Glutamate-sensitive imaging and evaluation of cognitive impairment in multiple sclerosis

O’Grady, Kristin P.; Dula, Adrienne N.; Lyttle, Bailey D.; Thompson, Lindsey; Conrad, Benjamin; Box, Bailey A.; McKeithan, Lydia; Pawate, Siddharama; Bagnato, Francesca; Landman, Bennett A.; Newhouse, Paul; Smith, Seth A.

doi:10.1177/1352458518799583

Cited by 22 publications

(29 citation statements)

References 40 publications

(74 reference statements)

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“…GluCEST has since been applied to the study of several neurological disorders, including Alzheimer's disease, 10,11 Huntington's disease, 12 epilepsy, 13 psychosis spectrum, 14 dopamine deficiency, 15 and multiple sclerosis. 16,17 One potential confounding factor in interpreting GluCEST results is the signal contribution from protein lysine amine protons, which also resonate close to 3 ppm and undergo fast exchange with water. 18,19 However, such potential contributions have been overlooked in previous GluCEST studies.…”

Section: Introductionmentioning

confidence: 99%

Towards the molecular origin of glutamate CEST (GluCEST) imaging in rat brain

Cui

2019

Magnetic Resonance in Med

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Purpose: Chemical exchange saturation transfer (CEST) signals at 3 ppm acquired with high irradiation powers, termed GluCEST, have been suggested as an indicator of glutamate in neural systems. However, amines in proteins may also contribute to the GluCEST signal, but they have been ignored in previous studies. This study aims to investigate the molecular origins and specificity of GluCEST signal in rat brain. Methods: Dialysis was used to selectively remove small molecules, such as glutamate and other metabolites, from tissue homogenates prepared from rat brain. This approach allowed the specific influence of proteins on GluCEST to be measured. Clean CEST effects were also quantified by a 2-step analysis, which first used a fitting approach to quantify the asymmetric magnetization transfer effect and an inverse subtraction to remove it, and then combined an apparent exchange-dependent relaxation method with asymmetric analysis to remove the direct water saturation and T 1 weighting. Results: The removal of glutamate and other small metabolites by dialysis decreases the GluCEST signal by approximately 24%, indicating that a major contributor to GluCEST in the brain is amines in proteins under our experimental conditions. Conclusion: Data from in vivo GluCEST measurements should be interpreted with caution, especially in disorders in which changes in the content or conformation of proteins are expected.

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Section: Introductionmentioning

confidence: 99%

Towards the molecular origin of glutamate CEST (GluCEST) imaging in rat brain

Cui

2019

Magnetic Resonance in Med

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“…Unfortunately, neither of these methods allows validation of the MT effect with existing qMT literature; there is either no parameter to investigate the MT effect (MTR asym ) or the parameter describing the MT effect is derived using different methodologies (AREX), meaning it has a different parameter range than what has already been established in the literature. By harmonizing the estimates derived from a CEST analysis with established methods in the qMT literature, we can better correlate the structural (qMT) and chemical (CEST) environments, particularly in pathologies such as multiple sclerosis, and cancer …”

Section: Discussionmentioning

confidence: 99%

“…Importantly, the magnitude of the attenuation of the water signal is related to both the chemical exchange rate, which has been correlated with pH, and the concentration of the exchanging solute. CEST imaging is thus a unique imaging technique which can be used to investigate how pathology perturbs the underlying biochemistry and pH balance in the body and has been used to study pathologies such as stroke, cancer, and multiple sclerosis …”

Section: Introductionmentioning

confidence: 99%

Does the magnetization transfer effect bias chemical exchange saturation transfer effects? Quantifying chemical exchange saturation transfer in the presence of magnetization transfer

Smith

Ray

Larkin

et al. 2020

Magnetic Resonance in Med

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Purpose: Chemical exchange saturation transfer (CEST) is an MRI technique sensitive to the presence of low-concentration solute protons exchanging with water. However, magnetization transfer (MT) effects also arise when large semisolid molecules interact with water, which biases CEST parameter estimates if quantitative models do not account for macromolecular effects. This study establishes under what conditions this bias is significant and demonstrates how using an appropriate model provides more accurate quantitative CEST measurements. Methods: CEST and MT data were acquired in phantoms containing bovine serum albumin and agarose. Several quantitative CEST and MT models were used with the phantom data to demonstrate how underfitting can influence estimates of the CEST effect. CEST and MT data were acquired in healthy volunteers, and a twopool model was fit in vivo and in vitro, whereas removing increasing amounts of CEST data to show biases in the CEST analysis also corrupts MT parameter estimates. Results: When all significant CEST/MT effects were included, the derived parameter estimates for each CEST/MT pool significantly correlated (P < .05) with bovine serum albumin/agarose concentration; minimal or negative correlations were found with underfitted data. Additionally, a bootstrap analysis demonstrated that significant biases occur in MT parameter estimates (P < .001) when unmodeled CEST data are included in the analysis. Conclusions: These results indicate that current practices of simultaneously fitting both CEST and MT effects in model-based analyses can lead to significant bias in all 1360 | SMITH eT al. | THEORYSimilar to the analytical solution for a two-pool model described in the various papers by Yarnykh et al 36,37 and Zhou et al,4,38 we parameter estimates unless a sufficiently detailed model is utilized. Therefore, care must be taken when quantifying CEST and MT effects in vivo by properly modeling data to minimize these biases. K E Y W O R D S amide, CEST, MT, NOE, qMT, quantitative 1366 | SMITH eT al. F I G U R E 3 Semisolid (PSR), and amide and NOE (MTR*) maps for the variable agarose phantom experiment. The top row illustrates the full, four-pool model estimation, the middle displays the fixed-qMT estimation, and the bottom row shows the same fit assuming the NOE and MT pools are a single pool, similar to Tee et al 34 F I G U R E 4 Semisolid (PSR), and amide and NOE (MTR*) maps for the variable BSA phantom experiment. The top row illustrates the full, four-pool model estimation, the middle displays the fixed-qMT estimation, and the bottom row shows the same fit assuming the NOE and MT pools are a single pool, similar to similar to Tee et al 34

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“…20,22 Glutamate (Glu)-sensitive CEST MRI (with S sat /S 0 set at 3.0 ppm) was reported to have utility as an imaging biomarker for GM pathology. 23 In fact, other MS-or inflammationassociated metabolites, including creatine (Cr) 10,24 and myo-inositol (MI), 25 could also be detected by CEST MRI. Besides, the pH of the tissue microenvironment affects the exchange rate, and therefore could also be sensed by CEST.…”

Section: Introductionmentioning

confidence: 99%

CEST MRI with distribution‐based analysis for assessment of early stage disease activity in a mouse model of multiple sclerosis: An initial study

et al. 2019

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Imaging biomarkers that can detect pathological changes at an early stage of multiple sclerosis (MS) may allow earlier therapeutic intervention with an improved outcome. Using a mouse model of MS, termed as experimental autoimmune encephalomyelitis (EAE), we performed chemical exchange saturation transfer (CEST) MRI at a very early stage before symptom onset (6 days post‐induction) for assessment of changes in tissues that appear “normal” with conventional MRI. The collected CEST Z‐spectra signals (Ssat/S0) were analyzed using a histogram‐guided method to determine the contributions from various offset frequencies. Histogram analysis showed that EAE mice exhibit a more heterogeneous distribution with lower peak heights in the hindbrain compared with naïve mice at saturation offsets of 1 and 2 ppm. At these two offsets, both the mean Ssat/S0 and the mean MTRasym values in the cerebellum and brain stem are significantly different between EAE and naïve mice (P < 0.05). Immunofluorescent staining validated the presence of neuroinflammation, with IBA1‐positive cells detected throughout the hindbrain including the cerebellum and brain stem. Follow‐up MRI at the symptom onset (score = 1.5–2.5, 13 days post‐induction) confirmed gadolinium‐enhanced periventricular lesions. CEST Z‐spectra signals also changed by this time. The proposed three‐level histogram‐oriented analysis is simple to execute and robust for detecting subtle changes in Z‐spectra signals, which does not require a priori knowledge of damage locations or contributing offset components. CEST MRI signals at 1 and 2 ppm were sensitive to the subtle pathological changes at an early stage in EAE mice, and have potential as novel imaging biomarkers complementary to functional and physiological MRI measures.

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Glutamate-sensitive imaging and evaluation of cognitive impairment in multiple sclerosis

Cited by 22 publications

References 40 publications

Towards the molecular origin of glutamate CEST (GluCEST) imaging in rat brain

Towards the molecular origin of glutamate CEST (GluCEST) imaging in rat brain

Does the magnetization transfer effect bias chemical exchange saturation transfer effects? Quantifying chemical exchange saturation transfer in the presence of magnetization transfer

CEST MRI with distribution‐based analysis for assessment of early stage disease activity in a mouse model of multiple sclerosis: An initial study

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