Macromolecular Proton Fraction (MPF): Quantitative Myelin Mapping Technique for Neuroscience

Member-Initiated Symposium at ISMRM 2021: Macromolecular Proton Fraction (MPF): An Emerging Quantitative Myelin Biomarker for Preclinical & Clinical Studies

Macromolecular Proton Fraction (MPF): An Emerging Quantitative Myelin Biomarker for Preclinical & Clinical Studies
Member-Initiated Symposium

Tuesday, 18 May 2021, 16:00 -18:00 UTC

Moderators: Anna Naumova & Vasily Yarnykh

The development of imaging methods for quantitative assessment of myelin has been an area of active research for more than decade. Macromolecular proton fraction (MPF), a parameter derived from magnetization transfer (MT) imaging has received particular attention as a myelin biomarker validated by a number of histological studies in animal models. A recently developed fast MPF mapping methodology revealed the opportunity of clinical translation of MPF measurements providing a simple and robust tool for myelin imaging. Fast MPF mapping offers several practical advantages including high-resolution neuroanatomical applications, independence of magnetic field strength, high reproducibility, insensitivity to confounders associated with tissue relaxation and microstructure, and easy protocol harmonization across MRI equipment of different manufacturers. The proposed symposium is focused on the application of MPF as a myelin biomarker for a broad range of pre-clinical and clinical applications. The symposium properly fits to the ISMRM Annual Meeting content, since the dissemination of novel quantitative MRI methods is of paramount importance for the MRI community. The symposium will contain four lectures followed by open discussion. The lectures will describe the principles of quantitative MT imaging and the technical background of fast MPF mapping, summarize the histological evidence supporting the utility of MPF as a myelin biomarker, and review recent neuroscience applications.

Target Audience
Researchers and clinicians interested in quantitative MRI techniques for neuroscience.

Educational Objectives
As a result of attending this course, participants should be able to:
Upon completion of this course, participants should be able to: - Describe the physical principles of quantitative magnetization transfer MRI; - Identify experimental methodology and reconstruction algorithms for fast clinically targeted mapping of the macromolecular proton fraction (MPF) with the use of commonly available human and animal MRI equipment; - Name the advantages and challenges in the application of MPF as a myelin biomarker in clinical and preclinical studies; and - Recognize state-of-the-art applications of MPF mapping in human brain diseases, animal models, and brain development studies.


Presenter & Talk Details

1.       Greg Stanisz, PhD. Sunnybrook Research Institute, Toronto, Canada.

Magnetization Transfer Contrast - Historical Perspective

The magnetization transfer (MT) contrast was introduced into MRI technology over 30 years ago. Initially viewed as a way to probe tissue macromolecular composition, interpretation of MT imaging evolved from a phenomenological description of signal intensity changes caused by the presence of biological macromolecules to complex biophysical models involving multiple proton pools and magnetization exchange processes. The classic two-pool model still remains the basic theoretical tool for the interpretation of MT phenomena. One parameter defined within this model, macromolecular proton fraction (MPF) attracted significant practical interest over the past decade due to its close relationship to the myelin content in neural tissues. MPF and other MT model parameters can be measured by a number of experimental methods varying in the degree of complexity and underlying model assumptions. The lecture will overview historical milestones in the understanding and applications of MT contrast, theoretical models used for the description of the MT effect, experimental approaches to characterize proton magnetization exchange in tissues, and current problems and controversies in the interpretation of MT phenomena.


2.       Alexey Samsonov, PhD. University of Wisconsin – Madison, Madison, WI, USA.

Fast Macromolecular Proton Fraction Mapping: Physical Principles and Clinical Applications 

Over the years, Macromolecular Proton Fraction (MPF) mapping demonstrated high utility in characterization of tissue macromolecular content. Specifically, high sensitivity and specificity of MPF to myelin made it an ideal candidate for deployment in neuroimaging applications; yet, its utility was hampered by the lack of clinically feasible MPF methodology. Recent advances in modeling and acquisition, however, culminated in the development of fast, accurate, high-resolution imaging protocols suitable for widespread clinical use. In this presentation, we will first overview basic principles of MPF mapping using cross-relaxation imaging framework. Then, we will discuss several optimization solutions for clinically feasible MPF mapping. We will also discuss advanced MPF modeling approaches for correction of practical confounders such as cerebrospinal fluid partial voluming and tissue edema effects. We will conclude with a demonstration of recent clinical results of the application of the fast MPF methodology in multiple sclerosis, mild traumatic brain injury, and pediatric brain development.


3.       Marina Khodanovich, PhD. Tomsk State University, Tomsk, Russia.

Histological validation and preclinical applications of MPF as a myelin biomarker

Histological validation on appropriate animal models is the most important evidence that proves reliability of a specific biomarker in preclinical and clinical applications. To date, numerous studies had confirmed high accuracy of macromolecular proton fraction (MPF) mapping for quantitative measurements of myelination. Strong correlations between MPF and histological markers of myelin have been shown in the normal brain tissue in a wide range of animal species as well as in specific models of demyelination, such as murine cuprizone-induced demyelination, rat experimental autoimmune encephalomyelitis, lipopolysacharide-induced focal lesion, feline irradiated diet-induced demyelination, and genetic dysmyelination (shiverer mouse, shaking pup). Similar correlations were also observed in the models of stroke and traumatic brain injury, where myelin destruction is an important pathological component of neural tissue damage. Moreover, the recent studies have demonstrated the feasibility of using MPF as a quantitative biomarker of remyelination, as well as a surrogate marker of restorative processes of oligodendrogenesis and neurogenesis in the models of cuprizone-induced demyelination and ischemic stroke. The lecture will summarize the key findings of the earlier studies focused on histological and immunohistochemical validation of MPF as a myelin biomarker and discuss the accuracy, reliability, and potential confounders of MPF measurements in preclinical small animal studies.


4.       Neva Corrigan, PhD. University of Washington, Seattle, WA, USA.

High-resolution 3D macromolecular proton fraction mapping of the human brain: a new tool for quantitative neuroscience

Macromolecular proton fraction (MPF) maps of the human brain can be obtained at high spatial resolution (1-1.3 mm voxel size) and in a clinically-feasible scan time using a recently developed fast single-point method. MPF maps provide high contrast between white and gray matter, which is driven by the distinctions in the myelin content. The method also includes inherent correction for B0 and B1 field inhomogeneities and receiver coil non-uniformity. These features make high-resolution MPF mapping an attractive imaging modality for various structural neuroscience tasks including segmentation of the brain anatomic structures, cortical parcellation, and construction of standard templates.  In addition, MPF maps provide objective quantitative information about myelination of brain tissues and its change over time. The lecture will summarize recent experience in the application of high-resolution 3D MPF maps in large-scale neurobehavioral studies of children and adolescents and provide practical recommendations for the design of image processing pipelines utilizing MPF maps with the use of common neuroscience software packages (FSL, FreeSurfer, ANTS). Another focus of the lecture will be on the reproducibility of MPF mapping in the context of serial clinical applications.​​