Magnetization Transfer Parameters Research Articles

Longitudinal analysis of new multiple sclerosis lesions with magnetization transfer and diffusion tensor imaging

ObjectiveThe potential of magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI) for the detection and evolution of new multiple sclerosis (MS) lesions was analyzed.MethodsNineteen 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 mm3 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).ResultsAt 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.ConclusionsMTI 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 statementWhen 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.

High-resolution magnetization-transfer imaging of post-mortem marmoset brain: Comparisons with relaxometry and histology

Cell membranes and macromolecules or paramagnetic compounds interact with water proton spins, which modulates magnetic resonance imaging (MRI) contrast providing information on tissue composition. For a further investigation, quantitative magnetization transfer (qMT) parameters (at 3T), including the ratio of the macromolecular and water proton pools, F, and the exchange-rate constant as well as the (observed) longitudinal and the effective transverse relaxation rates (at 3T and 7T), R1obs and R2*, respectively, were measured at high spatial resolution (200 µm) in a slice of fixed marmoset brain and compared to histology results obtained with Gallyas’ myelin stain and Perls’ iron stain. R1obs and R2* were linearly correlated with the iron content for the entire slice, whereas distinct differences were obtained between gray and white matter for correlations of relaxometry and qMT parameters with myelin content. The combined results suggest that the macromolecular pool interacting with water consists of myelin and (less efficient) non-myelin contributions. Despite strong correlation of F and R1obs, none of these parameters was uniquely specific to myelination. Due to additional sensitivity to iron stores, R1obs and R2* were more sensitive for depicting microstructural differences between cortical layers than F.

Microscopic theory of spin-spin and spin-lattice relaxation of bound protons in cellular and myelin membranes-A lateral diffusion model (LDM).

Deciphering salient features of biological tissue cellular microstructure in health and diseases is an ultimate goal of MRI. While most MRI approaches are based on studying MR properties of tissue "free" water indirectly affected by tissue microstructure, other approaches, such as magnetization transfer (MT), directly target signals from tissue-forming macromolecules. However, despite three-decades of successful applications, relationships between MT measurements and tissue microstructure remain elusive, hampering interpretation of experimental results. The goal of this paper is to develop microscopic theory connecting the structure of cellular and myelin membranes to their MR properties. Herein we introduce a lateral diffusion model (LDM) that explains the T2 (spin-spin) and T1 (spin-lattice) MRI relaxation properties of the macromolecular-bound protons by their dipole-dipole interaction modulated by the lateral diffusion of long lipid molecules forming cellular and myelin membranes. LDM predicts anisotropic T1 and T2 relaxation of membrane-bound protons. Moreover, their T2 relaxation cannot be described in terms of a standard R2 =1/T2 relaxation rate parameter, but rather by a relaxation rate function R2 (t) that depends on time t after RF excitation, having, in the main approximation, a logarithmic behavior: R2 (t) ∼ lnt. This anisotropic non-linear relaxation leads to an absorption lineshape that is different from Super-Lorentzian traditionally used in interpreting MT experiments. LDM-derived analytical equations connect the membrane-bound protons T1 and T2 relaxation with dynamic distances between protons in neighboring membrane-forming lipid molecules and their lateral diffusion. This sheds new light on relationships between MT parameters and microstructure of cellular and myelin membranes.

Primary Multiparametric Quantitative Brain MRI: State-of-the-Art Relaxometric and Proton Density Mapping Techniques.

This review on brain multiparametric quantitative MRI (MP-qMRI) focuses on the primary subset of quantitative MRI (qMRI) parameters that represent the mobile ("free") and bound ("motion-restricted") proton pools. Such primary parameters are the proton densities, relaxation times, and magnetization transfer parameters. Diffusion qMRI is also included because of its wide implementation in complete clinical MP-qMRI application. MP-qMRI advances were reviewed over the past 2 decades, with substantial progress observed toward accelerating image acquisition and increasing mapping accuracy. Areas that need further investigation and refinement are identified as follows: (a) the biologic underpinnings of qMRI parameter values and their changes with age and/or disease and (b) the theoretical limitations implicitly built into most qMRI mapping algorithms that do not distinguish between the different spatial scales of voxels versus spin packets, the central physical object of the Bloch theory. With rapidly improving image processing techniques and continuous advances in computer hardware, MP-qMRI has the potential for implementation in a wide range of clinical applications. Currently, three emerging MP-qMRI applications are synthetic MRI, macrostructural qMRI, and microstructural tissue modeling.

Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?

Introduction: Nusinersen is a recent promising therapy approved for the treatment of spinal muscular atrophy (SMA), a rare disease characterized by the degeneration of alpha motor neurons (αMN) in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction. Muscle and cervical SC quantitative magnetic resonance imaging (qMRI) has never been used to monitor drug treatment in SMA. The aim of this pilot study is to investigate whether qMRI can provide useful biomarkers for monitoring treatment efficacy in SMA.Methods: Three adult SMA 3a patients under treatment with nusinersen underwent longitudinal clinical and qMRI examinations every 4 months from baseline to 21-month follow-up. The qMRI protocol aimed to quantify thigh muscle fat fraction (FF) and water-T2 (w-T2) and to characterize SC volumes and microstructure. Eleven healthy controls underwent the same SC protocol (single time point). We evaluated clinical and imaging outcomes of SMA patients longitudinally and compared SC data between groups transversally.Results: Patient motor function was stable, with only Patient 2 showing moderate improvements. Average muscle FF was already high at baseline (50%) and progressed over time (57%). w-T2 was also slightly higher than previously published data at baseline and slightly decreased over time. Cross-sectional area of the whole SC, gray matter (GM), and ventral horns (VHs) of Patients 1 and 3 were reduced compared to controls and remained stable over time, while GM and VHs areas of Patient 2 slightly increased. We found altered diffusion and magnetization transfer parameters in SC structures of SMA patients compared to controls, thus suggesting changes in tissue microstructure and myelin content.Conclusion: In this pilot study, we found a progression of FF in thigh muscles of SMA 3a patients during nusinersen therapy and a concurrent slight reduction of w-T2 over time. The SC qMRI analysis confirmed previous imaging and histopathological studies suggesting degeneration of αMN of the VHs, resulting in GM atrophy and demyelination. Our longitudinal data suggest that qMRI could represent a feasible technique for capturing microstructural changes induced by SMA in vivo and a candidate methodology for monitoring the effects of treatment, once replicated on a larger cohort.

RAFF-4, Magnetization Transfer and Diffusion Tensor MRI of Lysophosphatidylcholine Induced Demyelination and Remyelination in Rats.

Remyelination is a naturally occurring response to demyelination and has a central role in the pathophysiology of multiple sclerosis and traumatic brain injury. Recently we demonstrated that a novel MRI technique entitled Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank n (RAFFn) achieved exceptional sensitivity in detecting the demyelination processes induced by lysophosphatidylcholine (LPC) in rat brain. In the present work, our aim was to test whether RAFF4, along with magnetization transfer (MT) and diffusion tensor imaging (DTI), would be capable of detecting the changes in the myelin content and microstructure caused by modifications of myelin sheets around axons or by gliosis during the remyelination phase after LPC-induced demyelination in the corpus callosum of rats. We collected MRI data with RAFF4, MT and DTI at 3 days after injection (demyelination stage) and at 38 days after injection (remyelination stage) of LPC (n = 12) or vehicle (n = 9). Cell density and myelin content were assessed by histology. All MRI metrics detected differences between LPC-injected and control groups of animals in the demyelination stage, on day 3. In the remyelination phase (day 38), RAFF4, MT parameters, fractional anisotropy, and axial diffusivity detected signs of a partial recovery consistent with the remyelination evident in histology. Radial diffusivity had undergone a further increase from day 3 to 38 and mean diffusivity revealed a complete recovery correlating with the histological assessment of cell density attributed to gliosis. The combination of RAFF4, MT and DTI has the potential to differentiate between normal, demyelinated and remyelinated axons and gliosis and thus it may be able to provide a more detailed assessment of white matter pathologies in several neurological diseases.

3D magnetization transfer (MT) for the visualization of cardiac free-running Purkinje fibers: an ex vivo proof of concept

ObjectivesWe investigate the possibility to exploit high-field MRI to acquire 3D images of Purkinje network which plays a crucial role in cardiac function. Since Purkinje fibers (PF) have a distinct cellular structure and are surrounded by connective tissue, we investigated conventional contrast mechanisms along with the magnetization transfer (MT) imaging technique to improve image contrast between ventricular structures of differing macromolecular content.MethodsThree fixed porcine ventricular samples were used with free-running PFs on the endocardium. T1, T2*, T2, and M0 were evaluated on 2D slices for each sample at 9.4 T. MT parameters were optimized using hard pulses with different amplitudes, offset frequencies and durations. The cardiac structure was assessed through 2D and 3D T1w images with isotropic resolutions of 150 µm. Histology, immunofluorescence, and qPCR were performed to analyze collagen contents of cardiac tissue and PF.ResultsAn MT preparation module of 350 ms duration inserted into the sequence with a B1 = 10 µT and frequency offset = 3000 Hz showed the best contrast, approximately 0.4 between PFs and myocardium. Magnetization transfer ratio (MTR) appeared higher in the cardiac tissue (MTR = 44.7 ± 3.5%) than in the PFs (MTR = 25.2 ± 6.3%).DiscussionMT significantly improves contrast between PFs and ventricular myocardium and appears promising for imaging the 3D architecture of the Purkinje network.

The influence of iron oxidation state on quantitative MRI parameters in post mortem human brain

A variety of Magnetic Resonance Imaging (MRI) techniques are known to be sensitive to brain iron content. In principle, iron sensitive MRI techniques are based on local magnetic field variations caused by iron particles in tissue. The purpose of this study was to investigate the sensitivity of MR relaxation and magnetization transfer parameters to changes in iron oxidation state compared to changes in iron concentration. Therefore, quantitative MRI parameters including R1, R2, R2∗, quantitative susceptibility maps (QSM) and magnetization transfer ratio (MTR) of post mortem human brain tissue were acquired prior and after chemical iron reduction to change the iron oxidation state and chemical iron extraction to decrease the total iron concentration. All assessed parameters were shown to be sensitive to changes in iron concentration whereas only R2, R2∗ and QSM were also sensitive to changes in iron oxidation state. Mass spectrometry confirmed that iron accumulated in the extraction solution but not in the reduction solution. R2∗ and QSM are often used as markers for iron content. Changes in these parameters do not necessarily reflect variations in iron content but may also be a result of changes in the iron’s oxygenation state from ferric towards more ferrous iron or vice versa.

Does the magnetization transfer effect bias chemical exchange saturation transfer effects? Quantifying chemical exchange saturation transfer in the presence of magnetization transfer.

PurposeChemical exchange saturation transfer (CEST) is an MRI technique sensitive to the presence of low‐concentration solute protons exchanging with water. However, magnetization transfer (MT) effects also arise when large semisolid molecules interact with water, which biases CEST parameter estimates if quantitative models do not account for macromolecular effects. This study establishes under what conditions this bias is significant and demonstrates how using an appropriate model provides more accurate quantitative CEST measurements.MethodsCEST and MT data were acquired in phantoms containing bovine serum albumin and agarose. Several quantitative CEST and MT models were used with the phantom data to demonstrate how underfitting can influence estimates of the CEST effect. CEST and MT data were acquired in healthy volunteers, and a two‐pool model was fit in vivo and in vitro, whereas removing increasing amounts of CEST data to show biases in the CEST analysis also corrupts MT parameter estimates.ResultsWhen all significant CEST/MT effects were included, the derived parameter estimates for each CEST/MT pool significantly correlated (P < .05) with bovine serum albumin/agarose concentration; minimal or negative correlations were found with underfitted data. Additionally, a bootstrap analysis demonstrated that significant biases occur in MT parameter estimates (P < .001) when unmodeled CEST data are included in the analysis.ConclusionsThese results indicate that current practices of simultaneously fitting both CEST and MT effects in model‐based analyses can lead to significant bias in all parameter estimates unless a sufficiently detailed model is utilized. Therefore, care must be taken when quantifying CEST and MT effects in vivo by properly modeling data to minimize these biases.

Improved MR fingerprinting for relaxation measurement in the presence of semisolid magnetization transfer.

To characterize and minimize the magnetization transfer (MT) effect in MR fingerprinting (MRF) relaxation measurements with a 2-pool (2P) MT model of multiple tissue types. Semisolid MT effect in MRF was modeled using 2P Bloch-McConnell equations. The combinations of MT parameters of multiple tissues (white [WM] and gray matter [GM]) were used to build the MRF dictionary. Both 1-pool (1P) and 2P models were simulated to characterize the dependence on MT. Relaxations measured using MRF with spin-echo saturation-recovery (SR) or inversion-recovery preparations were compared with conventional SR-prepared T1 and multiple spin-echo T2 measurements. The simulations results were validated with phantoms and brain tissue samples. The MRF signal was different from the 1P and 2P models. 1P MRF produced significantly (P < .05) underestimated T1 in WM (20-30%) and GM (7-10%), while 2P MRF measured consistent T1 and T2 in both WM and GM with conventional measurements (pairwise test P > .1; correlated P < .05). Simulations showed that SR-prepared MRF measuring T1 had much less errors against the variation of the macromolecular fraction. Compared with inversion-recovery preparation, SR-prepared MRF produced higher relaxation correlations (R > 0.9) with conventional measurements in both WM and GM across samples, suggesting that SR-prepared MRF was less sensitive to the compositive effect of multiple MT parameters variations. 2P MRF using a combination of MT parameters for multiple tissue types can measure consistent relaxations with conventional methods. With the 2P models, SR-prepared MRF would provide an option for robust relaxation measurement under heterogeneous MT.

Magnetization transfer and frequency distribution effects in the SSFP ellipse.

PurposeTo demonstrate that quantitative magnetization transfer (qMT) parameters can be extracted from steady‐state free‐precession (SSFP) data with no external T 1 map or banding artifacts.MethodsSSFP images with multiple MT weightings were acquired and qMT parameters fitted with a two‐stage elliptical signal model.ResultsMonte Carlo simulations and data from a 3T scanner indicated that most qMT parameters could be recovered with reasonable accuracy. Systematic deviations from theory were observed in white matter, consistent with previous literature on frequency distribution effects.ConclusionsqMT parameters can be extracted from SSFP data alone, in a manner robust to banding artifacts, despite several confounds.

Multiparameter MRI quantification of microstructural tissue alterations in multiple sclerosis.

ObjectivesConventional MRI is not sensitive to many pathological processes underpinning multiple sclerosis (MS) ongoing in normal appearing brain tissue (NABT). Quantitative MRI (qMRI) and a multiparameter mapping (MPM) protocol are used to simultaneously quantify magnetization transfer (MT) saturation, transverse relaxation rate R2* (1/T2*) and longitudinal relaxation rate R1 (1/T1), and assess differences in NABT microstructure between MS patients and healthy controls (HC).MethodsThis prospective cross-sectional study involves 36 MS patients (21 females, 15 males; age range 22–63 years; 15 relapsing-remitting MS - RRMS; 21 primary or secondary progressive MS - PMS) and 36 age-matched HC (20 females, 16 males); age range 21–61 years). The qMRI maps are computed and segmented in lesions and 3 normal appearing cerebral tissue classes: normal appearing cortical grey matter (NACGM), normal appearing deep grey matter (NADGM), normal appearing white matter (NAWM). Individual median values are extracted for each tissue class and MR parameter. MANOVAs and stepwise regressions assess differences between patients and HC.ResultsMS patients are characterized by a decrease in MT, R2* and R1 within NACGM (p < .0001) and NAWM (p < .0001). In NADGM, MT decreases (p < .0001) but R2* and R1 remain normal. These observations tend to be more pronounced in PMS. Quantitative MRI parameters are independent predictors of clinical status: EDSS is significantly related to R1 in NACGM and R2* in NADGM; the latter also predicts motor score. Cognitive score is best predicted by MT parameter within lesions.ConclusionsMultiparametric data of brain microstructure concord with the literature, predict clinical performance and suggest a diffuse reduction in myelin and/or iron content within NABT of MS patients.

Conventional and quantitative MRI in a novel feline model of demyelination and endogenous remyelination

BackgroundThe feeding of irradiated food to healthy adult cats results in widespread, noninflammatory demyelination of the central nervous system (CNS); a return to a normal diet results in endogenous remyelination with functional recovery. This recently discovered, reversible disease might provide a compelling clinical neuroimaging model system for the development and testing of myelin‐directed MRI methods as well as future remyelination therapies.PurposeIdentify the noninvasive imaging characteristics of this new disease model and determine whether it features measurable changes on conventional and quantitative MRI.Study TypePilot study.Animal ModelTen adult cats at various stages of demyelinating disease induced by an irradiated diet (35–55 kGy), and during recovery following a return to a normal diet.Field Strength/SequenceConventional (T2‐weighted) and quantitative (diffusion tensor, magnetization transfer) at 3T.AssessmentMRI of the brain, optic nerves, and cervical spinal cord; a subset of diseased cats was euthanized for comparative histopathology.Statistical TestsDescriptive statistics.ResultsDisease produced T2 prolongation, progressing from patchy to diffuse throughout most of the cerebral white matter (eventually involving U‐fibers) and spinal cord (primarily dorsal columns, reminiscent of subacute combined degeneration but without evidence of B12 deficiency). Magnetization transfer parameters decreased by 50–53% in cerebral white matter and by 25–30% in optic nerves and spinal cord dorsal columns. Fractional diffusion anisotropy decreased by up to 20% in pyramidal tracts, primarily driven by increased radial diffusivity consistent with axon preservation. Histopathology showed scattered myelin vacuolation of major white matter tracts as well as many thin myelin sheaths consistent with remyelination in the recovery phase, which was detectable on magnetization transfer imaging.Data ConclusionFeline irradiated diet‐induced demyelination features noninvasively imageable and quantifiable demyelination and remyelination of the CNS. It is therefore a compelling clinical neuroimaging model system. Level of Evidence: 4 Technical Efficacy: Stage 2J. Magn. Reson. Imaging 2019;49:1304–1311.

Polymer gel dosimetry by nuclear Overhauser enhancement (NOE) magnetic resonance imaging

The response to radiation of polymer gel dosimeters has previously been measured by magnetic resonance imaging (MRI) in terms of changes in the water transverse relaxation rate (R2w) or magnetization transfer (MT) parameters. Here we report a new MRI approach, based on detecting nuclear Overhauser enhancement (NOE) mediated saturation transfer effects, which can also be used to detect radiation and measure dose distributions in MAGIC-f (Methacrylic and Ascorbic Acid and Gelatin Initiated by Copper Solution with formaldehyde) polymer gels. Results show that the NOE effects produced by low powered radiofrequency (RF) irradiation at specific frequencies offset from water may be quantified by appropriate measurements and over a useful range depend linearly on the radiation dose. The NOE effect likely arises from the polymerization of methacrylic acid monomers which become less mobile, facilitating dipolar through-space cross-relaxation and/or relayed magnetization exchange between polymer and water protons. Our study suggests a potential new MRI method for polymer gel dosimetry.

Quantitative Magnetization Transfer of White Matter Tracts Correlates with Diffusion Tensor Imaging Indices in Predicting the Conversion from Mild Cognitive Impairment to Alzheimer's Disease.

Patients with amnestic mild cognitive impairment (aMCI) have higher probability to develop Alzheimer's disease (AD) than elderly controls. The detection of subtle changes in brain structure associated with disease progression and the development of tools to identify patients at high risk for dementia in a short time is crucial. Here, we used probabilistic white matter (WM) tractography to explore microstructural alterations within the main association, limbic, and commissural pathways in aMCI patients who converted to AD after 1 year follow-up (MCIconverters) and those who remained stable (MCIstable). Both diffusion tensor imaging (DTI) and quantitative magnetization transfer (qMT) parameters have been considered for a comprehensive pathophysiological characterization of the WM damage. Overall, tract-specific parameters derived from qMT and DTI at baseline were able to differentiate aMCI patients who converted to AD from those who remained stable in time. In particular, the qMT exchange rate, RMB0, of the right uncinate fasciculus was significantly decreased in MCIconverters, whereas fractional anisotropy was significantly decreased in the bilateral superior cingulum in MCIconverters compared to MCIstable. These results confirm the involvement of WM and particularly of association fibers in the progression of AD, highlighting disconnection as a potential mechanism.

Sensitivity of MRI parameters within intervertebral discs to the severity of adolescent idiopathic scoliosis.

To measure magnetic resonance imaging (MRI) parameters including relaxation times (T1 ρ, T2 ), magnetization transfer (MT) and diffusion parameters (mean diffusivity [MD], fractional anisotropy [FA]) of intervertebral discs in adolescents with idiopathic scoliosis, and to investigate the sensitivity of these MR parameters to the severity of the spine deformities. Thirteen patients with adolescent idiopathic scoliosis and three control volunteers with no history of spine disease underwent an MRI acquisition at 3T including the mapping of T1 ρ, T2 , MT, MD, and FA. The apical zone included all discs within the scoliotic curve while the control zone was composed of other discs. The severity was analyzed through low (<32°) versus high (>40°) Cobb angles. One-way analysis of variance (ANOVA) and agglomerative hierarchical clustering (AHC) were performed. Significant differences were found between the apical zone and the control zone for T2 (P = 0.047), and between low and high Cobb angles for T2 (P = 0.014) and MT (P = 0.002). AHC showed two distinct clusters, one with mainly low Cobb angles and one with mainly high Cobb angles, for the MRI parameters measured within the apical zone, with an accuracy of 0.9 and a Matthews correlation coefficient (MCC) of 0.8. Within the control zone, the AHC showed no clear classification (accuracy of 0.6 and MCC of 0.2). We successfully performed an in vivo multiparametric MRI investigation of young patients with adolescent idiopathic scoliosis. The MRI parameters measured within the intervertebral discs were found to be sensitive to intervertebral disc degeneration occurring with scoliosis and to the severity of scoliosis. J. Magn. Reson. Imaging 2016;44:1123-1131.

Simultaneous multi‐angular relaxometry of tissue with MRI (SMART MRI): Theoretical background and proof of concept

Accurate measurement of tissue-specific relaxation parameters is an ultimate goal of quantitative MRI. The objective of this study is to introduce a new technique, simultaneous multiangular relaxometry of tissue with MRI (SMART MRI), which provides naturally coregistered quantitative spin density, longitudinal and transverse relaxation rate constant maps along with parameters characterizing magnetization transfer (MT) effects. SMART MRI is based on a gradient-recalled echo MRI sequence with multiple flip angles and multiple gradient echoes and a derived theoretical expression for the MR signal generated in this experimental conditions. The theory, based on Bloch-McConnell equations, takes into consideration cross-relaxation between two water pools: "free" and "bound" to macromolecules. It describes the role of cross-relaxation effects in formation of longitudinal and transverse relaxation of "free" water signal, thus providing background for measurements of these effects without using MT pulses. Bayesian analysis is used to optimize SMART MRI sequence parameters. Data obtained on three participants demonstrate feasibility of the proposed approach. SMART MRI provides quantitative measurements of longitudinal and transverse relaxation rate constants of "free" water signal affected by cross-relaxation effects. It also provides information on some essential MT parameters without requiring off-resonance MT pulses. Magn Reson Med 77:1296-1306, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy

There is a need for accurate quantitative non-invasive biomarkers to monitor myelin pathology in vivo and distinguish myelin changes from other pathological features including inflammation and axonal loss. Conventional MRI metrics such as T2, magnetization transfer ratio and radial diffusivity have proven sensitivity but not specificity. In highly coherent white matter bundles, compartment-specific white matter tract integrity (WMTI) metrics can be directly derived from the diffusion and kurtosis tensors: axonal water fraction, intra-axonal diffusivity, and extra-axonal radial and axial diffusivities. We evaluate the potential of WMTI to quantify demyelination by monitoring the effects of both acute (6weeks) and chronic (12weeks) cuprizone intoxication and subsequent recovery in the mouse corpus callosum, and compare its performance with that of conventional metrics (T2, magnetization transfer, and DTI parameters). The changes observed in vivo correlated with those obtained from quantitative electron microscopy image analysis. A 6-week intoxication produced a significant decrease in axonal water fraction (p<0.001), with only mild changes in extra-axonal radial diffusivity, consistent with patchy demyelination, while a 12-week intoxication caused a more marked decrease in extra-axonal radial diffusivity (p=0.0135), consistent with more severe demyelination and clearance of the extra-axonal space. Results thus revealed increased specificity of the axonal water fraction and extra-axonal radial diffusivity parameters to different degrees and patterns of demyelination. The specificities of these parameters were corroborated by their respective correlations with microstructural features: the axonal water fraction correlated significantly with the electron microscopy derived total axonal water fraction (ρ=0.66; p=0.0014) but not with the g-ratio, while the extra-axonal radial diffusivity correlated with the g-ratio (ρ=0.48; p=0.0342) but not with the electron microscopy derived axonal water fraction. These parameters represent promising candidates as clinically feasible biomarkers of demyelination and remyelination in the white matter.

Rapid multicomponent relaxometry in steady state with correction of magnetization transfer effects.

To study the effects of magnetization transfer (MT) on multicomponent T2 parameters obtained using mcDESPOT in macromolecule-rich tissues and to propose a new method called mcRISE to correct MT-induced biases. The two-pool mcDESPOT model was modified by the addition of an exchanging macromolecule proton pool to model the MT effect in cartilage. The mcRISE acquisition scheme was developed to provide sensitivity to all pools. An incremental fitting was applied to estimate MT and relaxometry parameters with minimized coupling. The interaction between MT and relaxometry parameters, efficacy of MT correction, and feasibility of mcRISE in vivo were investigated in simulations and in healthy volunteers. The MT effect caused significant errors in multicomponent T1/T2 values and in fast-relaxing water fraction fF , which is consistent with previous experimental observations. fF increased significantly with macromolecule content if MT was ignored. mcRISE resulted in a multifold reduction of MT biases and yielded decoupled multicomponent T1/T2 relaxometry and quantitative MT parameters. mcRISE is an efficient approach for correcting MT biases in multicomponent relaxometry based on steady state sequences. Improved specificity of mcRISE may help to elucidate the sources of the previously described high sensitivity of noncorrected mcDESPOT parameters to disease-related changes in cartilage and the brain.

Orientation dependence of magnetization transfer parameters in human white matter

Quantification of magnetization-transfer (MT) experiments is typically based on a model comprising a liquid pool “a” of free water and a semisolid pool “b” of motionally restricted macromolecules or membrane compounds. By a comprehensive fitting approach, high quality MT parameter maps of the human brain are obtained. In particular, a distinct correlation between the diffusion-tensor orientation with respect to the B0-magnetic field and the apparent transverse relaxation time, T2b, of the semisolid pool (i.e., the width of its absorption line) is observed. This orientation dependence is quantitatively explained by a refined dipolar lineshape for pool b that explicitly considers the specific geometrical arrangement of lipid bilayers wrapped around a cylindrical axon. The model inherently reduces the myelin membrane to its lipid constituents, which is motivated by previous studies on efficient interaction sites (e.g., cholesterol or galactocerebrosides) in the myelin membrane and on the origin of ultrashort T2 signals in cerebral white matter. The agreement between MT orientation effects and corresponding forward simulations using empirical diffusion imaging results as input as well as results from fits employing the novel lineshape support previous suggestions that the fiber orientation distribution in a voxel can be modeled as a scaled Bingham distribution.