The Warburg effect, the theory that tumors metabolize acidic substances, is increasingly recognized by an increasing number of scientists studying tumors (1). In cutting-edge research, scientific experiments involving the abnormal accumulation of a series of acidic metabolites, such as methylglutaric acid, have repeatedly verified this viewpoint (2, 3). In the field of gliomas, Varun Venkataramani et al. proposed that glutamatergic synaptic input of glioma cells drives brain tumour progression, especially glioma progression (4). Compared with meningiomas with a significantly better survival prognosis, gliomas undoubtedly have a stronger ability to infiltrate the brain.

Due to the high recurrence rate and poor prognosis, gliomas have become a research hotspot in medicine (5). The main reason for the high recurrence rate of gliomas is the inability to effectively measure the boundary of the tumour infiltrated so that the gliomas cannot be radically removed (6). Neither long-term temozolomide chemotherapy nor radiotherapy in the later stage can effectively cure patients (7, 8). However, most meningiomas originating from the meninges, except for a very small number of malignant meningiomas, can be cured by excision. Meningiomas are directly supplied by meningeal blood vessels and show significant enhancement on enhanced magnetic resonance (MR) scans, and high-grade glioma (HGG)-induced blood–brain barrier (BBB) disruption can achieve a similar degree of enhancement (9).

According to the Warburg effect, malignant tumors cause acidic substances to accumulate in the infiltrating area. At present, clinical imaging technologies that can measure acidic metabolites include MR spectroscopy (MRS) and amide proton transfer imaging (APT) based on chemical exchange saturation transfer (CEST) (10, 11). APT technology can measure the amide proton content and indirectly reflect the protein content and pH value of a substance (12). At present, research on APT in gliomas mainly focuses on the use of the APT value for the evaluation of preoperative tumour malignancy and the identification of postoperative recurrence and pseudo-progression (13–15). However, there are only two studies on meningiomas, one on the content of Ki-67 in meningiomas and the other on the differential diagnosis of typical and atypical meningiomas (16, 17). At present, there is no research on the differential diagnosis of gliomas and meningiomas using APT technology.

In this study, APT was used to evaluate gliomas and meningiomas to obtain APT values, and the range of APT changes caused by tumors was measured and compared with the range of changes observed by conventional imaging of tumors. These analyses were performed to explore whether the changes in APT values and ranges caused by meningiomas and gliomas can be used for differential diagnosis.

APT technology was first established by Zhou et al. of Johns Hopkins University by applying the most classic two-pool model, namely, a free water pool (solution) and an amide proton pool (solute) (18). Since peptides and proteins in the body generally contain amide bonds (-NH), the resonance frequency of hydrogen protons is 0 ppm, the resonance frequency of amide protons is 3.5 ppm, and the asymmetrical magnetization transfer rate (MTRasym) calculated by using the Z-spectrum can reflect the APT rate (19). Amide protons were saturated under continuous selective saturating radio frequency (RF) pulse irradiation. Exchange with free water via chemical shifts resulted in a reduction in the water signal. The reduction in this signal can indirectly reflect the changes in metabolites and pH changes in the substance; hence, it can be used to determine the content of amide protons in this region (20). This study used APT technology to study patients with gliomas and meningiomas and found an interesting phenomenon. The changes in the range of APT images caused by gliomas were more obvious than those of relatively benign meningiomas.

The use of conventional MRI for the diagnosis of glioma and meningioma is quite mature. For example, typical meningiomas have some obvious signs, such as the “meningeal tail “ sign, which can be used for differential diagnosis. However, for the diagnosis of atypical meningioma or meningeal enhancement caused by glioma, APT technology can assist in the differential diagnosis to a certain extent. At the same time, combining APT with conventional MRI images has been shown to yield better diagnostic performance. For example, compared with significantly enhanced meningiomas, HGG has a higher APT_mean value, and the change range of APT images is larger than that of conventional images. APT measurements can help differentiate gliomas from meningiomas; however, these measurements are less effective for differentiating LGGs with a lower MTRasym from meningiomas. However, the enlargement range of APT compared with traditional MR images caused by HGGs or LGGs is more obvious than that of meningiomas. We cannot directly conclude that this is the extent of glioma brain infiltration. Moreover, we have no pathological confirmation, but this change does exist compared to more benign meningiomas. Our study can only indicate that APT imaging may have some value in the determination of malignant brain tumour boundaries, but there is no doubt that this approach can be used in the differential diagnosis between gliomas and meningiomas.

In fact, the use of APT in the differential diagnosis of brain tumors is well established, but its use has mainly focused on the differentiation of solitary brain metastases (SBMs) and glioblastomas (GBMs) (21). Both Yu and Kamimura’s studies found that the APT value of GBMs was higher than that of SBMs, which can be used for the differential diagnosis of GBMs (22, 23). However, it is interesting that, in Kamimura’s study, we found that the APT value in the nonenhanced T2WI-increased area around GBMs was significantly higher than that in the corresponding T2WI-increased area of SBMs. Our study on gliomas and meningiomas also had similar results. Relatively benign meningiomas had lower APT values, but we found that gliomas caused changes in the APT range that were even larger than the range detected by T2WI, and LGGs also had similar performance to HGGs. The range of these changes was more than 9%, and these changes can even be directly judged by the naked eye. Combined with the enhancement degree and APT value, these changes can effectively help clinicians accurately identify gliomas and meningiomas.

“Ischaemic penumbra” is a concept of acute cerebral ischaemia, referring to the area of brain tissue that can be recovered with prompt medical treatment, usually referring to the area of brain tissue between DWI and perfusion-weighted imaging (PWI) (24). Gliomas also lead to the appearance of similar areas of tissue due to tumour brain infiltration, that is, the areas shown by conventional MR and the true borders of gliomas. The delineation of this boundary determines the extent of the operation and the prognosis of the patient’s survival (25). Similar to the use of intraoperative fluorescent probes, tumors can be radically removed as much as possible while preserving the patient’s normal brain tissue area (26). Our thinking is similar to that of most scholars; the changes in gliomas should first be the infiltration of microscopic tumour cells and the accumulation of metabolites and then the formation of tumors and corresponding tumor blood vessels (27). Notably, there are many techniques used in the preoperative evaluation of brain stromal tumors, including PWI, DWI, MRS, etc. Compared with the improved enhancement caused by the destruction of the BBB (usually HGGs are more likely to cause BBB disruption than LGGs), PWI can more effectively respond to the blood supply of gliomas, and the range of APT that can respond to substance metabolism should be larger than that of PWI (28, 29). Some of our patients also underwent PWI. For example, the suitable range for PWI in the patient with HGG in Figure 4 was also significantly smaller than that of APT. If enough similar patients are evaluated, this result should be verifiable. Compared with PWI, DWI or conventional MRI, APT may have higher sensitivity in the early stage of brain tumour infiltration, and it also has a certain role in determining the tumour infiltration boundary. Thus, it is helpful for determining the scope of surgery.

Importantly, there are two main ways to verify the imaging boundary of glioma brain infiltration: 1. Pathological examination of the area showing changes on images; if the corresponding pathological results could be obtained, they could be directly confirmed. However, the main difficulty of this method lies in the extended clinical resection and the correspondence between pathological tissue and imaging. 2. For the correspondence between the scope of resection and preoperative images, the patients were followed up for recurrence, and the survival time was recorded. At present, many studies have proven that APT can be applied to the judgement of recurrence and pseudo-progression. However, if the lesions can be completely removed before surgery, the patients’ prognosis and treatment can be improved, and the need for a second surgery can be reduced (30).

Limitations of our research: 1. The number of patients was relatively small. 2. There was a lack of pathological results for whether the enlarged area of APT compared with conventional MR was a brain area infiltrated with tumors. 3. At present, this was only a study comparing APT and conventional MR images; if adequate functional imaging evaluation can be added, it will be possible to evaluate patients with brain tumors more comprehensively.

In conclusion, this study found that R^APT/E, R^APT/T2 and APT_mean can be better for the differential diagnosis of glioma and meningioma. APT combined with conventional imaging enhancement can better differentiate between LGGs, HGGs and meningiomas.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Clinical Research Ethics Committee of Shenzhen Second People’s Hospital. Written informed consent from the participants’ legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.

H-WZ contributed to the conception of the study; H-BZ, Y-QL, and X-LL contributed significantly to analysis and manuscript preparation; KD, FL, and Y-LW performed the data analyses and wrote the manuscript; YL, BH, and Y-NF helped perform the analysis with constructive discussions. All authors contributed to the article and approved the submitted version.

This study is supported by a grant from National Natural Science Foundation of China (Grant Number: 82071871),Youth Exploration Fund of Shenzhen Health Economics Society (Grant Number: 202211), Clinical Research Project of Shenzhen Second People's Hospital, China (Grant Number: 20193357021), and Clinical Research Project of Shenzhen Second People's Hospital, China (Grant Number: 20203357036).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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