Richard D Lawless1,2, Kristin O'Grady1,3, Mereze Visagie1, Anna Combes1, Haley Feiler1, Francesca Bagnato4, and Seth A. Smith1,2,3
1Vanderbilt University Institute of Imaging Sciences, Vanderbilt University Medical Center, Nashville, TN, United States, 2Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, United States, 3Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, United States, 4Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
Synopsis
Spinal cord damage in multiple
sclerosis often leads to the formation of inflammatory lesions. APT CEST has
been proposed as an MRI biomarker capable of detecting the underlying biochemical
changes associated with lesion formation, however, CEST findings are
susceptible to confounding influences such as the macromolecular magnetization transfer
contribution and changes to longitudinal relaxation. AREX is a proposed method
which corrects for these contributors and may improve measurement of the CEST
component in vivo. In this study we sought to compare MT- and T1-corrected
AREX to an uncorrected CEST quantification method in SC lesions of MS patients.
Introduction
Multiple sclerosis (MS) and many
other neurodegenerative diseases result in significant damage to the spinal
cord (SC), often presenting as lesions [1]. MRI is ubiquitously used to detect
lesions within the SC; however, these lesions are non-specific and often do not
reflect patient disability. Recently, chemical exchange saturation transfer
(CEST) has been proposed as an MRI biomarker capable of detecting the
underlying biochemical changes which occur prior to and during lesion development.
Amide proton transfer (APT) CEST
is an MRI contrast approach sensitive to mobile endogenous solutes such as
proteins and peptides, as well as tissue pH [2]. Endogenous CEST effects are
often confounded by a number of contributing factors, including the
macromolecular component present in all magnetization transfer experiments,
RF-spillover effects, and changes to T1 relaxation. Apparent exchange-dependent
relaxation rate (AREX) [3] is a proposed CEST quantification approach which
corrects for the previously mentioned confounders. In this study, we sought to evaluate
the changes in contrast between AREX and uncorrected APT measurements within
the lesions of early-stage MS patients. Methods
Fourteen healthy volunteers and
seven MS patients were recruited for this study after informed consent (Table
1 for demographics). A 3T whole body scanner (Philips, Best, Netherlands) and a 16-channel sensitivity encoding (SENSE)
neurovascular coil were used to acquire all images. We acquired a single slice
between the C3 and C4 vertebrae. All images were registered to a multi-slice,
multi-echo gradient echo (mFFE) prior to analysis. A WASSR sequence was
performed for B0 field correction. The CEST sequence consisted of a single
150ms 2µT saturation pulse acquired at 36 asymmetric offset frequencies between
±5 ppm and corrected for respiration according to By et al [4]. Additional parameters include: FOV = 160mm x160mm, voxel size =
1mm x 1mm, SENSE = 2(RL), TR/TE = 305/12ms, α = 20°, NSA = 5. T1 mapping for AREX
calculation was done using a multi flip angle sequence. Additional parameters
include: FOV= 160mm x 160mm, voxel size = 1.5mm x 1.5mm, TR/TE = 20/4.6ms, α = 5,15,20,25,30°.
Gray and white matter segmentation was done
using Spinal Cord Toolbox [5], while lesion segmentation was done manually and verified
by a trained clinician. Lesions were detected in each MS subject within the
region of interest. APT asymmetry was calculated by integrating the difference
between 3.2 to 3.8 ppm and -3.2 to -3.8 ppm. For AREX, we inverted the Z
spectrum generated by the CEST experiment, then multiplied by the R1 map
generated by our multi-flip angle sequence. Results
Figure 1 shows maps for a representative healthy
control (top) compared to an MS patient (bottom), as well as their respective Z
spectra (right). The healthy control shows a more homogeneous contrast in both
metrics when compared to the MS subject. The black arrows indicate the location
of 2 lesions within the white matter (WM) of the MS patient. In the APT map, we
see regions of decreased values in the areas associated with the lesions.
However, in the AREX map, the lesion in the dorsal column shows a stark
decrease, while the lesion in the lateral column shows a slight increase. In the
Z spectrum comparing the healthy control and MS patient, on the positive side
of the spectrum, where the CEST contribution lies, we see very little
difference between subjects. This is not the case on the negative side, where
the MT component would have the most influence. Here we see a large difference
in the two subjects, most likely due to the demyelination occurring in the MS patient.
Figure 2 compares the mean indices within three tissue types: healthy control WM,
the normal-appearing WM and MS patients, and lesions. Overall, significant differences in Wilcoxon
rank-sum tests were found between APT asymmetry of healthy control WM and
lesion (p <0.05), and normal appearing WM and lesion (p<0.05).Discussion
Our results suggest that the
sensitivity of uncorrected CEST metrics, such as APT asymmetry, to lesion
tissue is confounded by contributors such as the macromolecular component and changes
to longitudinal relaxation, even in this cohort of low-disability patients. We
suspect that the uniform decrease seen in our APT asymmetry values within
lesions is primarily due to the demyelination influencing the macromolecular
contribution. Once these contributions are removed and only the CEST component is
present, lesions have a much more heterogeneous presentation. We hypothesize
that the AREX metric gives a much more valid estimation of CEST contributions,
despite this nonuniformity, and may reflect the activity of the lesion. In the
future, we plan to investigate the correlation between AREX and Gadolinium
enhancement to identify if AREX can be a valid measurement of lesion activity. Acknowledgements
We
thank our study participants and VUIIS MRI technologists. Funding: Conrad
Hilton Foundation (SAS), National MS Society (SAS), NIH/NINDS 1R01NS109114-01
(SAS), and NIBIB T32EB021937.References
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