Anjan Bhattarai1,2, Zhaolin Chen2, Phillip G. D. Ward2, Paul Talman3, Susan Mathers4, Thanh Phan5, Caron Chapman4, James Howe4, Sarah Lee4, Yennie Lie4, Gary F Egan2, and Phyllis Chua1,4
1Department of Psychiatry, Monash University, Clayton, Australia, 2Monash Biomedical Imaging, Monash University, Clayton, Australia, 3Department of Neuroscience, Barwon Health, Geelong, Australia, 4Statewide Progressive Neurological Services, Calvary Health Care Bethlehem, South Caulfield, Australia, 5Department of Neuroscience, Monash Health, Clayton, Australia
Synopsis
We performed in-vivo measurements of the magnetic
susceptibility in the motor cortex in individuals with Amyotrophic Lateral
Sclerosis (ALS) at baseline and six-month follow-up, and healthy controls at
baseline using Quantitative Susceptibility Mapping (QSM). The results show
significant susceptibility difference between individuals with ALS compared to healthy
controls. There was a trend towards more pronounced susceptibility changes in
lumbar onset compared to healthy controls than cervical onset ALS compared to
healthy controls. These
findings may lead to the development of a sensitive neuroimaging biomarker that
can provide meaningful insights into pathophysiologic
changes in ALS
subtypes.
Introduction
Amyotrophic Lateral Sclerosis (ALS) is a progressive
neurodegenerative disorder which is known to affect both Upper Motor Neurons
(UMN) and Lower Motor Neurons (LMN).1 Diagnosis of ALS can be difficult due to its clinical
heterogeneity, unpredictable progression and the lack of a diagnostic test or
biomarker. A number of studies have suggested
dysregulation of iron in ALS brain,2, 3 including an
ex-vivo study which reported increased iron accumulation in the microglia of
the motor cortex of individuals with ALS.4 Disruptions in brain iron homeostasis are considered a
prominent hallmark of neuroinflammation,5 and
its role in ALS pathogenesis warrants further investigation.
Quantitative
Susceptibility Mapping (QSM) provides a surrogate measurement of iron, copper
and zinc in the brain with the measurement of magnetic susceptibility in-vivo.
In this abstract, we report our preliminary QSM findings in the primary motor
cortex of individuals with limb-onset phenotypes of ALS: i) lumbar onset ALS and
ii) cervical onset ALS compared to healthy controls. The QSM findings in limb-onset
ALS at six-month follow-up compared to baseline is also reported. Methods
MRI images of the individuals with limb-onset ALS and healthy controls were acquired on a 3T Siemens Skyra. MRI data
were obtained from 13 individuals with ALS (lumbar onset = 5, cervical onset =
6, and flail arm onset = 2) and 11 age and gender matched healthy controls at
baseline. 9 individuals with ALS received a follow-up at six-month.
MRI data acquisition protocol included T1-weighted MPRAGE and a
T2*-weighted GRE (TR=30ms, TE=20ms, FA= 15°, FOV= 230mm, 0.9 x 0.9 x 1.8 mm3,
72 slices per volume).
Individual coil images were reconstructed using raw k-space GRE data. Phase images were
processed using Laplacian Unwarping3 and VSHARP4. QSM reconstruction was
performed using iLSQR
algorithm.5
The primary
motor cortex region of interests (ROIs) of each participant were obtained from the
cortical parcellation of their anatomical T1-weighted images using FreeSurfer,6, 7 and linearly co-registered
registered to their respective QSM images using ANTs.8 The ROIs were individually
checked for their anatomical and registration accuracy. The ROIs were: left and
right primary motor cortex anterior (Brodmann area 4 anterior), and left and
right primary motor cortex posterior (Brodmann area 4 posterior). QSM values
were referenced to whole brain mean susceptibility value, and the mean
calculated for each ROI. QSM values are reported as group mean ±
standard error of the mean. False
Discovery Rate (FDR) adjusted p-values are reported when comparing the
subgroups (lumbar onset ALS and cervical onset ALS) to healthy controls. Results
QSM values at baseline were observed to be significantly
higher with strong effect sizes in the Right Anterior Primary Motor Cortex (RPMCa)
(ALS = 33 ± 0.9 ppb,
Controls = 29.7 ± 1.1
ppb, Wilcoxon rank sum p = 0.02, Cohen’s d = 0.92), and Left Posterior Primary Motor
Cortex (LPMCp) (ALS = 30.2 ± 1.2 ppb,
Controls = 27 ± 0.8 ppb,
p = 0.02, d = 0.90) of individuals with limb-onset ALS compared to healthy
controls.
QSM values in all the ROIs in subgroup of lumbar onset ALS
including RPMCa (lumbar onset ALS = 34.4 ± 1.9 ppb, Controls = 29.7 ± 1.1 ppb, p = 0.07, d = 1.21) and LPMCp (lumbar onset ALS = 30.5
± 1.32 ppb,
Controls = 27 ± 0.8 ppb,
p = 0.07, d = 1.34) were higher compared to healthy controls though the
differences were not statistically significant after FDR adjustment. QSM values
between cervical onset ALS and healthy controls were not significantly
different.
No significant change in QSM values was observed at 6-month
follow-up in RPMCa (Baseline ALS = 33.7 ± 1.2 ppb, Follow-up ALS = 34.4 ± 1.9 ppb, Wilcoxon signed rank p =
0.73, Cohen’s d = 0.23) and LPMCp (Baseline ALS = 31.2 ± 1.6 ppb, Follow-up ALS = 29.9 ±
1.4 ppb, p = 0.05, d = -0.77).
Discussion
This study used
QSM to measure magnetic susceptibility in-vivo in the primary motor cortex of
individuals with limb-onset ALS at 2 time points 6 months apart and in healthy
controls. The QSM values were significantly higher in ALS cohort compared to
healthy controls. Although not
significant, this trend was observed to be stronger, relative to controls, in
lumber onset ALS compared to cervical onset ALS.
The
differences observed in QSM measures may be a result of increased iron
accumulation in the motor cortex. Our current and future work will be to
examine QSM changes in ALS beyond the primary motor cortex and investigate
their correlations with clinical measures/scores. Conclusion
This study demonstrates
the efficacy of QSM in the detection susceptibility changes. QSM provides a
means to measure iron dysregulation in the primary motor cortex in limb-onset ALS.
The findings highlight its potential in characterizing disease progression in
different ALS subtypes. Future longitudinal studies with a larger cohort,
grouped on the basis of different clinical phenotypes, disease severity and
duration are needed for the validation of QSM as a sensitive and specific
marker of disease progression in ALS. Ongoing advances in QSM will improve the
value of this tool, particularly by addressing streaking artefacts, relative
rather than absolute measure of magnetic susceptibility, and lack of agreed
upon reconstruction technique.Acknowledgements
Funding
for this project was obtained through the Monash University Strategic Grant
Scheme. AB is supported by The Australian Rotary Health / Rotary Club of Sandy
Bay PhD Scholarship in Motor Neurone Disease. References
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