Synopsis
MRI offers a range of techniques for studying the white matter.This talk will showcase advantages and limitations of the most established ones, starting from the role of conventional techniques in detecting macroscopic abnormalities, to the potential for myelin mapping based on magnetization transfer and multi-component T2 mapping. Validation data and usefulness for clinical applications will be discussed.Highlights
• White matter is composed by axons
and glial cells
• Most MRI techniques show a sharp
contrast between grey and white matter
• Macroscopic white matter
abnormalities can be detected on T2-weighted MRI
• Magnetization transfer and
multi-compartment T2 relaxometry offer indices sensitive to myelin
• Diffusion MRI is sensitive to fiber
density and orientation
TARGET AUDIENCE:
Clinical and basic scientists interested in
white matter biomarkers based on MRI
OUTCOME/OBJECTIVES
After this lecture, participants should be able to understand the composition of white matter, the most common pathology occurring in the white matter, and what are the most suitable MRI techniques to detect such pathology. They should also be aware of the potential limitations of these techniques.
PURPOSE
The white matter of the human brain is composed by tightly
packed myelinated and non-myelinated axons and glial cells. The glial cells
include oligodendrocytes, astrocytes, microglia, and oligodendrocyte progenitor
cells (1). Pathology in the white matter thus consists mainly of demyelination,
axonal degeneration and loss, and gliosis.
Even pushing the resolution of MRI to its current limits, a single voxel
contains a huge amount of these cells and therefore non-invasive white matter
imaging is confined to exploiting the indirect average signal generated by
their combination. Nevertheless, MRI offers a wide range of techniques that
could reveal different aspects of white matter. This lecture will explore the
established techniques and their limitations.
METHODS
T2-weighted MRI is extremely sensitive to any change to
white matter, and it is routinely used to detect abnormalities, such as
demyelinating lesions, neoplastic masses, vascular lesions, and abnormalities
of infectious origin. The main limitation of conventional T2-weighted imaging
is its limited specificity. In the clinic, T2-weighted imaging is often
complemented by gadolinium-enhanced T1-weighted imaging, which provides
information about blood-brain barrier leakage. High-resolution T1-weighted MRI offer an
exquisite contrast between grey and white matter, at least at field strengths
<= 3T. The source of such sharp contrast is believed to be the myelin in the
white matter and its high lipid and protein content (2). These images can be
used to segment the brain in separate tissues, and therefore to quantify white
matter atrophy. While it is possible to achieve an excellent contrast with the
cortex, the subcortical grey matter is more difficult to isolate, and can lead
to errors in the segmentation, especially without the support of priors.
Recently, quantitative techniques based on magnetization transfer (MT) have
been developed to address this issue (3). MT provides a contrast mechanism
based on the exchange of magnetization occurring between groups of spins
characterised by different molecular environment (4), and is particularly
sensitive to the myelin in the white matter. While MT imaging has been
available for 3 decades now, the traditional approach to quantify it was based
on the so-called MT ratio (MTR), i.e., the percentage difference of two images,
one with off-resonance saturation and one without. By increasing the number of
acquisitions to 3, it becomes possible to separate the contributions of MT and
T1, and therefore to reduce the impact of other factors, including the T1-shortening
effects of iron, on image contrast. But the role of MT in characterising the
white matter is not limited to improve the grey-to-white matter contrast. Analytical
models of the MT-weighted signal exist (5), where each pool is characterised by
their longitudinal relaxation rates (RA and RB), their
transverse relaxation times (T2A and T2B), and their spin
densities (M0A and M0B). The exchange rate constant
between the pools is R. Assuming that myelin is the main contributor to MT in
white matter, the ratio M0B/M0A, known as F, or as the relative density of the macromolecular pool,
is believed to reflect myelin content. Myelination and demyelination have been
extensively studied by MRI. Alongside quantitative MT, alternative techniques,
such as multi-compartment T2 relaxometry (6) enable the quantification of the
myelin water fraction (MWF), a proxy of myelination. Finally, diffusion MRI
(dMRI) is based on the random motion of water molecules within tissue. As such
a motion is affected by tissue structure; dMRI can indirectly reflect white
matter microstructure. dMRI has evolved over the years from simple models such
as diffusion tensor imaging (DTI) to more complex, multi-compartment models.
Thanks to its sensitivity to tissue orientation, dMRI also enables the
reconstruction of the main white matter tracts with diffusion tractography. Recent
work has demonstrated that dMRI can be used to infer the distribution of axonal
radius and fiber density within an image voxel (7). Finally, it was recently
suggested that MT parameters other than F might be sensitive to inflammation,
such as activated microglia and astrocytosis (8).
RESULTS & DISCUSSION
A
significant amount of effort has been dedicated to validate MRI biomarkers of
myelination. Animal and post mortem data suggest that proxies derived from both
MT and T2 relaxometry are correlated by myelin content from histology (9,10).
Despite these observations, F and measures of myelination derived from short T2
mapping appear largely uncorrelated (11)
, prompting the debate on which technique better estimates myelin in vivo. By
contrast dMRI parameters are related to fiber density. Indices derived from DTI
are heavily affected by orientation dispersion, and novel models that account
for these factors are recommended.
CONCLUSIONS
MRI techniques for imaging the white matter range from
standard clinical scans to very sophisticated quantitative approaches, each
offering a different view of white matter structure and pathology. The main
limitation of these techniques is the lack of specify for a specific substrate.
This is particularly problematic as often demyelination, inflammation and
oedema can occur at the same time. Novel
methods under development fall essentially into 2 separate categories: ultra-high field techniques, such as
quantiative susceptibility imaging and chemical-exchange saturation transfer,
and multiparametric techniques, where several indices ae combined to improve
specificity.
Acknowledgements
No acknowledgement found.References
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