear extending to the body junction, mean±SD UTE-T2∗ across entire ROI=8±3 ms, and in (b) another 77-year-old male with a complex posterior tear, mean±SD UTE-T2∗=10±3 ms. Corresponding Saf-O images of these specimens (c, d) verify tears to the menisci (black arrows) and show moderate GAG staining. The saturation and contrast of these Saf-O images have been manipulated to more clearly demonstrate tissue morphology.
      Comparison across all three in vitro measures of meniscus status was performed by grossly binning each of the metrics: mean UTE-T2∗ value (≤8 ms or ≥10 ms); histopathic score (≤3 or ≥5); clinical MRI assessment by a musculoskeletal radiologist (tear/no tear, degenerate/normal signal). Five specimens demonstrated relatively low mean UTE-T2∗ values (≤8 ms), relatively normal histopathic scores (≤3) and showed no clinical signs of tear or degeneration [Fig. 3(a) ]. Five other specimens demonstrated relatively high mean UTE-T2∗ values (≥10 ms), relatively degenerate histopathic scores (≥5), and evidence of tear and/or degenerate signal in corresponding clinical MRI images of posterior meniscus [Fig. 3(c)]. Five of the remaining specimens demonstrated highly heterogeneous UTE-T2∗ maps, relatively high histopathic scores (≥5) and grade I–III degeneration on the clinical MRIs [Fig. 3(b)]. In the last specimen, UTE-T2∗ was high (11 ms), but histology (score 3) did not support the clinical diagnosis of grade II degeneration.
      Figure thumbnail gr3
      Fig. 3Sample UTE-T2∗ maps (a–c), PLM images at 4× from PSR-stained slides (d–f), and AB acquired at 4× and cropped (g–i) of three human menisci. Cross sections show posterior medial meniscus. UTE-T2∗ findings are consistent with both histologic and clinical MRI assessments by a musculoskeletal radiologist in the majority of cases examined, including the specimens in the left and right columns of this figure. Left column – clinically unremarkable and histopathically normal medial meniscus from 34-year-old female: UTE-T2∗ values are low (a, mean±SD 7±2 ms), and the matrix appears organized, tightly woven and brightly birefringent by PLM with smooth ground substance (d, g, histology score 0). Middle column – clinically and histologically degenerate specimen from 76-year-old male exhibiting a heterogeneous UTE-T2∗map. Although the mean UTE-T2∗ value is relatively low (b, mean±SD 8±3 ms), clinically this specimen demonstrated grade II degeneration and exhibits cyst formation with unorganized collagen fibers (e, h, score 6). Right column – elevated UTE-T2∗ values (c, mean±SD 13±4 ms), in specimen from a 75-year-old male with clinically diagnosed grade II degeneration throughout the meniscus. Histology demonstrates disorganized collagen with low birefringence and mucoid degeneration (f, i, histology score 7).

      Meniscus UTE-T2∗ mapping repeatability in vivo

      Example in vivo UTE-T2∗ maps from a representative asymptomatic subject of the repeatability analysis are shown in Fig. 4. UTE-T2∗ values in asymptomatic subjects' menisci (n=10, mean age=27 (95%CI=25–29) years, mean body mass index (BMI)=24 (95%CI=22–26), five females, 10 left) exhibited relative intersession precision errors of 9% (RMSA-CV) corresponding to absolute precision errors of 1.0 ms.
      Figure thumbnail gr4
      Fig. 4Example in vivo UTE-T2∗ maps of a representative asymptomatic subject from the 3-day intersession repeatability analysis. Repeated measures of UTE-T2∗ values were stable within 9% RMSA-CV (1.0 ms) for the posteromedial meniscus among asymptomatic subjects, with no known or suspected knee pathology. The posteromedial UTE-T2∗ values for the subject shown here were (mean±SD): (Day 1–10±4 ms, Day 2–11±4 ms; Day 3–10±3 ms).

      Regional UTE-T2∗ variations

      No differences were detected between the “inner” and “outer” aspects of the posteromedial menisci of asymptomatic subjects (n=10, Wilcoxon signed rank test, P=0.17) or ACL-injured subjects with (n=10, Wilcoxon signed rank test, P=0.68) or without concomitant medial meniscus pathology (n=15, Wilcoxon signed rank test, P=0.69). The mean age and BMI of ACL-injured subjects were 29 (95%CI=25–32) years and 28 (95%CI=26–30), respectively (n=25, 15 females, 16 left).

      Meniscus UTE-T2∗ quantitative comparisons

      UTE-T2∗ voxel values, calculated with a mono-exponential T2-fit, observed in menisci of asymptomatic subjects ranged approximately 6.2–17.1 ms (tenth, ninetieth percentiles, respectively). The average UTE-T2∗ value across the entirety of the posteromedial meniscus observed among the 10 asymptomatic subjects was 9.8 (95%CI=8.9–10.7) ms. Compared to asymptomatic subjects, the UTE-T2∗ maps of subjects with ACL-injury appeared more heterogeneous and demonstrated higher UTE-T2∗ values, as shown in Fig. 5. Quantitatively, meniscus UTE-T2∗ values varied significantly with degree of joint pathology (Kruskal–Wallis, P<0.0001), as shown in Fig. 5d. UTE-T2∗ menisci values in subjects with clinically diagnosed medial meniscus tear (n=10, mean=18.3 (95%CI=15.0–21.6) ms) were significantly greater (87% higher, Mann–Whitney test, P<0.0001) than the menisci of asymptomatic subjects. Menisci UTE-T2∗ values of ACL-injured subjects without clinical evidence of subsurface medial meniscus abnormality (n=15, mean=13.1 (95%CI=11.7–14.4) ms) were 33% higher (Mann–Whitney, P=0.001) than menisci UTE-T2∗ values of asymptomatic subjects. There was also a significant difference between ACL-injured subject groups: those with concomitant medial meniscus tear had significantly higher posteromedial UTE-T2∗ values than ACL-injured subjects without clinical evidence of subsurface meniscus pathology (Mann–Whitney, P=0.01).
      Figure thumbnail gr5
      Fig. 5Significant elevations of UTE-T2∗ values in the menisci of subjects with ACL-injury but without clinical evidence of subsurface meniscus pathology suggest that UTE-T2∗ mapping may be sensitive to sub-clinical meniscus degeneration. Example UTE-T2∗ maps (a–c) overlaid on AWSOS images acquired with UTE=0.6 ms demonstrate striking UTE-T2∗ differences between subjects. UTE-T2∗ values (mean±SD) of an asymptomatic subject are lower and more homogeneous (a, 8±2 ms) than observed in a patient without (b, 13±5 ms) or in a patient with tear to the medial meniscus (c, 21±7 ms). UTE-T2∗ values of the posterior meniscus varied significantly across subjects with degree of joint pathology (d, medial P<0.0001; e, lateral P=0.001). Posteromedial meniscus UTE-T2∗ values in subjects with clinically diagnosed medial meniscus tear (n=10) were 87% higher than asymptomatic subjects (n=10, P<0.0001). Posteromedial menisci UTE-T2∗ values of subjects with ACL without clinical evidence of concomitant subsurface medial meniscal abnormality (n=15) were 33% higher than asymptomatics (P=0.001). Posterolateral meniscus UTE-T2∗ values in subjects with lateral meniscus tear (n=6) were 77% higher than asymptomatics (n=10, P=0.001). Posterolateral menisci UTE-T2∗ values of subjects with ACL-injury without clinically diagnosed subsurface lateral meniscus pathology (n=19) were 23% higher than asymptomatics (P=0.005). Error bars represent±95% CIs. ∗∗P0.005; ∗P0.05.
      In lateral menisci, UTE-T2∗ values of the posterior aspect varied significantly with degree of joint pathology (Kruskal–Wallis, P=0.001), as shown in Fig. 5e. UTE-T2∗ menisci values in subjects with clinically diagnosed lateral meniscus tear (n=6, mean=16.7 (95%CI=11.3–22.1) ms) were 77% higher (Mann–Whitney, P=0.001) than the menisci of asymptomatic subjects (n=10, mean=9.4 (95%CI=8.6–10.2) ms). Menisci UTE-T2∗ values of ACL-injured subjects without lateral meniscus abnormality (n=19, mean=11.6 (95%CI=10.5–12.7) ms) were 23% higher (Mann–Whitney, P=0.005) than menisci UTE-T2∗ values of asymptomatic subjects. There was also a significant difference between ACL-injured groups: those with concomitant lateral meniscus tear had significantly higher posterolateral UTE-T2∗ values than ACL-injured subjects without clinical evidence of subsurface meniscus pathology (Mann–Whitney, P=0.019).

      Discussion

      In vivo 3D UTE-T2∗ mapping of the meniscus is feasible, repeatable, and achievable in scantimes tolerated by subjects with knee pain. This study demonstrates that non-invasive UTE-T2∗ mapping is sensitive to meniscus tears and can be used to quantitatively characterize meniscus degeneration in patients. Significant elevations of UTE-T2∗ values in the posterior horns of menisci of ACL-injured subjects without clinical evidence of subsurface meniscal abnormality suggest that UTE-T2∗mapping is sensitive to sub-clinical meniscus degeneration in knees known to be at risk for developing OA. This finding is not unexpected given that the posterior horn of the medial meniscus is a secondary restraint to anterior tibial translation and the posterior horns of both menisci are in the pathway of ACL-injury.
      The histopathic and clinical status of meniscus tissue is reflected by the magnitude and spatial distribution of UTE-T2∗ values in the tissue. In vitro, mean UTE-T2∗ values were relatively low (≤8 ms) in samples exhibiting no or only mild degeneration by histology and without clinical MRI evidence of tear or degeneration. Specimens exhibiting both histopathic and clinical MRI evidence of more severe degeneration had relatively high mean UTE-T2∗ values (≥10 ms). In 30% of the cases examined, however, relatively low mean UTE-T2∗ values (≤8 ms) were seen in meniscus tissue found to be degenerate both clinically and histologically. In each of these cases, UTE-T2∗ maps demonstrated highly heterogeneous distributions of UTE-T2∗ values with focal regions of elevated UTE-T2∗ values corresponding to clinically diagnosed regions of degeneration. These findings highlight the inadequacy of relying on a mean UTE-T2∗ value that is calculated by averaging across all UTE-T2∗ voxel values within an ROI. Measures of UTE-T2∗ texture, like heterogeneity, entropy or measures of order
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      • et al.
      The feasibility of characterizing the spatial distribution of cartilage T(2) using texture analysis.
      • Haralick R.M.
      Statistical and structural approaches to texture.
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      Separation of healthy and early osteoarthritis by automatic quantification of cartilage homogeneity.
      , may increase the sensitivity of UTE-T2∗ to different degrees of tissue degeneration and improve its ability to characterize the molecular integrity of the tissue.
      The meniscus histology grading system used in this study was adapted from the system developed by Pauli et al to ‘quantify zonal degeneration . . . for an improved assessment of progressive changes with aging and disease’
      • Peterfy C.G.
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      • Nevitt M.
      The osteoarthritis initiative: report on the design rationale for the magnetic resonance imaging protocol for the knee.
      . A zonal analysis of spatially matched MRI and histology images may help improve the correlation between UTE-T2∗ values and histopathic scores. However, because of the difference in scale between histology (micrometers) and the MRI images (millimeters) in this study, the images represented different quantities of tissue. Therefore, a finer zonal analysis of tissue sub-regions was not pursued.
      The time-course for UTE-T2∗ change in the meniscus following ACL-injury or due to OA has not to our knowledge been reported and has the potential to be highly variable between patients. Among asymptomatics, however, meniscus UTE-T2∗ maps were repeatable with intersession precision error of 9% RMSA-CV, corresponding to an absolute error within 1 ms. This is likely a conservative estimate of UTE-T2∗ repeatability because RMSA-CV emphasizes values not near to center of the distribution and is sensitive to small changes in UTE-T2∗ mean. The repeatability error reported here is in-line with intercession repeatability reports from other qMRI measures of meniscus physiology in the literature, including T1rho (3–13% CV)
      • Bolbos R.I.
      • Link T.M.
      • Ma C.B.
      • Majumdar S.
      • Li X.
      T1rho relaxation time of the meniscus and its relationship with T1rho of adjacent cartilage in knees with acute ACL injuries at 3 T.
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      • Diaz E.
      • Takahashi A.
      • Han E.
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      • et al.
      Ultrashort TE T1rho (UTE T1rho) imaging of the Achilles tendon and meniscus.
      • Rauscher I.
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      • Cheng J.
      • Li X.
      • Huber M.B.
      • Luke A.
      • et al.
      Meniscal measurements of T1rho and T2 at MR imaging in healthy subjects and patients with osteoarthritis.
      , T2 (4–13%)
      • Rauscher I.
      • Stahl R.
      • Cheng J.
      • Li X.
      • Huber M.B.
      • Luke A.
      • et al.
      Meniscal measurements of T1rho and T2 at MR imaging in healthy subjects and patients with osteoarthritis.
      , and UTE-T2∗ mapping of articular cartilage (8–15% RMSA-CV)
      • Williams A.
      • Qian Y.
      • Chu C.R.
      UTE-T2∗ mapping of human articular cartilage in vivo: a repeatability assessment.
      . Intersession UTE-T2∗ repeatability of 9% RMSA-CV measured in asymptomatics, a clinically stable population, helps to establish the difference between day-to-day fluctuations in the UTE-T2∗ metric from potentially clinically relevant changes observed in menisci of diseased or injured knees. It is important to point out that while UTE-T2∗ repeatability may be worse in an ACL-injured population, the 9% repeatability achieved here is likely more than sufficient to detect the 87% increase in UTE-T2∗ values between asymptomatics and subjects with torn menisci and the 33% increase between asymptomatics and ACL-surgery subjects without concomitant meniscus tear. Previously, Tsai et al reported the average T2 value of the posterior horn of the medial meniscus in normal young adults to be 9.65 ms
      • Tsai P.H.
      • Chou M.C.
      • Lee H.S.
      • Lee C.H.
      • Chung H.W.
      • Chang Y.C.
      • et al.
      MR T2 values of the knee menisci in the healthy young population: zonal and sex differences.
      . The UTE-T2∗ values measured in menisci of asymptomatic subjects in the current work (9.8 ms) are in excellent agreement with this prior value.
      An extensive macroscopic and histopathic analyses of 214 human menisci recently reported by Pauli et al concluded that ‘degeneration of the menisci initiates within the substance of the tissue rather than the surface’
      • Pauli C.
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      • Patil S.
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      • et al.
      Macroscopic and histopathologic analysis of human knee menisci in aging and osteoarthritis.
      . The results of the current work suggest that UTE-T2∗ mapping is sensitive to early degenerative changes within the substance of the meniscus. Specifically, ACL-injured subjects with intact menisci that do not exhibit evidence of degeneration detectable by gross inspection, arthroscopic palpation or clinical MRI evaluation, have significantly elevated meniscus UTE-T2∗ values compared to healthy controls. In light of these findings, it is reasonable to conclude that non-invasive MRI UTE-T2∗ mapping of subsurface meniscus structural integrity is sensitive to sub-clinical meniscus degeneration in a population known to be at risk for meniscal degeneration. Longitudinal evaluation is needed to determine the clinical implications of subsurface degeneration detected by UTE-T2∗, and whether UTE-T2∗ mapping of meniscus can be used to predict progressive meniscal degeneration or the development of broader joint pathology.
      The UTE-T2∗ value reported in this work is not a pure measure of any single component of T2∗ relaxation in meniscus. Rather, the UTE-T2∗ metric, calculated from a mono-exponential fit routine, represents a weighted combination of all T2∗ decay components present in the same voxel. An ex vivo examination of multi-component UTE-T2∗-fitting demonstrated that up to four types of T2∗ decay types could be detected in articular cartilage
      • Qian Y.
      • Williams A.A.
      • Chu C.R.
      • Boada F.E.
      Multicomponent T2∗ mapping of knee cartilage: technical feasibility ex vivo.
      . The primary short- and long-T2∗ components were found to have average values of 1–6 ms and 22 ms, respectively with the short-T2∗ showing better differentiation between healthy and diseased explants
      • Qian Y.
      • Williams A.A.
      • Chu C.R.
      • Boada F.E.
      Multicomponent T2∗ mapping of knee cartilage: technical feasibility ex vivo.
      . The meniscus is known to have an even higher abundance of short-T2 components compared to articular cartilage due to its highly organized and tightly bundled collagen fibrils
      • Ghadially F.N.
      • Lalonde J.M.
      • Wedge J.H.
      Ultrastructure of normal and torn menisci of the human knee joint.
      • Kambic H.E.
      • McDevitt C.A.
      Spatial organization of types I and II collagen in the canine meniscus.
      • Rattner J.B.
      • Matyas J.R.
      • Barclay L.
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      • Sciore P.
      • Lo I.K.
      • et al.
      New understanding of the complex structure of knee menisci: implications for injury risk and repair potential for athletes.
      . Therefore, it is expected that a larger proportion of total T2∗ signal from meniscus voxels will emanate from short-T2 components compared to articular cartilage. A preliminary exploration of multi-exponential analyses of UTE-T2∗ data from normal human menisci found that a bi-exponential model provided a better fit to the image data did a mono-exponential model
      • Diaz E.
      • Chung C.B.
      • Bae W.C.
      • Statum S.
      • Znamirowski R.
      • Bydder G.M.
      • et al.
      Ultrashort echo time spectroscopic imaging (UTESI): an efficient method for quantifying bound and free water.
      . Further, 46% of total UTE-T2∗ signal in meniscus was found to be due to short-T2 components in the tissue (mean short-T2∗ relaxation time of 1.54 ms), and 53% of total signal was due to long-T2∗ components (mean long-T2∗ relaxation time of 13.6 ms)
      • Diaz E.
      • Chung C.B.
      • Bae W.C.
      • Statum S.
      • Znamirowski R.
      • Bydder G.M.
      • et al.
      Ultrashort echo time spectroscopic imaging (UTESI): an efficient method for quantifying bound and free water.
      . The relative values and distributions of long and short-T2∗ components in torn and degenerate menisci have yet to be rigorously evaluated.
      In this work, degenerative menisci demonstrated higher UTE-T2∗ values than menisci of asymptomatic subjects, and only 10% of pixels in asymptomatic menisci had values less than 6.2 ms. Strictly speaking, a UTE (i.e., echo time <1 ms) is not required to study meniscus T2∗ relaxation. However, the inclusion of a UTE with high signal at 0.6 ms facilitates both capture and curve-fitting of rapidly decaying ‘short’ (i.e., <6 ms) T2∗ signals providing increased sensitivity to subtle differences between meniscus regions that may help to detect earlier changes to meniscus health. The choice of the 11 echoes acquired in this work was determined by Monte Carlo simulations
      • Qian Y.
      • Williams A.A.
      • Chu C.R.
      • Boada F.E.
      Multicomponent T2∗ mapping of knee cartilage: technical feasibility ex vivo.
      for covering both short- and long-components of T2∗ relaxation. Further work is needed to optimize the number of echoes needed to adequately detect subtle UTE-T2∗ differences across tissue regions and across patients while also reducing total scantime.
      UTE-T2∗ mapping is a novel tool for the detection and quantification of subsurface meniscus degeneration. The ability to diagnose and quantitatively stage meniscus status, prior the surface break-down is important to identifying disease states potentially amenable to interventions to delay or prevent the onset of OA. Further study is needed to determine whether elevated subsurface meniscus UTE-T2∗ values, particularly in the absence of clinically diagnosed abnormality, predict progression of meniscal degeneration and development of OA.

      Author contributions

      Ashley Williams contributed to conception and design of the study, collection and assembly of data, analysis and interpretation of data, drafting, critical revision and final approval of the article. Dr. Yongxian Qian contributed to acquisition of data, revising the article for critical intellectual content, and final approval of the article. Dr. Sara Golla contributed to analysis and interpretation of data, revising the article for critical intellectual content, and final approval of the article. Dr. Constance Chu is responsible for the integrity of the work as a whole, and she obtained the funding for this study. Dr. Chu also contributed to conception and design of the study, provision of patients and study materials, acquisition and interpretation of study data, revising the article for critically important intellectual content, final approval of the article.

      Funding source

      Funding for this work was provided by the NIH [ RO1 AR052784 (CR Chu) and P60 AR054731 (CR Chu/K Kwoh)]. The study sponsors had no involvement with collection, analysis or interpretation of data, nor any involvement with writing this manuscript or the decision to submit it to Osteoarthritis and Cartilage.

      Conflict of interest

      The authors of this work have no conflicts of interest to report relevant to this work.

      Acknowledgments

      The authors would like to acknowledge the contributions of Michele Mulkeen for her excellent histology preparations and Stephen Bruno for his tireless coordination of study subjects and scanner time.

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