Vanessa Wiggermann1,2, Shawna Abel3, Irene M Vavasour4, Enedino Hernández-Torres3, Christian Kames1,2, David KB Li4,5, Roger Tam4,5, Shannon H Kolind1,3, Anthony Traboulsee3, and Alexander Rauscher1,2
1Physics and Astronomy, University of British Columbia, Vancouver, BC, Canada, 2Pediatrics, University of British Columbia, Vancouver, BC, Canada, 3Medicine (Neurology), University of British Columbia, Vancouver, BC, Canada, 4Radiology, University of British Columbia, Vancouver, BC, Canada, 5MS/MRI Research (Neurology), University of British Columbia, Vancouver, BC, Canada
Synopsis
Abnormalities seen on clinical MRIs in the brain and spinal cord of multiple
sclerosis (MS) patients lack specificity to myelin. Thus,
efficacy of new treatments that aim to protect or remyelinate cannot be fully captured.
Quantitative MR metrics, such as R2* and quantitative susceptibility mapping (QSM),
have demonstrated good sensitivity to myelin and iron-related tissue changes, but the clinical
relevance of such changes has not yet been assessed. We showed that R2*
provides good group-wise distinction of MS patients and controls, while QSM values
reflected clinically meaningful variations in upper and lower motor function
as well as cognitive processing speed.
Introduction
On MRI, multiple sclerosis (MS) is characterized by focal and
diffuse damage in both white and gray matter1,2, reflecting
demyelination, axonal loss and glial scarring3. Due to the
inflammatory and often asymptomatic nature of MS lesions, measurements of lesion
count or volume typically fail to represent the probability and degree of
progression and clinical disability of patients4,5.
Moreover, because of the low
specificity of clinical MRI abnormalities to myelin, the efficacy of
new treatments that aim to protect or remyelinate axons in order to halt
progression6 cannot be fully captured7.
Susceptibility-sensitive imaging, including R2*8 and QSM9,10,
has demonstrated sensitivity to myelin-related changes11,12 and
therefore promises to aid in assessing treatment efficacy. Importantly, R2*
and QSM are also susceptible to tissue iron13,14, a notable contributor to myelin
health and maintenance15. However, specific clinical relevance of changes in R2*
and QSM has not yet been fully assessed. Here, we tested whether differences between
early MS patients and healthy controls can be detected by R2* or QSM.
Further, we assessed if these differences relate to clinical metrics of physical
and cognitive performance. Methods
25
relapsing MS patients were scanned at 3T at baseline as part of a substudy of a
phase III randomized double-blind placebo-controlled clinical trial (NCT01412333).
All patients were assessed with the expanded disability status scale (EDSS) and
participated in the timed 25 foot-walk (T25FW), the 9-hole peg test (9HPT), 3s paced
auditory serial addition test (PASAT) and symbol digit modalities test (SDMT). Table
1 summarizes demographic and clinical information. MRI data from 40 age-matched
healthy controls were collected for comparison. MRI included a T1-weighted
image, acquired at 1x1x3mm3 with TR/TE=28/4ms, and a 3D gradient-echo
for R2* and QSM, using 6 echoes with TR/TE/∆TE of 38/4/4.5ms, acquired
and reconstructed voxel sizes 0.5x0.75x2mm3 and 0.49x0.49x1mm3,
respectively. After upsampling to isotropic resolution, each echo of the phase
data was Laplacian unwrapped, V-SHARP background field removed and dipole inverted10.
QSM values were computed from echoes two to six and normalized to CSF. Six
regions-of-interest (ROIs) were extracted from the JHU-DTI-ICBM labels and
Harvard Oxford atlas in MNI space: the thalamus, putamen, genu and
splenium of the corpus callosum, the anterior and posterior internal capsules
(IC) and the superior longitudinal fasciculus (SLF). Image co-registration was
performed using FSL16,17 through the subject 3D pre-contrast FFE T1
image space. MS lesions, which had been semi-automatically identified18,
were excluded from the ROIs. Median regional R2* and QSM values were
obtained in subject space. Group differences were assessed using a Wilcoxon
rank sum test, adjusted by Holm-Sidak. A linear regression model predicted the
relative importance19 of the MR values to the clinical metrics.Results
On a group level, MS patients showed higher R2*
in the deep gray matter and significantly lower R2* in WM structures than observed in controls (Fig. 1, left). QSM values were significantly higher only in
the putamen in MS compared to controls. WM structures showed a trend to
increased QSM values in MS compared to controls (Fig. 1, right). Within the MS
group, higher R2* and QSM in the putamen and splenium related to
slower walking speed on the T25FW (Fig. 2). Other significant relationships
included negative associations between QSM values in the SLF, thalamus and IC
with 9HPT scores (Fig. 3). Finally, a positive association was observed between
QSM values in the IC and SDMT scores. All significant correlations were confirmed
to be relevant predictors of the clinical scores in the linear regression
analysis. Including age, sex and regional volume as covariates, putaminal R2*
and QSM had a relative importance (RI) of 47.5 and 51.8% in predicting T25FW
outcomes. In the splenium, RI of R2* and QSM was around 40% each,
behind age at 50%. RI of QSM for predicting 9HPT times were between 65-75% in
the different regions. The IC was the only region in which QSM was the primary
predictor of SDMT scores (RI 58.5%). No significant relationships were observed
between EDSS or PASAT with MRI measures in any region.Discussion
We demonstrated that both R2*
and QSM distinguished early MS patients from healthy controls on a group basis.
QSM reflected and predicted clinical outcomes, more so than age, sex and regional
volumes. The positive relationship between putaminal and splenial R2*
and QSM with T25FW is consistent with atrophy20-24, albeit
demyelination may contribute to these findings. In contrast, the negative
relationship between SLF-QSM and 9HPT suggests iron loss. Iron loss in white
matter correlates with disease duration in MS25, and iron deficiency
is known to contribute to impaired development and cognitive function26,27.
Correlations in the IC and thalamus with 9HPT scores are in good agreement with
their known involvement in motor functions and central connections. Finally,
the SDMT correlation with QSM-IC may be a combined reflection of cognitive as
well as motor impairment. Conclusion
Both,
R2* and QSM demonstrated significant sensitivity in distinguishing
patients from controls and changes in these metrics correlated with clinical
measures of physical and cognitive performance. While R2* provided a
better group-wise distinction, as it gives an overall picture of the damage due
to MS, QSM appeared to be an excellent reflection of clinically meaningful
differences between patients in functionally relevant ROIs.Acknowledgements
This study was sponsored by F. Hoffman-La Roche AG. Genentech (owned by F. Hoffman-La Roche) sponsored the collection of the data used in this study. VW was supported by a graduate studentship award from the MS Society of Canada. SHK is supported by the Michael Smith Foundation. AR is supported by Canada Research Chairs.References
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