Amide proton transfer‐weighted (APTw) imaging is a molecular MRI technique that generates image contrast based predominantly on the amide protons in mobile cellular proteins and peptides that are endogenous in tissue. This technique, the most studied type of chemical exchange saturation transfer imaging, has been used successfully for imaging of protein content and pH, the latter being possible due to the strong dependence of the amide proton exchange rate on pH. In this article we briefly review the basic principles and recent technical advances of APTw imaging, which is showing promise clinically, especially for characterizing brain tumors and distinguishing recurrent tumor from treatment effects. Early applications of this approach to stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and traumatic brain injury are also illustrated. Finally, we outline the technical challenges for clinical APT‐based imaging and discuss several controversies regarding the origin of APTw imaging signals in vivo. Level of Evidence: 3 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2019;50:347–364.

Background Stroke thrombolysis with alteplase is currently recommended 0-4•5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4•5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis.Methods In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4•5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. FindingsWe identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1•86, 95% CI 1•15-2•99, p=0•011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9•7, 95% CI 1•23-76•55, p=0•031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1•55, 0•81-2•96, p=0•66).Interpretation Patients with ischaemic stroke 4•5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis.

Purpose To evaluate the use of three EMR methods to quantify APT and NOE signals in human glioma. Methods Eleven patients with high-grade glioma were scanned at 3 T. aEMR2 (asymmetric magnetization-transfer or MT model to fit two-sided, wide-offset data), sEMR2 (symmetric MT model to fit two-sided, wide-offset data), and sEMR1 (symmetric MT model to fit one-sided, wide-offset data) were assessed. ZEMR and experimental data at 3.5 ppm and −3.5 ppm were subtracted to calculate the APT and NOE signals (APT# and NOE#), respectively. Results The aEMR2 and sEMR1 models provided quite similar APT# signals, while the sEMR2 provided somewhat lower APT# signals. The aEMR2 had an erroneous NOE# quantification. Calculated APT# signal intensities of glioma (~4%), much larger than the values reported previously, were significantly higher than those of edema and normal tissue. Compared to normal tissue, gadolinium-enhancing tumor cores were consistently hyperintense on the APT# maps and slightly hypointense on the NOE# maps. Conclusion The sEMR1 model is the best choice for accurately quantifying APT and NOE signals. The APT-weighted hyperintensity in the tumor was dominated by the APT effect, and the MT asymmetry at 3.5 ppm is a reliable and valid metric for APT imaging of gliomas at 3 T.

Purpose To assess amide proton transfer-weighted (APTW) imaging features in patients with malignant gliomas after chemoradiation and the diagnostic performance of APT imaging for distinguishing true progression from pseudoprogression. Materials and Methods After approval by the Institutional Review Board, 32 patients with clinically suspected tumor progression in the first three months after chemoradiation were enrolled and scanned at 3T. Longitudinal routine MRI changes and medical records were assessed to confirm true progression versus pseudoprogression. True progression was defined as lesions progressing on serial imaging over six months, and pseudoprogression was defined as lesions stabilizing or regressing without intervention. The APTWmean and APTWmax signals were obtained from three to five regions of interests for each patient and compared between the true progression and pseudoprogression groups. The diagnostic performance was assessed with receiver operating characteristic curve analysis. Results The true progression was associated with APTW hyperintensity (APTWmean = 2.75% ± 0.42%), while pseudoprogression was associated with APTW isointensity to mild hyperintensity (APTWmean = 1.56% ± 0.42%). The APTW signal intensities were significantly higher in the true progression group (n = 20) than in the pseudoprogression group (P < 0.001; n = 12). The cutoff APTWmean and APTWmax intensity values to distinguish between true progression and pseudoprogression were 2.42% (with a sensitivity of 85.0% and a specificity of 100%) and 2.54% (with a sensitivity of 95.0% and a specificity of 91.7%), respectively. Conclusion The APTW-MRI signal is a valuable imaging biomarker for distinguishing pseudoprogression from true progression in glioma patients.

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use. K E Y W O R D APTw standardization, APT-weighted imaging, brain tumor, CEST imaging How to cite this article: Zhou J, Zaiss M, Knutsson L, et al. Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors.

Purpose To quantify APT effects in acidic ischemic lesions and assess the spatial-temporal relationship between diffusion, perfusion, and pH deficits in acute stroke patients. Methods Thirty acute stroke patients were scanned at 3 T. Quantitative APT (APT#) effects in acidic ischemic lesions were measured using an extrapolated semisolid magnetization transfer reference signal (EMR) technique and compared with commonly used MTRasym(3.5ppm) or APT-weighted parameters. Results APT# images showed clear pH deficits in the ischemic lesion, whereas MTRasym(3.5ppm) signals were slightly hypointense. The APT# contrast between acidic ischemic lesions and normal tissue in acute stroke patients was more than 3 times larger than MTRasym(3.5ppm) contrast (−1.45 ± 0.40 % for APT# vs. −0.39 ± 0.52 % for MTRasym(3.5ppm), p < 4.6 × 10-4). Hypoperfused and acidic areas without an apparent diffusion coefficient abnormality were observed and assigned to an ischemic acidosis penumbra. Hypoperfused areas at normal pH were also observed and assigned to benign oligemia. Hyperintense APT signals were observed in a hemorrhage area in one case. Conclusion The quantitative APT study using the EMR approach enhances APT MRI sensitivity to pH compared to conventional APT-weighted MRI, allowing more reliable delineation of an ischemic acidosis in the penumbra.

Purpose: To quantify the accuracy of amide proton transfer-weighted (APTw) MRI for identifying active glioma after treatment via radiographically guided stereotactic tissue validation.Experimental Design: Twenty-one patients who were referred for surgery for MRI features concerning for tumor progression versus treatment effect underwent preoperative APTw imaging. Stereotactic biopsy samples were taken from regions of interest with varying APTw signal intensities. The relationship between final clinical pathology and the histopathology of each of the 64 specimens was analyzed relative to APTw results. Analysis of confirmed recurrent tumor or treatment effect tissue was used to perform ROC analysis.Results: Eighteen of 21 patients had recurrent tumor, and 3 had treatment effect on clinical pathology. In 12 patients, there were multiple histopathologic assignments confirmed within the same tumor. Of the 64 total specimens, 20 specimens were active glioma, 27 mixed active and quiescent glioma, and 17 quiescent/no identifiable tumor. APTw signal intensity and histopathologic assignment, cellularity, and proliferation index had significant positive correlations (R ¼ 0.651, 0.580, and 0.458, respectively; all P < 0.001). ROC analysis with a 1.79% APTw intensity cutoff differentiated active from nonactive tumor (AUC of 0.881) with 85.1% sensitivity and 94.1% specificity. Analysis of clinical pathology showed the mean APTw intensity for each patient had 94.4% sensitivity and 100% positive predictive value for identifying recurrent glioma at this cutoff.Conclusions: APTw imaging hyperintensity may be a marker of active malignant glioma. It is able to distinguish between regions of heterogeneous abnormality on anatomic brain MRI with high sensitivity and specificity. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

Purpose To assess the APTw-MRI features of isocitrate dehydrogenase (IDH)-wildtype and IDH-mutant grade-II gliomas and to test the hypothesis that the APTw signal is a surrogate imaging marker for identifying IDH mutation status preoperatively. Methods 27 patients with pathologically confirmed low-grade glioma, who were previously scanned at 3T, were retrospectively analyzed. The Mann-Whitney test was used to evaluate relationships between APTw intensities for IDH-mutant and IDH-wildtype groups, and the receiver-operator-characteristic analysis was used to assess the diagnostic performance of APTw. Results Based on histopathology and molecular analysis, seven cases were diagnosed as IDH-wildtype grade-II gliomas, and 20 cases as IDH-mutant grade-II gliomas. The maximum and minimum APTw values, based on multiple regions of interest, as well as the whole-tumor histogram-based mean and 50th percentile APTw values, were significantly higher in the IDH-wildtype gliomas than in the IDH-mutant groups. This corresponded to the areas under the receiver-operator-characteristic curves of 0.89, 0.76, 0.75, and 0.75, respectively, for the prediction of the IDH mutation status. Conclusions IDH-wildtype lesions were typically associated with relatively high APTw signal intensities, compared with IDH-mutant lesions. The APTw signal could be a valuable imaging biomarker by which to identify IDH1 mutation status in grade-II gliomas.