Mechanism and quantitative assessment of saturation transfer for water‐based detection of the aliphatic protons in carbohydrate polymers

Abstract

Purpose: CEST MRI experiments of mobile macromolecules, for example, proteins, carbohydrates, and phospholipids, often show signals due to saturation transfer from aliphatic protons to water. Currently, the mechanism of this nuclear Overhauser effect (NOE)-based transfer pathway is not completely understood and could be due either to NOEs directly to bound water or NOEs relayed intramolecularly via exchangeable protons. We used glycogen as a model system to investigate this saturation transfer pathway in sugar polymer solution. Methods: To determine whether proton exchange affected saturation transfer, saturation spectra (Z-spectra) were measured for glycogen solutions of different pH, D 2 O/H 2 O ratio, and glycogen particle size. A theoretical model was derived to analytically describe the NOE-based signals in these spectra. Numerical simulations were performed to verify this theory, which was further tested by fitting experimental data for different exchange regimes. Results: Signal intensities of aliphatic NOEs in Z-spectra of glycogen in D 2 O solution were influenced by hydroxyl proton exchange rates, whereas those in H 2 O were not. This indicates that the primary transfer pathway is an exchange-relayed NOE from these aliphatic protons to neighboring hydroxyl protons, followed by the exchange to water protons. Experimental data for glycogen solutions in D 2 O and H 2 O could be analyzed successfully using an analytical theory derived for such relayed NOE transfer, which was further validated using numerical simulations with the Bloch equations. Conclusion: The predominant mechanism underlying aliphatic signals in Z-spectra of mobile carbohydrate polymers is intramolecular relayed NOE transfer followed by proton exchange.

Whole‐brain amide CEST imaging at 3T with a steady‐state radial MRI acquisition

“…(w∕2 residual saturation transfer background signal remained over a broad frequency range even at pH 6 (purple arrow in Figure 2B). As expected for exchange-relayed NOEs and shown previously in phantoms, 59,60 the aliphatic rNOE at the opposite frequency range also demonstrated pH dependence. The Guan effect size first increased when lowering pH from 7.5 to 7, and then it stabilized and decreased with further reduction of pH, which was consistent with previous observations.…”

“…In contrast to a recent creatine validation study 45,63 using a knockout mouse model, validation of the amideCEST signal in the brain Z-spectrum cannot be easily achieved by removing the mobile proteins in tissue. However, we could exploit the property that CEST signals from amide and Guan protons are strongly pH-dependent, whereas rNOEs have weak pH dependence and MTC is insensitive to pH 60,64 in the physiological range. As demonstrated by the egg white model system (Figure 2), the amide CEST signal is visible at 3T with a peak around 3.5 ppm.…”

Role of chemical exchange on the relayed nuclear Overhauser enhancement signal in saturation transfer MRI

“…Recently, Murase published numerical analyses of the Z‐spectra in the presence of multiple exchanging pools which can be applied to exchange‐relayed NOE 47 . Zhou et al has reported a simplified analytical solution for relayed NOE 33 and showed that the pH‐sensitivity of the rNOE signal is determined by whether k CE is much faster than k NOE . This could lead to a conclusion that the rNOE signal observed in mobile protein would be independent of pH at physiological conditions, because even the slow exchanging amide (30 s −1 ) 10 is about an order of magnitude faster than the NOE transfer rate (2‐3 s −1 ) 30,39 .…”

“…Many previous studies have suggested that relayed NOE should be the dominant pathway for mobile proteins 31,32 ; thus, it is generally assumed that relayed NOE applies to in vivo brain CEST studies. A very recent study of glycogen has also suggested that the NOE signal may also be relayed in some carbohydrate macromolecules 19,33 …”

Magnetization Transfer Ratio in Lower Limbs of Late Onset Pompe Patients Correlates With Intramuscular Fat Fraction and Muscle Function Tests

“…We observed lower MTR values in symptomatic patients compared with non-symptomatic patients and controls. To fully understand the biophysical origins of MT in Pompe muscle, a more detailed quantitative MT study is warranted that takes into account pool sizes, T1, lipids, and multiple transfer magnetization transfer mechanisms ( 5 , 19 ).…”