Quantitative myelin imaging with MRI and PET: an overview of techniques and their validation status

Abstract

Myelin is the protective sheath wrapped around axons, consisting of a phospholipid bilayer with water between the wraps. The measurement of damage to the myelin sheaths, the evaluation of the efficacy of therapies aiming to promote remyelination and monitoring the degree of brain maturation in children all require non-invasive quantitative myelin imaging methods. To date, various myelin imaging techniques have been developed. Five different MRI approaches can be distinguished based on their biophysical principles: (i) imaging of the water between the lipid bilayers directly (e.g. myelin water imaging); (ii) imaging the non-aqueous protons of the phospholipid bilayer directly with ultra-short echo-time techniques; (iii) indirect imaging of the macromolecular content (e.g. magnetization transfer; inhomogeneous magnetization transfer); (iv) mapping of the effects of the myelin sheath's magnetic susceptibility on the MRI signal (e.g. quantitative susceptibility mapping); and (v) mapping of the effects of the myelin sheath on water diffusion. Myelin imaging with PET uses radioactive molecules with high affinity to specific myelin components, in particular myelin basic protein. This review aims to give an overview of the various myelin imaging techniques, their biophysical principles, image acquisition, data analysis and their validation status.

Keywords: MRI; PET; brain maturation; demyelination; myelin imaging.

Figure 1

Representation of CNS characteristics relevant for myelin MRI. Myelin is wrapped around the axon. Within the axon is intracellular water, and outside the myelin layer is extracellular water. The myelin sheath consists of myelin water and lipid bilayers that contain macromolecules. Figure inspired by Fig. 1 from Campbell et al.

Figure 2

Schematic overview of MRI characteristics of the water pools in brain tissue. The free water pool can be subdivided into two compartments, myelin water and intra/extracellular water. Magnetization is exchanged between the bound pool and the free water pool. Within the free water pool, magnetization is exchanged between myelin water and intra- and extracellular water. The compartments have characteristic T₂ relaxation times, which are ∼10 µs for the bound pool, 10–20 ms for myelin water and 65–100 ms for intra-/extracellular water.

Figure 3

Hydrogen precession frequency spectrum. The precession of free water protons is centred closely around the resonance frequency (f₀). On the other hand, the precession of macromolecular protons is spread over a broad spectrum and can therefore be saturated with RF pulses at negative and positive off-resonance frequencies.

Figure 4

T₂ spectrum used to estimate the MWF. On the y-axis is the T₂ amplitude, on the x-axis the T₂ relaxation time. The MWF is calculated as the ratio of myelin water and total free water.