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Magnetization transfer contrast has yielded insight into brain tissue microstructure changes across the lifespan and in a range of disorders. This progress has been aided by the development of quantitative magnetization transfer imaging techniques able to extract intrinsic properties of the tissue that are independent of the specifics of the data acquisition. While the tissue properties extracted by these techniques do not map directly onto specific cellular structures or pathological processes, a growing body of work from animal models and histopathological correlations aids the in vivo interpretation of magnetization transfer properties of tissue. This review examines the biophysical models that have been developed to describe magnetization transfer contrast in tissue as well as the experimental evidence for the biological interpretation of magnetization transfer data in health and disease.

Off-resonance saturation transfer images have shown intriguing differences in intensity in glioma compared to normal brain tissues. Interpretation of these differences is complicated, however, by the presence of multiple sources of exchanging magnetization including amide, amine, and hydroxyl protons, asymmetric magnetization transfer contrast (MTC) from macromolecules, and various protons with resonances in the aliphatic spectral region. We report a study targeted at separating these components and identifying their relative contributions to contrast in glioma. Off-resonance z-spectra at several saturation powers and durations were obtained from 6 healthy controls and 8 patients with high grade glioma. Results indicate that broad macromolecular MTC in normal brain tissue is responsible for the majority of contrast with glioma. Amide exchange could be detected with lower saturation power than has previously been reported in glioma, but it was a weak signal source with no detectable contrast from normal brain tissue. At higher saturation powers, amine proton exchange was a major contributor to the observed signal but showed no significant difference from normal brain. Robust acquisition strategies that effectively isolate the contributions of broad macromolecular MTC asymmetry from amine exchange were demonstrated that may provide improved contrast between glioma and normal tissue. •We describe robust methods to measure chemical exchange saturation transfer (CEST).•We separated amine and amide CEST effects from magnetization transfer (MT) asymmetry.•We measured CEST and MT asymmetry signal in patients with recurrent glioma.•MT asymmetry is mostly responsible for the contrast between glioma and normal brain.

  Objective The potential of magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI) for the detection and evolution of new multiple sclerosis (MS) lesions was analyzed. Methods Nineteen patients with MS obtained conventional MRI, MTI, and DTI examinations bimonthly for 12 months and again after 24 months at 1.5 T MRI. MTI was acquired with balanced steady-state free precession (bSSFP) in 10 min (1.3 mm 3 isotropic resolution) yielding both magnetization transfer ratio (MTR) and quantitative magnetization transfer (qMT) parameters (pool size ratio (F), exchange rate (kf), and relaxation times (T1/T2)). DTI provided fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Results At the time of their appearance on MRI, the 21 newly detected MS lesions showed significantly reduced MTR/F/kf and prolonged T1/T2 parameters, as well as significantly reduced FA and increased AD/MD/RD. Significant differences were already observed for MTR 4 months and for qMT parameters 2 months prior to lesions’ detection on MRI. DTI did not show any significant pre-lesional differences. Slightly reversed trends were observed for most lesions up to 8 months after their detection for qMT and less pronounced for MTR and three diffusion parameters, while appearing unchanged on MRI. Conclusions MTI provides more information than DTI in MS lesions and detects tissue changes 2 to 4 months prior to their appearance on MRI. After lesions’ detection, qMT parameter changes promise to be more sensitive than MTR for the lesions’ evolutional assessment. Overall, bSSFP-based MTI adumbrates to be more sensitive than MRI and DTI for the early detection and follow-up assessment of MS lesions. Clinical relevance statement When additionally acquired in routine MRI, fast bSSFP-based MTI can complement the MRI/DTI longitudinal lesion assessment by detecting MS lesions 2–4 months earlier than with MRI, which could implicate earlier clinical decisions and better follow-up/treatment assessment in MS patients. Key Points • Magnetization transfer imaging provides more information than DTI in multiple sclerosis lesions and can detect tissue changes 2 to 4 months prior to their appearance on MRI. • After lesions’ detection, quantitative magnetization transfer changes are more pronounced than magnetization transfer ratio changes and therefore promise to be more sensitive for the lesions’ evolutional assessment. • Balanced steady-state free precession–based magnetization transfer imaging is more sensitive than MRI and DTI for the early detection and follow-up assessment of multiple sclerosis lesions.

•Inhomogeneous magnetization transfer can characterize cortical myeloarchitecture.•Cortical ihMT and MT are correlated but regional differences exist.•The ratio ihMT/MT may represent a measure of fractional myelin content. Myelin specific imaging techniques to characterize white matter in demyelinating diseases such as multiple sclerosis (MS) have become an area of increasing focus. Gray matter myelination is an important marker of cortical microstructure, and its impairment is relevant in progressive MS. However, its assessment is challenging due to its thin layers. While myelin water imaging and ultra-short TE imaging have not yet been implemented to assess cortical myeloarchitecture, magnetization transfer (MT) shows promise. A recent development of the MT technique, ihMT, has demonstrated greater myelin sensitivity/specificity. Here we implemented a 3D ihMT acquisition and analysis to characterize cortical gray matter myeloarchitecture. 20 young healthy volunteers were imaged with a 3D ihMTRAGE sequence and quantitative metrics of ihMT (ihMTsat), and dual frequency-offset MT (dual MTsat) were calculated. Cortical surface-based analysis of ihMTsat and dual MTsat were performed and compared. We also compared the cortical ihMTsat map to a cortical surface-based map of T1-weighted images (T1w), defined as a proxy of myelin content. Cortical ihMTsat and dual MTsat maps were in qualitative agreement with previous work and the cortical T1w map, showing higher values in primary cortices and lower values in the insula. IhMTsat and dual MTsat were significantly correlated but with important regional differences. The ratio ihMTsat/dual MTsat highlighted higher ihMTsat values in the primary cortices and sulci. ihMTsat, a quantitative metric of ihMT, can be reliably measured in cortical gray matter and shows unique contrast between cortical regions. [Display omitted]

Despite the essential role of the brain energy generated from ATP hydrolysis in supporting cortical neuronal activity and brain function, it is challenging to noninvasively image and directly quantify the energy expenditure in the human brain. In this study, we applied an advanced in vivo31P MRS imaging approach to obtain regional cerebral metabolic rates of high-energy phosphate reactions catalyzed by ATPase (CMRATPase) and creatine kinase (CMRCK), and to determine CMRATPase and CMRCK in pure gray mater (GM) and white mater (WM), respectively. It was found that both ATPase and CK rates are three times higher in GM than WM; and CMRCK is seven times higher than CMRATPase in GM and WM. Among the total brain ATP consumption in the human cortical GM and WM, 77% of them are used by GM in which approximately 96% is by neurons. A single cortical neuron utilizes approximately 4.7billion ATPs per second in a resting human brain. This study demonstrates the unique utility of in vivo31P MRS imaging modality for direct imaging of brain energy generated from ATP hydrolysis, and provides new insights into the human brain energetics and its role in supporting neuronal activity and brain function. ► The ATP utilization rate is three times higher in GM than WM in the human brain. ► The majority of the cerebral ATP energy is utilized by cortical neurons in humans. ► 4.7 billion ATP molecules are utilized by a cortical neuron each second in humans. ► A resting-state human brain utilizes ~5.7 kg ATP/day, 5 times of the brain weight.

Purpose We sought to measure quantitative magnetization transfer (qMT) properties of the substantia nigra pars compacta (SNc) in patients with Parkinson’s disease (PD) and healthy controls (HCs) using a full qMT analysis and determine whether a rapid single-point measurement yields equivalent results for pool size ratio (PSR). Methods Sixteen different MT-prepared MRI scans were obtained at 3 T from 16 PD patients and eight HCs, along with B1, B0, and relaxation time maps. Maps of PSR, free and macromolecular pool transverse relaxation times ( T 2 f , T 2 m ) and rate of MT exchange between pools ( k mf ) were generated using a full qMT model. PSR maps were also generated using a single-point qMT model requiring just two MT-prepared images. qMT parameter values of the SNc, red nucleus, cerebral crus, and gray matter were compared between groups and methods. Results PSR of the SNc was the only qMT parameter to differ significantly between groups ( p  < 0.05). PSR measured via single-point analysis was less variable than with the full MT model, provided slightly better differentiation of PD patients from HCs (area under curve 0.77 vs. 0.75) with sensitivity of 0.75 and specificity of 0.87, and was better than transverse relaxation time in distinguishing PD patients from HCs (area under curve 0.71, sensitivity 0.87, and specificity 0.50). Conclusion The increased PSR observed in the SNc of PD patients may provide a novel biomarker of PD, possibly associated with an increased macromolecular content. Single-point PSR mapping with reduced variability and shorter scan times relative to the full qMT model appears clinically feasible.

Cross-relaxation imaging (CRI) is a quantitative magnetic resonance technique that measures the kinetic parameters of magnetization transfer between protons bound to water and protons bound to macromolecules. In this study, in vivo, four-parameter CRI of normal rat brains (N=5) at 3.0 T was first directly compared to histology. The bound pool fraction, f, was strongly associated with myelin density (Pearson's r=0.99, p<0.001). The correlation persisted in separate analyses of gray matter (GM; r=0.89, p=0.046) and white matter (WM; r=0.97, p=0.029). Subsequently, a new time-efficient approach for solely capturing the whole-brain parametric map of f was proposed, validated with histology, and used to estimate myelin density. Since the described approach for the rapid acquisition of f applied constraints to other CRI parameters, a theoretical analysis of error was performed. Estimates of f in normal and pathologic tissue were expected to have <10% error. A comparison of values for f obtained from the traditional four-parameter fit of CRI data versus the proposed rapid acquisition of f was within this expected margin for in vivo rat brain gliomas (N=4; mean±SE; 3.9±0.2% vs. 4.0±0.2%, respectively). In both whole-brain f maps and myelin density maps, replacement of normal GM and WM by proliferating and invading tumor cells could be readily identified. The rapid, whole-brain acquisition of the bound pool fraction may provide a reliable method for detection of glioma invasion in both GM and WM during animal and human imaging. ►The bound pool fraction, f, strongly correlates to in vivo myelin density. ►Time-efficient bound pool fraction imaging provides whole-brain parametric f maps. ►Glioma invasion reduces f in gray matter, white matter (WM), and WM fiber tracts.

As the use of ultra-high field (UHF; ≥7T) magnetic resonance (MR) imaging expands, there is an increasing need to establish high-resolution MR imaging protocols for patients with neurological disease. Magnetization transfer (MT) imaging has been used to provide information about changes in the magnitude of the restricted protons that are caused by tissue damages. Several studies have found that MTR has a good sensitivity to measure changes in myelin concentration within the brain. Because of the much higher specific absorption rate (SAR) of tissue and longer acquisition time required for UHF, however, in-vivo studies using conventional pulsed MT sequences at UHF have not been well utilized. In this study, we introduce a new MT data acquisition approach using a 7T MR system, variable density magnetization transfer (vdMT) imaging, which can be reasonably included in a routine patient scan protocol with a much shorter scan time and reduced discomfort to the patient. To reduce SAR and scan time while maintaining at least similar MTR image quality to that obtained with the conventional method, a higher density of MT RF pulses was applied in the center of k-space, and sparsely applied MT RF pulses were used in the outer part of k-space. The fraction of k-space receiving 100% MT RF density and TR were optimized based on in-vivo ROI analysis, and results were confirmed with high-resolution MTR map using a vdMT approach from healthy controls and patients with multiple sclerosis (MS). The experimental results confirmed that vdMT imaging can cover a whole brain volume in an acceptable scan time for routine patient scans while providing MTR image quality at least similar to that obtained with conventional MT imaging (correlation coefficient=0.95 in an agar-gel phantom [MT offset frequency=1kH], 0.90 in a postmortem MS brain, and 0.85 in the 4 healthy volunteers). MS lesions were associated with signal reductions in the postmortem MS brains and in the patients with MS. In this study, we have described a new approach for acquiring high-resolution MTR map of the whole brain volume using 7T MR imaging. This vdMT method provides similar image quality to that obtained with the conventional method, and shortens the scan time by reducing SAR. These results suggest that vdMT approach is a method that could be used for UHF scans of patients with neurological disease. [Display omitted] •vdMT shortens the scan time by reducing SAR.•vdMT method provides image quality at least similar to that obtained with conventional method.•vdMT generates high resolution MT data in clinically reasonable scan time (<6 min).•vdMT method is appealing for clinical neuroimaging applications in UHF.

In neuroimaging, there is increasing interest in magnetization transfer (MT) techniques which yield information about bound water protons. One of the main applications is the investigation of the myelin integrity in the central nervous system (CNS). However, several problems may arise, in particular at high magnetic field strengths: B1 inhomogeneities may yield deviations of the MT saturation angle and thus non-uniformities of the measured MT ratio (MTR). This effect can be corrected for but requires in general additional time consuming B1 mapping. Furthermore, increased values of the specific absorption rate (SAR) may require a reduction of the saturation angle for individual subjects, impairing comparability of results. In this work, a B1 mapping method based on magnetization-prepared FLASH with slice selective preparation and excitation pulses and correction for relaxation effects is presented, yielding B1 maps with whole brain coverage, an in-plane resolution of 4 mm, a slice thickness of 3 mm, and a clinically acceptable duration of 46 s. The method is tested both in vitro and in vivo and applied in a subsequent in vivo study to show that MTR values in human brain tissue depend approximately linearly on the preparation angle, with a slope similar to values reported for 1.5 T. Calibration data and B1 maps are applied to B1 inhomogeneity corrections of MTR maps. Subsequently, it is shown that B1-corrected MTR maps acquired at reduced preparation angles due to individual SAR restrictions can be normalized, allowing for a direct comparison with maps acquired at the full angle.

As the use of ultra-high field (UHF; ≥7T) magnetic resonance (MR) imaging expands, there is an increasing need to establish high-resolution MR imaging protocols for patients with neurological disease. Magnetization transfer (MT) imaging has been used to provide information about changes in the magnitude of the restricted protons that are caused by tissue damages. Several studies have found that MTR has a good sensitivity to measure changes in myelin concentration within the brain. Because of the much higher specific absorption rate (SAR) of tissue and longer acquisition time required for UHF, however, in-vivo studies using conventional pulsed MT sequences at UHF have not been well utilized.In this study, we introduce a new MT data acquisition approach using a 7T MR system, variable density magnetization transfer (vdMT) imaging, which can be reasonably included in a routine patient scan protocol with a much shorter scan time and reduced discomfort to the patient.To reduce SAR and scan time while maintaining at least similar MTR image quality to that obtained with the conventional method, a higher density of MT RF pulses was applied in the center of k-space, and sparsely applied MT RF pulses were used in the outer part of k-space. The fraction of k-space receiving 100% MT RF density and TR were optimized based on in-vivo ROI analysis, and results were confirmed with high-resolution MTR map using a vdMT approach from healthy controls and patients with multiple sclerosis (MS).The experimental results confirmed that vdMT imaging can cover a whole brain volume in an acceptable scan time for routine patient scans while providing MTR image quality at least similar to that obtained with conventional MT imaging (correlation coefficient=0.95 in an agar-gel phantom [MT offset frequency=1kH], 0.90 in a postmortem MS brain, and 0.85 in the 4 healthy volunteers). MS lesions were associated with signal reductions in the postmortem MS brains and in the patients with MS.In this study, we have described a new approach for acquiring high-resolution MTR map of the whole brain volume using 7T MR imaging. This vdMT method provides similar image quality to that obtained with the conventional method, and shortens the scan time by reducing SAR. These results suggest that vdMT approach is a method that could be used for UHF scans of patients with neurological disease.