Amide proton transfer: A new magnetic resonance imaging technology toward individualized assessment

To the Editor: The amide proton transfer (APT) magnetic resonance imaging (MRI) is an emerging molecular imaging method for detecting mobile proteins/peptides and the potential of hydrogen (pH) with enhanced detection sensitivity compared to direct measurement without external magnetic resonance contrast agents [Figure 1]. Such changes may be potential markers for tumor aggressiveness, treatment efficacy, and overall prognosis. Consequently, the utilization of APT can assist medical professionals in devising treatment regimens tailored to the individual needs of cancer patients, resulting in improved therapeutic outcomes.Figure 1: Schematic diagram of the biophysical principle of amide proton transfer. (A) Protein with amide protons is surrounded by moving water molecules. (B) Saturated pre-pulse at the frequency of the amide protons of the protein invalidates the magnetic resonance signal of these protons. (C) As a result of chemical exchange, the nulled protons move from protein to water molecule.Historically, the primary emphasis in tumor imaging has been on visualizing anatomical structures. In recent years, there has been a growing interest in understanding how the complex biology of gliomas manifests as an imaging phenotype. The utilization of imaging techniques in the study of glioma biology exhibits significant potential in elucidating the intricate characteristics of these neoplasms. In addition to established imaging techniques such as O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-positron emission tomography (PET) and dynamic susceptibility contrast (DSC) perfusion imaging, the utilization of amide proton transfer-weighted (APTw) imaging has emerged as a promising and innovative magnetic resonance (MR) technique.[1] To enhance comprehension of the correlation between imaging biomarkers and their ability to depict cellularity and vascularity in newly diagnosed gliomas accurately, the preoperative MRI and FET-PET data of a total of 46 patients, consisting of 31 cases of glioblastoma and 15 cases of lower-grade glioma, were subjected to segmentation to identify and delineate the contrast-enhancing and fluid-attenuated inversion recovery (FLAIR)-hyperintense areas. The researchers employed predetermined thresholds to compute the hot-spot volumes (HSV) and assessed their spatial convergence. A significant spatial concurrence was observed in glioblastomas between areas of heightened APTw and FET signals, evident in both the regions of contrast enhancement and FLAIR-hyperintense tumor. As indicated by previous research, the APTw values were lower in lower-grade gliomas than in glioblastomas. The utilization of APTw significantly enhances the efficacy of biological imaging in gliomas. The biological plausibility of the partial overlap between APTw and FET can be inferred from the available evidence. Further research is necessary to enhance our understanding of various biological imaging techniques' benefit. Bladder cancer is categorized into high and low grades, associated with distinct clinical interventions and prognostic outcomes. Therefore, precise preoperative assessment of the histologic grade using imaging modalities is imperative. A study aims to explore the feasibility of utilizing APTw MRI for assessing the severity of bladder cancer and to evaluate the potential of APTw MRI as a complementary tool to diffusion-weighted imaging (DWI) in MRI.[2] In summary, the research conducted by the authors has shown that the utilization of APTw MRI is advantageous in assessing the histologic grade of bladder cancer. Furthermore, it has been found that APTw MRI can offer supplementary data to enhance the outcomes of diffusion-weighted MRI. Additional prospective investigations with increased sample sizes from various centers are necessary to confirm the durability and consistency of these findings. Subsequent studies must address specific technical issues and challenges, including using advanced APTw MRI and postprocessing methods to enhance image quality and effectively isolate the pure APT signal from other components. The assessment of tumors in the transition zone of the prostate on MRI is complicated by the fact that there is an overlap in the appearance of transition zone prostate cancer (TZ PCa) and benign prostatic hyperplasia (BPH) on T2-weighted imaging (T2WI) and DWI. This overlap presents additional challenges in accurately evaluating TZ tumors on MRI. Prior research has established a positive association between elevated tumor cellularity and proliferation and increased APT signals. This correlation enables the distinction between tumor tissues and normal tissues, and the utilization of APT has been successfully demonstrated in prostate cancer. The potential of APTw values as imaging predictors and biomarkers of disease has been previously reported. Furthermore, the validity of utilizing T2* in the assessment of prostate cancer has been established. To enhance the discriminatory effects of TZ PCa and BPH, mitigating the risk of undertreating certain patients or subjecting others to unnecessarily aggressive treatment is imperative. Several investigators are examining the potential of utilizing APTw, apparent diffusion coefficient (ADC), and T2* values to differentiate between TZ PCa, stromal BPH, and glandular BPH. Additionally, they aim to investigate whether integrating these values could enhance the diagnostic efficacy of TZ PCa.[3] The initial findings suggested that APTw and ADC values played distinct yet mutually beneficial roles in the characterization of TZ lesions. The utilization of ADC with APTw imaging holds promise in distinguishing between TZ PCa, BPH, and stromal BPH, enhancing its diagnostic capabilities. Undoubtedly, further investigation and empirical studies are required in subsequent endeavors to delve into the prospective capabilities of APT technology. The study's limitations included its restriction to a single center, single scanner, single vendor, single field strength analysis, and relatively small sample size. These factors may have introduced selection bias into the findings. Furthermore, the evaluation of the diagnostic accuracy of individual APTw parameters and the combined diagnostic approach in Prostate Imaging and Reporting Data System (PI-RADS) category 3 lesions, considered indeterminate for cancer, was not conducted due to the limited size of the sample. The utilization of freehand region of interest (ROI) analysis may result in the generation of spurious errors, thereby compromising the overall accuracy of the analysis. The utilization of APT imaging in cervical cancer is progressively on the rise. Nevertheless, the existing body of research on cervical cancer primarily emphasizes differential diagnosis and histological characteristics related to APT. However, a limited number of reports evaluate the viability of APT in predicting treatment response to concurrent chemoradiotherapy (CCRT) in cervical cancer. The present investigation intends to examine the potential of APT imaging and intravoxel incoherent motion (IVIM) imaging as predictive tools for assessing tumor response to CCRT in individuals diagnosed with squamous cell carcinoma of the cervix (SCCC).[4] Fifty-nine female individuals diagnosed with pathologically confirmed SCCC underwent a comprehensive pelvic MRI examination, including assessing ADC maps using the IVIM technique before receiving CCRT. The participants were categorized into two groups based on their therapeutic response: complete remission (CR) and non-CR groups. The study involved the measurement of APT values and parameters derived from IVIM. The intraobserver and interobserver agreement assessment for IVIM and APT parameters was conducted using the intraclass correlation coefficient (ICC). The findings of their investigation indicate that the utilization of pretreatment APT and IVIM can aid in predicting tumor response to CCRT in individuals diagnosed with SCCC. However, additional prospective studies are required to validate these findings. APT MRI can elucidate the antitumor effects by capturing the biologically active tumor region, offering different insights than DWI or DSC imaging. To assess the potential of changes in APT signal intensity following antiangiogenic therapy as a predictive indicator for early treatment response in patients with recurrent glioblastoma, several researchers conducted a retrospective study utilizing APT MRI, DWI, and DSC imaging techniques.[5] This study focused on patients diagnosed with recurrent glioblastoma between July 2015 and April 2019. The imaging procedures were performed both before treatment and 4–6 weeks after the initiation of bevacizumab. The progression determination was established through either pathologic confirmation or clinical–radiologic assessment. The patterns of progression were categorized as either locally enhancing or diffuse non-enhancing. The study computed the average and histogram characteristics alterations, specifically the 5th and 95th percentiles, of APT signal intensity, ADC, and normalized cerebral blood volume (CBV) across different imaging time points. The study employed logistic regression and Cox proportional hazard modeling to identify 12-month progression and progression-free survival (PFS) predictors, stratified by progression type. The results demonstrate an improvement in this study, indicating that a decrease in the average signal intensity of APT at 4–6 weeks following the start of antiangiogenic therapy can serve as a prognostic indicator for improved response and extended PFS in individuals with recurrent glioblastoma. This association is particularly notable in patients experiencing diffuse non-enhancing progression. Further investigation is warranted to examine the prognostic value of imaging biomarkers in predicting disease progression following antiangiogenic treatment, utilizing well-designed prospective studies. The APT imaging technique can employ the naturally occurring contrast agent to depict the tissue's cellular and molecular level information. Concurrently, using APT imaging technology can prevent probable harm to the central nervous system and kidney fibrosis that may arise due to gadolinium deposition in the gadolinium-containing contrast agent, owing to the distinctive imaging properties of APT imaging technology. Over the past few years, there has been a progression in APT imaging from two-dimensional imaging of a single layer to three-dimensional imaging of the entire brain. The enhancement of signal-to-noise ratio and reduction of scanning time has resulted in a more comprehensive assessment of lesions, thereby expanding its scope of application. The resolution of the image obtained through fitting is progressively enhanced by utilizing the initial fitting as a basis, and the outcome of the previous low-resolution image fitting is employed as the novel initial value for the higher-resolution image until the original acquisition image resolution is attained. However, it is recommended to incorporate supplementary measures such as enhancing scan sequence parameters, mitigating motion and cerebrospinal fluid artifacts, augmenting scan velocity, and optimizing imaging algorithms to improve APT imaging technology. The advancement of technology has led to the emergence of APT imaging, which is poised to offer medical practitioners valuable insights for diagnosing tumors, monitoring diseases, predictive analysis, and treatment decisions. Funding This work was supported by grants from the Fundamental Research Funds for the Central Universities, Natural Science Foundation of Liaoning Province (Nos. 2022-YGJC-86 and 2020-ZLLH-38), Young and Middle-aged Technological Innovation Talents in Shenyang (No. RC200491), and Excellent Talent Fund of Liaoning Province Cancer Hospital. Conflicts of interest None.