Rebecca Sara Samson1, Manuel Jorge Cardoso2,3, Wallace J Brownlee1, J William Brown1,4, Matteo Pardini5, Sebastian Ourselin2,3, Claudia Angela Michela Gandini Wheeler-Kingshott1,6, David H Miller1,7, and Declan T Chard1,7
1NMR Research Unit, Queen Square MS Centre, Department of Neuroinflammation, UCL Institute of Neurology, University College London, London, United Kingdom, 2Translational Imaging Group, Centre for Medical Image Computing, Department of Medical Physics and Bioengineering, University College London, London, United Kingdom, 3Dementia Research Centre, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, United Kingdom, 4Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom, 5Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy, 6Brain Connectivity Center, C. Mondino National Neurological Institute, Pavia, Italy, 7National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, London, United Kingdom
Synopsis
Cortical magnetization transfer ratio (cMTR) is potentially a sensitive
measure of pathology linked with disease progression in relapse-onset multiple
sclerosis (MS). We investigated outer cMTR changes in people following a clinically
isolated syndrome (CIS), and compared those who later developed MS with those
who did not. Compared with controls, the outer-to-inner cMTR ratio was
significantly lower in patients who developed MS after 15 years but not in
those who remained CIS. This suggests that the pathological processes
underlying preferential reductions in outer cMTR start early in the clinical
course of MS, and may be relevant to conversion to MS.PURPOSE
To
investigate inner and outer
cortical magnetisation transfer ratio (MTR) changes in people with a
clinically-isolated syndrome (CIS) and compare MTR abnormalities in those who remained
CIS and those who went on to develop multiple sclerosis (MS) after
15 years.
BACKGROUND
Cortical grey matter
(CGM) pathology is common in MS (1-3). Histopathological studies have shown
that demyelinating lesions preferentially form in the outer (subpial) CGM (4,5). In some people with secondary progressive (SP) MS neuroaxonal loss is also greater
adjacent to the outer surface of the brain, and it has been suggested that these
abnormalities may be associated with meningeal inflammation (6). While most
marked in SPMS, a recent biopsy study has shown evidence of
CGM pathology in clinically early MS (1). CGM abnormalities are difficult to
detect using MRI. A recent study used MTR to investigate inner and outer
cortical abnormalities in relapse-onset MS (7), and consistent with
histopathological findings, found greater disease effects on outer when
compared with inner cortical MTR (cMTR) in people with relapsing-remitting and
SPMS. We wanted to investigate whether inner and outer cMTR
abnormalities are present in patients with CIS, which is often the first
clinical manifestation of relapse-onset MS.
METHODS
Subjects:
Seventy-two people with
clinically-isolated optic neuritis (ON) underwent MRI scanning within 6 months
of onset (mean age 33.4 years, 51 female) and were followed up 15 years later.
MS was diagnosed using the McDonald 2010 criteria (8). Thirty-six healthy
controls (mean age 34.0, 24 female) were also scanned.
MRI acquisition: Imaging
was performed using a 1.5 T GE Signa scanner (GE, Milwaukee, WI). The following
data were acquired (sequence details are given in Figure 1):
(i)
Dual-echo proton-density (PD)/T2-weighted
images
(ii)
3D fast spoiled gradient recalled (FSPGR)
images
(iii)
MTR
data using a dual-echo, spin-echo sequence
Image Analysis:
White matter lesions were outlined
on PD/T2-weighted images using Jim v6.0 (Xinapse systems, Aldwincle, UK) by one
investigator (WJB). Lesion masks were registered to corresponding 3D-FSPGR (T1-weighted) images via pseudo-T1-weighted images (9). Transformations were computed using NiftyReg
(10,11) and applied to lesion masks to enable lesion filling (12, 13).
Segmentation of lesion filled T1-weighted images was performed
using SPM12 (Wellcome Trust Centre for Neuroimaging, London, UK)). Maximum
likelihood classification of all voxels was performed, and resulting tissue
probability maps were binarised using a ≥90% probability threshold (7). Brain parenchymal
fractions (BPF) were calculated for use as a covariate in the statistical models, and
T1-weighted lesion filled brain extracted volumes were also generated, as
required by the NiftySeg software (14).
Following cortical segmentation (14) sub-division of CGM
into inner and outer cortical bands was performed using methods described
previously (7, 15, 16) (a conservative 99% threshold was applied to CGM
probability maps to limit potential partial volume effects). T1-weighted data
were affine registered to each subject’s MTR data, via the pseudo-T1-weighted
images (10, 11), and MTR maps were calculated (using the short echo data
because of its higher signal-to-noise ratio (SNR) than the longer echo data).
Statistical Analysis:
All statistical analyses were
performed using SPSS (IBM SPSS version 22 for Windows (SPSS, Inc., Chicago, IL,
USA)). Between-group differences in inner and outer mean cMTR were examined
using one-way analysis of covariance (ANCOVA) tests (with post-hoc paired
comparisons), adjusted for age, gender and BPF.
RESULTS
At baseline the ON group had significantly lower outer (p<0.001) and inner cMTR
(p<0.001) compared with controls. The outer-to inner cMTR ratio was
significantly lower in ON than controls (p<0.001) (values reported in Figure 2).
In the ON group, inner and outer
cMTR were lower in both those who developed MS after 15 years (n=56, p<0.001)
and in those that remained CIS (n=16, p<0.05) compared with controls. The outer-to-inner cMTR ratio was also
significantly lower in patients who developed MS (p<0.001) compared with
controls. There was no difference in the outer-to-inner cMTR ratio between
those who remained CIS and controls.
Example healthy control single
slice images with inner and outer cortical bands superimposed are shown in
Figure 3.
DISCUSSION AND CONCLUSIONS
Soon after a clinically isolated ON we found
reductions in the outer and inner cMTR similar to previous findings in
established relapse-onset MS (7). When compared with
controls, a significant reduction in outer-to-inner cMTR ratio was observed in
those who developed MS within the next 15 years, but not those who remained
CIS. These findings suggest
that the pathological changes underlying abnormal outer-to-inner cMTR ratios start
early in the course of relapse-onset MS, and greater outer cortical changes may
be relevant to the development of MS in patients with CIS.
Acknowledgements
The authors would like to thank the MS Society of the UK, the EPSRC and the UCL-UCLH Biomedical Research Centre for ongoing support. We would also like to thank all the participants of this study.References
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