Fast Macromolecular Proton Fraction Research Articles

The effect of corpus callosum abnormalities on myelin development in the fetal brain using the fast macromolecular proton fraction mapping

INTRODUCTION: There is evidence, indicate early compensatory axonal remodeling connections in the prenatal period, providing a favorable neurological outcome in isolated anomalies of the corpus callosum (CC). Mapping of the macromolecular proton fraction (MPF) is proven method of quantitative determination of myelin, which has been adapted for prenatal studies.OBJECTIVE: To investigate the relationship between CC anomalies and prenatal myelination of the brain using the fast macromolecular proton fraction (MPF) mapping.MATERIALS AND METHODS: Fetal MR imaging were performed on a 1.5 scanner (Achieva, Philips) using a 16-channel body coil. Of 66 fetal brains MRI, 12 studies were selected with MT abnormalities (22.8±2.8, 19–28.5 WG) and 21 without brain pathology (23.1±2.3, 20–29.5 WG). The images were analyzed according to structural MRI data (T2-Ssh and T1-GE, EPI, DWI, MYUR, T2-BFE-DYN) by two experienced radiologists. Fast-3D-MPF scan protocol with the MPF maps reconstruction was carried out according to a specialized protocol (open-source software: https://www.macroatomicmri.org /). Quantitative data were obtained by choosing the region of interest (ROI) in numerous brain structures bilateral (bridge, medulla oblongata, thalamus, cerebellum, and cerebral hemispheres). Statistics: distinctions between the groups and structures were assessed using repeated-measures analysis of covariance (ANCOVA), Pearson correlation analysis.RESULTS: MPF was significantly increased in the CC anomalies group as compared to controls in the medulla (3.26±0.63% vs. 2.75±0.59%, р=0.001) and cerebellum (2.02±0.55% vs. 1.76±0.34%, р=0.006). In hemispheres significant correlation with GA was observed in CC anomalies group (r=0.81, р=0.002), but was absent in controls (r=0.32, р=0.16).CONCLUSION: Primary observed MPF increase in the medulla and cerebellum as well as the dependence of the large hemispheres myelination on gestational age indicates that fetal cerebral matter undergoes early compensatory axonal remodeling in the cases of the interhemispheric connections’ reduction.

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.

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.

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.

Quantitative Imaging of White and Gray Matter Remyelination in the Cuprizone Demyelination Model Using the Macromolecular Proton Fraction.

Macromolecular proton fraction (MPF) has been established as a quantitative clinically-targeted MRI myelin biomarker based on recent demyelination studies. This study aimed to assess the capability of MPF to quantify remyelination using the murine cuprizone-induced reversible demyelination model. MPF was measured in vivo using the fast single-point method in three animal groups (control, cuprizone-induced demyelination, and remyelination after cuprizone withdrawal) and compared to quantitative immunohistochemistry for myelin basic protein (MBP), myelinating oligodendrocytes (CNP-positive cells), and oligodendrocyte precursor cells (OPC, NG2-positive cells) in the corpus callosum, caudate putamen, hippocampus, and cortex. In the demyelination group, MPF, MBP-stained area, and oligodendrocyte count were significantly reduced, while OPC count was significantly increased as compared to both control and remyelination groups in all anatomic structures (p < 0.05). All variables were similar in the control and remyelination groups. MPF and MBP-stained area strongly correlated in each anatomic structure (Pearson’s correlation coefficients, r = 0.80–0.90, p < 0.001). MPF and MBP correlated positively with oligodendrocyte count (r = 0.70–0.84, p < 0.01 for MPF; r = 0.81–0.92, p < 0.001 for MBP) and negatively with OPC count (r = −0.69–−0.77, p < 0.01 for MPF; r = −0.72–−0.89, p < 0.01 for MBP). This study provides immunohistological validation of fast MPF mapping as a non-invasive tool for quantitative assessment of de- and remyelination in white and gray matter and indicates the feasibility of using MPF as a surrogate marker of reparative processes in demyelinating diseases.

Quantitative Assessment of Normal Fetal Brain Myelination Using Fast Macromolecular Proton Fraction Mapping.

Fast macromolecular proton fraction mapping is a recently emerged MRI method for quantitative myelin imaging. Our aim was to develop a clinically targeted technique for macromolecular proton fraction mapping of the fetal brain and test its capability to characterize normal prenatal myelination. This prospective study included 41 pregnant women (gestational age range, 18-38 weeks) without abnormal findings on fetal brain MR imaging performed for clinical indications. A fast fetal brain macromolecular proton fraction mapping protocol was implemented on a clinical 1.5T MR imaging scanner without software modifications and was performed after a clinical examination with an additional scan time of <5 minutes. 3D macromolecular proton fraction maps were reconstructed from magnetization transfer-weighted, T1-weighted, and proton density-weighted images by the single-point method. Mean macromolecular proton fraction in the brain stem, cerebellum, and thalamus and frontal, temporal, and occipital WM was compared between structures and pregnancy trimesters using analysis of variance. Gestational age dependence of the macromolecular proton fraction was assessed using the Pearson correlation coefficient (r). The mean macromolecular proton fraction in the fetal brain structures varied between 2.3% and 4.3%, being 5-fold lower than macromolecular proton fraction in adult WM. The macromolecular proton fraction in the third trimester was higher compared with the second trimester in the brain stem, cerebellum, and thalamus. The highest macromolecular proton fraction was observed in the brain stem, followed by the thalamus, cerebellum, and cerebral WM. The macromolecular proton fraction in the brain stem, cerebellum, and thalamus strongly correlated with gestational age (r = 0.88, 0.80, and 0.73; P < .001). No significant correlations were found for cerebral WM regions. Myelin is the main factor determining macromolecular proton fraction in brain tissues. Macromolecular proton fraction mapping is sensitive to the earliest stages of the fetal brain myelination and can be implemented in a clinical setting.

Iron-Insensitive Quantitative Assessment of Subcortical Gray Matter Demyelination in Multiple Sclerosis Using the Macromolecular Proton Fraction.

Fast macromolecular proton fraction mapping is a recent quantitative MR imaging method for myelin assessment. The objectives of this study were to evaluate the macromolecular proton fraction as a measure of demyelination in subcortical GM structures in multiple sclerosis and assess a potential relationship between demyelination and excess iron deposition using the macromolecular proton fraction and T2* mapping. Macromolecular proton fraction and T2* maps were obtained from 12 healthy controls, 18 patients with relapsing-remitting MS, and 12 patients with secondary-progressive MS using 3T MR imaging. Parameter values in the caudate nucleus, globus pallidus, putamen, substantia nigra, and thalamus were compared between groups and correlated to clinical data. The macromolecular proton fraction in all subcortical structures and T2* in the globus pallidus, putamen, and caudate nucleus demonstrated a significant monotonic decrease from controls to patients with relapsing-remitting MS and from those with relapsing-remitting MS to patients with secondary-progressive MS. The macromolecular proton fraction in all subcortical structures significantly correlated with the Expanded Disability Status Scale and MS Functional Composite scores with absolute Pearson correlation coefficient (r) values in a range of 0.4-0.6. Significant correlations (r = -0.4 to -0.6) were also identified between the macromolecular proton fraction and the 9-Hole Peg Test, indicating a potential relationship with nigrostriatal pathway damage. Among T2* values, weak significant correlations with clinical variables were found only in the putamen. The macromolecular proton fraction did not correlate with T2* in any of the studied anatomic structures. The macromolecular proton fraction provides an iron-insensitive measure of demyelination. Myelin loss in subcortical GM structures in MS is unrelated to excess iron deposition. Subcortical GM demyelination is more closely associated with the disease phenotype and disability than iron overload.

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.

Implementation of fast macromolecular proton fraction mapping on 1.5 and 3 Tesla clinical MRI scanners: preliminary experience

Macromolecular proton fraction (MPF) is a biophysical parameter describing the amount of macromolecular protons involved into magnetization exchange with water protons in tissues. MPF represents a significant interest as a magnetic resonance imaging (MRI) biomarker of myelin for clinical applications. A recent fast MPF mapping method enabled clinical translation of MPF measurements due to time-efficient acquisition based on the single-point constrained fit algorithm. However, previous MPF mapping applications utilized only 3 Tesla MRI scanners and modified pulse sequences, which are not commonly available. This study aimed to test the feasibility of MPF mapping implementation on a 1.5 Tesla clinical scanner using standard manufacturer’s sequences and compare the performance of this method between 1.5 and 3 Tesla scanners. MPF mapping was implemented on 1.5 and 3 Tesla MRI units of one manufacturer with either optimized custom-written or standard product pulse sequences. Whole-brain three-dimensional MPF maps obtained from a single volunteer were compared between field strengths and implementation options. MPF maps demonstrated similar quality at both field strengths. MPF values in segmented brain tissues and specific anatomic regions appeared in close agreement. This experiment demonstrates the feasibility of fast MPF mapping using standard sequences on 1.5 T and 3 T clinical scanners.

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.

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.

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%.