Structural basis for the activation and inhibition of the UCH37 deubiquitylase.

The UCH37 deubiquitylase functions in two large and very different complexes, the 26S proteasome and the INO80 chromatin remodeler. We have performed biochemical characterization and determined crystal structures of UCH37 in complexes with RPN13 and NFRKB, which mediate its recruitment to the proteasome and INO80, respectively. RPN13 and NFRKB make similar contacts to the UCH37 C-terminal domain but quite different contacts to the catalytic UCH domain. RPN13 can activate UCH37 by disrupting dimerization, although physiologically relevant activation likely results from stabilization of a surface competent for ubiquitin binding and modulation of the active-site crossover loop. In contrast, NFRKB inhibits UCH37 by blocking the ubiquitin-binding site and by disrupting the enzyme active site. These findings reveal remarkable commonality in mechanisms of recruitment, yet very different mechanisms of regulating enzyme activity, and provide a foundation for understanding the roles of UCH37 in the unrelated proteasome and INO80 complexes.

CEST MRI provides amide/amine surrogate biomarkers for treatment-naïve glioma sub-typing.

PURPOSE: Accurate glioma classification affects patient management and is challenging on non- or low-enhancing gliomas. This study investigated the clinical value of different chemical exchange saturation transfer (CEST) metrics for glioma classification and assessed the diagnostic effect of the presence of abundant fluid in glioma subpopulations. METHODS: Forty-five treatment-naïve glioma patients with known isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion status received CEST MRI (B1rms = 2µT, Tsat = 3.5 s) at 3 T. Magnetization transfer ratio asymmetry and CEST metrics (amides: offset range 3-4 ppm, amines: 1.5-2.5 ppm, amide/amine ratio) were calculated with two models: 'asymmetry-based' (AB) and 'fluid-suppressed' (FS). The presence of T2/FLAIR mismatch was noted. RESULTS: IDH-wild type had higher amide/amine ratio than IDH-mutant_1p/19qcodel (p < 0.022). Amide/amine ratio and amine levels differentiated IDH-wild type from IDH-mutant (p < 0.0045) and from IDH-mutant_1p/19qret (p < 0.021). IDH-mutant_1p/19qret had higher amides and amines than IDH-mutant_1p/19qcodel (p < 0.035). IDH-mutant_1p/19qret with AB/FS mismatch had higher amines than IDH-mutant_1p/19qret without AB/FS mismatch ( < 0.016). In IDH-mutant_1p/19qret, the presence of AB/FS mismatch was closely related to the presence of T2/FLAIR mismatch (p = 0.014). CONCLUSIONS: CEST-derived biomarkers for amides, amines, and their ratio can help with histomolecular staging in gliomas without intense contrast enhancement. T2/FLAIR mismatch is reflected in the presence of AB/FS CEST mismatch. The AB/FS CEST mismatch identifies glioma subgroups that may have prognostic and clinical relevance.

A comparison of static and dynamic ∆B0 mapping methods for correction of CEST MRI in the presence of temporal B0 field variations.

PURPOSE: To assess the performance, in the presence of scanner instabilities, of three dynamic correction methods which integrate ∆B0 mapping into the chemical exchange saturation transfer (CEST) measurement and three established static ∆B0 -correction approaches. METHODS: A homogeneous phantom and five healthy volunteers were scanned with a CEST sequence at 7 T. The in vivo measurements were performed twice: first with unaltered system frequency and again applying frequency shifts during the CEST acquisition. In all cases, retrospective voxel-wise ∆B0 -correction was performed using one intrinsic and two extrinsic [prescans with dual-echo gradient-echo and water saturation shift referencing (WASSR)] static approaches. These were compared with two intrinsic [using phase data directly generated by single-echo or double-echo GRE (gradient-echo) CEST readout (CEST-GRE-2TE)] and one extrinsic [phase from interleaved dual-echo EPI (echo planar imaging) navigator (NAV-EPI-2TE)] dynamic ∆B0 -correction approaches [allowing correction of each Z-spectral point before magnetization transfer ratio asymmetry (MTRasym) analysis]. RESULTS: All three dynamic methods successfully mapped the induced drift. The intrinsic approaches were affected by the CEST labeling near water (∆ω < |0.3| ppm). The MTRasym contrast was distorted by the frequency drift in the brain by up to 0.21%/Hz when static ∆B0 -corrections were applied, whereas the dynamic ∆B0 corrections reduced this to <0.01%/Hz without the need of external scans. The CEST-GRE-2TE and NAV-EPI-2TE resulted in highly consistent MTRasym values with/without drift for all subjects. CONCLUSION: Reliable correction of scanner instabilities is essential to establish clinical CEST MRI. The three dynamic approaches presented improved the ∆B0 -correction performance significantly in the presence of frequency drift compared to established static methods. Among them, the self-corrected CEST-GRE-2TE was the most accurate and straightforward to implement.

Multiple interleaved mode saturation (MIMOSA) for B1+ inhomogeneity mitigation in chemical exchange saturation transfer.

PURPOSE: To mitigate B1+ inhomogeneity in quantitative CEST MRI at ultra-high magnetic field strengths (B0 ≥ 7 Tesla) using a parallel transmit system. METHODS: Multiple interleaved mode saturation employs interleaving of 2 complementary phase sets during the saturation pulse train. Phase differences of 45° (first mode) and 90° (second mode) between 2 adjacent transmitter coil channels are used. The influence of the new saturation scheme on the CEST contrast was analyzed using Bloch-McConnell simulations. The presented method was verified in phantom and in vivo measurements of the healthy human brain. The relayed nuclear Overhauser effect was evaluated, and the inverse magnetic transfer ratio metric was calculated. Results were compared to a published B1+ correction method. All measurements were conducted on a whole-body 7 Tesla MRI system using an 8 transmitter and 32 receiver channel head coil. RESULTS: Simulations showed that the inverse magnetic transfer ratio metric contrast of relayed nuclear Overhauser effect shows a smaller dependency on the relative amplitudes of the 2 different modes than the contrasts of Cr and amide proton transfer. Measurements of an egg white phantom showed markedly improved homogeneity compared to the uncorrected inverse magnetic transfer ratio metric (relayed nuclear Overhauser effect) images and slightly improved results compared to B1+ corrected images. In vivo multiple interleaved mode saturation images showed similar contrast compared to B1+ corrected images. CONCLUSION: Multiple interleaved mode saturation can be used as a simple method to mitigate B1+ inhomogeneity effects in CEST MRI at ultra-high magnetic field strengths. Compared to previous B1+ correction methods, acquisition time can be reduced because an additional scan, usually required for B1+ correction, can be omitted.

Ammonia-weighted imaging by chemical exchange saturation transfer MRI at 3 T.

Hepatic encephalopathy (HE) is triggered by liver cirrhosis and is associated with an increased ammonia level within the brain tissue. The goal of this study was to investigate effects of ammonia on in vitro amide proton transfer (APT)-weighted chemical exchange saturation transfer (CEST) imaging in order to develop an ammonia-sensitive brain imaging method. APT-weighted CEST imaging was performed on phantom solutions including pure ammonia, bovine serum albumin (BSA), and tissue homogenate samples doped with various ammonia concentrations. All CEST data were assessed by magnetization transfer ratio asymmetry. In addition, optical methods were used to determine possible structural changes of the proteins in the BSA phantom. In vivo feasibility measurements were acquired in one healthy participant and two patients suffering from HE, a disease associated with increased brain ammonia levels. The CEST effect of pure ammonia showed a base-catalyzed behavior. At pH values greater than 5.6 no CEST effect was observed. The APT-weighted signal was significantly reduced for ammonia concentrations of 5mM or more at fixed pH values within the different protein phantom solutions. The optical methods revealed no protein aggregation or denaturation for ammonia concentrations less than 5mM. The in vivo measurements showed tissue specific and global reduction of the observed CEST signal in patients with HE, possibly linked to pathologically increased ammonia levels. APT-weighted CEST imaging is sensitive to changes in ammonia concentrations. Thus, it seems useful for the investigation of pathologies with altered tissue ammonia concentrations such as HE. However, the underlying mechanism needs to be explored in more detail in future in vitro and in vivo investigations.

Good clinical and MRI outcome after arthroscopic autologous chondrocyte implantation for cartilage repair in the knee.

PURPOSE: To analyze the clinical outcome and cartilage regeneration after all-arthroscopic Autologous Chondrocyte Implantation (ACI) using chondrospheres® (ACT3D) for the treatment of full-size articular cartilage lesions at the knee. METHODS: Thirty consecutive patients treated by all-arthroscopic ACI for full-size articular cartilage lesions in an otherwise healthy knee were enrolled. The defects were located on the femoral condyles (n = 18), in the trochlea (n = 7) and at the patella (n = 5). Follow-up consisted of a clinical evaluation with assessment of subjective scores. Patient satisfaction was evaluated on a visual analog scale (VAS). 3-Tesla MRI and T2 mapping of the operated and the contralateral healthy knees were included to control the quality of the regenerated cartilage. The MOCART score was assessed by three blinded independent radiologists. RESULTS: At the mean follow-up of 3 years ± 10.2 months 26 of the 30 patients (86.6%) were subjectively highly satisfied with the surgical result and assured they would undergo the same procedure again. The mean Lysholm score increased to 77.7 ± 14.6, the mean subjective IKDC significantly to 84.2 ± 5.6 (p < 0.05) and all five subgroups of the KOOS improved significantly (p < 0.05). The subjective outcome was not influenced by the duration of symptoms, age, location, size of defects nor dose of spheroids. The modified MOCART score was a mean of 60 ± 21 (0-80) points. Twenty-four patients (82.7%) were rated higher than 60 points. T2 mapping documented similar cartilage quality of the area of the ACI and the same location at the contralateral knee. Three patients had a MOCART score of 0 with few or no cartilage regeneration on MRI and were considered as failure of the ACI. CONCLUSION: In this small cohort of 30 patients, minimal invasive all-arthroscopic ACT 3D using spheroids led to convincing clinical short-to-mid-term results with a significant increase in patients quality of life, satisfaction, reduction of pain, and improvement in knee function. The high morphologic integrity and quality of the ACI was reconfirmed by the Mocart Score and T2 mapping. LEVEL OF EVIDENCE: IV.

Higher resolution cine imaging with compressed sensing for accelerated clinical left ventricular evaluation.

PURPOSE: To assess the clinical feasibility of a compressed sensing cine magnetic resonance imaging (MRI) sequence of both high temporal and spatial resolution (CS_bSSFP) in comparison to a balanced steady-state free precession cine (bSSFP) sequence for reliable quantification of left ventricular (LV) volumes and mass. MATERIALS AND METHODS: Segmented MRI cine images were acquired on a 1.5T scanner in 50 patients in the LV short-axis stack orientation using a retrospectively gated conventional bSSFP sequence (generalized autocalibrating partially parallel acquisition [GRAPPA] acceleration factor 2), followed by a prospectively triggered CS_bSSFP sequence with net acceleration factor of 8. Image quality was assessed by published criteria. Comparison of sequences was made in LV volumes and mass, image quality score, quantitative regional myocardial wall motion, and imaging time using Pearson's correlation, Bland-Altman and paired 2-tailed Student's t-test. RESULTS: Differences (bSSFP minus CS_bSSFP, mean ± SD) and Pearson's correlations were 14.8 ± 16.3 (P = 0.31) and r = 0.98 (P < 0.0001) for end-diastolic volume (EDV), 8.4 ± 11.3 (P = 0.54) and r = 0.99 (P < 0.0001) for end-systolic volume (ESV), -0.4 ± 2.5 (P = 0.87) and r = 0.97 (P < 0.0001) for EF, and -0.9 ± 11.8 (P = 0.92) and r = 0.97 (P < 0.0001) for LV mass. Bland-Altman analyses [bias and (limits of agreement)] revealed strong agreement in LVEDV [8.7 ml, (-12.1, 29.6)], LVESV [4.3 ml, (-11.9, 20.6)], LVEF [-0.02%, (-5.37, 5.33)], and myocardial mass [-6.1 g, (-14.7, 26.9)]. Image quality was comparable with a similar mean score (P = 0.42), with a good correlation in image quality observed (r = 0.68, P < 0.0001). Quantitative regional myocardial wall motion demonstrated strong correlation between the sequences (r = 0.87, P < 0.0001). Imaging time was significantly shorter for the CS_bSSFP sequence (1.1 ± 0.5 versus 5.6 ± 1.6 min, P < 0.0001). CONCLUSION: The novel high-resolution cine CS_bSSFP accurately and reliably quantitates LV volumes and mass, shortens acquisition times, and is clinically feasible. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;45:1693-1699.

Evaluating the cartilage adjacent to the site of repair surgery with glycosaminoglycan-specific magnetic resonance imaging.

PURPOSE: The glycosaminoglycan (GAG) chemical exchange saturation transfer (CEST) imaging method (gagCEST) makes it possible to assess and quantify the GAG concentration in human cartilage. This biochemical imaging technique facilitates detection of the loss of GAG in the course of osteoarthritis. The gagCEST technique was used to analyse the perilesional zone (PLZ) adjacent to repair tissue after cartilage repair surgery, to determine whether there are biochemical changes present in the sense of degeneration. METHOD: Asymmetries in the PLZ of cartilage defects in 11 patients, who had been treated by microfracturing or matrix-associated autologous chondrocyte transplantation (MACT), were measured by gagCEST on a 7-T whole-body system. These results were correlated with gagCEST asymmetries of healthy reference cartilage (RC), measured anterior and posterior to the PLZ and to the repair tissue (RT). RESULTS: The mean gagCEST asymmetry for the anterior PLZ was 4.8% (±4.4), for the posterior PLZ 5.4% (±2.3), for the anterior RC 6.6% (±3.5) and 7.2% (±3.3) for the posterior RC and 4.5% (±2.3) for the RT. The difference between the anterior PLZ and the anterior RC (p = 0.019), the posterior PLZ and the posterior RC (p = 0.005), and the mean RC and the RT (p = 0.021) were all statistically significant. The measurements between RT and mean PLZ did not reveal significant results (p = 0.398). CONCLUSIONS: The gagCEST method provides a potentially useful biomarker for the loss of GAGs, indicating cartilage degeneration in the PLZ. Pre-operative and post-operative monitoring of the biomechanical state of the cartilage might influence intra-operative decision-making concerning the extent of cartilage resection or might give information of the success of the treatment post-operatively.

An MRspec database query and visualization engine with applications as a clinical diagnostic and research tool.

PURPOSE: Proton magnetic resonance spectroscopy (MRspec), one of the very few techniques for in vivo assessment of neuro-metabolic profiles, is often complicated by lack of standard population norms and paucity of computational tools. METHODS: 7035 scans and clinical information from 4430 pediatric patients were collected from 2008 to 2014. Scans were conducted using a 1.5T (n=3664) or 3T scanner (n=3371), and with either a long (144ms, n=5559) or short echo time (35ms, n=1476). 3055 of these scans were localized in the basal ganglia (BG), 1211 in parieto-occipital white matter (WM). 34 metabolites were quantified using LCModel. A web application using MySQL, Python and Flask was developed to facilitate the exploration of the data set. RESULTS: Already piloting the application revealed numerous insights. (1), N-acetylaspartate (NAA) increased throughout all ages. During early infancy, total choline was highly varied and myo-inositol demonstrated a downward trend. (2), Total creatine (tCr) and creatine increased throughout childhood and adolescence, though phosphocreatine (PCr) remained constant beyond 200days. (3), tCr was higher in BG than WM. (4), No obvious gender-related differences were observed. (5), Field strength affects quantification using LCModel for some metabolites, most prominently for tCr and total NAA. (6), Outlier analysis identified patients treated with vigabatrin through elevated γ-aminobutyrate, and patients with Klippel-Feil syndrome, Leigh disease and L2-hydroxyglutaric aciduria through low choline in BG. CONCLUSIONS: We have established the largest MRSpec database and developed a robust and flexible computational tool for facilitating the exploration of vast metabolite datasets that proved its value for discovering neurochemical trends for clinical diagnosis, treatment monitoring, and research. Open access will lead to its widespread use, improving the diagnostic yield and contributing to better understanding of metabolic processes and conditions in the brain.

Reproducibility and regional variations of an improved gagCEST protocol for the in vivo evaluation of knee cartilage at 7 T.

OBJECTIVE: The objective was to establish a gagCEST protocol that would enable robust and reproducible assessment of the glycosaminoglycan (GAG) content in knee cartilage at 7 T within a clinically feasible measurement time. MATERIALS AND METHODS: Ten young healthy volunteers (mean age 26 years, range 24-28, five males, five females) were examined on a 7 T MR system. Informed consent was obtained from all individual participants prior to enrollment into the study. Each volunteer was measured twice for reproducibility assessment. The examined knee was immobilized using a custom-made fixation device. For the gagCEST measurement, a prototype segmented 3-D RF-spoiled gradient-echo sequence with an improved saturation scheme employing adiabatic pulses was used in a scan time of 19 min. The asymmetry of the Z-spectra (MTRasym) in selected regions of interest in knee cartilage was calculated. Differences in MTRasym between different regions were evaluated using ANOVA and the Bonferroni corrected post hoc test. RESULTS: The improvement of the saturation scheme reduced the influence of field inhomogeneities, resulted in more uniform saturation, and allowed for good reproducibility in a reasonable measurement time (19 min), as demonstrated by an intraclass correlation coefficient of 0.77. Improved fixation helped to reduce motion artifacts. Whereas similar MTRasym values were found for weight-bearing and non-weight-bearing femoral cartilage, lower values were observed in the trochlear groove (p = 0.028), patellar (p = 0.015) and tibial cartilage (p < 0.001) when compared to non-weight-bearing femoral cartilage. CONCLUSION: Reasonable reproducibility and sensitivity to regional differences in GAG content suggests that the improved gagCEST protocol might be useful for assessing the biochemical changes in articular cartilage that are associated with early stages of cartilage degeneration.

Glycosaminoglycan chemical exchange saturation transfer at 3T MRI in asymptomatic knee joints.

BACKGROUND: Biochemical alterations such as glycosaminoglycan (GAG) depletion occur early in the course of osteoarthritis, but cannot be detected with standard magnetic resonance techniques. With glycosaminoglycan chemical exchange saturation transfer (gagCEST), a biochemical imaging technique, it is feasible to detect biochemical components in knee joint cartilage. PURPOSE: To establish baseline values for gagCEST magnetic resonance imaging (MRI) in knee joint cartilage at 3 Tesla (T). MATERIAL AND METHODS: Twenty volunteers (8 women, 12 men; mean age, 24.55 ± 2.35 years;age range, 21-29 years) with no history or clinical findings indicative of knee joint pathologies underwent MRI at 3T. The imaging protocol included three-dimensional (3D) double-echo steady-state sequence for morphological cartilage assessment and a prototype 3D CEST pulse sequence to evaluate the CEST effects in six cartilage regions of the knee joint: (i) lateral femoral condyle; (ii) medial femoral condyle; (iii) lateral tibial plateau; (iv) medial tibial plateau; (v) patella; and (vi) trochlea. We used the asymmetry of the magnetization transfer ratio (MTRasym) parameter to quantify the gagCEST effects in these regions. RESULTS: Regional differences revealed high MTRasym values in the patellar (1.62% ± 1.19%) and the trochlear (1.17% ± 1.29%) cartilages, and low MTRasym values in the medial femoral condyle (0.41% ± 0.58%) and the lateral tibial plateau (0.52% ± 0.53%) cartilages. CONCLUSION: Regional differences in the gagCEST values must be considered when conducting gagCEST imaging of knee joint cartilage. In the future gagCEST imaging may be an additional feature in the evaluation of the biochemical composition of knee joint cartilage.

Biochemical imaging of cervical intervertebral discs with glycosaminoglycan chemical exchange saturation transfer magnetic resonance imaging: feasibility and initial results.

OBJECTIVE: To evaluate glycosaminoglycan chemical exchange saturation transfer (gagCEST) imaging at 3T in the assessment of the GAG content of cervical IVDs in healthy volunteers. MATERIALS AND METHODS: Forty-two cervical intervertebral discs of seven healthy volunteers (four females, three males; mean age: 21.4 ± 1.4 years; range: 19-24 years) were examined at a 3T MRI scanner in this prospective study. The MRI protocol comprised standard morphological, sagittal T2 weighted (T2w) images to assess the magnetic resonance imaging (MRI) based grading system for cervical intervertebral disc degeneration (IVD) and biochemical imaging with gagCEST to calculate a region-of-interest analysis of nucleus pulposus (NP) and annulus fibrosus (AF). RESULTS: GagCEST of cervical IVDs was technically successful at 3T with significant higher gagCEST values in NP compared to AF (1.17% ± 1.03% vs. 0.79% ± 1.75%; p = 0.005). We found topological differences of gagCEST values of the cervical spine with significant higher gagCEST effects in lower IVDs (r = 1; p = 0). We could demonstrate a significant, negative correlation between gagCEST values and cervical disc degeneration of NP (r = -0.360; p = 0.019). Non-degenerated IVDs had significantly higher gagCEST effects compared to degenerated IVDs in NP (1.76% ± 0.92% vs. 0.52% ± 1.17%; p < 0.001). CONCLUSION: Biochemical imaging of cervical IVDs is feasible at 3T. GagCEST analysis demonstrated a topological GAG distribution of the cervical spine. The depletion of GAG in the NP with increasing level of morphological degeneration can be assessed using gagCEST imaging.

[Chemical Exchange Saturation Transfer Imaging of Creatine Metabolites: a 3.0 T MRI Pilot].

OBJECTIVE: To determine the feasibility of using chemical exchange saturation transfer (CEST) imaging to measure creatine (Cr) metabolites with 3.0 T MR. METHODS: Phantoms containing different concentrations of Cr under various pH conditions were studied with CEST sequence on 3.0 T MR imaging. CEST effect and Z spectra were analyzed. RESULTS: Cr exhibited significant CEST effect (± 1.8 ppm, F = 99.08, P < 0.001) on 3.0 T MR imaging, and positive correlation was found between the signal intensity and concentration of Cr (r = 0.963, P < 0.001). The CEST effect showed pH dependency of Cr (r = 0.41, P = 0.035). CONCLUSION: Creatine CEST imaging can be performed on 3.0 T MR imaging. Creatine concentrations and pH influence CEST effect.

Relaxation-compensated CEST-MRI of the human brain at 7T: Unbiased insight into NOE and amide signal changes in human glioblastoma.

Endogenous chemical exchange saturation transfer (CEST) effects of protons resonating near to water protons are always diluted by competing effects such as direct water saturation and semi-solid magnetization transfer (MT). This leads to unwanted T2 and MT signal contributions that contaminate the observed CEST signal. Furthermore, all CEST effects appear to be scaled by the T1 relaxation time of the mediating water pool. As MT, T1 and T2 are also altered in tumor regions, a recently published correction algorithm yielding the apparent exchange-dependent relaxation AREX, is used to evaluate in vivo CEST effects. This study focuses on CEST effects of amides (3.5ppm) and Nuclear-Overhauser-mediated saturation transfer (NOE, -3.5ppm) that can be properly isolated at 7T. These were obtained in 10 glioblastoma patients, and this is the first comprehensive study where AREX is applied in human brain as well as in human glioblastoma. The correction of CEST effects alters the contrast significantly: after correction, the CEST effect of amides does not show significant contrast between contrast enhancing tumor regions and normal tissue, whereas NOE drops significantly in the tumor area. In addition, new features in the AREX contrasts are visible. This suggests that previous CEST approaches might not have shown pure CEST effects, but rather water relaxation shine-through effects. Our insights help to improve understanding of the CEST effect changes in tumors and correlations on a cellular and molecular level.

Evidence of lensing of the cosmic microwave background by dark matter halos.

We present evidence of the gravitational lensing of the cosmic microwave background by 10(13) solar mass dark matter halos. Lensing convergence maps from the Atacama Cosmology Telescope Polarimeter (ACTPol) are stacked at the positions of around 12 000 optically selected CMASS galaxies from the SDSS-III/BOSS survey. The mean lensing signal is consistent with simulated dark matter halo profiles and is favored over a null signal at 3.2σ significance. This result demonstrates the potential of microwave background lensing to probe the dark matter distribution in galaxy group and galaxy cluster halos.

Age-dependency of glycosaminoglycan content in lumbar discs: A 3t gagcEST study.

PURPOSE: To analyze age-dependency of glycosaminoglycan content using gagCEST (glycosaminoglycan chemical exchange saturation transfer) imaging in lumbar intervertebral discs of healthy volunteers. MATERIALS AND METHODS: In all, 70 volunteers without low back pain (mean age 44 ± 14 years, range: 21-69 years) were examined with T2 -weighted and gagCEST imaging with a 3T MR scanner, with approval of the local Ethics Committee after written informed consent was obtained. Pfirrmann grading and classification into discs without bulging and herniation, discs with bulging, and discs with herniation were performed. Only intervertebral discs without bulging and herniation were analyzed. A region-of-interest-based gagCEST analysis of nucleus pulposus (NP) and annulus fibrosus (AF) was performed. Correlation between age and gagCEST was tested within groups of equal Pfirrmann score. RESULTS: GagCEST effects decreased significantly from 3.09 ± 1.12% in 20-29 years old volunteers to -0.24 ± 1.36% in 50-59 years old volunteers (P < 0.001). In the case of Pfirrmann scores 2 and 3, a significant correlation was observed between gagCEST effect and age (Pfirrmann score 2, NP: ρ = -0.558, P < 0.001; Pfirrmann score 3, NP: ρ = -0.337, P = 0.048). For Pfirrmann scores 1 and 4, no significant correlation was obtained (Pfirrmann score 1, NP: ρ = -0.046, P = 0.824; Pfirrmann score 4, NP: ρ = -0.316, P = 0.188). CONCLUSION: We show a decreased gagCEST effect likely corresponding to decreasing glycosaminoglycans with aging. Hence, age-matched analysis of gagCEST imaging may be necessary in future studies.

Glycosaminoglycan chemical exchange saturation transfer of lumbar intervertebral discs in patients with spondyloarthritis.

PURPOSE: To assess glycosaminoglycan (GAG) content of lumbar intervertebral discs (IVD) in patients with spondyloarthritis (SpA) using glycosaminoglycan chemical exchange saturation transfer (gagCEST). MATERIALS AND METHODS: Ninety lumbar intervertebral discs of nine patients with SpA and nine age-matched healthy controls (eight patients with ankylosing spondylitis; one patient with spondylitis related to inflammatory bowel disease; mean age: 44.1 ± 14.0 years; range: 27-72 years) were examined with a 3T magnetic resonance imaging (MRI) scanner in this prospective study. The MRI protocol included standard morphological, sagittal T2 -weighted (T2 w) images to assess Pfirrmann score of the five lumbar IVDs (L1 to S1) and biochemical imaging with gagCEST to calculate a region of interest analysis of nucleus pulposus (NP) and annulus fibrosus (AF). Prior to statistical testing of gagCEST effects (MTRasym values in percent) in patients and controls, IVDs were classified according to the Pfirrmann score. RESULTS: Significantly lower gagCEST values of NP and AF were found in SpA patients compared with healthy volunteers (NP: 1.41% ± 0.41%, P = 0.001; 95% confidence interval, CI [0.600%-2.226%]; AF: 1.19% ± 0.32%, P < 0.001; CI [0.560%-1.822%]) by comparing the differences of the means. Pooled nondegenerative IVDs (Pfirrmann 1 and 2) had significantly lower gagCEST effects in patients suffering from SpA compared with healthy controls in NP (P < 0.001; CI [1.176%-2.337%]) and AF (P < 0.001; CI [0.858%-1.779%]). No significant difference of MTRasym values was found in degenerative IVDs between patients and controls in NP (P = 0.204; CI [-0.504%-2.170%]). CONCLUSION: GagCEST analysis of morphologically nondegenerative IVDs (Pfirrmann score 1 and 2) in T2 w images demonstrated significantly lower GAG values in patients with spondyloarthritis in NP and AF, possibly representing a depletion of GAG in spondyloarthritis in the absence of morphologic degeneration.

Grading glial tumors with amide proton transfer MR imaging: different analytical approaches.

Amide proton transfer (APT) magnetic resonance imaging is gaining attention for its capability for grading glial tumors. Usually, a representative slice is analyzed. Different definitions of tumor areas have been employed in previous studies. We hypothesized that the accuracy of APT imaging for brain tumor grading may depend upon the analytical methodology used, such as selection of regions of interest (ROIs), single or multiple tumor slices, and whether or not there is normalization to the contralateral white matter. This study was approved by the institutional review board, and written informed consent was waived. Twenty-six patients with histologically proven glial tumors underwent preoperative APT imaging with a three-dimensional gradient-echo sequence. Two neuroradiologists independently analyzed APT asymmetry (APTasym) images by placing ROIs on both a single representative slice (RS) and all slices including tumor (i.e. whole tumor: WT). ROIs indicating tumor extent were separately defined on both FLAIR and, if applicable, contrast-enhanced T1-weighted images (CE-T1WI), yielding four mean APTasym values (RS-FLAIR, WT-FLAIR, RS-CE-T1WI, and WT-CE-T1WI). The maximum values were also measured using small ROIs, and their differences among grades were evaluated. Receiver operating characteristic (ROC) curve analysis was also conducted on mean and maximum values. Intra-class correlation coefficients for inter-observer agreement were excellent. Significant differences were observed between high- and low-grade gliomas for all five methods (P < 0.01). ROC curve analysis found no statistically significant difference among them. This study clarifies that single-slice APT analysis is robust despite tumor heterogeneity, and can grade glial tumors with or without the use of contrast material.