Amide Proton Research Articles

Amide proton transfer imaging in rats after heatstroke.

Metabolic acidosis is the most common acid-base change following heatstroke. This study aimed to evaluate the internal environment changes caused by heatstroke using amide proton transfer (APT) imaging. Nineteen male Sprague-Dawley rats were randomly divided into the control group (CTRL, n = 7) and the heatstroke group (HS, n = 12). All the rats underwent a 7.0-T MRI, which included T2-weighted imaging (T2WI) and APT imaging. Subsequently, the surviving HS group rats repeated the same magnetic resonance scanning after 25 days and were designated as the follow-up group (FU, n = 7). APT values were measured in the hippocampus, thalamus, and corpus callosum. The APT values of the three groups were statistically analyzed and found in the hippocampus (CTRL vs. HS, P = 0.011; CTRL vs. FU, P = 0.078; HS vs. FU, P = 0.484; η ² = 0.276), left thalamus (CTRL vs. HS, P = 0.004; CTRL vs. FU, P = 0.014; HS vs. FU, P = 0.822; η ² = 0.331), right thalamus (CTRL vs. HS, P = 0.003; CTRL vs. FU, P = 0.015; HS vs. FU P = 0.769; η ² = 0.336), and corpus callosum (CTRL vs. HS, P < 0.001; CTRL vs. FU, P = 0.005; HS vs. FU, P = 0.523; η ² = 0.437). APT imaging can be a viable and practical tool for diagnosing heatstroke and monitoring its progression.

Role of amide proton transfer imaging in maximizing tumor resection in malignant glioma: a possibility to take the place of 11C-methionine positron emission tomography.

Amide proton transfer (APT) imaging has been proposed as a technique to assess tumor metabolism. However, the relationship between APT imaging and other quantitative modalities including positron emission tomography (PET) has not been investigated in detail. This study aimed to evaluate the clinical usefulness of APT imaging in determining the metabolic status of malignant glioma and to compare findings with those from 11C-methionine (Met)-PET. This research analyzed APT imaging data from 20 consecutive patients with malignant glioma treated between January 2022 and July 2023. Patients underwent tumor resection and correlations between tumor activity and intensity of APT signal were investigated. We also compared 11C-Met-PET and APT imaging for the same regions of the perifocal tumor invasion area. Clear, diagnostic APT images were obtained from all 20 cases. Mean APT intensity (APTmean) was significantly higher in the glioblastoma (GBM), IDH wild type group (27.2 ± 12.8%) than in other gliomas (6.0 ± 4.7%; p < 0.001). The cut-off APTmean to optimally distinguish between GBM and other malignant gliomas was 12.8%, offering 100% sensitivity and 83.3% specificity. These values for APTmean broadly matched the tumor-to-contralateral normal brain tissue ratio from 11C-Met-PET analysis (r = 0.66). The APT signal was also observed in the gadolinium non-contrast region on T1-weighted imaging, appearing to reflect the surrounding tumor-infiltrated area. APT imaging can be used to evaluate the area of tumor invasion, similar to 11C-Met-PET. APT imaging revealed low invasiveness in patients and was useful in preoperative planning for tumor resection, facilitating maximum tumor resection including the tumor invasive area.

Multi-parametric MRI assessment of melatonin regulating the polarization of microglia in rats after cerebral ischemia/reperfusion injury

ObjectivesMulti-parametric magnetic resonance imaging (MRI) can provide comprehensive and valuable information for precise diagnosis and treatment evaluation of a number of diseases. In this study, the neuroprotective effects of melatonin (Mel) on a rat model of cerebral ischemia/reperfusion injury (CIRI) were assessed by multi-parametric MRI combined with histopathological techniques for longitudinal monitoring of the lesion microenvironment. MethodsSixty Sprague Dawley (SD) rats were randomly divided into three groups: the Sham, CIRI and CIRI + Mel groups. At multiple time points after ischemia, MRI scanning was performed on a 7.0 Tesla MRI scanner. Multi-parametric MRI includes T2-weighted imaging (T2WI), diffusion weighted imaging (DWI), and chemical exchange saturation transfer (CEST)-MRI. CEST effects were calculated by the Lorentzian difference method, 3.5 ppm indicates amide protons of mobile proteins/peptide (Amide-CEST) and 2.0 ppm indicates amine protons (Guan-CEST). Multiple histopathological techniques were used to examine the histopathological changes and explore the therapeutic effects of Mel. ResultsT2WI and DWI-MRI could localize the infarct foci and areas in CIRI rats, which was further validated by staining, 2, 3, 5-triphenyl tetrazolium chloride (TTC) staining, hematoxylin and eosin (H&E) staining, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL) staining. After Mel treatment, T2WI and DWI-MRI showed smaller infarct volume, and neurons displayed improved morphology with less apoptosis rates. Notably, Amide-CEST and Guan-CEST signal decreased as early as 2 h after CIRI (all P <0.001), reflecting the change of pH after ischemia. After Mel treatment, both Amide-CEST and Guan-CEST signal increased in ischemic cortex and striatum compared with control group (all P < 0.001). The immunofluorescence staining and western blotting analysis suggested the expression of M2 microglia increased after Mel treatment; While，after Mel treatment the inflammatory factor interleukin-1β (IL-1β) decreased compared with control CIRI rats. ConclusionsMulti-parametric MRI was shown to be an effective method to monitor the brain damage in a rat model of CIRI and assess the therapeutic effects of Mel treatment. Amide-CEST and Guan-CEST were especially sensitive to the changes in brain microenvironment during the early stage after CIRI. Furthermore, the neuroprotective effect of Mel treatment is associated with its promotion of the microglia polarized to M2 type in CIRI rats.

Effects of Breathing Patterns on Amide Proton Transfer MRI in the Kidney: A Preliminary Comparative Study in Healthy Volunteers and Patients With Tumors.

The amide proton transfer-weighted (APTw) imaging for kidney diseases is important. However, the breathing patterns on APTw imaging remains unexplored. This study aimed to investigate the effects of intermittent breath-hold (IBH) and free breathing (FB) on renal 3D-APTw imaging. Healthy volunteers were enrolled prospectively, and renal clear cell carcinoma (RCCC) patients were included retrospectively. 58 healthy volunteers and 10 RCCC patients. 3-T, turbo spin echo, and fast field echo. 3D-APTw imaging was scanned using the IBH and FB methods in volunteers and using the IBH method in RCCC patients. The image quality was evaluated by three observers according to the 5-point Likert scale. Optimal images rated at three points or higher were used to measure the APT values. The measurement repeatability was assessed using the intraclass correlation coefficient (ICC) and the Bland-Altman plot. The APT values were analyzed using McNemar's test, one-way analysis of variance, and t test. 50 healthy volunteers and 8 RCCC patients were enrolled. Renal 3D-APTw imaging using the IBH method revealed a higher success rate (88% vs 78%). The ICCs were excellent in the IBH group (ICCs > 0.74) and were good in the FB group (ICCs < 0.74). No significant differences in the APT values among various zones using the IBH (P = 0.263) or FB method (P = 0.506). The mean APT value using the IBH method (2.091% ± 0.388%) was slightly lower than the FB method (2.176% ± 0.292%), but no significant difference (P = 0.233). The APT value of RCCC (4.832% ± 1.361%) was considerably higher than normal renal using the IBH method. The study demonstrated that the IBH method substantially increased the image quality of renal 3D-APTw imaging. Furthermore, APT values may vary between normal and tumor tissues. 2 TECHNICAL EFFICACY: Stage 2.

Predicting histopathological types and molecular subtype of breast tumors: A comparative study using amide proton transfer-weighted imaging, intravoxel incoherent motion and diffusion kurtosis imaging

PurposeTo evaluate the predictive performance of multiparameter and histogram features derived from amide proton transfer-weighted imaging (APTWI), intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) for histopathological types of breast tumors. MethodsRegion of interest (ROI) was delineated by outlining the largest slice of the tumor on the false-color images of the DKI, IVIM and APTWI parameters, and extracted the histogram features. Receiver operating characteristic (ROC) curve was used to evaluate the performance of parameters in predicting benign and malignant breast lesions, molecular prognostic biomarkers, lymph node status, and subtypes of breast lesions. The Spearman correlation coefficient was used to determine the correlations between each parameter and clinical-pathological factors. ResultsAll 52 breast lesions were enrolled in this prospective study, including 8 benign lesions and 44 breast cancers. To diagnose malignant and benign breast lesions, the value of APT (min) performed best, with the AUC reaching 0.983. According to the different imaging methods, the APTWI performed best. To predict the positive status of ER, PR, Ki67, the value of Dapp (uniformity), Dapp (uniformity), f (entropy) performed best, with the AUC values reaching 0.743, 0.770, 0.848, respectively. For the identification of Luminal B, HER2-enriched, and TNBC breast cancers, Kapp (max), f (kurtosis), and Dapp (uniformity) performed best, with AUC values reaching 0.679, 0.826, 0.771, respectively. ConclusionThis study found the APTWI, IVIM and DKI parameters could diagnose breast cancer. The histogram features of DKI and IVIM, based on tumor heterogeneity, may help to predict breast cancer subtypes.

The added value of relative amide proton transfer (rAPT) to advanced multiparametric MR imaging for brain glioma characterization

BackgroundDifferentiation between the grades of brain gliomas is a crucial step in the management of patients. The gold standard technique for grading is biopsy but MR imaging may play a more substantial role as a non-invasive method by using promising molecular sequences. Our purpose was to assess the added value of the relative amide proton transfer signal [rAPT] to advanced multiparametric MRI protocol.MethodsWe enrolled a pathologically confirmed 102 patients with low-grade glioma [n = 38] and high-grade glioma [n = 64] who underwent advanced multiparametric MRI protocol on the same scanner. The protocol included anatomic, diffusion, MRS, and perfusion sequences. The newly added sequence was Amide proton transfer. The rAPT values of all lesions were investigated by two neuroradiologists to assess the inter-rater agreement of using interclass correlation coefficient [ICC]. HGGs demonstrated significantly higher mean values of relative cerebral blood volume (rCBV), choline to creatine ratio (Cho/cr), and rAPT with lower Apparent diffusion coefficient (ADC) values compared to LGGs. ROC analyses revealed medium to high diagnostic performance with an AUC of 0.941 for rAPT, 0.907 for mean ADC, and 0.906 for rCBV. Discriminant function analysis of two models, the first one included mean ADC, rCBV, and Cho/Cr, while in the second Model, we added rAPT to them. Model two demonstrated higher accuracy and a significant difference in the AUC after adding the rAPT. The inter-rater agreement was reasonable (ICC 0.61).ConclusionsrAPT adds significant value to multiparametric MRI for distinguishing LGG from HGG.

Predicting Preoperative Pathologic Grades of Bladder Cancer Using Intravoxel Incoherent Motion and Amide Proton Transfer-Weighted Imaging

To investigate the predictive value of intravoxel incoherent motion (IVIM) combined with amide proton transfer-weighted (APTw) imaging for the preoperative grading of bladder cancer (BC). A total of 69 patients with histopathologically confirmed BC underwent diffusion-weighted imaging (DWI), IVIM, and APTw imaging at 3.0T MRI. Two radiologists independently measured the mean apparent diffusion coefficient (ADC) in DWI, true diffusion coefficient (D), perfusion-related pseudo-diffusion coefficient (D*), and perfusion fraction (f) in IVIM, and APTw values, respectively. The areas under the receiver operating characteristic curves (AUCs) were utilized to compare the diagnostic efficacy of these single and combined quantitative parameters. ADC and D values of low-grade BC were significantly higher than those of high-grade BC ([1.42±0.20×10-3 mm2/s] vs. [1.09±0.25×10-3 mm2/s] and [1.24±0.24×10-3 mm2/s] vs. [0.89±0.18×10-3 mm2/s], respectively; all P<0.001). Opposite patterns were found for APTw ( [1.53±0.42]% vs. [2.38±0.71]%, P<0.001). The ROC curves indicated that the combination of D and APTw values could distinguish low- from high-grades of BC with the highest predictive efficacy (AUC = 0.96), as well as a significant difference compared to those by ADC, D, and APTw values separately(AUC = 0.84, 0.88, 0.85, respectively; all P<0.05). IVIM combined with APTw imaging significantly improved the predictive efficacy of assessing low-and high-grade BC compared to the individual parameters on their own, providing an effective non-invasive method for clinical preoperative prediction of BC grading.

Fast and robust pulsed chemical exchange saturation transfer (CEST) MRI using a quasi-steady-state (QUASS) algorithm at 3 T

Chemical exchange saturation transfer (CEST) has emerged as a powerful technique to image dilute labile protons. However, its measurement depends on the RF saturation duration (Tsat) and relaxation delay (Trec). Although the recently developed quasi-steady-state (QUASS) solution can reconstruct equilibrium CEST effects under continuous-wave RF saturation, it does not apply to pulsed-CEST MRI on clinical scanners with restricted hardware or specific absorption rate limits. This study proposed a QUASS algorithm for pulsed-CEST MRI and evaluated its performance in muscle CEST measurement. An approximated expression of a steady-state pulsed-CEST signal was incorporated in the off-resonance spin-lock model, from which the QUASS pulsed-CEST effect was derived. Numerical simulation, creatine phantom, and healthy volunteer scans were conducted at 3 T. The CEST effect was quantified with asymmetry analysis in the simulation and phantom experiments. CEST effects of creatine, amide proton transfer, phosphocreatine, and combined magnetization transfer and nuclear Overhauser effects were isolated from a multi-pool Lorentzian model in muscles. Apparent and QUASS CEST measurements were compared under different Tsat/Trec and duty cycles. Paired Student's t-test was employed with P < 0.05 as statistically significant. The simulation, phantom, and human studies showed the strong impact of Tsat/Trec on apparent CEST measurements, which were significantly smaller than the corresponding QUASS CEST measures, especially under short Tsat/Trec times. In comparison, the QUASS algorithm mitigates such impact and enables accurate CEST measurements under short Tsat/Trec times. In conclusion, the QUASS algorithm can accelerate robust pulsed-CEST MRI, promising the efficient detection and evaluation of muscle diseases in clinical settings.

Reproducibility of APT-weighted CEST-MRI at 3T in healthy brain and tumor across sessions and scanners

Amide proton transfer (APT)-weighted chemical exchange saturation transfer (CEST) imaging is a recent MRI technique making its way into clinical application. In this work, we investigated whether APT-weighted CEST imaging can provide reproducible measurements across scan sessions and scanners. Within-session, between-session and between scanner reproducibility was calculated for 19 healthy volunteers and 7 patients with a brain tumor on two 3T MRI scanners. The APT-weighted CEST effect was evaluated by calculating the Lorentzian Difference (LD), magnetization transfer ratio asymmetry (MTRasym), and relaxation-compensated inverse magnetization transfer ratio (MTRREX) averaged in whole brain white matter (WM), enhancing tumor and necrosis. Within subject coefficient of variation (COV) calculations, Bland–Altman plots and mixed effect modeling were performed to assess the repeatability and reproducibility of averaged values. The group median COVs of LD APT were 0.56% (N = 19), 0.84% (N = 6), 0.80% (N = 9) in WM within-session, between-session and between-scanner respectively. The between-session COV of LD APT in enhancing tumor (N = 6) and necrotic core (N = 3) were 4.57% and 5.67%, respectively. There were no significant differences in within session, between session and between scanner comparisons of the APT effect. The COVs of LD and MTRREX were consistently lower than MTRasym in all experiments, both in healthy tissues and tumor. The repeatability and reproducibility of APT-weighted CEST was clinically acceptable across scan sessions and scanners. Although MTRasym is simple to acquire and compute and sufficient to provide robust measurement, it is beneficial to include LD and MTRREX to obtain higher reproducibility for detecting minor signal difference in different tissue types.

Accelerating CEST imaging using a model-based deep neural network with synthetic training data.

To develop a model-based deep neural network for high-quality image reconstruction of undersampled multi-coil CEST data. Inspired by the variational network (VN), the CEST image reconstruction equation is unrolled into a deep neural network (CEST-VN) with a k-space data-sharing block that takes advantage of the inherent redundancy in adjacent CEST frames and 3D spatial-frequential convolution kernels that exploit correlations in the x-ω domain. Additionally, a new pipeline based on multiple-pool Bloch-McConnell simulations is devised to synthesize multi-coil CEST data from publicly available anatomical MRI data. The proposed network is trained on simulated data with a CEST-specific loss function that jointly measures the structural and CEST contrast. The performance of CEST-VN was evaluated on four healthy volunteers and five brain tumor patients using retrospectively or prospectively undersampled data with various acceleration factors, and then compared with other conventional and state-of-the-art reconstruction methods. The proposed CEST-VN method generated high-quality CEST source images and amide proton transfer-weighted maps in healthy and brain tumor subjects, consistently outperforming GRAPPA, blind compressed sensing, and the original VN. With the acceleration factors increasing from 3 to 6, CEST-VN with the same hyperparameters yielded similar and accurate reconstruction without apparent loss of details or increase of artifacts. The ablation studies confirmed the effectiveness of the CEST-specific loss function and data-sharing block used. The proposed CEST-VN method can offer high-quality CEST source images and amide proton transfer-weighted maps from highly undersampled multi-coil data by integrating the deep learning prior and multi-coil sensitivity encoding model.

Assignment of the disordered, proline-rich N-terminal domain of the tumour suppressor p53 protein using 1HN and 1Hα-detected NMR measurements

Protein p53 is mostly known for playing a key role in tumour suppression, and mutations in the p53 gene are amongst the most frequent genomic events accompanying oncogenic transformation. Continuous research is conducted to target disordered proteins/protein regions for cancer therapy, for which atomic level information is also necessary. The disordered N-terminal part of p53 contains the transactivation and the proline-rich domains—which besides being abundant in proline residues—contains repetitive Pro-Ala motifs. NMR assignment of such repetitive, proline-rich regions is challenging due to the lack of amide protons in the 1HN-detected approaches, as well as due to the small chemical shift dispersion. In the present study we perform the full assignment of the p531–100 region by applying a combination of 1HN- and 1Hα-detected NMR experiments. We also show the increased information content when using real-time homo- and heteronuclear decoupled acquisition schemes. On the other hand, we highlight the presence of minor proline species, and using Pro-selective experiments we determine the corresponding cis or trans conformation. Secondary chemical shifts for (Cα–Cβ) atoms indicate the disordered nature of this region, with expected helical tendency for the TAD1 region. As the role of the proline-rich domain is yet not well understood our results can contribute to further successful investigations.

Amide proton transfer-weighted imagingand derived radiomics in the classification of adult-type diffuse gliomas.

To evaluate the utility of amide proton transfer-weighted (APTw) MRI imaging and its derived radiomics in classifying adult-type diffuse glioma. In this prospective study, APTw imaging was performed on 129 patients with adult-type diffuse gliomas. The mean APTw-related metrics (chemical exchange saturation transfer ratio (CESTR), CESTR normalized with the reference value (CESTRnr), and relaxation-compensated inverse magnetization transfer ratio (MTRRex)) and radiomic features within 3D tumor masks were extracted. APTw-radiomics models were developed using a support vector machine (SVM) classifier. Sensitivity analysis with tumor area of interest, different histogram cutoff values, and other classifiers were conducted. CESTR, CESTRnr, and MTRRex in glioblastomas were all significantly higher (p < 0.0003) than those of oligodendrogliomas and astrocytomas, with no significant difference between oligodendrogliomas and astrocytomas. The APTw-related metrics for IDH-wildtype and high-grade gliomas were significantly higher (p < 0.001) than those for the IDH-mutant and low-grade gliomas, with area under the curve (AUCs) of 0.88 for CESTR. The CESTR-radiomics models demonstrated accuracies of 84% (AUC 0.87), 83% (AUC 0.83), 90% (AUC 0.95), and 84% (AUC 0.86) in predicting the IDH mutation status, differentiating glioblastomas from astrocytomas, distinguishing glioblastomas from oligodendrogliomas, and determining high/low grade prediction, respectively, but showed poor performance in distinguishing oligodendrogliomas from astrocytomas (accuracy 63%, AUC 0.63). The sensitivity analysis affirmed the robustness of the APTw signal and APTw-derived radiomics prediction models. APTw imaging, along with its derived radiomics, presents a promising quantitative approach for prediction IDH mutation and grading adult-type diffuse glioma. Amide proton transfer-weighted imaging, a quantitative imaging biomarker, coupled with its derived radiomics, offers a promising non-invasive approach for predicting IDH mutation status and grading adult-type diffuse gliomas, thereby informing individualized clinical diagnostics and treatment strategies. • This study evaluates the differences of different amide proton transfer-weighted metrics across three molecular subtypes and their efficacy in classifying adult-type diffuse glioma. • Chemical exchange saturation transfer ratio normalized with the reference value and relaxation-compensated inverse magnetization transfer ratio effectively predicts IDH mutation/grading, notably the first one. • Amide proton transfer-weighted imaging and its derived radiomics holds potential to be used as a diagnostic tool in routine clinical characterizing adult-type diffuse glioma.

Amide proton transfer could be a surrogate imaging marker for predicting vascular cognitive impairment

BackgroudEmerging evidence suggests an overlap in the underlying pathways contributing to both cerebral small vessel disease (CSVD) and the neurodegenerative disease. Studies investigating the progression of CSVD should incorporate markers that reflect neurodegenerative lesions. ObjectiveWe aim to investigate whether Amide proton transfer (APT) can serve as a potential marker for reflecting vascular cognitive impairment (VCI). MethodParticipants were categorized into one of three groups based on their Montreal Cognitive Assessment (MoCA) scores: normal control group (age,54.9 ± 7.9; male, 52.9%), mild cognitive impairment (MCI) group (age,55.7 ± 6.9; male, 42.6%), or vascular dementia (VaD) group (age,57.6 ± 5.5, male, 58.5%). One way analysis of variance was performed to compare the demographic and APT variables between groups. Multiple logistic regression analysis wwas constructed to examine the relationship between APT values and VCI grouping. A hierarchical linear regression model was employed to examine the associations between patients' demographic factors, imaging markers, APT values, and MoCA. ResultsThe APT values of frontal white matter, hippocampus, amygdala, and thalamus were significantly different among different groups (p < 0.05). The APT values of frontal white matter, amygdala, and thalamus indicate a significant positive effect on MCI grouping. the APT values of frontal white matter, amygdala, and thalamus indicate a significant positive effect on VaD grouping. The demographic data, CSVD imaging markers and APT values can account for 5.1%, 20.1% and 27.7% of the variation in MoCA, respectively. ConclusionAPT imaging can partially identifying and predicting the occurrence of VCI.

Amide Proton Transfer-Weighted Imaging and Multiple Models Intravoxel Incoherent Motion-Based 18F-FDG PET/MRI for Predicting Progression-Free Survival in Non-Small Cell Lung Cancer.

Amide proton transfer-weighted imaging (APTWI) and multiple models intravoxel incoherent motion (IVIM) based 18F-FDG PET/MR could reflect the microscopic information of the tumor from multiple perspectives. However, its value in the prognostic assessment of non-small cell lung cancer (NSCLC) still needs to be further explored. To determine whether pretreatment APTWI, mono-, bi-, and stretched-exponential model IVIM, and 18F-FDG PET-derived parameters of the primary lesion may be associated with progression-free survival (PFS) in NSCLC. Prospective. Seventy-seven patients (mean age, 62 years, range, 20-81 years) with 37 men and 40 women were included. 3.0 T 18F-FDG PET/MRI, single shot echo planar imaging sequences for IVIM and fast spin-echo sequences with magnetization transfer pulses for APTWI. Patient clinical characteristics (age, sex, smoke, subtype, TNM stage, and surgery), PFS (chest CT every 3 months, median follow-up was 18 months, range, 4-27 months), and APTWI (MTRasym(3.5 ppm)), IVIM (ADCstand, D, D*, f, DDC, and α), and 18F-FDG PET (SUVmax, MTV, and TLG) parameters were recorded. Proportional hazards model, concordance index, calibration curve, decision curve analysis (DCA), and Log-rank test. A P value <0.05 was considered statistically significant. Histological subtype, TNM stage, MTV, D*, and MTRasym(3.5 ppm) were all independent predictors of PFS. A prediction model based on these predictors was developed with a C-index of 0.895 (95% CI: 0.839-0.951), which was significantly superior to each of the above predictors alone (C-index = 0.629, 0.707, 0.692, 0.678, and 0.558, respectively). The calibration curve and DCA indicated good consistency and clinical utility of the prediction model, respectively. Log-rank test results showed a significant difference in PFS between the high- and low-risk groups. APTWI and multiple models IVIM based 18F-FDG PET/MRI can be used for PFS assessment in NSCLC. 3 TECHNICAL EFFICACY: Stage 2.

Natalizumab Treatment for Relapsing Multiple Sclerosis Stabilises Normal-Appearing White Matter Microstructure: A One-Year Prospective Ultra-High-Field Quantitative Imaging Study.

(1) Background: Natalizumab dramatically reduces relapses and MRI inflammatory activity (new lesions and enhancing lesions) in multiple sclerosis (MS). Chemical exchange saturation transfer (CEST) MRI can explore brain tissue in vivo with high resolution and sensitivity. We investigated if natalizumab can prevent microstructural tissue damage progression measured with MRI at ultra-high field (7 Tesla) over the first year of treatment. (2) Methods: In this one-year prospective longitudinal study, patients with active relapsing-remitting MS were assessed clinically and scanned at ultra-high-field MRI at the time of their first natalizumab infusion, at 6 and 12 months, with quantitative imaging aimed to detect microstructural changes in the normal-appearing white matter (NAWM), including sequences sensitive to magnetisation transfer (MT) effects from amide proton transfer (MTRAPT) and the nuclear Overhauser effect (MTRNOE). (3) Results: 12 patients were recruited, and 10 patients completed the study. The difference in the T1 relaxation times at month 6 and month 12 of natalizumab treatment was not significant, suggesting the lack of accumulation of tissue damage, while improvements were seen in MTR (MTRAPT and MTRNOE measures) at month 12, suggesting a tissue repair effect. This paralleled the expected lack of clinical and radiological worsening of conventional MRI measures of disease activity (new lesions or gadolinium-enhancing lesions). (4) Conclusion: Natalizumab prevents microstructural brain damage and has effects suggesting an improved white matter microstructure measured at ultra-high field during the first year of treatment.

Amide isomerization pathways: Electronic and structural background of protonation- and deprotonation-mediated cis-trans interconversions.

The cis-trans isomerization of amide bonds leads to wide range of structural and functional changes in proteins and can easily be the rate-limiting step in folding. The trans isomer is thermodynamically more stable than the cis, nevertheless the cis form can play a role in biopolymers' function. The molecular system of N-methylacetamide · 2H2O is complex enough to reveal energetics of the cis-trans isomerization at coupled cluster single-double and coupled cluster single-double and perturbative triple [CCSD(T)] levels of theory. The cis-trans isomerization cannot be oversimplified by a rotation along ω, since this rotation is coupled with the N-atom pyramidal inversion, requesting the introduction of a second dihedral angle "α." Full f(ω,α) potential energy surfaces of the different amide protonation states, critical points and isomerization reaction paths were determined, and the barriers of the neutral, O-protonated and N-deprotonated amides were found too high to allow cis-trans interconversion at room temperature: ∼85, ∼140, and ∼110 kJ mol-1, respectively. For the N-protonated amide bond, the cis form (ω = 0°) is a maximum rather than a minimum, and each ω state is accessible for less than ∼10 kJ mol-1. Here we outline a cis-trans isomerization pathway with a previously undescribed low energy transition state, which suggests that the proton is transferred from the more favorable O- to the N-protonation site with the aid of nearby water molecules, allowing the trans → cis transition to occur at an energy cost of ≤11.6 kJ mol-1. Our results help to explain why isomerase enzymes operate via protonated amide bonds and how N-protonation of the peptide bond occurs via O-protonation.

Amide Proton Transfer-Weighted MRI and Diffusion-Weighted Imaging in Bladder Cancer: A Complementary Tool to the VI-RADS

To investigate the feasibility of amide proton transfer-weighted (APTw) and diffusion-weighted Magnetic Resonance Imaging (MRI) as a means by which to add value to the Vesical Imaging Reporting and Data System (VI-RADS) for discriminating muscle invasive bladder cancer (MIBC) from nonmuscle invasive bladder cancer (NMIBC). This prospective study enrolled participants with pathologically confirmed bladder cancer (BCa) who underwent preoperative multiparametric MRI, including APTw and diffusion-weighted MRI, from July 2020 to January 2023. The exclusion criteria were lesions smaller than 10mm, missing smooth muscle layer in the operation specimen, neoadjuvant therapy before MRI, inadequate image quality, and malignancy other than urothelial neoplasm. Two radiologists independently assigned the VI-RADS score for each participant. Quantitative parameters derived from APTw and diffusion-weighted MRI were obtained by another two radiologists. Receiver operating characteristic (ROC) curve analysis with the area under the ROC curve (AUC) was performed to evaluate the diagnostic performances of quantitative parameters for discriminating BCa detrusor muscle invasion status. A total of 106 participants were enrolled (mean age, 64 ± 12 years [SD]; 90 men): 32 with MIBC and 74 with NMIBC. Lower apparent diffusion coefficient (ADC)values (0.88×10-3 mm2/s±0.12 vs. 1.08×10-3 mm2/s±0.25; P<0.001) and higher APTw values (6.89% [interquartile range {IQR}, 5.05%-12.17%] vs. 3.61% [IQR, 2.23%-6.83%]; P<0.001) were observed in the MIBC group. Compared to VI-RADS alone, both APTw (P=0.003) and ADC (P=0.020) values could improve the diagnostic performance of VI-RADS in differentiating MIBC from NMIBC. The combination of the three yielded the highest diagnostic performance (AUC, 0.93; 95% CI:0.87,0.97) for evaluating muscle invasion status. The addition of the APTw values to the combination of VI-RADS and ADC values notably improved the diagnostic performance for differentiating NMIBC from MIBC (VI-RADS+ADC vs. VI-RADS+APTw+ADC, P=0.046). MRI parameters derived from APTw and diffusion-weighted MRI can be used to accurately assess muscle invasion status in BCa and provide additional value to VI-RADS.

Dual contrast CEST MRI for pH-weighted imaging in stroke.

pH enhanced (pHenh ) CEST imaging combines the pH sensitivity from amide and guanidino signals, but the saturation parameters have not been optimized. We propose pHdual as a variant of pHenh that suppresses background signal variations, while enhancing pH sensitivity and potential for imaging ischemic brain injury of stroke. Simulation and in vivo rodent stroke experiments of pHenh MRI were performed with varied RF saturation powers for both amide and guanidino protons to optimize the contrast between lesion/normal tissues, while simultaneously minimizing signal variations across different types of normal tissues. In acute stroke, contrast and volume ratio measured by pHdual imaging were compared with an amide-CEST approach, and perfusion and diffusion MRI. Simulation experiments indicated that amide and guanidino CEST signals exhibit unique sensitivities across different pH ranges, with pHenh producing greater sensitivity over a broader pH regime. The pHenh data of rodent stroke brain demonstrated that the lesion/normal tissue contrast was maximized for an RF saturation power pair of 0.5 μT at 2.0 ppm and 1.0 μT at 3.6 ppm, whereas an optimal contrast-to-variation ratio (CVR) was obtained with a 0.7 μT saturation at 2.0 ppm and 0.8 μT at 3.6 ppm. In acute stroke, CVR optimized pHenh (i.e., pHdual ) achieved a higher sensitivity than the three-point amide-CEST approach, and distinct patterns of lesion tissue compared to diffusion and perfusion MRI. pHdual MRI improves the sensitivity of pH-weighted imaging and will be a valuable tool for assessing tissue viability in stroke.

Amide proton transfer imaging-arterial spin labeling mismatch: a new imaging biomarker for pilocytic astrocytoma

We describe the potential utility of Amide Proton Transfer weighted (APTw) Magnetic Resonance Imaging and arterial spin labeling (ASL) in characterizing pilocytic astrocytoma (PA), a type of brain tumor that can be challenging to accurately diagnose and treat. The study included 50 patients with solid or predominantly solid intra-cranial and intra-axial tumors, with 25 patients diagnosed with PA and 25 patients diagnosed with other types of tumors. The study found that the APTw imaging-arterial spin labeling (ASL) mismatch is a new imaging biomarker that could be used to differentiate PA from other types of tumors with a high degree of sensitivity and specificity. The results suggest that APTw imaging and ASL may be useful in characterizing PA, potentially improving diagnosis and treatment planning for this type of brain tumor.

The importance of the PapR7 C-terminus and amide protons in mediating quorum sensing in Bacilluscereus

The opportunistic human pathogen Bacillus cereus controls the expression of key infection-promoting phenotypes using bacterial quorum sensing (QS). QS signal transduction within the species is controlled by an autoinducing peptide, PapR7, and its cognate receptor, PlcR, indicating that the PlcR:PapR interface is a prime target for QS inhibitor development. The C-terminal region of the peptide (PapR7; ADLPFEF) has been successfully employed as a scaffold to develop potent QS modulators. Despite the noted importance of the C-terminal carboxylate and amide protons in crystallographic data, their role in QS activity has yet to be explored. In this study, an N-methyl scan of PapR7 was conducted in conjunction with a C-terminal modification of previously identified B. cereus QS inhibitors. The results indicate that the amide proton at Glu6 and the C-terminal carboxylate are important for effective QS inhibition of the PlcR regulon. Through β-galactosidase and hemolysis assays, a series of QS inhibitors were discovered, including several capable of inhibiting QS with nanomolar potency. These inhibitors, along with the structure–activity data reported, will serve as valuable tools for disrupting the B. cereus QS pathway towards developing novel anti-infective strategies.