Language Experience during Infancy Predicts White Matter Myelination at Age 2 Years.

Parental input is considered a key predictor of language achievement during the first years of life, yet relatively few studies have assessed the effects of parental language input and parent-infant interactions on early brain development. We examined the relationship between measures of parent and child language, obtained from naturalistic home recordings at child ages 6, 10, 14, 18, and 24 months, and estimates of white matter myelination, derived from quantitative MRI at age 2 years (mean = 26.30 months, SD = 1.62, N = 22). Analysis of the white matter focused on dorsal pathways associated with expressive language development and long-term language ability, namely, the left arcuate fasciculus (AF) and superior longitudinal fasciculus (SLF). Frequency of parent-infant conversational turns (CT) uniquely predicted myelin density estimates in both the AF and SLF. Moreover, the effect of CT remained significant while controlling for total adult speech and child speech-related utterances, suggesting a specific role for interactive language experience, rather than simply speech exposure or production. An exploratory analysis of 18 additional tracts, including the right AF and SLF, indicated a high degree of anatomic specificity. Longitudinal analyses of parent and child language variables indicated an effect of CT as early as 6 months of age, as well as an ongoing effect over infancy. Together, these results link parent-infant conversational turns to white matter myelination at age 2 years, and suggest that early, interactive experiences with language uniquely contribute to the development of white matter associated with long-term language ability.SIGNIFICANCE STATEMENT Children's earliest experiences with language are thought to have profound and lasting developmental effects. Recent studies suggest that intervention can increase the quality of parental language input and improve children's learning outcomes. However, important questions remain about the optimal timing of intervention, and the relationship between specific aspects of language experience and brain development. We report that parent-infant turn-taking during home language interactions correlates with myelination of language related white matter pathways through age 2 years. Effects were independent of total speech exposure and infant vocalizations and evident starting at 6 months of age, suggesting that structured language interactions throughout infancy may uniquely support the ongoing development of brain systems critical to long-term language ability.

Accurate actual flip angle imaging (AFI) in the presence of fat.

PURPOSE: To investigate the effect of incomplete fat spoiling on the accuracy of B1 mapping with actual flip angle imaging (AFI) and to propose a method to minimize the errors using the chemical shift properties of fat. THEORY AND METHODS: Diffusion-based dephasing is the main spoiling mechanism exploited in AFI. However, a very low diffusion in fat may make the spoiling insufficient, leading to ghosts in the B1 maps. As the errors retain the chemical-shift signature of fat, their impact can be minimized using chemical-shift-based fat signal removal from AFI acquisition modified to include multi-echo readout. The source of the errors and the proposed correction were studied in simulations and phantom and in-vivo imaging experiments. RESULTS: Our results support that AFI artifacts are caused by the incomplete fat spoiling present in clinically attractive short TR acquisition regimes. The correction eliminated the ghosting and significantly improved the B1 mapping accuracy as well as the accuracy of R1 mapping performed with AFI-derived B1 maps. CONCLUSIONS: The incomplete fat signal spoiling may be a source of AFI B1 mapping errors, especially in subjects with high fat content. Achieving complete fat spoiling requires longer TR, which is undesirable in clinical applications. The proposed approach based on fat signal removal can reduce errors without significant prolongation of the AFI pulse sequence. We propose that, when attaining complete fat spoiling is not feasible, AFI mapping should be performed in a multi-echo regime with appropriate fat separation or suppression to minimize these errors.

Temporal trajectories of normal myelination and axonal development assessed by quantitative macromolecular and diffusion MRI: Ultrastructural and immunochemical validation in a rabbit model.

INTRODUCTION: Quantitative and non-invasive measures of brain myelination and maturation during development are of great importance to both clinical and translational research communities. While the metrics derived from diffusion tensor imaging, are sensitive to developmental changes and some pathologies, they remain difficult to relate to the actual microstructure of the brain tissue. The advent of advanced model-based microstructural metrics requires histological validation. The purpose of the study was to validate novel, model-based MRI techniques, such as macromolecular proton fraction mapping (MPF) and neurite orientation and dispersion indexing (NODDI), against histologically derived indexes of myelination and microstructural maturation at various stages of development. METHODS: New Zealand White rabbit kits underwent serial in-vivo MRI examination at postnatal days 1, 5, 11, 18, and 25, and as adults. Multi-shell, diffusion-weighted experiments were processed to fit NODDI model to obtain estimates, intracellular volume fraction (ICVF) and orientation dispersion index (ODI). Macromolecular proton fraction (MPF) maps were obtained from three source (MT-, PD-, and T1-weighted) images. After MRI sessions, a subset of animals was euthanized and regional samples of gray and white matter were taken for western blot analysis, to determine myelin basic protein (MBP), and electron microscopy, to estimate axonal, myelin fractions and g-ratio. RESULTS: MPF of white matter regions showed a period of fast growth between P5 and P11 in the internal capsule, with a later onset in the corpus callosum. This MPF trajectory was in agreement with levels of myelination in the corresponding brain region, as assessed by western blot and electron microscopy. In the cortex, the greatest increase of MPF occurred between P18 and P26. In contrast, myelin, according to MBP western blot, saw the largest hike between P5 and P11 in the sensorimotor cortex and between P11 and P18 in the frontal cortex, which then seemingly plateaued after P11 and P18 respectively. G-ratio by MRI markers decreased with age in the white matter. However, electron microscopy suggest a relatively stable g-ratio throughout development. CONCLUSION: Developmental trajectories of MPF accurately reflected regional differences of myelination rate in different cortical regions and white matter tracts. MRI-derived estimation of g-ratio was inaccurate during early development, likely due to the overestimation of axonal volume fraction by NODDI due to the presence of a large proportion of unmyelinated axons.

Developmental and regional dependence of macromolecular proton fraction and fractional anisotropy in fixed brain tissue.

An important advantage of imaging fixed tissue is a gain in signal-to-noise ratio and in resolution due to unlimited scan time. However, the fidelity of quantitative MRI parameters in fixed brain tissue, particularly in developmental settings, requires validation. Macromolecular proton fraction (MPF) and fractional anisotropy (FA) indices are quantitative markers of myelination and axonal integrity relevant to preclinical and clinical research. The goal of this study was to assert the correspondence of MR-derived markers of brain development MPF and FA between in vivo and fixed tissue measures. MPF and FA were compared in several white and gray matter structures of the normal mouse brain at 2, 4, and 12 weeks of age. At each developmental stage, in vivo imaging was performed, followed by paraformaldehyde fixation and a second imaging session. MPF maps were acquired from three source images (magnetization transfer weighted, proton density weighted, and T1 weighted), and FA was obtained from diffusion tensor imaging. The MPF and FA values, measured in the cortex, striatum, and major fiber tracts, were compared before and after fixation using Bland-Altman plots, regression analysis, and analysis of variance. MPF values of the fixed tissue were consistently greater than those from in vivo measurements. Importantly, this bias varied significantly with brain region and the developmental stage of the tissue. At the same time, FA values were preserved after fixation, across tissue types and developmental stages. The results of this study suggest that MPF and FA in fixed brain tissue can be used as a proxy for in vivo measurements, but additional considerations should be made to correct for the bias in MPF.

Brain myelination at 7 months of age predicts later language development.

Between 6 and 12 months of age there are dramatic changes in infants' processing of language. The neurostructural underpinnings of these changes are virtually unknown. The objectives of this study were to (1) examine changes in brain myelination during this developmental period and (2) examine the relationship between myelination during this period and later language development. Macromolecular proton fraction (MPF) was used as a marker of myelination. Whole-brain MPF maps were obtained with 1.25 mm3 isotropic spatial resolution from typically developing children at 7 and 11 months of age. Effective myelin density was calculated from MPF based on a linear relationship known from the literature. Voxel-based analyses were used to identify longitudinal changes in myelin density and to calculate correlations between myelin density at these ages and later language development. Increases in myelin density were more predominant in white matter than in gray matter. A strong predictive relationship was found between myelin density at 7 months of age, language production at 24 and 30 months of age, and rate of language growth. No relationships were found between myelin density at 11 months, or change in myelin density between 7 and 11 months of age, and later language measures. Our findings suggest that critical changes in brain structure may precede periods of pronounced change in early language skills.

Development of executive function-relevant skills is related to both neural structure and function in infants.

The development of skills related to executive function (EF) in infancy, including their emergence, underlying neural mechanisms, and interconnections to other cognitive skills, is an area of increasing research interest. Here, we report on findings from a multidimensional dataset demonstrating that infants' behavioral performance on a flexible learning task improved across development and that the task performance is highly correlated with both neural structure and neural function. The flexible learning task probed infants' ability to learn two different associations, concurrently, over 16 trials, requiring multiple skills relevant to EF. We examined infants' neural structure by measuring myelin density in the brain, using a novel macromolecular proton fraction (MPF) mapping method. We further examined an important neural function of speech processing by characterizing the mismatch response (MMR) to speech contrasts using magnetoencephalography (MEG). All measurements were performed longitudinally in monolingual English-learning infants at 7- and 11-months of age. At the group level, 11-month-olds, but not 7-month-olds, demonstrated evidence of learning both associations in the behavioral task. Myelin density in the prefrontal region at 7 months of age was found to be highly predictive of behavioral task performance at 11 months of age, suggesting that myelination may support the development of these skills. Furthermore, a machine-learning regression analysis revealed that individual differences in the behavioral task are predicted by concurrent neural speech processing at both ages, suggesting that these skills do not develop in isolation. Together, these cross-modality results revealed novel insights into EF-related skills. HIGHLIGHT: Monolingual infants demonstrated flexible learning on a task requiring executive function skills at 11 months, but not at 7 months. Infants' myelin density at 7 months is highly predictive of their behavioral performance in the flexible learning task at 11 months of age. Individual differences in the flexible learning task performance are also correlated with concurrent neural processing of speech at both ages.

Myelin development in cerebral gray and white matter during adolescence and late childhood.

Myelin development during adolescence is becoming an area of growing interest in view of its potential relationship to cognition, behavior, and learning. While recent investigations suggest that both white matter (WM) and gray matter (GM) undergo protracted myelination during adolescence, quantitative relations between myelin development in WM and GM have not been previously studied. We quantitatively characterized the dependence of cortical GM, WM, and subcortical myelin density across the brain on age, gender, and puberty status during adolescence with the use of a novel macromolecular proton fraction (MPF) mapping method. Whole-brain MPF maps from a cross-sectional sample of 146 adolescents (age range 9-17 years) were collected. Myelin density was calculated from MPF values in GM and WM of all brain lobes, as well as in subcortical structures. In general, myelination of cortical GM was widespread and more significantly correlated with age than that of WM. Myelination of GM in the parietal lobe was found to have a significantly stronger age dependence than that of GM in the frontal, occipital, temporal and insular lobes. Myelination of WM in the temporal lobe had the strongest association with age as compared to WM in other lobes. Myelin density was found to be higher in males as compared to females when averaged across all cortical lobes, as well as in a bilateral subcortical region. Puberty stage was significantly correlated with myelin density in several cortical areas and in the subcortical GM. These findings point to significant differences in the trajectories of myelination of GM and WM across brain regions and suggest that cortical GM myelination plays a dominant role during adolescent development.

Scan-Rescan Repeatability and Impact of B0 and B1 Field Nonuniformity Corrections in Single-Point Whole-Brain Macromolecular Proton Fraction Mapping.

BACKGROUND: Single-point macromolecular proton fraction (MPF) mapping is a recent quantitative MRI method for fast assessment of brain myelination. Information about reproducibility and sensitivity of MPF mapping to magnetic field nonuniformity is important for clinical applications. PURPOSE: To assess scan-rescan repeatability and a value of B0 and B1 field inhomogeneity corrections in single-point synthetic-reference MPF mapping. STUDY TYPE: Prospective. POPULATION: Eight healthy adult volunteers underwent two scans with 11.5 ± 2.3 months interval. FIELD STRENGTH/SEQUENCE: 3T; whole-brain 3D MPF mapping protocol included three spoiled gradient-echo sequences providing T1 , proton density, and magnetization transfer contrasts with 1.25 × 1.25 × 1.25 mm3 resolution and B0 and B1 mapping sequences. ASSESSMENT: MPF maps were reconstructed with B0 and B1 field nonuniformity correction, B0 - and B1 -only corrections, and without corrections. Mean MPF values were measured in automatically segmented white matter (WM) and gray matter (GM). STATISTICAL TESTS: Within-subject coefficient of variation (CV), intraclass correlation coefficient (ICC), Bland-Altman plots, and paired t-tests to assess scan-rescan repeatability. Repeated-measures analysis of variance (ANOVA) to compare field corrections. RESULTS: Maximal relative local MPF errors without correction in the areas of largest field nonuniformities were about 5% and 27% for B0 and B1 , respectively. The effect of B0 correction was insignificant for whole-brain WM (P > 0.25) and GM (P > 0.98) MPF. The absence of B1 correction caused a positive relative bias of 4-5% (P < 0.001) in both tissues. Scan-rescan agreement was similar for all field correction options with ICCs 0.80-0.81 for WM and 0.89-0.92 for GM. CVs were 1.6-1.7% for WM and 0.7-1.0% for GM. DATA CONCLUSION: The single-point method enables high repeatability of MPF maps obtained with the same equipment. Correction of B0 inhomogeneity may be disregarded to shorten the examination time. B1 nonuniformity correction improves accuracy of MPF measurements at 3T. Reliability of whole-brain MPF measurements in WM and GM is not affected by B0 and B1 field corrections. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:1789-1798.

pH-triggered delivery of magnetic nanoparticles depends on tumor volume.

Nowadays there is growing recognition of the fact that biological systems have a greater impact on nanoparticle target delivery in tumors than nanoparticle design. Here we investigate the targeted delivery of Fe3O4 magnetic nanoparticles conjugated with pH-low-insertion peptide (MNP-pHLIP) on orthotopically induced MDA-MB-231 human breast carcinoma xenografts of varying volumes as a model of cancer progression. Using in vivo magnetic resonance imaging and subsequent determination of iron content in tumor samples by inductively coupled plasma atomic emission spectroscopy we found that MNP-pHLIP accumulation depends on tumor volume. Transmission electron microscopy, histological analysis and immunohistochemical staining of tumor samples suggest that blood vessel distribution is the key factor in determining the success of the accumulation of nanoparticles in tumors.

Direct comparison between apparent diffusion coefficient and macromolecular proton fraction as quantitative biomarkers of the human fetal brain maturation.

BACKGROUND: Apparent diffusion coefficient (ADC) is known as a quantitative biomarker of prenatal brain maturation. Fast macromolecular proton fraction (MPF) mapping is an emerging method for quantitative assessment of myelination that was recently adapted to fetal MRI. PURPOSE: To compare the capability of ADC and MPF to quantify the normal fetal brain development. STUDY TYPE: Prospective. POPULATION: Forty-two human fetuses in utero (gestational age [GA] = 27.7 ± 6.0, range 20-38 weeks). FIELD STRENGTH/SEQUENCE: 1.5 T; diffusion-weighted single-shot echo-planar spin-echo with five b-values for ADC mapping; spoiled multishot echo-planar gradient-echo with T1 , proton density, and magnetization transfer contrast weightings for single-point MPF mapping. ASSESSMENT: Two operators measured ADC and MPF in the medulla, pons, cerebellum, thalamus, and frontal, occipital, and temporal cerebral white matter (WM). STATISTICAL TESTS: Mixed repeated-measures analysis of variance (ANOVA) with the factors of pregnancy trimester and brain structure; Pearson correlation coefficient (r); Hotelling-Williams test to compare strengths of correlations. RESULTS: From the 2nd to 3rd trimester, ADC significantly decreased in the thalamus and cerebellum (P < 0.005). MPF significantly increased in the medulla, pons, thalamus, and cerebellum (P < 0.005). Cerebral WM had significantly higher ADC and lower MPF compared with the medulla and pons in both trimesters. MPF (r range 0.83, 0.89, P < 0.001) and ADC (r range -0.43, -0.75, P ≤ 0.004) significantly correlated with GA and each other (r range -0.32, -0.60, P ≤ 0.04) in the medulla, pons, thalamus, and cerebellum. No significant correlations or distinctions between regions and trimesters were observed for cerebral WM (P range 0.1-0.75). Correlations with GA were significantly stronger for MPF compared with ADC in the medulla, pons, and cerebellum (Hotelling-Williams test, P < 0.003) and similar in the thalamus. Structure-averaged MPF and ADC values strongly correlated (r = 0.95, P < 0.001). DATA CONCLUSION: MPF and ADC demonstrated qualitatively similar but quantitatively different spatiotemporal patterns. MPF appeared more sensitive to changes in the brain structures with prenatal onset of myelination. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:52-61.

Plant polyprenols reduce demyelination and recover impaired oligodendrogenesis and neurogenesis in the cuprizone murine model of multiple sclerosis.

Recent studies showed hepatoprotective, neuroprotective, and immunomodulatory properties of polyprenols isolated from the green verdure of Picea abies (L.) Karst. This study aimed to investigate effects of polyprenols on oligodendrogenesis, neurogenesis, and myelin content in the cuprizone demyelination model. Demyelination was induced by 0.5% cuprizone in CD-1 mice during 10 weeks. Nine cuprizone-treated animals received daily injections of polyprenols intraperitoneally at a dose of 12-mg/kg body weight during Weeks 6-10. Nine control animals and other nine cuprizone-treated received sham oil injections. At Week 10, brain sections were stained for myelin basic protein, neuro-glial antigen-2, and doublecortin to evaluate demyelination, oligodendrogenesis, and neurogenesis. Cuprizone administration caused a decrease in myelin basic protein in the corpus callosum, cortex, hippocampus, and the caudate putamen compared with the controls. Oligodendrogenesis was increased, and neurogenesis in the subventricular zone and the dentate gyrus of the hippocampus was decreased in the cuprizone-treated group compared with the controls. Mice treated with cuprizone and polyprenols did not show significant demyelination and differences in oligodendrogenesis and neurogenesis as compared with the controls. Our results suggest that polyprenols can halt demyelination, restore impaired neurogenesis, and mitigate reactive overproduction of oligodendrocytes caused by cuprizone neurotoxicity.

Effects of Fluoxetine on Hippocampal Neurogenesis and Neuroprotection in the Model of Global Cerebral Ischemia in Rats.

A selective serotonin reuptake inhibitor, fluoxetine, has recently attracted a significant interest as a neuroprotective therapeutic agent. There is substantial evidence of improved neurogenesis under fluoxetine treatment of brain ischemia in animal stroke models. We studied long-term effects of fluoxetine treatment on hippocampal neurogenesis, neuronal loss, inflammation, and functional recovery in a new model of global cerebral ischemia (GCI). Brain ischemia was induced in adult Wistar male rats by transient occlusion of three main vessels originating from the aortic arch and providing brain blood supply. Fluoxetine was injected intraperitoneally in a dose of 20 mg/kg for 10 days after surgery. To evaluate hippocampal neurogenesis at time points 10 and 30 days, 5-Bromo-2'-deoxyuridine was injected at days 8-10 after GCI. According to our results, 10-day fluoxetine injections decreased neuronal loss and inflammation, improved survival and functional recovery of animals, enhanced neurogenesis, and prevented an early pathological increase in neural stem cell recruitment in the subgranular zone (SGZ) of the hippocampus without reducing the number of mature neurons at day 30 after GCI. In summary, this study suggests that fluoxetine may provide a promising therapy in cerebral ischemia due to its neuroprotective, anti-inflammatory, and neurorestorative effect.

High-resolution three-dimensional macromolecular proton fraction mapping for quantitative neuroanatomical imaging of the rodent brain in ultra-high magnetic fields.

A well-known problem in ultra-high-field MRI is generation of high-resolution three-dimensional images for detailed characterization of white and gray matter anatomical structures. T1-weighted imaging traditionally used for this purpose suffers from the loss of contrast between white and gray matter with an increase of magnetic field strength. Macromolecular proton fraction (MPF) mapping is a new method potentially capable to mitigate this problem due to strong myelin-based contrast and independence of this parameter of field strength. MPF is a key parameter determining the magnetization transfer effect in tissues and defined within the two-pool model as a relative amount of macromolecular protons involved into magnetization exchange with water protons. The objectives of this study were to characterize the two-pool model parameters in brain tissues in ultra-high magnetic fields and introduce fast high-field 3D MPF mapping as both anatomical and quantitative neuroimaging modality for small animal applications. In vivo imaging data were obtained from four adult male rats using an 11.7T animal MRI scanner. Comprehensive comparison of brain tissue contrast was performed for standard R1 and T2 maps and reconstructed from Z-spectroscopic images two-pool model parameter maps including MPF, cross-relaxation rate constant, and T2 of pools. Additionally, high-resolution whole-brain 3D MPF maps were obtained with isotropic 170µm voxel size using the single-point synthetic-reference method. MPF maps showed 3-6-fold increase in contrast between white and gray matter compared to other parameters. MPF measurements by the single-point synthetic reference method were in excellent agreement with the Z-spectroscopic method. MPF values in rat brain structures at 11.7T were similar to those at lower field strengths, thus confirming field independence of MPF. 3D MPF mapping provides a useful tool for neuroimaging in ultra-high magnetic fields enabling both quantitative tissue characterization based on the myelin content and high-resolution neuroanatomical visualization with high contrast between white and gray matter.

Time-efficient, high-resolution, whole brain three-dimensional macromolecular proton fraction mapping.

PURPOSE: Macromolecular proton fraction (MPF) mapping is a quantitative MRI method that reconstructs parametric maps of a relative amount of macromolecular protons causing the magnetization transfer (MT) effect and provides a biomarker of myelination in neural tissues. This study aimed to develop a high-resolution whole brain MPF mapping technique using a minimal number of source images for scan time reduction. METHODS: The described technique was based on replacement of an actually acquired reference image without MT saturation by a synthetic one reconstructed from R1 and proton density maps, thus requiring only three source images. This approach enabled whole brain three-dimensional MPF mapping with isotropic 1.25 × 1.25 × 1.25 mm(3) voxel size and a scan time of 20 min. The synthetic reference method was validated against standard MPF mapping with acquired reference images based on data from eight healthy subjects. RESULTS: Mean MPF values in segmented white and gray matter appeared in close agreement with no significant bias and small within-subject coefficients of variation (<2%). High-resolution MPF maps demonstrated sharp white-gray matter contrast and clear visualization of anatomical details, including gray matter structures with high iron content. CONCLUSIONS: The proposed synthetic reference method improves resolution of MPF mapping and combines accurate MPF measurements with unique neuroanatomical contrast features.

Fast whole-brain three-dimensional macromolecular proton fraction mapping in multiple sclerosis.

PURPOSE: To evaluate the clinical utility of fast whole-brain macromolecular proton fraction ( MPF macromolecular proton fraction ) mapping in multiple sclerosis ( MS multiple sclerosis ) and compare MPF macromolecular proton fraction with established quantitative magnetic resonance (MR) imaging measures of tissue damage including magnetization transfer ( MT magnetization transfer ) ratio and relaxation rate (R1). MATERIALS AND METHODS: In this institutional review board-approved and HIPAA-compliant study, 14 healthy control participants, 18 relapsing-remitting MS multiple sclerosis ( RRMS relaxing-remitting MS ) patients, and 12 secondary progressive MS multiple sclerosis ( SPMS secondary progressive MS ) patients provided written informed consent and underwent 3-T MR imaging. Three-dimensional MPF macromolecular proton fraction maps were reconstructed from MT magnetization transfer -weighted images and R1 maps by the single-point method. Mean MPF macromolecular proton fraction , R1, and MT magnetization transfer ratio in normal-appearing white matter ( WM white matter ), gray matter ( GM gray matter ), and lesions were compared between subject groups by using analysis of variance. Correlations (Pearson r) between imaging data and clinical scores (Expanded Disability Status Scale [EDSS] and MS multiple sclerosis Functional Composite [ MSFC MS functional composite ]) were compared by using Hotelling-Williams test. RESULTS: RRMS relaxing-remitting MS patients had lower WM white matter and GM gray matter MPF macromolecular proton fraction than controls, with percentage decreases of 6.5% (P < .005) and 5.4% (P < .05). MPF macromolecular proton fraction in SPMS secondary progressive MS was reduced relative to RRMS relaxing-remitting MS in WM white matter , GM gray matter , and lesions by 6.4% (P < .005), 13.4% (P < .005), and 11.7% (P < .05), respectively. EDSS Expanded Disability Status Scale and MSFC MS functional composite demonstrated strongest correlations with MPF macromolecular proton fraction in GM gray matter (r = -0.74 and 0.81; P < .001) followed by WM white matter (r = -0.57 and 0.72; P < .01) and lesions (r = -0.42 and 0.50; P < .05). R1 and MT magnetization transfer ratio in all tissues were significantly less correlated with clinical scores than GM gray matter MPF macromolecular proton fraction (P < .05). CONCLUSION: MPF macromolecular proton fraction mapping enables quantitative assessment of demyelination in normal-appearing brain tissues and shows primary clinical relevance of GM gray matter damage in MS multiple sclerosis . MPF macromolecular proton fraction outperforms MT magnetization transfer ratio and R1 in detection of MS multiple sclerosis -related tissue changes.

Fast macromolecular proton fraction mapping of the human liver in vivo for quantitative assessment of hepatic fibrosis.

The macromolecular proton fraction (MPF) is a quantitative MRI parameter determining the magnetization transfer (MT) effect in tissues, and is defined as the relative amount of immobile macromolecular protons involved in magnetization exchange with mobile water protons. MPF has the potential to provide a quantitative assessment of fibrous tissue because of the intrinsically high MPF specific for collagen. The goal of this study was to investigate the relationship between histologically determined fibrosis stage and MPF in the liver parenchyma measured using a recently developed fast single-point clinically targeted MPF mapping method. Optimal saturation parameters for single-point liver MPF measurements were determined from the analysis of liver Z spectra in vivo based on the error propagation model. Sixteen patients with chronic hepatitis C viral infection underwent 3-T MRI using an optimized liver MPF mapping protocol. Fourteen patients had prior liver biopsy with histologically staged fibrosis (METAVIR scores F0-F3) and two patients had clinically diagnosed cirrhosis (score F4 was assigned). The protocol included four breath-hold three-dimensional scans with 2 × 3 × 6-mm(3) resolution and 10 transverse sections: dynamic acquisition of MT-weighted and reference images; dynamic acquisition of three images for variable flip angle T1 mapping; dual-echo B0 map; and actual flip angle imaging B1 map. The average liver MPF was determined as the mode of the MPF histograms. MPF was significantly increased in patients with clinically significant fibrosis (scores F2-F4, n = 6) relative to patients with no or mild fibrosis (scores F0-F1, n = 10): 6.49 ± 0.36% versus 5.94 ± 0.26%, p < 0.01 (Mann-Whitney test). MPF and fibrosis scores were strongly positively correlated, with a Spearman's rank correlation coefficient of 0.80 (p < 0.001). This study demonstrates the feasibility of fast MPF mapping of the human liver in vivo and confirms the hypothesis that MPF is increased in hepatic fibrosis and associated with fibrosis stage. MPF may be useful as a non-invasive imaging biomarker of hepatic fibrosis.

Analysis and correction of biases in cross-relaxation MRI due to biexponential longitudinal relaxation.

PURPOSE: Cross-relaxation imaging (CRI) is a family of quantitative magnetization transfer techniques that utilize images obtained with off-resonance saturation and longitudinal relaxation rate (R1) maps reconstructed by the variable flip angle (VFA) method. It was demonstrated recently that a significant bias in an apparent VFA R1 estimation occurs in macromolecule-rich tissues due to magnetization transfer (MT)-induced biexponential behavior of longitudinal relaxation of water protons. The purpose of this article is to characterize theoretically and experimentally the resulting bias in the CRI maps and propose methods to correct it. THEORY: The modified CRI algorithm is proposed, which corrects for such biases and yields accurate parametric bound pool fraction f, cross-relaxation rate k, and R1 maps. Additionally, an analytical correction procedure is introduced to recalculate previously obtained parameter values. RESULTS: The systematic errors due to unaccounted MT-induced biexponential relaxation can be characterized as an overestimation of R1, f, and k, with a relative bias comparable with the magnitude of f. The phantom and human in vivo experiments demonstrate that both proposed modified CRI and analytical correction approaches significantly improve the accuracy of the CRI method. CONCLUSION: The accuracy of the CRI method can be considerably improved by taking into account the contribution of MT-induced biexponential longitudinal relaxation into variable flip angle R1 measurements.

Age-Related Decline in Brain Myelination: Quantitative Macromolecular Proton Fraction Mapping, T2-FLAIR Hyperintensity Volume, and Anti-Myelin Antibodies Seven Years Apart.

Age-related myelination decrease is considered one of the likely mechanisms of cognitive decline. The present preliminary study is based on the longitudinal assessment of global and regional myelination of the normal adult human brain using fast macromolecular fraction (MPF) mapping. Additional markers were age-related changes in white matter (WM) hyperintensities on FLAIR-MRI and the levels of anti-myelin autoantibodies in serum. Eleven healthy subjects (33-60 years in the first study) were scanned twice, seven years apart. An age-related decrease in MPF was found in global WM, grey matter (GM), and mixed WM-GM, as well as in 48 out of 82 examined WM and GM regions. The greatest decrease in MPF was observed for the frontal WM (2-5%), genu of the corpus callosum (CC) (4.0%), and caudate nucleus (5.9%). The age-related decrease in MPF significantly correlated with an increase in the level of antibodies against myelin basic protein (MBP) in serum (r = 0.69 and r = 0.63 for global WM and mixed WM-GM, correspondingly). The volume of FLAIR hyperintensities increased with age but did not correlate with MPF changes and the levels of anti-myelin antibodies. MPF mapping showed high sensitivity to age-related changes in brain myelination, providing the feasibility of this method in clinics.

Fast macromolecular proton fraction mapping from a single off-resonance magnetization transfer measurement.

A new method was developed for fast quantitative mapping of the macromolecular proton fraction defined within the two-pool model of magnetization transfer. The method utilizes a single image with off-resonance saturation, a reference image for data normalization, and T(1), B(0), and B(1) maps with the total acquisition time ~10 min for whole-brain imaging. Macromolecular proton fraction maps are reconstructed by iterative solution of the matrix pulsed magnetization transfer equation with constrained values of other model parameters. Theoretical error model describing the variance due to noise and the bias due to deviations of constrained parameters from their actual values was formulated based on error propagation rules. The method was validated by comparison with the conventional multiparameter multipoint fit of the pulsed magnetization transfer model based on data from two healthy subjects and two multiple sclerosis patients. It was demonstrated theoretically and experimentally that accuracy of the method depends on the offset frequency and flip angle of the saturation pulse, and optimal ranges of these parameters are 4-7 kHz and 600°-900°, respectively. At optimal sampling conditions, the single-point method enables <10% relative macromolecular proton fraction errors. Comparison with the multiparameter fitting method revealed very good agreement with no significant bias and limits of agreement around ± 0.7%.

Simultaneous variable flip angle-actual flip angle imaging method for improved accuracy and precision of three-dimensional T1 and B1 measurements.

A new time-efficient and accurate technique for simultaneous mapping of T(1) and B(1) is proposed based on a combination of the actual flip angle (FA) imaging and variable FA methods. Variable FA-actual FA imaging utilizes a single actual FA imaging and one or more spoiled gradient-echo acquisitions with a simultaneous nonlinear fitting procedure to yield accurate T(1)/B(1) maps. The advantage of variable FA-actual FA imaging is high accuracy at either short T(1) times or long repetition times in the actual FA imaging sequence. Simulations show this method is accurate to 0.03% in FA and 0.07% in T(1) for ratios of repetition time to T1 time over the range of 0.01-0.45. We show for the case of brain imaging that it is sufficient to use only one small FA spoiled gradient-echo acquisition, which results in reduced spoiling requirements and a significant scan time reduction compared to the original variable FA method. In vivo validation yielded high-quality 3D T(1) maps and T(1) measurements within 10% of previously published values and within a clinically acceptable scan time. The variable FA-actual FA imaging method will increase the accuracy and clinical feasibility of many quantitative MRI methods requiring T(1)/B(1) mapping such as dynamic contrast enhanced perfusion and quantitative magnetization transfer imaging.