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.

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.

Language input in late infancy scaffolds emergent literacy skills and predicts reading related white matter development.

Longitudinal studies provide the unique opportunity to test whether early language provides a scaffolding for the acquisition of the ability to read. This study tests the hypothesis that parental language input during the first 2 years of life predicts emergent literacy skills at 5 years of age, and that white matter development observed early in the 3rd year (at 26 months) may help to account for these effects. We collected naturalistic recordings of parent and child language at 6, 10, 14, 18, and 24 months using the Language ENvironment Analysis system (LENA) in a group of typically developing infants. We then examined the relationship between language measures during infancy and follow-up measures of reading related skills at age 5 years, in the same group of participants (N = 53). A subset of these children also completed diffusion and quantitative MRI scans at age 2 years (N = 20). Within this subgroup, diffusion tractography was used to identify white matter pathways that are considered critical to language and reading development, namely, the arcuate fasciculus (AF), superior and inferior longitudinal fasciculi, and inferior occipital-frontal fasciculus. Quantitative macromolecular proton fraction (MPF) mapping was used to characterize myelin density within these separately defined regions of interest. The longitudinal data were then used to test correlations between early language input and output, white matter measures at age 2 years, and pre-literacy skills at age 5 years. Parental language input, child speech output, and parent-child conversational turns correlated with pre-literacy skills, as well as myelin density estimates within the left arcuate and superior longitudinal fasciculus. Mediation analyses indicated that the left AF accounted for longitudinal relationships between infant home language measures and 5-year letter identification and letter-sound knowledge, suggesting that the left AF myelination at 2 years may serve as a mechanism by which early language experience supports emergent literacy.

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.

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.

Macromolecular Proton Fraction as a Myelin Biomarker: Principles, Validation, and Applications.

Macromolecular proton fraction (MPF) is a quantitative MRI parameter describing the magnetization transfer (MT) effect and defined as a relative amount of protons bound to biological macromolecules with restricted molecular motion, which participate in magnetic cross-relaxation with water protons. MPF attracted significant interest during past decade as a biomarker of myelin. The purpose of this mini review is to provide a brief but comprehensive summary of MPF mapping methods, histological validation studies, and MPF applications in neuroscience. Technically, MPF maps can be obtained using a variety of quantitative MT methods. Some of them enable clinically reasonable scan time and resolution. Recent studies demonstrated the feasibility of MPF mapping using standard clinical MRI pulse sequences, thus substantially enhancing the method availability. A number of studies in animal models demonstrated strong correlations between MPF and histological markers of myelin with a minor influence of potential confounders. Histological studies validated the capability of MPF to monitor both demyelination and re-myelination. Clinical applications of MPF have been mainly focused on multiple sclerosis where this method provided new insights into both white and gray matter pathology. Besides, several studies used MPF to investigate myelin role in other neurological and psychiatric conditions. Another promising area of MPF applications is the brain development studies. MPF demonstrated the capabilities to quantitatively characterize the earliest stage of myelination during prenatal brain maturation and protracted myelin development in adolescence. In summary, MPF mapping provides a technically mature and comprehensively validated myelin imaging technology for various preclinical and clinical neuroscience applications.

Global hypomyelination of the brain white and gray matter in schizophrenia: quantitative imaging using macromolecular proton fraction.

Myelin deficiency is commonly recognized as an important pathological feature of brain tissues in schizophrenia (SZ). In this pilot study, global myelin content abnormalities in white matter (WM) and gray matter (GM) of SZ patients were non-invasively investigated using a novel clinically-targeted quantitative myelin imaging technique, fast macromolecular proton fraction (MPF) mapping. MPF maps were obtained from 23 healthy subjects and 31 SZ patients using a clinical 1.5T magnetic resonance imaging (MRI) scanner. Mean MPF in WM and GM was compared between the healthy control subjects and SZ patients with positive and negative leading symptoms using the multivariate analysis of covariance. The SZ patients had significantly reduced MPF in GM (p < 0.001) and WM (p = 0.02) with the corresponding relative decrease of 5% and 3%, respectively. The effect sizes for the myelin content loss in SZ relative to the control group were 1.0 and 1.5 for WM and GM, respectively. The SZ patients with leading negative symptoms had significantly lower MPF in GM (p < 0.001) and WM (p = 0.003) as compared to the controls and showed a significant MPF decrease in WM (p = 0.03) relative to the patients with leading positive symptoms. MPF in WM significantly negatively correlated with the disease duration in SZ patients (Pearson's r = -0.51; p = 0.004). This study demonstrates that chronic SZ is characterized by global microscopic brain hypomyelination of both WM and GM, which is associated with the disease duration and negative symptoms. Myelin deficiency in SZ can be detected and quantified by the fast MPF mapping method.

Long-term monitoring of chronic demyelination and remyelination in a rat ischemic stroke model using macromolecular proton fraction mapping.

Remyelination is a key process enabling post-stroke brain tissue recovery and plasticity. This study aimed to explore the feasibility of demyelination and remyelination monitoring in experimental stroke from the acute to chronic stage using an emerging myelin imaging biomarker, macromolecular proton fraction (MPF). After stroke induction by transient middle cerebral artery occlusion, rats underwent repeated MRI examinations during 85 days after surgery with histological endpoints for the animal subgroups on the 7th, 21st, 56th, and 85th days. MPF maps revealed two sub-regions within the infarct characterized by distinct temporal profiles exhibiting either a persistent decrease by 30%-40% or a transient decrease followed by return to nearly normal values after one month of observation. Myelin histology confirmed that these sub-regions had nearly similar extent of demyelination in the sub-acute phase and then demonstrated either chronic demyelination or remyelination. The remyelination zones also exhibited active axonal regrowth, reconstitution of compact fiber bundles, and proliferation of neuronal and oligodendroglial precursors. The demyelination zones showed more extensive astrogliosis from the 21st day endpoint. Both sub-regions had substantially depleted neuronal population over all endpoints. These results histologically validate MPF mapping as a novel approach for quantitative assessment of myelin damage and repair in ischemic stroke.

Data-Driven Retrospective Correction of B1 Field Inhomogeneity in Fast Macromolecular Proton Fraction and R1 Mapping.

Correction of B1 field non-uniformity is critical for many quantitative MRI methods including variable flip angle (VFA) T1 mapping and single-point macromolecular proton fraction (MPF) mapping. The latter method showed promising results as a fast and robust quantitative myelin imaging approach and involves VFA-based R1=1/T1 map reconstruction as an intermediate processing step. The need for B1 correction restricts applications of the above methods, since B1 mapping sequences increase the examination time and are not commonly available in clinics. A new algorithm was developed to enable retrospective data-driven simultaneous B1 correction in VFA R1 and single-point MPF mapping. The principle of the algorithm is based on different mathematical dependences of B1 -related errors in R1 and MPF allowing extraction of a surrogate B1 field map from uncorrected R1 and MPF maps. To validate the method, whole-brain R1 and MPF maps with isotropic 1.25 mm3 resolution were obtained on a 3 T MRI scanner from 11 volunteers. Mean parameter values in segmented brain tissues were compared between three reconstruction options including the absence of correction, actual B1 correction, and surrogate B1 correction. Surrogate B1 maps closely reproduced actual patterns of B1 inhomogeneity. Without correction, B1 non-uniformity caused highly significant biases in R1 and MPF ( ). Surrogate B1 field correction reduced the biases in both R1 and MPF to a non-significant level ( 0.1 ≤ P ≤ 0.8 ). The described algorithm obviates the use of dedicated B1 mapping sequences in fast single-point MPF mapping and provides an alternative solution for correction of B1 non-uniformities in VFA R1 mapping.

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.

Three-dimensional fast single-point macromolecular proton fraction mapping of the human brain at 0.5 Tesla.

Fast single-point macromolecular proton fraction (MPF) mapping is a recent magnetic resonance imaging (MRI) method enabling quantitative assessment of myelin content in neural tissues. To date, the reported technical implementations of MPF mapping utilized high-field MRI equipment (1.5 T or higher), while low-field applications might pose challenges due to signal-to-noise ratio (SNR) limitations and short T1 . This study aimed to evaluate the feasibility of MPF mapping of the human brain at 0.5 T. The three-dimensional MPF mapping protocol was implemented according to the single-point synthetic-reference method, which includes three spoiled gradient-echo sequences providing proton density, T1 , and magnetization transfer contrast weightings. Whole-brain MPF maps were obtained from three healthy volunteers with spatial resolution of 1.5×1.5×2 mm3 and the total scan time of 19 minutes. MPF values were measured in a series of white and gray matter structures and compared with literature data for 3 T magnetic field. MPF maps enabled high contrast between white and gray matter with notable insensitivity to paramagnetic effects in iron-rich structures, such as globus pallidus, substantia nigra, and dentate nucleus. MPF values at 0.5 T appeared in close agreement with those at 3 T. This study demonstrates the feasibility of fast MPF mapping with low-field MRI equipment and the independence of brain MPF values of magnetic field. The presented results confirm the utility of MPF as an absolute scale for MRI-based myelin content measurements across a wide range of magnetic field strengths and extend the applicability of fast MPF mapping to inexpensive low-field MRI hardware.

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.

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.

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.

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.

Congenital medulloblastoma: Fetal and postnatal longitudinal observation with quantitative MRI.

Congenital medulloblastoma is extremely rare. MRI appearance of this tumor in the fetal brain has not been described. A case of congenital medulloblastoma initially observed by antenatal MRI with postnatal follow-up and treatment is presented. A pregnant female underwent fetal MRI on the 31st gestational week for routine indications. Midline cerebellar lesion of ≤2 cm in size with minor T2 hypointensity and T1 hyperintensity was identified. Additionally, quantitative MRI including apparent diffusion coefficient (ADC) and fast macromolecular proton fraction (MPF) mapping was performed. The lesion showed a marked ADC decrease and MPF increase. MPF maps depicted the lesion most conspicuously. After term delivery, a male neonate presented with symptoms of increased intracranial pressure. Postnatal MRI identified obstructive hydrocephalus caused by a large posterior fossa mass. The child was treated by cerebrospinal fluid shunt placement. Follow-up quantitative MRI on the fifth month revealed tumor growth and vivid changes of its tissue contrast associated with brain maturation. The tumor appeared nearly isointense on T1- and T2-weighted images and slightly hypointense on the ADC map. MPF contrast showed the most remarkable change from hyper- to hypointensity due to brain myelination with stable MPF in the tumor. Subsequently, the child underwent partial tumor resection, and currently continues treatment with chemotherapy. The pathological diagnosis was desmoplastic/nodular medulloblastoma. The described case illustrates evolution of the tumor contrast in the course of fetal and postnatal brain development and highlights the added diagnostic value of MPF mapping in fetal and neonatal neuroimaging.

Quantitative assessment of demyelination in ischemic stroke in vivo using macromolecular proton fraction mapping.

A recent MRI method, fast macromolecular proton fraction (MPF) mapping, was used to quantify demyelination in the transient middle cerebral artery occlusion (MCAO) rat stroke model. MPF and other quantitative MRI parameters (T1, T2, proton density, and apparent diffusion coefficient) were compared with histological and immunohistochemical markers of demyelination (Luxol Fast Blue stain, (LFB)), neuronal loss (NeuN immunofluorescence), axonal loss (Bielschowsky stain), and inflammation (Iba1 immunofluorescence) in three animal groups ( n = 5 per group) on the 1st, 3rd, and 10th day after MCAO. MPF and LFB optical density (OD) were significantly reduced in the ischemic lesion on all days after MCAO relative to the symmetrical regions of the contralateral hemisphere. Percentage changes in MPF and LFB OD in the ischemic lesion relative to the contralateral hemisphere significantly differed on the first day only. Percentage changes in LFB OD and MPF were strongly correlated (R = 0.81, P < 0.001) and did not correlate with other MRI parameters. MPF also did not correlate with other histological variables. Addition of T2 into multivariate regression further improved agreement between MPF and LFB OD (R = 0.89, P < 0.001) due to correction of the edema effect. This study provides histological validation of MPF as an imaging biomarker of demyelination in ischemic stroke.

Histological validation of fast macromolecular proton fraction mapping as a quantitative myelin imaging method in the cuprizone demyelination model.

Cuprizone-induced demyelination in mice is a frequently used model in preclinical multiple sclerosis research. A recent quantitative clinically-targeted MRI method, fast macromolecular proton fraction (MPF) mapping demonstrated a promise as a myelin biomarker in human and animal studies with a particular advantage of sensitivity to both white matter (WM) and gray matter (GM) demyelination. This study aimed to histologically validate the capability of MPF mapping to quantify myelin loss in brain tissues using the cuprizone demyelination model. Whole-brain MPF maps were obtained in vivo on an 11.7T animal MRI scanner from 7 cuprizone-treated and 7 control С57BL/6 mice using the fast single-point synthetic-reference method. Brain sections were histologically stained with Luxol Fast Blue (LFB) for myelin quantification. Significant (p < 0.05) demyelination in cuprizone-treated animals was found according to both LFB staining and MPF in all anatomical structures (corpus callosum, anterior commissure, internal capsule, thalamus, caudoputamen, and cortex). MPF strongly correlated with quantitative histology in all animals (r = 0.95, p < 0.001) as well as in treatment and control groups taken separately (r = 0.96, p = 0.002 and r = 0.93, p = 0.007, respectively). Close agreement between histological myelin staining and MPF suggests that fast MPF mapping enables robust and accurate quantitative assessment of demyelination in both WM and GM.

High-resolution three-dimensional quantitative map of the macromolecular proton fraction distribution in the normal rat brain.

The presented dataset provides a normative high-resolution three-dimensional (3D) macromolecular proton fraction (MPF) map of the healthy rat brain in vivo and source images used for its reconstruction. The images were acquired using the protocol described elsewhere (Naumova, et al. High-resolution three-dimensional macromolecular proton fraction mapping for quantitative neuroanatomical imaging of the rodent brain in ultra-high magnetic fields. Neuroimage (2016) doi: 10.1016/j.neuroimage.2016.09.036). The map was reconstructed from three source images with different contrast weightings (proton density, T1, and magnetization transfer) using the single-point algorithm with a synthetic reference image. Source images were acquired from a living animal on an 11.7 T small animal MRI scanner with isotropic spatial resolution of 170 µm3 and total acquisition time about 1.5 h. The 3D dataset can be used for multiple purposes including interactive viewing of rat brain anatomy, measurements of reference MPF values in various brain structures, and development of image processing techniques for the rodent brain segmentation. It also can serve as a gold standard image for implementation and optimization of rodent brain MRI protocols.

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.