Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques.

OBJECTIVES: To explore the effects of tofacitinib-an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)-with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand. METHODS: In this exploratory, phase 2, randomised, double-blind, parallel-group study, patients received tofacitinib 10 mg twice daily + MTX, tofacitinib 10 mg twice daily + placebo (tofacitinib monotherapy), or MTX + placebo (MTX monotherapy), for 1 year. MRI endpoints (Outcome Measures in Rheumatology Clinical Trials RA MRI score (RAMRIS), quantitative RAMRIS (RAMRIQ) and dynamic contrast-enhanced (DCE) MRI) were assessed using a mixed-effect model for repeated measures. Treatment differences with p<0.05 (vs MTX monotherapy) were considered significant. RESULTS: In total, 109 patients were randomised and treated. Treatment differences in RAMRIS bone marrow oedema (BME) at month 6 were -1.55 (90% CI -2.52 to -0.58) for tofacitinib + MTX and -1.74 (-2.72 to -0.76) for tofacitinib monotherapy (both p<0.01 vs MTX monotherapy). Numerical improvements in RAMRIS synovitis at month 3 were -0.63 (-1.58 to 0.31) for tofacitinib + MTX and -0.52 (-1.46 to 0.41) for tofacitinib monotherapy (both p>0.05 vs MTX monotherapy). Treatment differences in RAMRIQ synovitis were statistically significant at month 3, consistent with DCE MRI findings. Less deterioration of RAMRIS and RAMRIQ erosive damage was seen at months 6 and 12 in both tofacitinib groups versus MTX monotherapy. CONCLUSIONS: These results provide consistent evidence using three different MRI technologies that tofacitinib treatment leads to early reduction of inflammation and inhibits progression of structural damage. TRIAL REGISTRATION NUMBER: NCT01164579.

Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity.

The serotonergic system is widely distributed throughout the central nervous system. It is well known as a mood regulating system, although it also contributes to many other functions. With resting state functional magnetic resonance imaging (RS-fMRI) it is possible to investigate whole brain functional connectivity. We used this non-invasive neuroimaging technique to measure acute pharmacological effects of the selective serotonin reuptake inhibitor sertraline (75 mg) in 12 healthy volunteers. In this randomized, double blind, placebo-controlled, crossover study, RS-fMRI scans were repeatedly acquired during both visits (at baseline and 3, 5, 7 and 9h after administering sertraline or placebo). Within-group comparisons of voxelwise functional connectivity with ten functional networks were examined (p<0.005, corrected) using a mixed effects model with cerebrospinal fluid, white matter, motion parameters, heart rate and respiration as covariates. Sertraline induced widespread effects on functional connectivity with multiple networks; the default mode network, the executive control network, visual networks, the sensorimotor network and the auditory network. A common factor among these networks was the involvement of the precuneus and posterior cingulate cortex. Cognitive and subjective measures were taken as well, but yielded no significant treatment effects, emphasizing the sensitivity of RS-fMRI to pharmacological challenges. The results are consistent with the existence of an extensive serotonergic system relating to multiple brain functions with a possible key role for the precuneus and cingulate.

Changes in MR relaxation times of the meniscus with acute loading: an in vivo pilot study in knee osteoarthritis.

PURPOSE: To prospectively evaluate changes in T1ρ and T2 relaxation times in the meniscal body with acute loading using MRI in osteoarthritic knees and to compare these findings with those of age-matched healthy controls. MATERIALS AND METHODS: Female subjects above 40 years of age with (N1 = 20) and without osteoarthritis (OA) (N2 = 10) were imaged on a 3 Tesla 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 radiographic evidence of OA. Three different zones (outer, middle, and inner) of meniscus body were defined (each occupying 1/3rd the width). After adjusting for age and body mass index in the general linear regression model, repeated measures analysis of variance was used to detect significant differences in T1ρ and T2 with and without loading. RESULTS: In the unloaded condition, the average T1ρ and T2 times were elevated in the outer and middle zones of the medial meniscus in OA subjects compared with the controls. In the loaded condition, T1ρ and T2 times of the outer zone of the medial meniscus was significantly elevated in OA subjects compared with controls. Finally the change (from unloaded to loaded) was significantly higher in controls than OA subjects (15.1% versus 8.3%; P = 0.039 for ΔT1ρ , and 11.5% versus 6.9%, P = 0.049 for ΔT2 ). CONCLUSION: These findings suggest that while the OA process appears to affect the relaxation times of all regions within the meniscus, it may affect some regions sooner or to a greater degree. Furthermore, the differences in the change in relaxation times between unloaded and loaded conditions may reveal evidence about load transmission failure of the outer zone of the medial meniscus in subjects with knee OA. It is possible that these metrics (ΔT1ρ and ΔT2 ) may be valuable as an early biomechanical biomarker, which could be used to predict load transmission to the underlying articular cartilage.

Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study.

OBJECTIVE: The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported. METHODS: In this double-blind, parallel-group, placebo-controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily. At month 3, nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo-treated patients were advanced at 6 months. Four primary efficacy end points were all analyzed in a step-down procedure. RESULTS: At month 6, response rates according to the American College of Rheumatology 20% improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (51.5% and 61.8%, respectively, versus 25.3%; both P < 0.0001). At month 6, least squares mean (LSM) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06, respectively, versus 0.47 for placebo (P = 0.0792 and P ≤ 0.05, respectively). At month 3, LSM changes in the Health Assessment Questionnaire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 (significance not declared due to step-down procedure) and -0.54 (P < 0.0001), respectively, versus -0.15 for placebo. At month 6, rates of remission (defined as a value <2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate) for tofacitinib at 5 mg and 10 mg twice daily were 7.2% (significance not declared due to step-down procedure) and 16.0% (P < 0.0001), respectively, versus 1.6% for placebo. The safety profile was consistent with findings in previous studies. CONCLUSION: Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX.

Standardization of analysis sets for reporting results from ADNI MRI data.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) three-dimensional T1-weighted magnetic resonance imaging (MRI) acquisitions provide a rich data set for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI-1 have been created, comprising screening visits, 1-year completers (subjects who all have screening, 6- and 12-month scans), 2-year annual completers (screening, 1-year and 2-year scans), 2-year completers (screening, 6-months, 1-year, 18-months [mild cognitive impaired (MCI) only], and 2-year scans), and complete visits (screening, 6-month, 1-year, 18-month [MCI only], 2-year, and 3-year [normal and MCI only] scans). As the ADNI-GO/ADNI-2 data become available, updated standard analysis sets will be posted regularly.

A computational neurodegenerative disease progression score: method and results with the Alzheimer's disease Neuroimaging Initiative cohort.

While neurodegenerative diseases are characterized by steady degeneration over relatively long timelines, it is widely believed that the early stages are the most promising for therapeutic intervention, before irreversible neuronal loss occurs. Developing a therapeutic response requires a precise measure of disease progression. However, since the early stages are for the most part asymptomatic, obtaining accurate measures of disease progression is difficult. Longitudinal databases of hundreds of subjects observed during several years with tens of validated biomarkers are becoming available, allowing the use of computational methods. We propose a widely applicable statistical methodology for creating a disease progression score (DPS), using multiple biomarkers, for subjects with a neurodegenerative disease. The proposed methodology was evaluated for Alzheimer's disease (AD) using the publicly available AD Neuroimaging Initiative (ADNI) database, yielding an Alzheimer's DPS or ADPS score for each subject and each time-point in the database. In addition, a common description of biomarker changes was produced allowing for an ordering of the biomarkers. The Rey Auditory Verbal Learning Test delayed recall was found to be the earliest biomarker to become abnormal. The group of biomarkers comprising the volume of the hippocampus and the protein concentration amyloid beta and Tau were next in the timeline, and these were followed by three cognitive biomarkers. The proposed methodology thus has potential to stage individuals according to their state of disease progression relative to a population and to deduce common behaviors of biomarkers in the disease itself.

In vivo tibiofemoral cartilage-to-cartilage contact area of females with medial osteoarthritis under acute loading using MRI.

PURPOSE: To investigate the effect of acute loading on in vivo tibiofemoral contact area changes in both compartments, and to determine whether in vivo tibiofemoral contact area differs between subjects with medial knee osteoarthritis (OA) and healthy controls. MATERIALS AND METHODS: Ten subjects with medial knee OA (KL3) and 11 control subjects (KL0) were tested. Coronal three-dimensional spoiled gradient-recalled (3D-SPGR) and T(2) -weighted fast spin-echo FSE magnetic resonance imaging (MRI) of the knee were acquired under both unloaded and loaded conditions. Tibiofemoral cartilage contact areas were measured using image-based 3D models. RESULTS: Tibiofemoral contact areas in both compartments significantly increased under loading (P < 0.001) and the increased contact area in the medial compartment was significantly larger than in the lateral compartment (P < 0.05). Medial compartment contact area was significantly larger in KL3 subjects than KL0 subjects, both at unloaded and loaded conditions (P < 0.05). Contact areas measured from 3D-SPGR and T(2) -weighted FSE images were strongly correlated (r = 0.904). CONCLUSION: Females with medial OA increased tibiofemoral contact area in the medial compartment compared to healthy subjects under both unloaded and loaded conditions. The contact area data presented in this study may provide a quantitative reference for further cartilage contact biomechanics such as contact stress analysis and cartilage biomechanical function difference between osteoarthritic and healthy knees.

The relationship between prevalent medial meniscal intrasubstance signal changes and incident medial meniscal tears in women over a 1-year period assessed with 3.0 T MRI.

OBJECTIVE: Intrasubstance meniscal signal changes not reaching the articular surface on fast spin echo (FSE) sequences are considered to represent mucoid degeneration on MRI. The aim of this study was to evaluate the association of prevalent intrasubstance signal changes with incident tears of the medial meniscus detected on 3.0 T MRI over a 1-year period. MATERIALS AND METHODS: A total of 161 women aged ≥ 40 years participated in a longitudinal 1-year observational study of knee osteoarthritis. MRI (3.0 T) was performed at baseline and 12-month follow-up. The anterior horn, body, and posterior horn of the medial meniscus were scored by two experienced musculoskeletal radiologists using the Boston-Leeds Osteoarthritis Knee Score (BLOKS) system. Four grades were used to describe the meniscal morphology: grade 0 (normal), grade 1 (intrasubstance signal changes not reaching the articular surface), grade 2 (single tears), and grade 3 (complex tears and maceration). Fisher's exact test and the Cochran-Armitage trend test were performed to evaluate whether baseline intrasubstance signal changes (grade 1) predict incident meniscal tears/maceration (grades 2 and/or 3) in the same subregion of the medial meniscus, when compared to subregions without pathology as the reference group (grade 0). RESULTS: Medial meniscal intrasubstance signal changes at baseline did not predict tears at follow-up when evaluating the anterior and posterior horns (left-sided p-values 0.06 and 0.59, respectively). No incident tears were detected in the body. CONCLUSION: We could not demonstrate an association between prevalent medial meniscal intrasubstance signal changes with incident tears over a 1-year period.

Osteoarthritis of the knee at 3.0 T: comparison of a quantitative and a semi-quantitative score for the assessment of the extent of cartilage lesion and bone marrow edema pattern in a 24-month longitudinal study.

OBJECTIVE: To compare a semi-quantitative and a quantitative morphological score for assessment of early osteoarthritis (OA) evolution. MATERIALS AND METHODS: 3.0 T MRI of the knee was performed in 60 women, 30 with early OA (each 15 with Kellgren-Lawrence grade 2 and 3) and 30 age-matched controls at baseline and at 12 and 24 months. Pathological condition was assessed with the whole-organ magnetic resonance imaging score (WORMS). Cartilage abnormalities and bone marrow edema pattern (BMEP) were also quantified using a previously introduced morphological quantitative score. These data were correlated with changes in clinical parameters and joint space width using generalized estimation equations (GEE). RESULTS: At baseline, OA patients had significantly (p < 0.05) more and larger cartilage lesions and BMEP. During follow-up, cartilage lesions increased significantly (p < 0.05) in the patients compared with controls: WORMS showed progression only at the lateral patella, whereas the quantitative score revealed progression additionally at the trochlea and at the medial compartment. Both scores showed a significant (p < 0.05) increase in BMEP at the lateral femur in OA patients. In addition, quantitative scores of BMEP of the whole knee decreased significantly (p < 0.05) after 12 months and increased after 24 months in the patients, but showed an increase in controls at all follow-up examinations. Only weak correlations between structural imaging findings and clinical parameters were observed. CONCLUSION: Quantitative assessment of cartilage lesions and BMEP is more sensitive to changes during the course of the disease than semi-quantitative scoring. However, structural imaging findings do not correlate well with the clinical progression of OA.

An efficient subset of morphological measures for articular cartilage in the healthy and diseased human knee.

The relationship between three-dimensional, MRI-based morphologic measurements commonly taken of knee cartilage was examined to determine whether a subset of variables fully reflects differences observed in cartilage in cross-sectional and longitudinal studies. The benefits of a subset of measures include increased statistical power due to reduced multiple comparisons, improved understanding of relationships between the morphologic measures of articular knee cartilage, and greater efficiency in reporting results. One hundred fifty-two women (77 healthy and 75 with knee osteoarthritis) had coronal 3-T MR images of the knee acquired at baseline and at 24 months. Measures of femorotibial cartilage morphology (surface area, thickness, volume, etc.) were determined in the medial and lateral tibia and femur. Cartilage thickness (mean cartilage thickness over the total area of the [subchondral] bone), total subchondral bone area, and percentage of denuded area of the subchondral bone were found to explain over 90% of the cross-sectional and longitudinal variation observed in other measures of cartilage morphology commonly reported in knee osteoarthritis. Hence, these three measures of cartilage morphology explain nearly all variation in a larger set of common cartilage morphology measures both cross-sectionally and longitudinally, both in healthy and in osteoarthritic knees. These variables hence define an efficient subset for describing structural status and change in osteoarthritic cartilage.

A three-dimensional quantitative method to measure meniscus shape, position, and signal intensity using MR images: a pilot study and preliminary results in knee osteoarthritis.

This pilot study presents a technique for three-dimensional and quantitative analysis of meniscus shape, position, and signal intensity and compares results in knees with (n = 20) and without (n = 11) radiographic osteoarthritis. 3-T MR images with 2mm section thickness were acquired using a proton density-weighted, fat-suppressed, coronal, fast spin-echo sequence. Segmentation of the tibial, femoral, and external surface of the medial meniscus and the tibial joint surface was performed. Three-dimensional parameters were computed to describe the shape, position, and signal intensity of the entire meniscus and three subregions (body, anterior, and posterior horn). Key results included a greater size (i.e., volume, surface areas, and thickness), increased medial extrusion (i.e., greater extrusion distance, greater meniscal area uncovered by tibial surface), and elevated signal intensity of the medial meniscus in osteoarthritis than in nonosteoarthritis knees, particularly in the meniscus body. These results need to be confirmed in larger cohorts, preferably under weight-bearing conditions.

Longitudinal quantitative MR imaging of cartilage morphology in the presence of gadopentetate dimeglumine (Gd-DTPA).

MRI-based cartilage morphometry can monitor cartilage loss in osteoarthritis. Intravenous Gd-DTPA injection is needed for compositional (proteoglycan) cartilage imaging with delayed gadolinium enhanced MRI (dGEMRIC). However, longitudinal changes of cartilage morphology have not been compared in the presence and absence of Gd-DTPA. Baseline and 2-year follow-up images were acquired in 41 female participants with definite medial radiographic osteoarthritis, both before and 2 h after Gd-DTPA injection, and cartilage thickness was measured. In the absence of Gd-DTPA, a 2.6% reduction in cartilage thickness was observed between baseline and follow-up in the central subregion of the medial femorotibial compartment (standardized response mean [SRM]= -0.33; P<0.05), but only a 0.7% reduction (SRM= -0.10; P=0.51) in the presence of Gd-DTPA. The findings suggest that morphometric cartilage measurement in the presence of Gd-DTPA needs to undergo further validation, before one can recommend longitudinal dGEMRIC and morphological cartilage imaging to be performed in a single session.

Carotid plaque morphology and composition: initial comparison between 1.5- and 3.0-T magnetic field strengths.

PURPOSE: To prospectively compare the interpretation and quantification of carotid vessel wall morphology and plaque composition at 1.5-T with those at 3.0-T magnetic resonance (MR) imaging. MATERIALS AND METHODS: Twenty participants (mean age, 69.8 years [standard deviation] +/- 10.5; 75% men) with 16%-79% carotid stenosis at duplex ultrasonography were imaged with 1.5-T and 3.0-T MR imaging units with bilateral four-element phased-array surface coils. This HIPAA-compliant study was approved by the institutional review board, and all participants gave written informed consent. Protocols designed for similar signal-to-noise ratios across platforms were implemented to acquire axial T1-weighted, T2-weighted, intermediate-weighted, time-of-flight, and contrast material-enhanced T1-weighted images. Lumen area, wall area, total vessel area, wall thickness, and presence or absence and area of plaque components were documented. Continuous variables from different field strengths were compared by using the intraclass correlation coefficient (ICC) and repeated measures analysis. The Cohen kappa was used to evaluate agreement between 1.5 T and 3.0 T on compositional dichotomous variables. RESULTS: There was a strong level of agreement between field strengths for all morphologic variables, with ICCs ranging from 0.88 to 0.96. Agreement in the identification of presence or absence of plaque components was very good for calcification (kappa = 0.72), lipid-rich necrotic core (kappa = 0.73), and hemorrhage (kappa = 0.66). However, the visualization of hemorrhage was greater at 1.5 T than at 3.0 T (14.7% vs 7.8%, P < .001). Calcifications measured significantly (P = .03) larger at 3.0 T, while lipid-rich necrotic cores without hemorrhage were similar between field strengths (P = .9). CONCLUSION: At higher field strengths, the increased susceptibility of calcification and paramagnetic ferric iron in hemorrhage may alter quantification and/or detection. Nevertheless, imaging criteria at 1.5 T for carotid vessel wall interpretation are applicable at 3.0 T.

Changes in Brain Volume with Bapineuzumab in Mild to Moderate Alzheimer's Disease.

BACKGROUND: Bapineuzumab, an anti-amyloid-ß monoclonal antibody, was evaluated in two placebo-controlled trials in APOE*ɛ4 carriers and noncarriers, respectively, with Alzheimer's disease. OBJECTIVES: A volumetric magnetic resonance imaging substudy was performed to determine if bapineuzumab altered brain volume rate of change. METHODS: Bapineuzumab dosages included 0.5 mg/kg in carriers and 0.5 or 1.0 mg/kg in noncarriers, every 13 weeks for 78 weeks. Volumetric outcomes included annualized brain, ventricular, and mean hippocampal boundary shift integrals (BBSI; VBSI; HBSI) up to Week 71. Treatment differences were estimated using mixed models for repeated measures. RESULTS: For BBSI and HBSI, there were no significant treatment-related differences within either study, but, compared to pooled carriers and noncarriers receiving placebo, noncarriers receiving1.0 mg/kg bapineuzumab had greater increases in these measures. Bapineuzumab-treated patients showed significantly greater VBSI rates compared with placebo for 0.5 mg/kg in carriers and 1.0 mg/kg (but not 0.5 mg/kg) in noncarriers. CONCLUSIONS: Bapineuzumab produced an increase in ventricular volume compared with placebo. Etiology for this increase is unclear but may be related to amyloid-ß clearance or its consequences.

Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials.

BACKGROUND: Our objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer's disease (AD). METHODS: Two of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.5 mg/kg (both trials) or 1.0 mg/kg (noncarrier trial) or placebo every 13 weeks. Coprimary endpoints were change from baseline to week 78 on the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale and the Disability Assessment for Dementia. RESULTS: A total of 683 and 329 patients completed the current carrier and noncarrier trials, respectively, which were terminated prematurely owing to lack of efficacy in the two other phase 3 trials of bapineuzumab in AD. The current trials showed no significant difference between bapineuzumab and placebo for the coprimary endpoints and no effect of bapineuzumab on amyloid load or cerebrospinal fluid phosphorylated tau. (Both measures were stable over time in the placebo group.) Amyloid-related imaging abnormalities with edema or effusion were confirmed as the most notable adverse event. CONCLUSIONS: These phase 3 global trials confirmed lack of efficacy of bapineuzumab at tested doses on clinical endpoints in patients with mild to moderate AD. Some differences in the biomarker results were seen compared with the other phase 3 bapineuzumab trials. No unexpected adverse events were observed. TRIAL REGISTRATION: Noncarriers (3000) ClinicalTrials.gov identifier NCT00667810 ; registered 24 Apr 2008. Carriers (3001) ClinicalTrials.gov identifier NCT00676143 ; registered 2 May 2008.

Carotid magnetic resonance imaging for monitoring atherosclerotic plaque progression: a multicenter reproducibility study.

This study sought to determine the multicenter reproducibility of magnetic resonance imaging (MRI) and the compatibility of different scanner platforms in assessing carotid plaque morphology and composition. A standardized multi-contrast MRI protocol was implemented at 16 imaging sites (GE: 8; Philips: 8). Sixty-eight subjects (61 ± 8 years; 52 males) were dispersedly recruited and scanned twice within 2 weeks on the same magnet. Images were reviewed centrally using a streamlined semiautomatic approach. Quantitative volumetric measurements on plaque morphology (lumen, wall, and outer wall) and plaque tissue composition [lipid-rich necrotic core (LRNC), calcification, and fibrous tissue] were obtained. Inter-scan reproducibility was summarized using the within-subject standard deviation, coefficient of variation (CV) and intraclass correlation coefficient (ICC). Good to excellent reproducibility was observed for both morphological (ICC range 0.98-0.99) and compositional (ICC range 0.88-0.96) measurements. Measurement precision was related to the size of structures (CV range 2.5-4.9 % for morphology, 36-44 % for LRNC and calcification). Comparable measurement variability was found between the two platforms on both plaque morphology and tissue composition. In conclusion, good to excellent inter-scan reproducibility of carotid MRI can be achieved in multicenter settings with comparable measurement precision between platforms, which may facilitate future multicenter endeavors that use serial MRI to monitor atherosclerotic plaque progression.

Amyloid-ß 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials.

OBJECTIVE: To evaluate the effects of bapineuzumab on brain ß-amyloid (Aß) burden using (11)C-Pittsburgh compound B ((11)C-PiB)-PET. METHODS: Two phase 3 clinical trials, 1 each in apolipoprotein APOE ε4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aß monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Aß over 71 weeks using an (11)C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region. RESULTS: A total of 115 carriers and 39 noncarriers were analyzed. The difference (δ) in mean baseline to 71 week change in (11)C-PiB-PET GCA between bapineuzumab and placebo was significant in carriers (0.5 mg/kg vs placebo δ = -0.101; p = 0.004) and in pooled analyses of both carriers and noncarriers (0.5 mg/kg vs placebo δ = -0.068; p = 0.027; 1.0 mg/kg vs placebo δ = -0.133; p = 0.028) but not in the noncarrier trial separately. Analyses by individual region of interest and in mild disease yielded findings similar to the main trial results. CONCLUSIONS: The (11)C-PiB-PET imaging results demonstrated reduction of fibrillar Aß accumulation in patients with Alzheimer disease treated with bapineuzumab; however, as no clinical benefit was observed, the findings are consistent with the hypotheses that bapineuzumab may not have been initiated early enough in the disease course, the doses were insufficient, or the most critical Aß species were inadequately targeted.

Disease progression modeling using Hidden Markov Models.

The development of novel treatments for many slowly progressing diseases, such as Alzheimer's disease (AD), is dependent on the ability to monitor and detect changes in disease progression. In some diseases the distinct clinical stages of the disease progress far too slowly to enable a quick evaluation of the efficacy of a given proposed treatment. To help improve the assessment of disease progression, we propose using Hidden Markov Models (HMM's) to model, in a more granular fashion, disease progression as compared to the clinical stages of the disease. Unlike many other applications of Hidden Markov Models, we train our HMM in an unsupervised way and then evaluate how effective the model is at uncovering underlying statistical patterns in disease progression by considering HMM states as disease stages. In this study, we focus on AD and show that our model, when evaluated on the cross validation data, can identify more granular disease stages than the three currently accepted clinical stages of "Normal", "MCI" (Mild Cognitive Impairment), and "AD".

Loading of the knee during 3.0T MRI is associated with significantly increased medial meniscus extrusion in mild and moderate osteoarthritis.

PURPOSE: Standard knee MRI is performed under unloading (ULC) conditions and not much is known about changes of the meniscus, ligaments or cartilage under loading conditions (LC). The aim is to study the influence of loading of different knee structures at 3Tesla (T) in subjects with osteoarthritis (OA) and normal controls. MATERIALS AND METHODS: 30 subjects, 10 healthy and 20 with radiographic evidence of OA (10 mild and 10 moderate) underwent 3T MRI under ULC and LC at 50% body weight. All images were analyzed by two musculoskeletal radiologists identifying and grading cartilage, meniscal, ligamentous abnormalities. The changes between ULC and LC were assessed. For meniscus, cartilage and ligaments the changes of lesions, signal and shape were evaluated. In addition, for the meniscus changes in extrusion were examined. A multivariate regression model was used for correlations to correct the data for the impact of age, gender, BMI. A paired T-Test was performed to calculate the differences in meniscus extrusion. RESULTS: Subjects with degenerative knee abnormalities demonstrated significantly increased meniscus extrusion under LC when compared to normal subjects (p=0.0008-0.0027). Subjects with knee abnormalities and higher KL scores showed significantly more changes in lesion, signal and shape of the meniscus (80% (16/20) vs. 20% (2/10); p=0.0025), ligaments and cartilage during LC. CONCLUSION: The study demonstrates that axial loading has an effect on articular cartilage, ligament, and meniscus morphology, which is more significant in subjects with degenerative disease and may serve as an additional diagnostic tool for disease diagnosis and assessing progression in subjects with knee OA.

Femorotibial subchondral bone area and regional cartilage thickness: a cross-sectional description in healthy reference cases and various radiographic stages of osteoarthritis in 1,003 knees from the Osteoarthritis Initiative.

OBJECTIVE: To identify structural differences in total subchondral bone area (tAB) and cartilage thickness between healthy reference knees and knees with radiographic osteoarthritis (OA). METHODS: Baseline magnetic resonance images from 1 knee of 1,003 Osteoarthritis Initiative participants were studied: 112 healthy reference knees without radiographic OA, symptoms, or risk factors; 70 preradiographic OA knees (calculated Kellgren/Lawrence [K/L] grade 0/1); and 821 radiographic OA knees (calculated K/L grade ≥2). Means and standard (Z) scores (SD unit differences compared with normal subjects) of the tAB and regional cartilage thickness were assessed in the weight-bearing femorotibial joint and compared between groups. RESULTS: In men, tAB was 8.2% larger in preradiographic OA knees and 6.6%, 8.1%, and 8.5% larger in calculated K/L grade 2, 3, and 4 radiographic OA knees, respectively, than in reference knees. In women, the differences were +6.8%, +7.3%, +9.9%, and +8.1%, respectively. The external medial tibia showed the greatest reduction in cartilage thickness (Z scores -5.1/-5.6 in men/women) with Osteoarthritis Research Society International medial joint space narrowing (JSN) grade 3, and the external lateral tibia (Z scores -6.0 for both sexes) showed the greatest reduction with lateral JSN grade 3. In all subregions of end-stage radiographic OA knees, ≥25% of the average normal cartilage thickness was maintained. An overall trend toward thicker cartilage was found in preradiographic OA and calculated K/L grade 2 knees, especially in the external central medial femur. CONCLUSION: tABs were larger in preradiographic OA and radiographic OA knees than in healthy reference knees, and the difference did not become larger with higher calculated K/L grades. Specific subregions with substantial cartilage thickening or thinning were identified in pre-, early, and late radiographic OA.