Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Individuals with Early Alzheimer's Disease: Amyloid Imaging Positron Emission Tomography and Safety Results from a Phase 2 Study.

BACKGROUND: ACC-001 is an investigational therapeutic vaccine designed to elicit antibodies against the N-terminal peptide 1-7 of the amyloid-beta peptide, believed to be important in the pathogenesis of Alzheimer's disease. OBJECTIVES: To evaluate safety, immunogenicity, impact on brain amyloid, and other exploratory endpoints in participants receiving ACC-001. DESIGN: Randomized, phase 2, interventional study. TRIAL REGISTRATION: Clinicaltrials.gov ID NCT01227564. PARTICIPANTS: Individuals with early Alzheimer's disease (Mini-Mental State Examination scores ≥25, a global Clinical Dementia Rating of 0.5, and evidence of elevated baseline brain amyloid burden). INTERVENTION: Participants were randomized to ACC-001 3 µg or 10 µg with QS-21 adjuvant (50 µg), or placebo. MEASUREMENTS: The primary endpoint was change in brain amyloid burden by 18F-florbetapir positron emission tomography in composite cortical standard uptake value ratio. RESULTS: A total of 63 participants were randomized and 51 completed the study. At week 104, no significant differences were observed in 18F-florbetapir positron emission tomography composite cortical standard uptake value ratio between either ACC-001 dose compared with placebo. In both ACC-001 + QS-21 treatment groups, following the initial immunization, the anti-amyloid-beta geometric mean titers increased after each subsequent vaccination and then declined, with less apparent decline after the later compared with earlier immunizations. The majority of treatment-emergent adverse events in the ACC-001 + QS-21 groups were injection site reactions, which occurred at a greater rate in active treatment groups than in the placebo group. No amyloid-related imaging abnormalities of edema or effusion were reported. CONCLUSION: No statistically significant differences were observed between groups in the change from baseline brain amyloid burden despite apparently robust systemically measured anti-amyloid-beta antibody response at both dose levels. Insufficient antibody titers, poor quality immune response, short duration of treatment, or small sample size may have resulted in these findings. The safety and tolerability profile was acceptable.

Differences between X-ray and MRI-determined knee cartilage thickness in weight-bearing and non-weight-bearing conditions.

OBJECTIVE: Determine the effect of loading upon MRI-based mean medial femorotibial cartilage thickness (mMFT_th) and radiograph-based minimum joint space width (mJSW), and determine loading's effect on the relationship between these measures. METHODS: MRI and radiographs were analyzed of 25 knees in weight-bearing and non-weight-bearing conditions. Eight subjects had a Kellgren-Lawrence (KL) grade of 0, indicating no evidence of radiographic OA. The rest were KL = 2 or KL = 3, indicating mild to moderate OA. The change from unloaded to loaded conditions was calculated. RESULTS: Joint space measures decreased from unloaded to loaded conditions for both radiographs (mJSW = 3.29 mm unloaded to 3.16 mm loaded, P < 0.05) and MRI (mMFT_th = 2.70 mm unloaded to 2.55 mm loaded P < 0.001). The mean absolute difference measured from radiographs was larger for the OA group than the control group, at -0.20 mm for OA vs +0.01 mm for control. Loaded X-ray and loaded MRI joint space values from our study were no better correlated to one another than loaded X-ray and unloaded MRI. CONCLUSION: Knee loading does not add a very significant value to the study of joint space on healthy knees, but loading may play a role in the study of OA knees. Unloaded MRI assessments of cartilage thickness are as correlated to loaded JSW as to loaded MRI measurements. More study is necessary to determine whether loaded MRI adds significant value to the study of OA progression.

Relationship between knee pain and the presence, location, size and phenotype of femorotibial denuded areas of subchondral bone as visualized by MRI.

OBJECTIVE: Conflicting associations between imaging biomarkers and pain in knee osteoarthritis (OA) have been reported. A relation between pain and denuded areas of subchondral bone (dABs) has been suggested and this study explores this relationship further by relating the presence, phenotype, location and size of dABs to different measures of knee pain. METHODS: 633 right knees from the Osteoarthritis Initiative (OAI) (250 men, age 61.7 ± 9.6 yrs, BMI 29.4 ± 4.7 kg/m(2)) were included. Manual segmentation of the femorotibial cartilage plates was performed on 3 T coronal fast low angle shot with water excitation (FLASHwe) images. dABs were defined as areas where the subchondral bone was uncovered by cartilage. The following measures of pain were used: weightbearing-, non-weightbearing-, moderate-to-severe-, infrequent- and frequent knee pain. RESULTS: Using pain measures from subjects without dABs as a reference, those with at least one dAB had a 1.64-fold higher prevalence ratio [PR, 95% confidence interval (CI) 1.24-2.18] to have frequent and 1.45-fold higher for moderate-to-severe knee pain (95% CI 1.13-1.85). Subjects with dABs in central subregions had a 1.53-fold increased prevalence of having weightbearing pain (95% CI 1.20-1.97), especially when the central subregion was moderately (>10%) denuded (PR 1.81, 95% CI 1.35-2.42). Individuals with cartilage-loss-type dABs had a slightly higher prevalence (PR 1.13, 95% CI 1.00-1.27) of having frequent knee pain compared to individuals with intra-chondral-osteophyte-type dABs. CONCLUSION: This study supports a positive relation between femorotibial dABs and knee pain, especially when the dABs are located centrally (i.e., in weightbearing regions) or when the respective central subregion is moderately denuded.

Association of MR relaxation and cartilage deformation in knee osteoarthritis.

We assessed the relationship between cartilage MR relaxation times and biomechanical response of tibiofemoral articular cartilage to physiological loading in healthy subjects and patients with osteoarthritis (OA). Female subjects above 40 years of age with (N(1) = 20) and without (N(2) = 10) OA were imaged on a 3T MR scanner using a custom made loading device. MR images were acquired with the knee flexed at 20° with and without a compressive load of 50% of the subject's bodyweight. The subjects were categorized based on the clinical MRI scoring of medial and lateral cartilage surfaces. Data were stratified twice into two equal groups (low and high) at the median value of T(1ρ) and T(2) relaxation time. The change in contact area and cartilage deformation was measured within these groups. Paired Student's t-test (α = 0.05) was used to analyze the effect of loading on contact area and deformation. The average area of the contact region in the medial compartment was significantly higher in OA subjects compared with normal subjects in both unloaded (314 ± 112 mm(2) vs. 227 ± 106 mm(2), p = 0.023) and loaded (425 ± 128 mm(2) vs. 316 ± 107 mm(2), p = 0.01) conditions. The overall relative change of cartilage thickness in the medial compartment was significantly higher than the lateral compartment (-5.3 ± 9.9% vs. -1.9 ± 9.2%, p = 0.042). When cartilage was divided into deep and superficial layers, superficial layers showed higher changes in relaxation time (T(1ρ) and T(2)) than the changes in relaxation time of whole cartilage (Normal: 12.5% vs. 6.9%; OA: 10.9% vs. 4.6%). The average T(1ρ) and T(2) times, change in area of contact region, and change in cartilage thickness in subjects with OA were higher when compared to normal subjects. This study provides support for a relationship between the mechanical response of cartilage to physiological loading (cartilage-on-cartilage contact area and cartilage deformation) and MR relaxation times (T(1ρ) and T(2)) in both OA patients and normal subjects.

Clinical, radiographic, molecular and MRI-based predictors of cartilage loss in knee osteoarthritis.

OBJECTIVE: To examine the relationship of baseline clinical, radiographic, molecular and MRI measures with structural progression (subregional MRI-based femorotibial cartilage loss) in knee osteoarthritis (OA). METHODS: Single knees of 75 female participants with radiographic knee OA (and 77 healthy control participants) were examined over 24 months using MRI. Subregional femorotibial cartilage thickness was determined at baseline and follow-up. Baseline clinical, radiographic, molecular (n=16) and quantitative MRI-based measures of the meniscus and cartilage, including delayed gadolinium-enhanced MRI (dGEMRIC) and T2, were obtained. Differences in these baseline measures between radiographic osteoarthritic knees with longitudinal cartilage thinning (or thickening) and those with no significant change were evaluated by receiver operator characteristic analyses and Wilcoxon rank sum tests. RESULTS: The relatively strongest predictors of longitudinal cartilage thinning were reduced baseline cartilage thickness in the medial femur (area under the curve (AUC)=0.81), varus malalignment (AUC=0.77), reduced minimum joint space width and a greater radiographic joint space narrowing (JSN) score (both AUC=0.74). These remained significant after adjusting for multiple comparisons using false discovery rates. Reduced bone resorption (C-terminal telopeptide of type I collagen; AUC=0.65) and a low dGEMRIC index (reflecting low proteoglycan content) in the medial tibia (AUC=0.68) were associated with longitudinal cartilage thinning, but failed to reach statistical significance after correction for multiple testing in this (small) sample. CONCLUSIONS: This exploratory study indicates that baseline molecular or MRI cartilage compositional markers may not provide better discrimination between knees with cartilage thinning and those without longitudinal change than simple radiographic measures, such as greater JSN score.

Using ordered values of subregional cartilage thickness change increases sensitivity in detecting risk factors for osteoarthritis progression.

OBJECTIVE: To examine whether ordered values of (sub)regional femorotibial cartilage thickness change are superior to region-based approaches in detecting risk factors for cartilage loss in osteoarthritis (OA). METHODS: 58 women with knee OA had 3 Tesla MR images acquired at baseline and 24 months. Changes in cartilage thickness (∆ThCtAB) were determined in eight medial femorotibial subregions. An ascending sort of individual ∆ThCtAB measurements was done to create "ordered values". Risk factors for cartilage loss considered were: age, BMI, anatomical knee axis (AAA), minimal (medial) joint space width (mJSW), and percent of medial tibial plateau covered by the meniscus (percent cover). All change metrics were tested for association with the risk factors using Kendall's τ and relative sensitivity of multiple tests of subregions and ordered values were compared with single metrics of change from plate and compartment summaries and the first ordered value. RESULTS: The associations between subregion ∆ThCtAB and AAA (P=0.0002), mJSW (P=0.016), and age (P=0.011) were significant, but only AAA (at α=0.05) and age (at α=0.1) remained significant after adjusting for multiple subregions. In contrast, cMFTC had P-values<0.05 for AAA (P=0.0001), mJSW (P=0.016), and meniscus subluxation (0.04). The first ordered value had significant associations with AAA (P=0.0004), mJSW (P=0.003), meniscus subluxation (P=0.02) and percent cover (P=0.031) all of which were significant at α=0.05 after adjusting for tests on multiple risk factors. CONCLUSION: Ordered values of ∆ThCtAB were more sensitive in detecting risk factors of cartilage loss than subregional ∆ThCtAB. Sensitivity was further enhanced by considering the minimum ordered value as a single test, thus not requiring adjustment for multiple tests. Using ordered values there was a significant association between ∆ThCtAB and baseline AAA, mJSW, meniscus subluxation and meniscus percent cover. This study provides an important step in validating ordered values of cartilage change.

Comparison of 1-year vs 2-year change in regional cartilage thickness in osteoarthritis results from 346 participants from the Osteoarthritis Initiative.

OBJECTIVE: To compare femorotibial cartilage thickness changes over a 2- vs a 1-year observation period in knees with radiographic knee osteoarthritis (OA). METHODS: One knee of 346 Osteoarthritis Initiative (OAI) participants was studied at three time points [baseline (BL), year-1 (Y1), year-2 (Y2) follow-up]: 239 using coronal fast low angle shot (FLASH) and 107 using sagittal double echo at steady state (DESS) MR imaging. Changes in cartilage thickness were assessed in femorotibial cartilage plates and subregions, after manual segmentation with blinding to time-point. RESULTS: The standardized response mean (SRM) of total joint cartilage thickness over 2 years was modestly higher than over 1 year (FLASH: -0.44 vs -0.32/-0.28 [first/second year]; DESS: -0.42 vs -0.39/-0.18). For the subregion showing the largest change per knee (OV1), the 2-year SRM was similar or lower (FLASH: -1.20 vs -1.22/-1.61; DESS: -1.38 vs -1.64/-1.51) than the 1-year SRM. The changes in total joint cartilage thickness were not significantly different in the first and second year (FLASH: -0.8% vs -0.7%; DESS: -1.3% vs -0.8%) and were negatively correlated. Analysis of smallest detectable changes (SDCs) revealed that only few participants displayed significant progression in both consecutive periods. The location of the subregion contributing to OV1 in each knee was highly inconsistent between the first and second year observation period. CONCLUSIONS: The SRM of region-based cartilage thickness change in OA is modestly larger following a 2-year vs a 1-year observation period, while it is relatively similar when an OV-approach is chosen. Structural progression displays strong temporal and spatial heterogeneity at an individual knee level that should be considered when planning clinical trials.

The effects of acute loading on T1rho and T2 relaxation times of tibiofemoral articular cartilage.

OBJECTIVE: To evaluate the effect of acute loading on healthy and osteoarthritic knee cartilage T(1ρ) and T(2) relaxation times. DESIGN: Twenty subjects with radiographic evidence of osteoarthritis (OA) and 10 age-matched controls were enrolled. Magnetic resonance imaging (MRI) acquisition, including T(1ρ) and T(2) map sequences were performed unloaded and loaded at 50% body mass. Cartilage masks were segmented semi-automatically on registered high-resolution spoiled gradient-echo (SPGR) images for each compartment (medial and lateral). Cartilage lesions were identified using a modified Whole Organ Magnetic Resonance Imaging Score (WORMS) score. Statistical differences were explored using separate two-way (group×loading condition) Analysis of Variance (ANOVA) using age as a covariate to evaluate the effects of loading on T(1ρ) and T(2) relaxation times. RESULTS: A significant decrease in T(1ρ) (44.5±3.8 vs 40.2±4.8ms for unloaded and loaded, respectively; P<0.001) and T(2) (31.8±3.8 vs 30.5±4.8ms for unloaded and loaded, respectively; P<0.001) relaxation times was observed in the medial compartment with loading while no differences were observed in the lateral compartment. This behavior occurred independent of WORMS score. Cartilage compartments with small focal lesions experienced greater T(1ρ) change scores with loading when compared to cartilage without lesions or cartilage with larger defects (P=0.05). CONCLUSIONS: Acute loading resulted in a significant decrease in T(1ρ) and T(2) relaxation times of the medial compartment, with greater change scores observed in cartilage regions with small focal lesions. These data suggest that changes of T(1ρ) values with loading may be related to cartilage biomechanical properties (i.e., tissue elasticity) and may be a valuable tool for the scientist and clinician at identifying early cartilage disease.

Femorotibial cartilage morphology: reproducibility of different metrics and femoral regions, and sensitivity to change in disease.

This study was designed to characterize the reproducibility and sensitivity to change of magnetic resonance imaging-based cartilage morphology metrics and femoral regions of interest (ROIs), in order to provide preferable outcome measures in longitudinal studies of cartilage morphology. Test-retest acquisitions were obtained at 3 tesla (T) in 33 subjects with and without radiographic signs of osteoarthritis (OA) (reproducibility study) as well as baseline and 2-year follow-up acquisitions in 28 subjects with radiographic signs of advanced OA (sensitivity study). Cartilage was segmented in the tibia and two distinct anatomical femoral ROIs, a 'long' ROI extending 60% from the trochlear notch to the posterior end of the condyles, and a 'short' ROI extending to the intercondylar bone bridge. Coefficients of variation (reproducibility study) and standardized response means (SRMs, sensitivity study) were obtained for different morphology metrics and anatomical regions. The subchondral bone area of the long ROI was 20% greater and less variable than that of the short ROI; cartilage morphology metrics were generally more reproducible in the long ROI. Normalized cartilage volume (VCtAB) and mean cartilage thickness (over the entire subchondral bone area; ThCtAB.Me) tended to be more reproducible and more sensitive to change (SRM up to -0.62) than cartilage volume (SRM up to -0.44), cartilage thickness over the cartilaginous area (ThCcAB; SRM up to -0.48) or maximum cartilage thickness (ThCtAB; SRM up to -0.35). The long femoral cartilage ROI provided more reproducible measurements than the short one. VCtAB and ThCtAB.Me may be preferable metrics in longitudinal studies of articular cartilage adaptation or OA.

Presence, location, type and size of denuded areas of subchondral bone in the knee as a function of radiographic stage of OA - data from the OA initiative.

OBJECTIVE: To assess the presence, location, type and size of denuded areas of subchondral bone (dAB) in the femorotibial joint, measured quantitatively with 3T MRI, in a large subset of OAI participants. METHODS: One knee of 633 subjects (250 men, 383 women, aged 61.7+/-9.6 y) were studied, spanning all radiographic osteoarthritis (OA) stages. dABs were determined quantitatively using segmentations of coronal FLASHwe images, representing areas where the subchondral bone was not covered by cartilage. Post hoc visual examination of segmented images determined whether dABs represented full thickness cartilage loss or internal osteophyte. RESULTS: 7% Of the knees were Kellgren & Lawrence (KL) grade 0, 6% grade 1, 41% grade 2, 41% grade 3, and 5% grade 4. 39% Of the participants (48% of the men and 33% of the women) displayed dABs; 61% of the dABs represented internal osteophytes. 1/47 Participants with KL grade 0 displayed 'any' dAB whereas 29/32 of the KL grade 4 knees were affected. Even as early as KL grade 1, 29% of the participants showed dABs. There were significant relationships of dAB with increasing KL grades (P<0.001) and with ipsi-compartimental JSN (P< or =0.001). Internal osteophytes were more frequent laterally (mainly posterior tibia and internal femur) whereas full thickness cartilage loss was more frequent medially (mainly external tibia and femur). CONCLUSIONS: dABs occur already at earliest stages of radiographic OA (KL grades 1 and 2) and become more common (and larger) with increasing disease severity. Almost all KL grade 4 knees exhibited dABs, with cartilage loss being more frequent than internal osteophytes.

Osteoarthritis may not be a one-way-road of cartilage loss--comparison of spatial patterns of cartilage change between osteoarthritic and healthy knees.

OBJECTIVE: To explore whether longitudinal change in cartilage thickness in femorotibial subregions of knees with radiographic osteoarthritis (ROA) differs from that in healthy knees. METHODS: 3T coronal magnetic resonance (MR) images were acquired in 152 women at seven clinical centers at baseline (BL) and 24 months. Knees from 75 women with signs of ROA in either anterior-posterior or Lyon schuss radiographs were compared with those from 77 asymptomatic healthy controls without ROA to identify knees showing greater change in cartilage thickness than expected based on observations in healthy knees. The femorotibial cartilage thickness was determined in BL and follow-up MR images across five tibial and three femoral subregions in the medial/lateral compartment, respectively. RESULTS: A substantial portion of knees with ROA were classified as having longitudinal cartilage thinning (28%) or thickening (20%) in at least one medial femorotibial subregion based on comparisons to longitudinal changes observed in healthy knees; only 5% showed both subregional thinning and thickening across (different) medial subregions at the same time. Whereas the estimated proportion of Kellgren Lawrence grade (KLG) 3 knees (n=28) with significant medial cartilage thinning (46%) was substantially greater than that with cartilage thickening (18%), the estimated percentages of KLG2 knees (n=30) with significant medial thinning (20%) and thickening (23%) were similar. CONCLUSION: This exploratory study indicates that OA may not be a one-way-road of cartilage loss. Subregional analysis suggests that, compared with healthy knees, cartilage changes in ROA may occur in both directions. Medial femorotibial cartilage thickening was observed as frequently as cartilage thinning in KLG2 knees.

The association of prevalent medial meniscal pathology with cartilage loss in the medial tibiofemoral compartment over a 2-year period.

OBJECTIVE: To investigate the association of different types of magnetic resonance imaging (MRI)-detected medial meniscal pathology with subregional cartilage loss in the medial tibiofemoral compartment. METHODS: A total of 152 women aged >or=40 years, with and without knee osteoarthritis (OA) were included in a longitudinal 24-month observational study. Spoiled gradient recalled acquisitions at steady state (SPGR) and T2-weighted fat-suppressed MRI sequences were acquired. Medial meniscal status of the anterior horn (AH), body, and posterior horn (PH) was graded at baseline: 0 (normal), 1 (intrasubstance meniscal signal changes), 2 (single tears), and 3 (complex tears/maceration). Cartilage segmentation was performed at baseline and 24-month follow-up in various tibiofemoral subregions using computation software. Multiple linear regression models were applied for the analysis with cartilage loss as the outcome. In a first model, the results were adjusted for age and body mass index (BMI). In a second model, the results were adjusted for age, BMI and medial meniscal extrusion. RESULTS: After adjusting for age, BMI, and medial meniscal extrusion, cartilage loss in the total medial tibia (MT) (0.04 mm, P=0.04) and the external medial tibia (eMT) (0.068 mm, P=0.04) increased significantly for compartments with grade 3 lesions. Cartilage loss in the total central medial femoral condyle (cMF) (0.071 mm, P=0.03) also increased significantly for compartments with grade 2 lesions. Cartilage loss at the eMT was significantly related to tears of the PH (0.074 mm; P=0.03). Cartilage loss was not significantly increased for compartments with grade 1 lesions. CONCLUSION: The protective function of the meniscus appears to be preserved in the presence of intrasubstance meniscal signal changes. Prevalent single tears and meniscal maceration were found to be associated with increased cartilage loss in the same compartment, especially at the PH.

Change in regional cartilage morphology and joint space width in osteoarthritis participants versus healthy controls: a multicentre study using 3.0 Tesla MRI and Lyon-Schuss radiography.

OBJECTIVE: Cartilage morphology displays sensitivity to change in osteoarthritis (OA) with quantitative MRI (qMRI). However, (sub)regional cartilage thickness change at 3.0 Tesla (T) has not been directly compared with radiographic progression of joint space narrowing in OA participants and non-arthritic controls. METHODS: A total of 145 women were imaged at 7 clinical centres: 86 were non-obese and asymptomatic without radiographic OA and 55 were obese with symptomatic and radiographic OA (27 Kellgren-Lawrence grade (KLG)2 and 28 KLG3). Lyon-Schuss (LS) and fixed flexion (FF) radiographs were obtained at baseline, 12 and 24 months, and coronal spoiled gradient echo MRI sequences at 3.0 T at baseline, 6, 12 and 24 months. (Sub)regional, femorotibial cartilage thickness and minimum joint space width (mJSW) in the medial femorotibial compartment were measured and the standardised response means (SRMs) determined. RESULTS: At 6 months, qMRI demonstrated a -3.7% "annualised" change in cartilage thickness (SRM -0.33) in the central medial femorotibial compartment (cMFTC) of KLG3 subjects, but no change in KLG2 subjects. The SRM for mJSW in 12-month LS/FF radiographs of KLG3 participants was -0.68/-0.13 and at 24 months was -0.62/-0.20. The SRM for cMFTC changes measured with qMRI was -0.32 (12 months; -2.0%) and -0.48 (24 months; -2.2%), respectively. CONCLUSIONS: qMRI and LS radiography detected significant change in KLG3 participants at high risk of progression, but not in KLG2 participants, and only small changes in controls. At 12 and 24 months, LS displayed greater, and FF less, sensitivity to change in KLG3 participants than qMRI.

Subregional femorotibial cartilage morphology in women--comparison between healthy controls and participants with different grades of radiographic knee osteoarthritis.

OBJECTIVE: To identify subregional differences in femorotibial cartilage morphology between healthy controls and women with different grades of radiographic knee osteoarthritis (OA). DESIGN: 158 women aged > or =40 years were studied. Weight-bearing extended anterior-posterior (AP) and Lyon schuss radiographs were obtained and the Kellgren Lawrence grade (KLG) determined. 97 women had a body mass index (BMI)< or =28, no symptoms, and were AP KLG0. 61 women had a BMI> or =30, symptoms in the target knee, and mild (KLG2=31) to moderate (KLG3=30) medial femorotibial radiographic OA in the AP views. Coronal spoiled gradient echo water excitation sequences were acquired at 3.0 Tesla. Total plate and regional measures of cartilage morphology of the weight-bearing femorotibial joint were quantified. RESULTS: KLG2 participants displayed, on average, thicker cartilage than healthy controls in the medial femorotibial compartment (particularly anterior subregion of the medial tibia (MT) and peripheral [external, internal] subregions of the medial femur), and in the lateral femur. KLG3 participants displayed significantly thinner cartilage than KLG0 participants in the medial weight-bearing femur (central subregion), in the external subregion of the MT, and in the internal subregion of the lateral tibia. These differences were generally unaffected when possible effects of demographic covariates were considered. CONCLUSIONS: The results indicate that in femorotibial OA regional cartilage thickening and thinning may occur, dependent on the (radiographic) disease status of the joint. These changes appear to display a heterogeneous spatial pattern, where certain subregions are more strongly affected than others.

Relation of regional articular cartilage morphometry and meniscal position by MRI to joint space width in knee radiographs.

OBJECTIVE: To ascertain the contribution of articular cartilage morphometry and meniscal position on MRI to joint space width (JSW) measured in the Lyon schuss radiograph of the knee. DESIGN: 62 obese women with knee OA and 99 non-obese female controls (mean age 56.6 years) were imaged using 3T MRI and coronal water excitation spoiled gradient echo sequences. Segmentation of femorotibial cartilage morphology and regional morphometric analysis was performed using custom software. Meniscal position was measured quantitatively in sagittal and coronal planes. Minimum space width (mJSW) was measured in the Lyon Schuss knee radiograph; Kellgren and Lawrence grades (KLG) were assigned on standing anteroposterior knee films. The relative contribution of regional cartilage thickness and meniscal position to mJSW was assessed initially in univariate models and subsequently with multivariable modelling. RESULTS: 65% of the variation in mJSW was explained by regional cartilage thickness measures, different KLG and meniscal coverage. Of these measures the medial tibia cartilage thickness measures and central region of the central medial femur (ccMF) play a consistent role in variations in mJSW observed across all KLG. Further ccMF and the addition of percent meniscal coverage to this model explains the remaining differences in mean mJSW found between those subjects with definite joint space narrowing (KLG3) and those without OA. CONCLUSION: The variation in radiographic mJSW is best described by five regional cartilage thickness measures and percent meniscal coverage. The magnitude of each measures contribution differs according to radiographic severity with more variability explained by cartilage thickness of ccMF cartilage thickness and percent meniscal coverage with more severe disease.

Regional analysis of femorotibial cartilage loss in a subsample from the Osteoarthritis Initiative progression subcohort.

OBJECTIVE: The Osteoarthritis Initiative (OAI) is aimed at validating (imaging) biomarkers for monitoring progression of knee OA. Here we analyze regional femorotibial (FT) cartilage thickness changes over 1 year using 3 Tesla MRI. Specifically, we tested whether changes in central subregions exceed those in the total cartilage plates. METHODS: The right knees of a subsample of the OAI progression subcohort (n=156, age 60.9+/-9.9 years) were studied. Fifty-four participants had definite radiographic osteoarthritis (OA) (KLG 2 or 3) and a BMI>30. Mean and minimal cartilage thickness were determined in subregions of the medial/lateral tibia (MT/LT), and of the medial/lateral weight-bearing femoral condyle (cMF/cLF), after paired (baseline, follow up) segmentation of coronal FLASHwe images with blinding to the order of acquisition. RESULTS: The central aspect of cMF displayed a 5.8%/2.8% change in mean thickness in the group of 54/156 participants, respectively, with a standardized response mean (SRM) of -0.47/-0.31, whereas cartilage loss in the total cMF was 4.1%/1.9% (SRM -0.49/-0.30). In the central MT, the rate of change was -1.6%/-0.9% and the SRM -0.29/-0.20, whereas for the entire MT the rate was -1.0%/-0.5% and the SRM -0.21/-0.12. Minimal thickness displayed greater rates of change, but lower SRMs than mean thickness. CONCLUSIONS: This study shows that the rate of cartilage loss is greater in central subregions than in entire FT cartilage plates. The sensitivity to change in central subregions was higher than for the total cartilage plate in the MT and was similar to the total plate in the medial weight-bearing femur.

Predictors of systolic augmentation from left ventricular preexcitation in patients with dilated cardiomyopathy and intraventricular conduction delay.

BACKGROUND: VDD pacing can enhance systolic function in patients with dilated cardiomyopathy and discoordinate contraction; however, identification of patients likely to benefit is unclear. We tested predictors of systolic responsiveness on the basis of global parameters as well as directly assessed mechanical dyssynchrony. METHODS AND RESULTS: Twenty-two DCM patients with conduction delay were studied by cardiac catheterization with a dual-sensor micromanometer to measure LV and aortic pressures during sinus rhythm and LV free-wall pacing. Pacing enhanced isovolumetric (dP/dt(max)) and ejection-phase (pulse pressure, PP) systolic function by 35+/-21% and 16.4+/-11%, respectively, and these changes correlated directly (r=0.7, P=0.001). %DeltadP/dt(max) was weakly predicted by baseline QRS (r=0.6, P<0.02), more strongly by baseline dP/dt(max) (r=0.7, P=0.001), and best by bidiscriminate analysis combining baseline dP/dt(max) < or =700 mm Hg/s and QRS > or =155 ms to predict %DeltadP/dt(max) > or =25% and %DeltaPP > or =10% (P<0.0005, chi(2)), with no false-positives. Benefit could not be predicted by %DeltaQRS. To test whether basal mechanical dyssynchrony predicted responsiveness to LV pacing, circumferential strains were determined at approximately 80 sites throughout the LV by tagged MRI in 8 DCM patients and 7 additional control subjects. Strain variance at time of maximal shortening indexed dyssynchrony, averaging 28.0+/-7.1% in normal subjects versus 201.4+/-84.3% in DCM patients (P=0.001). Mechanical dyssynchrony also correlated directly with %DeltadP/dt(max) (r=0.85, P=0.008). Conclusions-These results show that although mechanical dyssynchrony is a key predictor for pacing efficacy in DCM patients with conduction delay, combining information about QRS and basal dP/dt(max) provides an excellent tool to identify maximal responders.

Mapping of regional myocardial strain and work during ventricular pacing: experimental study using magnetic resonance imaging tagging.

OBJECTIVES: The purpose of this study was to determine the spatial distribution of myocardial function (myofiber shortening and work) within the left ventricular (LV) wall during ventricular pacing. BACKGROUND: Asynchronous electrical activation, as induced by ventricular pacing, causes various abnormalities in LV function, perfusion and structure. These derangements may be caused by abnormalities in regional contraction patterns. However, insight into these patterns during pacing is as yet limited. METHODS: In seven anesthetized dogs, high spatial and temporal resolution magnetic resonance-tagged images were acquired in three orthogonal planes. Three-dimensional deformation data and LV cavity pressure and volume were used to determine midwall circumferential strain and external and total mechanical work at 192 sites around the left ventricle. RESULTS: During ventricular pacing, systolic fiber strain and external work were approximately zero in regions near the pacing site, and gradually increased to more than twice the normal value in the most remote regions. Total mechanical work, normalized to the value during right atrial pacing, was 38 +/- 13% (right ventricular apex [RVapex] pacing) and 61 +/- 23% (left ventricular base [LVbase] pacing) close to the pacing site, and 125 +/- 48% and 171 +/- 60% in remote regions, respectively (p < 0.05 between RVapex and LVbase pacing). The number of regions with reduced work was significantly larger during RVapex than during LVbase pacing. This was associated with a reduction of global LV pump function during RVapex pacing. CONCLUSIONS: Ventricular pacing causes a threefold difference in myofiber work within the LV wall. This difference appears large enough to regard local myocardial function as an important determinant for abnormalities in perfusion, metabolism, structure and pump function during asynchronous electrical activation. Pacing at sites that cause more synchronous activation may limit the occurrence of such derangements.

Mapping propagation of mechanical activation in the paced heart with MRI tagging.

The temporal evolution of three-dimensional (3-D) strain maps derived from magnetic resonance imaging (MRI) tagging were used to noninvasively evaluate mechanical activation in the left ventricle (LV) while seven canine hearts were paced in situ from three different sites: the base of the LV free wall (LVb), the right ventricular apex (RVa), and the right atrium (RA). Strain maps plotted against time showed the evolution of shortening over the entire LV midwall and were used to generate mechanical activation maps showing the onset of circumferential shortening. RA pacing showed rapid synchronous shortening; LVb pacing showed a wave front of mechanical activation propagating slowly and steadily from the pacing site, whereas RVa pacing showed regions of rapid and slower propagation. The mechanical (M) activation times correlated linearly with the electrical (E) activation (M = 1.06E + 8.4 ms, R = 0.95). The time for 90% activation of the LV was 63.1 +/- 24.3 ms for RA pacing, 130.2 +/- 9.8 ms for LVb pacing, and 121.3 +/- 17.9 ms for RVa pacing. The velocity of mechanical activation was calculated for LVb and RVa pacing and was similar to values reported for electrical conduction in myocardium. The propagation of mechanical activation for RVa pacing showed regional variations, whereas LVb pacing did not.