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.

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.

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.

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.