Optimization of 1 H MR spectroscopy methods for large volume acquisition of low concentration downfield resonances at 3T and 7T.

Purpose: This goal of this study was to optimize spectrally selective 1 H MRS methods for large volume acquisition of low concentration metabolites with downfield resonances at 7T and 3T, with particular attention paid to detection of nicotinamide adenine dinucleotide (NAD + ) and tryptophan. Methods: Spectrally selective excitation was used to avoid magnetization transfer effects with water, and various sinc pulses were compared to a pure-phase E-BURP pulse. Localization using a single slice selective pulse was compared to voxel-based localization that used three orthogonal refocusing pulses, and low bandwidth refocusing pulses were used to take advantage of the chemical shift displacement of water. A technique for water sideband removal was added, and a method of coil channel combination for large volumes was introduced. Results: Proposed methods were compared qualitatively to previously-reported techniques at 7T. Sinc pulses resulted in reduced water signal excitation and improved spectral quality, with a symmetric, low bandwidth-time product pulse performing best. Single slice localization allowed shorter TEs with large volumes, enhancing signal, while low bandwidth slice selective localization greatly reduced the observed water signal. Gradient cycling helped remove water sidebands, and frequency aligning and pruning individual channels narrowed spectral linewidths. High quality brain spectra of NAD + and tryptophan are shown in four subjects at 3T. Conclusion: Improved spectral quality with higher downfield signal, shorter TE, lower nuisance signal, reduced artifacts, and narrower peaks was realized at 7T. These methodological improvements allowed for previously unachievable detection of NAD + and tryptophan in human brain at 3T in under five minutes.

Quantification of NAD + T 1 and T 2 relaxation times using downfield 1 H MRS at 7 T in human brain in vivo.

Introduction: The purpose of this study was to use a single-slice spectrally-selective sequence to measure T 1 and T 2 relaxation times of NAD + proton resonances in the downfield 1 H MRS spectrum in human brain at 7 T in vivo and assess the propagation of relaxation time uncertainty in NAD + quantification. Methods: Downfield spectra from 7 healthy volunteers were acquired at multiple echo times in all subjects to measure T 2 relaxation, and saturation recovery data were to measure T 1 relaxation. The downfield acquisition used a spectrally-selective 90° sinc pulse for excitation centered at 9.1 ppm with a bandwidth of 2 ppm, followed by a 180° spatially-selective Shinnar-Le Roux refocusing pulse for localization. For the multiple echo experiment, spectra were collected with echo times ranging from 13 to 33 ms. For the saturation recovery experiment, saturation was performed prior to excitation using the same spectrally-selective sinc pulse as was used for excitation. Saturation delay times (TS) ranged from 100 to 600 ms. Uncertainty propagation analysis was performed analytically and with Monte Carlo simulation. Results: The mean ± standard deviation of T 1 relaxation times of the H2, H6, and H4 protons were 152.7 ± 16.6, 163.6 ± 22.3, and 169.9 ± 11.2 ms, respectively. The mean ± standard deviation of T 2 relaxation times of the H2, H6, and H4 protons were 32.5 ± 7.0, 27.4 ± 5.2, and 38.1 ± 11.7 ms, respectively. The mean R 2 of the H2 and H6 T 1 fits were 0.98. The mean R 2 of the H4 proton T 1 fit was 0.96. The mean R 2 of the T 2 fits of the H2 and H4 proton resonances were 0.98, while the mean R 2 of the T 2 fits of the H4 proton was 0.93. The relative uncertainty in NAD + concentration due to relaxation time uncertainty was 8.5%-11%. Conclusion: Using downfield spectrally-selective spectroscopy with single-slice localization, we found NAD + T 1 and T 2 relaxation times to be approximately 162 ms and 32 ms respectively in the human brain in vivo at 7 T.

Deep learning approach for automated segmentation of myocardium using bone scintigraphy single-photon emission computed tomography/computed tomography in patients with suspected cardiac amyloidosis.

BACKGROUND: We employed deep learning to automatically detect myocardial bone-seeking uptake as a marker of transthyretin cardiac amyloid cardiomyopathy (ATTR-CM) in patients undergoing 99mTc-pyrophosphate (PYP) or hydroxydiphosphonate (HDP) single-photon emission computed tomography (SPECT)/computed tomography (CT). METHODS: We identified a primary cohort of 77 subjects at Brigham and Women's Hospital and a validation cohort of 93 consecutive patients imaged at the University of Pennsylvania who underwent SPECT/CT with PYP and HDP, respectively, for evaluation of ATTR-CM. Global heart regions of interest (ROIs) were traced on CT axial slices from the apex of the ventricle to the carina. Myocardial images were visually scored as grade 0 (no uptake), 1 (uptakeribs). A 2D U-net architecture was used to develop whole-heart segmentations for CT scans. Uptake was determined by calculating a heart-to-blood pool (HBP) ratio between the maximal counts value of the total heart region and the maximal counts value of the most superior ROI. RESULTS: Deep learning and ground truth segmentations were comparable (p=0.63). A total of 42 (55%) patients had abnormal myocardial uptake on visual assessment. Automated quantification of the mean HBP ratio in the primary cohort was 3.1±1.4 versus 1.4±0.2 (p<0.01) for patients with positive and negative cardiac uptake, respectively. The model had 100% accuracy in the primary cohort and 98% in the validation cohort. CONCLUSION: We have developed a highly accurate diagnostic tool for automatically segmenting and identifying myocardial uptake suggestive of ATTR-CM.

Clinical correlates of CT imaging-derived phenotypes among lean and overweight patients with hepatic steatosis.

The objective of this study is to define CT imaging derived phenotypes for patients with hepatic steatosis, a common metabolic liver condition, and determine its association with patient data from a medical biobank. There is a need to further characterize hepatic steatosis in lean patients, as its epidemiology may differ from that in overweight patients. A deep learning method determined the spleen-hepatic attenuation difference (SHAD) in Hounsfield Units (HU) on abdominal CT scans as a quantitative measure of hepatic steatosis. The patient cohort was stratified by BMI with a threshold of 25 kg/m2 and hepatic steatosis with threshold SHAD ≥ - 1 HU or liver mean attenuation ≤ 40 HU. Patient characteristics, diagnoses, and laboratory results representing metabolism and liver function were investigated. A phenome-wide association study (PheWAS) was performed for the statistical interaction between SHAD and the binary characteristic LEAN. The cohort contained 8914 patients-lean patients with (N = 278, 3.1%) and without (N = 1867, 20.9%) steatosis, and overweight patients with (N = 1863, 20.9%) and without (N = 4906, 55.0%) steatosis. Among all lean patients, those with steatosis had increased rates of cardiovascular disease (41.7 vs 27.8%), hypertension (86.7 vs 49.8%), and type 2 diabetes mellitus (29.1 vs 15.7%) (all p < 0.0001). Ten phenotypes were significant in the PheWAS, including chronic kidney disease, renal failure, and cardiovascular disease. Hepatic steatosis was found to be associated with cardiovascular, kidney, and metabolic conditions, separate from overweight BMI.

Identification of new resonances in downfield 1 H MRS of human calf muscle in vivo: Potentially metabolite precursors for skeletal muscle NAD.

PURPOSE: The purpose of this study was to identify and characterize newly discovered resonances appearing in the downfield proton MR spectrum (DF 1 H MRS) of the human calf muscle in vivo at 7T. METHODS: Downfield 1 H MRS was performed on the calf muscle of five healthy volunteers at 7T. A spectrally selective 90° E-BURP RF pulse with an excitation center frequency at 10.3 ppm and an excitation bandwidth of 2 ppm was used for DF 1 H MRS acquisition. RESULTS: In all participants, we observed new resonances at 9.7, 10.1, 10.3, and 10.9 ppm in the DF 1 H MRS. Phantom experiments at 37°C strongly suggest the new resonance at 9.7 ppm could be from H2-proton of the nicotinamide rings in nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) while the resonance at 10.1 ppm could be attributed to the indole -NH proton of L-tryptophan. We observed that the resonances at 10.1 and 10.9 ppm are significantly suppressed when the water resonance is saturated, indicating that these peaks have either 1 H chemical exchange or cross-relaxation with water. Conversely, the resonances at 9.7 and 10.3 ppm exhibit moderate signal reduction in the presence of water saturation. CONCLUSION: We have identified new proton resonances in vivo in human calf muscle occurring at chemical shifts of 9.7, 10.1, 10.3, and 10.9 ppm. These preliminary results are promising for investigating the role of NR/NMN and L-tryptophan metabolism in understanding the de novo and salvage pathways of NAD+ synthesis in skeletal muscle.

Quantification of cross-relaxation in downfield 1 H MRS at 7 T in human calf muscle.

PURPOSE: The purpose of this study was to characterize the 1 H downfield MR spectrum from 8.0 to 10.0 ppm of human skeletal muscle at 7 T and determine the T1 and cross-relaxation rates of observed resonances. METHODS: We performed downfield MRS in the calf muscle of 7 healthy volunteers. Single-voxel downfield MRS was collected using alternately selective or broadband inversion-recovery sequences and spectrally selective 90° E-BURP RF pulse excitation centered at 9.0 ppm with bandwidth = 600 Hz (2.0 ppm). MRS was collected using TIs of 50-2500 ms. We modeled recovery of the longitudinal magnetization of three observable resonances using two models: (1) a three-parameter model accounting for the apparent T1 recovery and (2) a Solomon model explicitly including cross-relaxation effects. RESULTS: Three resonances were observed in human calf muscle at 7 T at 8.0, 8.2, and 8.5 ppm. We found broadband (broad) and selective (sel) inversion recovery T1 = mean ± SD (ms): T1-broad,8.0ppm = 2108.2 ± 664.5, T1-sel,8.0ppm = 753.6 ± 141.0 (p = 0.003); T1-broad,8.2ppm = 2033.5 ± 338.4, T1-sel,8.2ppm = 135.3 ± 35.3 (p < 0.0001); and T1-broad,8.5ppm = 1395.4 ± 75.4, T1-sel,8.5ppm = 107.1 ± 40.0 (p < 0.0001). Using the Solomon model, we found T1 = mean ± SD (ms): T1-8.0ppm = 1595.6 ± 491.1, T1-8.2ppm = 1737.2 ± 963.7, and T1-8.5ppm = 849.8 ± 282.0 (p = 0.04). Post hoc tests corrected for multiple comparisons showed no significant difference in T1 between peaks. The cross-relaxation rate σAB = mean ± SD (Hz) of each peak was σAB,8.0ppm = 0.76 ± 0.20, σAB,8.2ppm = 5.31 ± 2.27, and σAB,8.5ppm = 7.90 ± 2.74 (p < 0.0001); post hoc t-tests revealed the cross-relaxation rate of the 8.0 ppm peak was significantly slower than the peaks at 8.2 ppm (p = 0.0018) and 8.5 ppm (p = 0.0005). CONCLUSION: We found significant differences in effective T1 and cross-relaxation rates of 1 H resonances between 8.0 and 8.5 ppm in the healthy human calf muscle at 7 T.

Identification of l-Tryptophan by down-field 1 H MRS: A precursor for brain NAD+ and serotonin syntheses.

PURPOSE: To explore the presence of new resonances beyond 9.4 ppm from the human brain, down-field proton MRS was performed in vivo in the human brain on 6 healthy volunteers at 7 T. METHODS: To maximize the SNR, a large voxel was placed within the brain to cover the maximal area in such a way that sinus cavities were avoided. A spectrally selective 90° E-BURP pulse with an excitation bandwidth of 2 ppm was used to probe the spectral chemical shift range between 9.1 and 10.5 ppm. The E-BURP pulse was integrated with PRESS spatial localization to obtain non-water-suppressed proton MR spectra from the desired spectral region. RESULTS: In the down-field proton MRS obtained from all of the volunteers scanned, we identified a new peak consistently resonating at 10.1 ppm. Protons associated with this resonance are in cross-relaxation with the bulk water, as demonstrated by the water saturation and deuterium exchange experiments. CONCLUSION: Based on the chemical shift, this new peak was identified as the indole (-NH) proton of l-tryptophan (l-TRP) and was further confirmed from phantom experiments on l-TRP. These promising preliminary results potentially pave the way to investigate the role of cerebral metabolism of l-TRP in healthy and disease conditions.

Integrating 1H MRS and deuterium labeled glucose for mapping the dynamics of neural metabolism in humans.

In the technique presented here, dubbed 'qMRS', we quantify the change in 1H MRS signal following administration of 2H-labeled glucose. As in recent human DMRS studies, we administer [6,6'-2H2]-glucose orally to healthy subjects. Since 2H is not detectable by 1H MRS, the transfer of the 2H label from glucose to a downstream metabolite leads to a reduction in the corresponding 1H MRS resonance of the metabolite, even if the total concentration of both isoforms remains constant. Moreover, introduction of the deuterium label alters the splitting pattern of the proton resonances, making indirect detection of the deuterated forms- as well as the direct detection of the decrease in unlabeled form- possible even without a 2H coil. Because qMRS requires only standard 1H MRS acquisition methods, it can be performed using commonly implemented single voxel spectroscopy (SVS) and chemical shift imaging (CSI) sequences. In this work, we implement qMRS in semi-LASER based CSI, generating dynamic maps arising from the fitted spectra, and demonstrating the feasibility of using qMRS and qCSI to monitor dynamic metabolism in the human brain using a 7T scanner with no auxiliary hardware.

Magnetic susceptibility and R2* of myocardial reperfusion injury at 3T and 7T.

PURPOSE: Magnetic susceptibility (Δχ) alterations have shown association with myocardial infarction (MI) iron deposition, yet there remains limited understanding of the relationship between relaxation rates and susceptibility or the effect of magnetic field strength. Hence, Δχ and R2∗ in MI were compared at 3T and 7T. METHODS: Subacute MI was induced by coronary artery ligation in male Yorkshire swine. 3D multiecho gradient echo imaging was performed at 1-week postinfarction at 3T and 7T. Quantitative susceptibility mapping images were reconstructed using a morphology-enabled dipole inversion. R2∗ maps and quantitative susceptibility mapping were generated to assess the relationship between R2∗ , Δχ, and field strength. Infarct histopathology was investigated. RESULTS: Magnetic susceptibility was not significantly different across field strengths (7T: 126.8 ± 41.7 ppb; 3T: 110.2 ± 21.0 ppb, P = NS), unlike R2∗ (7T: 247.0 ± 14.8 Hz; 3T: 106.1 ± 6.5 Hz, P < .001). Additionally, infarct Δχ and R2∗ were significantly higher than remote myocardium. Magnetic susceptibility at 7T versus 3T had a significant association (ß = 1.02, R2 = 0.82, P < .001), as did R2∗ (ß = 2.35, R2 = 0.98, P < .001). Infarct pathophysiology and iron deposition were detected through histology and compared with imaging findings. CONCLUSION: R2∗ showed dependence and Δχ showed independence of field strength. Histology validated the presence of iron and supported imaging findings.

Endogenous T1ρ cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by increased left ventricular wall thickness, cardiomyocyte hypertrophy, and fibrosis. Adverse cardiac risk characterization has been performed using late gadolinium enhancement (LGE), native T1, and extracellular volume (ECV). Relaxation time constants are affected by background field inhomogeneity. T1ρ utilizes a spin-lock pulse to decrease the effect of unwanted relaxation. The objective of this study was to study T1ρ as compared to T1, ECV, and LGE in HCM patients. METHODS: HCM patients were recruited as part of the Novel Markers of Prognosis in Hypertrophic Cardiomyopathy study, and healthy controls were matched for comparison. In addition to cardiac functional imaging, subjects underwent T1 and T1ρ cardiovascular magnetic resonance imaging at short-axis positions at 1.5T. Subjects received gadolinium and underwent LGE imaging 15-20 min after injection covering the entire heart. Corresponding basal and mid short axis LGE slices were selected for comparison with T1 and T1ρ. Full-width half-maximum thresholding was used to determine the percent enhancement area in each LGE-positive slice by LGE, T1, and T1ρ. Two clinicians independently reviewed LGE images for presence or absence of enhancement. If in agreement, the image was labeled positive (LGE + +) or negative (LGE --); otherwise, the image was labeled equivocal (LGE + -). RESULTS: In 40 HCM patients and 10 controls, T1 percent enhancement area (Spearman's rho = 0.61, p < 1e-5) and T1ρ percent enhancement area (Spearman's rho = 0.48, p < 0.001e-3) correlated with LGE percent enhancement area. T1 and T1ρ percent enhancement areas were also correlated (Spearman's rho = 0.28, p = 0.047). For both T1 and T1ρ, HCM patients demonstrated significantly longer relaxation times compared to controls in each LGE category (p < 0.001 for all). HCM patients also showed significantly higher ECV compared to controls in each LGE category (p < 0.01 for all), and LGE -- slices had lower ECV than LGE + + (p = 0.01). CONCLUSIONS: Hyperenhancement areas as measured by T1ρ and LGE are moderately correlated. T1, T1ρ, and ECV were elevated in HCM patients compared to controls, irrespective of the presence of LGE. These findings warrant additional studies to investigate the prognostic utility of T1ρ imaging in the evaluation of HCM patients.

Smaller subcortical volumes and enlarged lateral ventricles are associated with higher global functioning in young adults with 22q11.2 deletion syndrome with prodromal symptoms of schizophrenia.

The 22q11.2 deletion syndrome (22q11DS) is a developmental genetic syndrome associated with a 30% risk for developing schizophrenia. Lateral ventricles and subcortical structures are abnormal in this syndrome as well as in schizophrenia. Here, we investigated whether these structures are related in young adults with 22q11DS with and without prodromal symptoms (PS) for schizophrenia and whether abnormalities in volumes are associated with global functioning. MR images were acquired on a 3T scanner from 51 individuals with 22q11DS and 30 healthy controls (mean age: 21±2 years). Correlations were performed to evaluate the relationship between ventricular and subcortical volumes, with Global Assessment of Functioning (GAF) and Premorbid Adjustment Scale (PAS) in each group. Lateral ventricular volumes correlated negatively with subcortical volumes in individuals with 22q11DS. In individuals with 22q11DS with PS only, GAF correlated positively with volumes of the lateral ventricles and negatively with subcortical volumes. PAS correlated negatively with lateral ventricle volumes, and positively with volumes of subcortical structures. The results suggest a common neurodevelopmental mechanism related to the growth of these brain structures. Further, the ratio between the volumes and clinical measures could potentially be used to characterize individuals with 22q11DS and those from the general population for the risk of the development of schizophrenia.

Emotional Awareness in Schizophrenia Is Associated With Gray Matter Volume of Right Precuneus.

Objectives: We assessed the relationship between emotional awareness (e.g., the ability to identify and differentiate our own feelings and feelings of others) and regional brain volumes in healthy and in schizophrenia groups. Methods: Magnetic resonance images of 29 subjects with schizophrenia and 33 matched healthy controls were acquired. Brain gray matter was parcellated using FreeSurfer and 28 regions of interest associated with emotional awareness were analyzed. All participants were assessed using the Levels of Emotional Awareness Scale (LEAS) of Self and of Other. LEAS scores were correlated with gray matter volume for each hemisphere on the 14 brain regions of the emotional awareness network. Results: Individuals with schizophrenia showed decreased emotional awareness on both LEAS Self and LEAS Other compared to healthy controls. There were no statistically significant between-group differences in gray matter volumes of the emotional awareness network. The performance on LEAS Other correlated negatively with right precuneus gray matter volume only in the schizophrenia group. Conclusion: Our findings suggest a relationship between gray matter volume of the right precuneus and deficits in understanding of emotional states of others in schizophrenia.