Quantitative longitudinal imaging of activated microglia as a marker of inflammation in the pilocarpine rat model of epilepsy using [11C]-( R)-PK11195 PET and MRI.

Inflammation may play a role in the development of epilepsy after brain insults. [11C]-( R)-PK11195 binds to TSPO, expressed by activated microglia. We quantified [11C]-( R)-PK11195 binding during epileptogenesis after pilocarpine-induced status epilepticus (SE), a model of temporal lobe epilepsy. Nine male rats were studied thrice (D0-1, D0 + 6, D0 + 35, D0 = SE induction). In the same session, 7T T2-weighted images and DTI for mean diffusivity (MD) and fractional anisotropy (FA) maps were acquired, followed by dynamic PET/CT. On D0 + 35, femoral arterial blood was sampled for rat-specific metabolite-corrected arterial plasma input functions (AIFs). In multiple MR-derived ROIs, we assessed four kinetic models (two with AIFs; two using a reference region), standard uptake values (SUVs), and a model with a mean AIF. All models showed large (up to two-fold) and significant TSPO binding increases in regions expected to be affected, and comparatively little change in the brainstem, at D0 + 6. Some individuals showed increases at D0 + 35. AIF models yielded more consistent increases at D0 + 6. FA values were decreased at D0 + 6 and had recovered by D0 + 35. MD was increased at D0 + 6 and more so at D0 + 35. [11C]-( R)-PK11195 PET binding and MR biomarker changes could be detected with only nine rats, highlighting the potential of longitudinal imaging studies.

Selective serotonin 5-HT1A receptor biased agonists elicitdistinct brain activation patterns: a pharmacoMRI study.

Serotonin 1A (5-HT1A) receptors are involved in several physiological and pathological processes and constitute therefore an important therapeutic target. The recent pharmacological concept of biased agonism asserts that highly selective agonists can preferentially direct receptor signaling to specific intracellular responses, opening the possibility of drugs targeting a receptor subtype in specific brain regions. The present study brings additional support to this concept thanks to functional magnetic resonance imaging (7 Tesla-fMRI) in anaesthetized rats. Three 5-HT1A receptor agonists (8-OH-DPAT, F13714 and F15599) and one 5-HT1A receptor antagonist (MPPF) were compared in terms of influence on the brain blood oxygen level-dependent (BOLD) signal. Our study revealed for the first time contrasting BOLD signal patterns of biased agonists in comparison to a classical agonist and a silent antagonist. By providing functional information on the influence of pharmacological activation of 5-HT1A receptors in specific brain regions, this neuroimaging approach, translatable to the clinic, promises to be useful in exploring the new concept of biased agonism in neuropsychopharmacology.

Cartilage and meniscus assessment using T1rho and T2 measurements in healthy subjects and patients with osteoarthritis.

OBJECTIVE: The purpose of this study was to evaluate meniscal degeneration in healthy subjects and subjects with osteoarthritis (OA) using T(1ρ) and T(2) measurements and to examine the interrelationship between cartilage and meniscus abnormalities. METHODS: Quantitative assessment of cartilage and meniscus was performed using 3T Magnetic Resonance Imaging (MRI) with a T(1ρ) and T(2) mapping technique in 19 controls and 44 OA patients. A sagittal T(2)-weighted fast spin echo (FSE) fat-saturated image was acquired for cartilage and meniscal Whole-Organ Magnetic Resonance Imaging Score (WORMS) assessment. Western Ontario and McMasters Universities Arthritis Index (WOMAC) scores were obtained to assess clinical symptoms. RESULTS: The posterior horn of the medial meniscus (PHMED) had the highest incidence of degeneration. Stratifying subjects on the basis of PHMED grade revealed that the T(1ρ) and the T(2) measurements of the PHMED and the medial tibial (MT) cartilage were higher in subjects having a meniscal tear (meniscal grade 2-4) compared to subjects with a meniscal grade of 0 or 1 (P<0.05). While not statistically significant, there was a trend for T(1ρ) and T(2) being higher in PHMED grade 1 compared to grade 0 (P=0.094, P=0.073 respectively). WOMAC scores had a stronger correlation with meniscus relaxation measures than cartilage measures. CONCLUSIONS: Magnetic Resonance (MR) T(1ρ) and T(2) measurements provide a non-invasive means of detecting and quantifying the severity of meniscal degeneration. Meniscal damage has been implicated in OA progression and is correlated with cartilage degeneration. Early detection of meniscal damage represented by elevations in meniscal relaxation measures may identify subjects at increased risk for OA.

T1rho relaxation time of the meniscus and its relationship with T1rho of adjacent cartilage in knees with acute ACL injuries at 3 T.

OBJECTIVE: The aim of this study was to assess the reproducibility of meniscus T1rho measurements, and to study T1rho relaxation time in the lateral meniscus (LM) and its relationship with adjacent cartilage T1rho in knees with acute anterior cruciate ligament (ACL) injuries at 3T magnetic resonance imaging. METHOD: Quantitative assessment of the meniscus and cartilage was performed in 15 healthy controls and 16 ACL-injured patients using a T1rho mapping technique. All ACL-injured patients were imaged prior to surgery within 1-3 months of injury. The anterior and posterior horns of LM and medial meniscus (MM) were associated with partitioned weight-bearing cartilage sub-compartments (anterior, central, and posterior). RESULTS: T1rho measurements in the meniscus showed excellent reproducibility (coefficient of variation (CV)<5%). Significantly elevated T1rho values were found in the LM in patients compared with controls (P<0.01). No differences were found in the MM. Significantly higher T1rho values were found at the posterior horn compared with the anterior horn of patients' meniscus (P=0.005). At the posterior sub-compartment of lateral tibia (LT), significantly increased cartilage T1rho values were found in patients compared with controls (P=0.002). A significant correlation (R(2)=0.47, P=0.007) was found between T1rho values of posterior horn of LM and T1rho values of posterior sub-compartment of LT cartilage in patients. CONCLUSION: A strong injury-related relationship was demonstrated between meniscus and cartilage biochemical changes. T1rho mapping techniques provide tools to quantitatively evaluate meniscus and cartilage matrix in patients with ACL injuries.

Relationship between trabecular bone structure and articular cartilage morphology and relaxation times in early OA of the knee joint using parallel MRI at 3 T.

OBJECTIVE: To evaluate trabecular bone structure in relationship with cartilage parameters in distal femur and proximal tibia of the human knee at 3Tesla (3T) using high-resolution magnetic resonance imaging (MRI) with parallel imaging. METHOD: Sixteen healthy controls and 16 patients with mild osteoarthritis (OA) were studied using a 3T magnetic resonance (MR) scanner and an eight-channel phased-array knee coil. Axial 3D GeneRalized Autocalibrating Partially Parallel Acquisition (GRAPPA)-based phase cycled Fast Imaging Employing Steady State Acquisition (FIESTA-c) images were acquired in order to quantify the trabecular bone structure. For assessing cartilage morphology (thickness, volume), sagittal high-resolution 3D spoiled gradient echo (SPGR) images were acquired. In a subset of the subjects, sagittal images were acquired for measuring T1rho and T2 relaxation times, using 3D T1rho and T2 mapping techniques. RESULTS: Good measurement reproducibility was observed for bone parameters, the coefficients of variations (CVs) ranging from 1.8% for trabecular number (app. Tb.N) to 5.5% for trabecular separation (app. Tb.Sp). Significant differences between control and OA groups were found for bone volume fraction bone volume over total volume (app. BV/TV) and app. Tb.Sp in all compartments. Significantly increased values in T1rho and T2 were demonstrated in OA patients compared with controls at the femur, but not at the tibia. T1rho was negatively correlated with app. BV/TV, app. Tb.N and app. Tb.Sp both at the medial femoral condyle (MFC) and lateral tibia (LT), while T2 was only correlated at the LT. Also, medial tibia (MT) T1rho was negatively correlated with app. BV/TV (R(2)=-0.49, P<0.05) and app. Tb.N (R(2)=-0.42, P<0.05) from the opposite side of lateral femoral condyle (LFC). Significant correlations were found between trabecular bone parameters and cartilage thickness and normalized volume, mainly at LT, tibia (T) and femur (F). CONCLUSION: At this early stage of OA, an overall decrease in bone structure parameters and an increase in cartilage parameters (T1rho, T2) were noticed in patients. Trabecular bone structure correlated with articular cartilage parameters suggesting that loss of mineralized bone is associated with cartilage degeneration.

Measurement of knee cartilage thickness using MRI: a reproducibility study in a meniscectomized guinea pig model of osteoarthritis.

The in vivo precision (reproducibility) of quantitative MRI is of particular importance in osteoarthritis (OA) progression of small magnitude and response to therapy. In this study, three-dimensional high-resolution MRI performed at 7 T was used to assess the short-term reproducibility of measurements of mean tibial cartilage thickness in a meniscectomized guinea pig model of OA. MR image acquisition was repeated five times in nine controls (SHAM) and 10 osteoarthritic animals 3 months after meniscectomy (MNX), in vivo. The animals were then killed for histomorphometric assessment and correlation with the MRI-based measurements. Medial tibial cartilage thickness was measured on MR images using semi-automatic dedicated 3D software developed in-house. The reproducibility of measurements of cartilage thickness was assessed by five repeated MRI examinations with a short recovery delay between examinations (48 h). The computed coefficients of variation were 8.9% for the SHAM group and 8.2% for the MNX group. The coefficients of variation were compatible with expected thickness variations between normal and pathological animals. A positive agreement and significant partial correlation (Spearman r' = 0.74; P < 0.01) between the MRI and histomorphometric data was established. Three-dimensional high-resolution MRI is a promising non-invasive research tool for in vivo follow-up. This modality could be used for staging and monitoring therapy response in small-animal models of OA.

A dedicated two-element phased array receiver coil for high resolution MRI of rat knee cartilage at 7T.

Despite that on clinical systems phased array technology is now widely used, the high field MRI experimental systems with multiple receiver channels just became available few years ago. For this reason and due to the large range of magnetic field (frequencies between 200 and 500 MHz for proton resonance), commercial phased arrays implemented in narrow bore for high field applications are rare and relatively expensive. Array coil imaging is an advanced method for acquiring high resolution images with enhanced Signal-to-Noise Ratio (SNR) and/or enlarged Field Of View (FOV) compared for example to single loop surface coil. The volume of interest is then covered by several coil elements and images reconstructed for every single channel are combined afterwards. The goal of this work was to develop a dedicated two-element array coil operating at 300 MHz (7T) for high-resolution imaging of rat knee joint in order to quantify cartilage thickness and volume. A dedicated two-element array coil with two square elements encompassing knee joint was designed and built. Decoupling between elements was achieved with a capacitor inserted on the common leg of the two elements. The average gain in SNR compared to a 15 mm reference single loop coil was 2.2. This SNR gain was used to improve spatial resolution of 3D acquisition by decreasing the voxel size from 59 x 59 x 156 microm(3) to 51 x 51 x 94 microm(3) without time penalty.

Knee cartilage thickness measurements using MRI: a 4(1/2)-month longitudinal study in the meniscectomized guinea pig model of OA.

OBJECTIVE: The aim of this study was to follow, over a 4(1/2)-month period, the medial tibia cartilage thickness on a meniscectomy (MNX) guinea pig osteoarthritis (OA) model and to compare with control animals, using three-dimensional high-resolution magnetic resonance imaging (3D HR-MRI). METHODS: MRI experimentations were performed in vivo at 7 T on guinea pig knee joints. 3D HR-MR images were acquired in 60 controls (SHAM) and 45 osteoarthritic animals (MNX) at four time-points (15, 45, 90 and 135 days) after surgery. Medial tibial cartilage thickness was measured from MRI images using in-house dedicated 3D software followed by a statistical analysis. At each time-point 15 SHAM and 15 MNX animals were sacrificed for histomorphometric assessments. RESULTS: No significant difference of mean cartilage thickness between the groups was found at early stage (D45) using MRI; however, significant differences were found between the groups at D90 (P<0.001) and D135 (P<0.001). Histomorphometry data confirmed the pathological status of the animals and was well correlated with MRI at D15 (r=0.79, P<0.01), D45 (r=0.67, P<0.01), and D135 (r=0.39, P<0.05) for SHAM, and at D45 (r=0.63, P<0.01), and D135 (r=0.81, P<0.01) for MNX. CONCLUSION: Medial tibial cartilage measurement based on HR-MR images enables the monitoring of longitudinal cartilage thickness changes. This technique showed significant differences between SHAM and MNX as from D90 after surgery. It could be used as a noninvasive and reproducible tool to monitor therapeutic response in this OA model.