Relaxation-Compensated Chemical Exchange Saturation Transfer MRI in the Brain at 7T: Application in Relapsing-Remitting Multiple Sclerosis

Abstract

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) can probe tissue biochemistry in vivo with high resolution and sensitivity without requiring exogenous contrast agents. Applying CEST MRI at ultrahigh field provides advantages of increasing spectral resolution and improving sensitivity to metabolites with faster proton exchange rates such as glutamate, a critical neurotransmitter in the brain. Prior magnetic resonance spectroscopy and CEST MRI studies have revealed altered regulation of glutamate in patients with multiple sclerosis (MS). While CEST imaging facilitates new strategies for investigating the pathology underlying this complex and heterogeneous neurological disease, CEST signals are contaminated or diluted by concurrent effects (e.g., semi-solid magnetization transfer (MT) and direct water saturation) and are scaled by the T₁ relaxation time of the free water pool which may also be altered in the context of disease. In this study of 20 relapsing-remitting MS patients and age- and sex-matched healthy volunteers, glutamate-weighted CEST data were acquired at 7.0 T. A Lorentzian fitting procedure was used to remove the asymmetric MT contribution from CEST z-spectra, and the apparent exchange-dependent relaxation (AREX) correction was applied using an R₁ map derived from an inversion recovery sequence to further isolate glutamate-weighted CEST signals from concurrent effects. Associations between AREX and cognitive function were examined using the Minimal Assessment of Cognitive Function in MS battery. After isolating CEST effects from MT, direct water saturation, and T₁ effects, glutamate-weighted AREX contrast remained higher in gray matter than in white matter, though the difference between these tissues decreased. Glutamate-weighted AREX in normal-appearing gray and white matter in MS patients did not differ from healthy gray and white matter but was significantly elevated in white matter lesions. AREX in some cortical regions and in white matter lesions correlated with disability and measures of cognitive function in MS patients. However, further studies with larger sample sizes are needed to confirm these relationships due to potential confounding effects. The application of MT and AREX corrections in this study demonstrates the importance of isolating CEST signals for more specific characterization of the contribution of metabolic changes to tissue pathology and symptoms in MS.

Keywords: apparent exchange-dependent relaxation (AREX); chemical exchange saturation transfer (CEST); cognition; glutamate; metabolic imaging; multiple sclerosis; ultrahigh field.

Figure 1

A representative anatomical MP2RAGE image, CEST image (individual dynamic at Δω = −5.0 ppm normalized to the unsaturated S₀ data), tissue segmentation, and R₁ map are shown for a healthy volunteer (top: 35-year-old female) and a patient with MS (bottom: 46-year-old female, EDSS = 2, duration = 1 year). All image volumes were registered to the 10 mm-thick CEST slice.

Figure 2

(A) A 2-pool Lorentzian model was fit to the measured z-spectrum (Z) in each voxel and the resulting MT Lorentzian component (Z_LorentzMT) is shown for representative voxels in different tissues. (B) The amplitude of the MT Lorentzian line shape at −2.4 ppm shows little to no MT contribution in CSF and the largest MT contribution in white matter. (C,D) Raw z-spectra and inverted z-spectra without the MT correction show differences due to broad MT saturation effects. (E,F) After subtracting the MT baseline, differences between gray and white matter z-spectra and inverted spectra due to MT effects are minimized. Example spectra shown are from a patient with MS (46-year-old male, EDSS = 4, duration = 16 years).

Figure 3

MTR asymmetry, MTR_Rex, and AREX maps for Δω = 3.0 ppm are shown with and without the MT baseline removal for a representative healthy volunteer (rows 1 and 2: 35-year-old female) and a patient with MS (rows 3 and 4: 26-year-old female, EDSS = 0, duration = 6 years). Before removing the MT contribution, there is a greater difference between GM and WM for all 3 CEST indices (rows 1 and 3). After removal of the asymmetric effect, CEST contrast shifts toward positive values and the difference between GM and WM is reduced but still present (rows 2 and 4). Lesions are outlined in the patient images.

Figure 4

AREX spectra and histograms for AREX contrast at Δω=3.0 ppm are shown without (top row) and with (bottom row) MT baseline removal for a representative patient with MS (46-year-old male, EDSS = 4, duration = 16 years). Before removing the MT contribution, there is a greater difference between GM and WM and the majority of the AREX values are negative. After removal of the asymmetric MT effect, AREX contrast shifts more toward positive values and the difference between GM and WM is reduced, but slightly higher AREX in GM remains as expected. After correction for MT effects, AREX in cortical lesions overlaps with that in GM, but WM lesions still show a slight increase in AREX relative to WM.

Figure 5

Mean values of MTRasym_Corr, MTR_RexCorr, AREX_Corr, and R₁ are shown for WM, GM, WM lesions, and cortical lesions for group comparisons. AREX_Corr values are also shown for each cortical GM region. WM lesion values differ significantly from normal-appearing WM in MS patients and from healthy control (HC) WM for all CEST-derived indices and for R₁. Significant differences between groups in GM and cortical lesions are only present in R₁. No group differences are significant for AREX_Corr within cortical regions. All indices differ significantly between GM and WM within each group. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 6

Matrix of Spearman rho values for partial correlations between clinical and cognitive variables and mean R₁ and AREX values in patients with MS. Age, education, and sex were included as covariates. Correlations are highlighted in yellow if p < 0.05. SDMT = Symbol Digit Modalities Test; BVMT-R = Brief Visuospatial Memory Test-Revised; CVLT-II = California Verbal Learning Test, 2nd edition; PASAT = Paced Auditory Serial Addition Test; D-KEFS ST = Delis-Kaplan Executive Function System Sorting Test; COWAT = Controlled Oral Word Association Test.