Multiparametric Aging Study Across Adulthood in the Leg Through Quantitative MR Imaging, 1H Spectroscopy, and 31P Spectroscopy at 3T.

BACKGROUND: Improved characterization of healthy muscle aging is needed to establish early biomarkers in age-related diseases. PURPOSE: To quantify age-related changes on multiple MRI and clinical variables evaluated in the same cohort and identify correlations among them. STUDY TYPE: Prospective. POPULATION: 70 healthy subjects (30 men) from 20 to 81 years old. FIELD STRENGTH/SEQUENCE: 3T/water T2 (multiecho SE, multi-TE STEAM), water T1 (GRE MR Fingerprinting), fat-fraction (multiecho GRE, multi-TE STEAM), carnosine (PRESS), multicomponent water T2 (ISIS-CPMG SE train), and 31P pulse-acquire spectroscopy. ASSESSMENT: Age- and sex-related changes on: Imaging: fat-fraction (FFMRI), water T1 (T1-H2O), and T2 (T2-H2O-MRI) and their heterogeneities ΔT1-H2O and ΔT2-H2O-MRI in the posterior compartment (PC) and anterior compartment (AC) of the leg. 1H spectroscopy: Carnosine concentration, pH, water T2 components (T2-H2O-CPMG), fat-fraction (FFMRS), and water T2 (T2-H2O-MRS) in the gastrocnemius medialis. 31P spectroscopy: Phosphodiesters (PDE), phosphomonoesters, inorganic phosphates (Pi), and phosphocreatine (PCr) normalized to adenosine triphosphate (ATP) and pH in the calf. Clinical evaluation: Body-mass index (BMI), gait speed (GS), plantar flexion strength, handgrip strength (HS), HS normalized to wrist circumference (HSnorm), physical activity assessment. STATISTICAL TESTS: Multilinear regressions with sex and age as fixed factors. Spearman correlations calculated between variables. Benjamini-Hochberg procedure for false positives reduction (5% rate). A P < 0.05 significance level was used. RESULTS: Significant age-related increases were found for BMI (ρAge = 0.04), HSnorm (ρAge = -0.01), PDE/ATP (ρAge = 2.8 × 10-3), Pi/ATP (ρAge = 2.0 × 10-3), Pi/PCr (ρAge = 0.3 × 10-3), T2-H2O-MRS (ρAge = 0.051 msec), FFMRS (ρAge = 0.036) the intermediate T2-H2O-CPMG component time (ρAge = 0.112 msec), and fraction (ρAge = -0.3 × 10-3); and in both compartments for FFMRI (ρAge = 0.06, PC; ρAge = 0.06, AC), T2-H2O-MRI (ρAge = 0.05, PC; ρAge = 0.05, AC; msec), ΔT2-H2O-MRI (ρAge = 0.02, PC; ρAge = 0.02, AC; msec), T1-H2O (ρAge = 1.08, PC; ρAge = 1.06, AC; msec), and ΔT1-H2O (ρAge = 0.22, PC; ρAge = 0.37, AC; msec). The best age predictors, accounting for sex-related differences, were HSnorm (R2 = 0.52) and PDE/ATP (R2 = 0.44). In both leg compartments, the imaging measures and HSnorm were intercorrelated. In PC, T2-H2O-MRS and FFMRS also showed numerous correlations to the imaging measures. PDE/ATP correlated to T1-H2O, T2-H2O-MRI, ΔT2-H2O-MRI, FFMRI, FFMRS, the intermediate T2-H2O-CPMG, BMI, Pi/PCr, and HSnorm. DATA CONCLUSION: Our multiparametric MRI approach provided an integrative view of age-related changes in the leg and revealed multiple correlations between these parameters and the normalized HS. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

Multi-nuclear sodium, diffusion, and perfusion MRI in human gliomas.

PURPOSE: There is limited knowledge about the associations between sodium and proton MRI measurements in brain tumors. The purpose of this study was to quantify intra- and intertumoral correlations between sodium, diffusion, and perfusion MRI in human gliomas. METHODS: Twenty glioma patients were prospectively studied on a 3T MRI system with multinuclear capabilities. Three mutually exclusive tumor volumes of interest (VOIs) were segmented: contrast-enhancing tumor (CET), T2/FLAIR hyperintense non-enhancing tumor (NET), and necrosis. Median and voxel-wise associations between apparent diffusion coefficient (ADC), normalized relative cerebral blood volume (nrCBV), and normalized sodium measurements were quantified for each VOI. RESULTS: Both relative sodium concentration and ADC were significantly higher in areas of necrosis compared to NET (P = 0.003 and P = 0.008, respectively) and CET (P = 0.02 and P = 0.02). Sodium concentration was higher in CET compared to NET (P = 0.04). Sodium and ADC were higher in treated compared to treatment-naïve gliomas within NET (P = 0.006 and P = 0.01, respectively), and ADC was elevated in CET (P = 0.03). Median ADC and sodium concentration were positively correlated across patients in NET (r = 0.77, P < 0.0001) and CET (r = 0.84, P < 0.0001), but not in areas of necrosis (r = 0.45, P = 0.12). Median nrCBV and sodium concentration were negatively correlated across patients in areas of NET (r=-0.63, P = 0.003). Similar associations were observed when examining voxel-wise correlations within VOIs. CONCLUSION: Sodium MRI is positively correlated with proton diffusion MRI measurements in gliomas, likely reflecting extracellular water. Unique areas of multinuclear MRI contrast may be useful in future studies to understand the chemistry of the tumor microenvironment.

New Insights into the Spread of MRS-Based Water T2 Values Observed in Highly Fatty Replaced Muscles.

BACKGROUND: The reference standard for assessing water T2 (T2,H2O ) at high fat fraction (FF) is 1 H MRS. T2,H2O (T2,H2O,MRS ) dependence on FF (FFMRS ) has recently been demonstrated in muscle at high FF (i.e. ≥60%). PURPOSE: To investigate the relationship between T2,H2O,MRS and FFMRS in the thigh/leg muscles of patients with neuromuscular diseases and to compare with quantitative MRI. STUDY TYPE: Retrospective case-control study. POPULATION: A total of 151 patients with neuromuscular disorders (mean age ± standard deviation = 52.5 ± 22.6 years, 54% male), 44 healthy volunteers (26.5 ± 13.0 years, 57% male). FIELD STRENGTH/SEQUENCE: A 3-T; single-voxel stimulated echo acquisition mode (STEAM) MRS, multispin echo (MSE) imaging (for T2 mapping, T2,H2O,MRI ), three-point Dixon imaging (for FFMRI and R 2 * mapping). ASSESSMENT: Mono-exponential and bi-exponential models were fitted to water T2 decay curves to extract T2,H2O,MRS and FFMRS . Water resonance full-width-at-half-maximum (FWHM) and B0 spread (∆B0 ) values were calculated. T2,H2O,MRI (mean), FFMRI (mean, kurtosis, and skewness), and R 2 * (mean) values were estimated in the MRS voxel. STATISTICAL TESTS: Mann-Whitney U tests, Kruskal-Wallis tests. A P-value <0.05 was considered statistically significant. RESULTS: Normal T2,H2O,MRS threshold was defined as the 90th percentile in healthy controls: 30.3 msec. T2,H2O,MRS was significantly higher in all patients with FFMRS < 60% compared to healthy controls. We discovered two subgroups in patients with FFMRS ≥ 60%: one with T2,H2O,MRS ≥ 30.3 msec and one with T2,H2O,MRS < 30.3 msec including abnormally low T2,H2O,MRS . The latter subgroup had significantly higher water resonance FWHM, ∆B0 , FFMRI kurtosis, and skewness values but nonsignificantly different R 2 * (P = 1.00) and long T2,H2O,MRS component and its fraction (P > 0.11) based on the bi-exponential analysis. DATA CONCLUSION: The findings suggest that the cause for (abnormally) T2,H2O,MRS at high FFMRS is biophysical, due to differences in susceptibility between muscle and fat (increased FWHM and ∆B0 ), rather than pathophysiological such as compartmentation changes, which would be reflected by the bi-exponential analysis. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Motion-corrected 23 Na MRI of the human brain using interleaved 1 H 3D navigator images.

PURPOSE: To evaluate the feasibility of motion correction for sodium (23 Na) MRI based on interleaved acquired 3D proton (1 H) navigator images. METHODS: A 3D radial density-adapted sequence for interleaved 23 Na/1 H MRI was implemented on a 7 Tesla whole-body MRI system. The 1 H data obtained during the 23 Na acquisition were used to reconstruct 140 navigator image volumes with a nominal spatial resolution of (2.5 mm)3 and a temporal resolution of 6 s. The motion information received from co-registration was then used to correct the 23 Na image dataset, which also had a nominal spatial resolution of (2.5 mm)3 . The approach was evaluated on six healthy volunteers, whose motion during the scans had different intensities and characteristics. RESULTS: Interleaved acquisition of two nuclei did not show any relevant influence on image quality (SNR of 13.0 for interleaved versus 13.2 for standard 23 Na MRI and 176.4 for interleaved versus 178.0 for standard 1 H MRI). The applied motion correction increased the consistency between two consecutive scans for all examined volunteers and improved the image quality for all kinds of motion. The SD of the differences ranged between 2.30% and 6.96% for the uncorrected and between 2.13% and 2.67% for the corrected images. CONCLUSION: The feasibility of interleaved acquired 1 H navigator images to be used for retrospective motion correction of 23 Na images was successfully demonstrated. The approach neither affected the 23 Na image quality nor elongated the scan time and can therefore be an important tool to improve the accuracy of quantitative 23 Na MRI.

Interleaved and simultaneous multi-nuclear magnetic resonance in vivo. Review of principles, applications and potential.

Magnetic resonance signals from different nuclei can be excited or received at the same time,rendering simultaneous or rapidly interleaved multi-nuclear acquisitions feasible. The advan-tages are a reduction of total scan time compared to sequential multi-nuclear acquisitions or that additional information from heteronuclear data is obtained at thesame time and anatomical position. Information content can be qualitatively increased by delivering a more comprehensive MR-based picture of a transient state (such as an exercise bout). Also, combiningnon-proton MR acquisitions with 1 Hinformation (e.g., dynamic shim updates and motion correction) can be used to improve data quality during long scans and benefits image coregistration. This work reviews the literature on interleaved and simultaneous multi-nuclear MRI and MRS in vivo. Prominent use cases for this methodology in clinical and research applications are brain and muscle, but studies have also been carried out in other targets, including the lung, knee, breast and heart. Simultaneous multi-nuclear measurements in the liver and kidney have also been performed, but exclusively in rodents. In this review, a consistent nomenclature is proposed, to help clarify the terminology used for this principle throughout the literature on in-vivo MR. An overview covers the basic principles, the technical requirements on the MR scanner and the implementations realised either by MR system vendors or research groups, from the early days until today. Considerations regarding the multi-tuned RF coils required and heteronuclear polarisation interactions are briefly discussed, and fields for future in-vivo applications for interleaved multi-nuclear MR pulse sequences are identified.

Repeatability of multinuclear interleaved acquisitions with nuclear Overhauser enhancement effect in dynamic experiments in the calf muscle at 3T.

PURPOSE: To evaluate the repeatability of multinuclear interleaved 1 H/31 P NMR dynamic acquisitions in skeletal muscle and the impact of nuclear Overhauser enhancement (nOe) on the 31 P results at 3T in exercise-recovery and ischemia-hyperemia paradigms. METHODS: A 1 H/31 P interleaved pulse sequence was used to measure every 2.5 s a perfusion-weighted image, a T2∗ map, a 31 P spectrum and 32 1 H spectra sensitive to deoxymyoglobin. 21 subjects performed a plantar flexion exercise and after recovery underwent an 8-min lower leg ischemia. The procedure was repeated in visit 2 with 12 subjects. An additional exercise bout without 1 H excitation was appended to visit 1. Individual 1 H RF pulse nOe was measured at rest in every visit. RESULTS: Repeatability scores (coefficient of variation, Bland-Altman analysis) were similar to those found in the literature using similar mono-nuclear acquisitions. |Pi]/[PCr], pH drop, creatine rephosphorylation rate (τPCr ), maximum perfusion, time to peak perfusion, and blood flow post-exercise showed high reliability (intraclass correlation coefficient > 0.7), whereas hemodynamic results from reactive hyperemia showed higher repeatability. After accounting for nOe, which increased Pi and PCr signal-to-noise ratio by 30%, no differences in 31 P results were observed between interleaved and 31 P MRS-only acquisitions. τPCr was unaffected by nOe. CONCLUSION: The method shows good repeatability for both paradigms while simultaneously providing multiple dynamic data sets on a clinical scanner. The nOe effects were accounted for on a per-subject and per-visit basis using a short 31 P reference scan. This multiparametric approach has a multitude of applications for the study of oxygen utilization and ATP turnover in the muscle.

Quantitative Skeletal Muscle Imaging Using 3D MR Fingerprinting With Water and Fat Separation.

BACKGROUND: Quantitative muscle MRI is a robust tool to monitor intramuscular fatty replacement and disease activity in patients with neuromuscular disorders (NMDs). PURPOSE: To implement a 3D sequence for quantifying simultaneously fat fraction (FF) and water T1 (T1,H2O ) in the skeletal muscle, evaluate regular undersampling in the partition-encoding direction, and compare it to a recently proposed 2D MR fingerprinting sequence with water and fat separation (MRF T1 -FF). STUDY TYPE: Prospective. PHANTOM/SUBJECTS: Seventeen-vial phantom at different FF and T1,H2O , 11 healthy volunteers, and 6 subjects with different NMDs. FIELD STRENGTH/SEQUENCE: 3T/3D MRF T1 -FF, 2D MRF T1 -FF, STEAM MRS ASSESSMENT: FF and T1,H2O measured with the 2D and 3D sequences were compared in the phantom and in vivo at different undersampling factors (US). Data were acquired in healthy subjects before and after plantar dorsiflexions and at rest in patients. STATISTICAL TESTS: Linear correlations, Bland-Altman analysis, two-way repeated measures analysis of variance (ANOVA), Student's t-test. RESULTS: Up to a US factor of 3, the undersampled acquisitions were in good agreement with the fully sampled sequence (R2 ≥ 0.98, T1,H2O bias ≤10 msec, FF bias ≤4 × 10-4 ) both in phantom and in vivo. The 2D and 3D MRF T1 -FF sequences provided comparable T1,H2O and FF values (R2 ≥ 0.95, absolute T1,H2O bias ≤35 msec, and absolute FF bias ≤0.003). The plantar dorsiflexion induced a significant increase of T1,H2O in the tibialis anterior and extensor digitorum (relative increase of +10.8 ± 1.7% and + 7.7 ± 1.4%, respectively, P < 0.05), that was accompanied by a significant reduction of FF in the tibialis anterior (relative decrease of -16.3 ± 4.0%, P < 0.05). Some subjects with NMDs presented increased and heterogeneous T1,H2O and FF values throughout the leg. DATA CONCLUSION: Quantitative 3D T1,H2O and FF maps covering the entire leg were obtained within acquisition times compatible with clinical research (4 minutes 20 seconds) and a 1 × 1 × 5 mm3 spatial resolution. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Free intramuscular Mg2+ concentration calculated using both 31 P and 1 H NMRS-based pH in the skeletal muscle of Duchenne muscular dystrophy patients.

Early studies have demonstrated that (total) magnesium was decreased in skeletal muscle of Duchenne muscular dystrophy (DMD) patients. Free intramuscular Mg2+ can be derived from 31 P NMRS measurements. The value of free intramuscular magnesium concentration ([Mg2+ ]) is highly dependent on precise knowledge of intracellular pH, which is abnormally alkaline in dystrophic muscle, possibly due to an expanded interstitial space, potentially causing an underestimation of [Mg2+ ]. We have recently shown that intracellular pH can be derived using 1 H NMRS of carnosine. Our aim was to determine whether 31 P NMRS-based [Mg2+ ] is, in fact, abnormally low in DMD patients, taking advantage of the 1 H NMRS-based pH. A comparative analysis was, therefore, made between [Mg2+ ] values calculated with both 1 H and 31 P NMRS-based approaches to determine pH in 25 DMD patients, on a 3-T clinical NMR scanner. [Mg2+ ] was also assessed with 31 P NMRS only in (forearm or leg) skeletal muscle of 60 DMD patients and 63 age-matched controls. Additionally, phosphodiester levels as well as quantitative NMRI indices including water T2 , fat fraction, contractile cross-sectional area and one-year changes were evaluated. The main finding was that the significant difference in [Mg2+ ] between DMD patients and controls was preserved even when the intracellular pH determined with 1 H NMRS was similar in both groups. Consequently, we observed that [Mg2+ ] is significantly lower in DMD patients compared with controls in the larger database where only 31 P NMRS data were obtained. Significant yet weak correlations existed between [Mg2+ ] and PDE, water T2 and fat fraction. We concluded that low [Mg2+ ] is an actual finding in DMD, whether intracellular pH is normal or alkaline, and that it is a likely consequence of membrane leakiness. The response of Mg2+ to therapeutic treatment remains to be investigated in neuromuscular disorders. Free [Mg2+ ] determination with 31 P NMRS is highly dependent on a precise knowledge of intracellular pH. The pH of Duchenne muscular dystrophy (DMD) patients, as determined by 31 P NMRS, is abnormally alkaline. We have recently shown that intracellular pH could be determined using 1 H NMRS of carnosine, and that intracellular pH was alkaline in a proportion of, but not all, DMD patients with a 31 P NMRS-based alkaline pH. Taking advantage of this 1 H NMRS-based intracellular pH, we found that free intramuscular [Mg2+ ] is in fact abnormally low in DMD patients.

Metabolite and macromolecule T1 and T2 relaxation times in the rat brain in vivo at 17.2T.

PURPOSE: To measure the T1 and T2 relaxation times of water, metabolites, and macromolecules in the rat brain in vivo at 17.2T and achieve absolute quantification of the neurochemical profile. Relaxation times were compared with values from the literature found at lower magnetic fields. METHODS: (1) H NMR spectra were measured using a LASER localization sequence. T1 - and T2 -weighted spectra were analyzed using LCModel with an original parameterization of the macromolecule baseline. RESULTS: The T1 relaxation times of 20 metabolites and the T2 relaxation times of 16 singlets and J-coupled metabolites were measured. The mean T1 and T2 relaxation times for metabolites were 1721 ± 237 ms and 148 ± 53 ms, respectively. In addition, we measured the T1 and T2 relaxation times of 4 macromolecule resonance groups, their mean T1 and T2 relaxation times being 690 ± 100 ms and 37 ± 15 ms, respectively. Absolute quantification of 21 metabolites and 4 groups of macromolecule resonances was achieved with Cramer-Rao Lower Bounds below 5% for Cr, Gln, Glu, GPC, Ins, NAA, PCr, and Tau and below 25% for the remaining resonances. CONCLUSION: Comparison of our relaxation times to previously published values suggests a small increase of T1 values and a clear decrease of T2 values between 11.7 and 17.2T.