Assessment of ischemic penumbra in patients with hyperacute stroke using amide proton transfer (APT) chemical exchange saturation transfer (CEST) MRI

Abstract

Chemical exchange saturation transfer (CEST)-derived pH-weighted Amide Proton Transfer (APT) MRI has shown promise in animal studies for predicting infarction risk in ischemic tissue. Here, APT MRI was translated to acute human stroke patients (1–24 hrs post-symptom-onset) and assessments between APT contrast, perfusion, diffusion, disability, and final infarct volume (23–92 days post-stroke) are reported. Healthy volunteers (n=5) and patients (n=10) with acute onset of symptoms (0–4h: n=7; uncertain onset <24h: n=3) were scanned with diffusion- and perfusion-weighted MRI, FLuid Attenuated Inversion Recovery (FLAIR) and CEST. Traditional asymmetry as well as a Lorentzian-based APT index were calculated in the infarct core, at-risk tissue (time-to-peak, TTP, lengthening), and the final infarct volume. On average (mean±s.d.), control white matter APT values (asymmetry: 0.019±0.005; Lorentzian: 0.045±0.006) were not significantly different (P>0.05) than APT values in normal-appearing-white-matter (NAWM) of patients (asymmetry: 0.022±0.003; Lorentzian: 0.048±0.003), however ischemic regions in patients had reduced (P=0.03) APT effects compared to NAWM. Representative cases are presented whereby the APT contrast is compared quantitatively to contrast from other imaging modalities. Findings vary between patients; in some patients a trend for a reduction of the APT signal in the final infarct region compared to at-risk tissue was observed, consistent with tissue acidosis. However, in other patients no relationship was observed in the infarct core and final infarct volume. Larger clinical studies in combination with focused efforts on sequence development at clinically available field strengths (e.g., 3.0T) are necessary to fully understand the potential of APT imaging for guiding hyperacute management of patients.

Amide Proton Transfer Imaging in Clinics: Basic Concepts and Current and Future Use in Brain Tumors and Stroke

“…Although the CEST effect is shown to be sensitive to changes in pH, the sensitivity of an amide proton was found to be lower than that of an amine proton, a faster-exchanging molecule in the physiologic range (i.e., pH 6.0-8.5) (3,8,38,59). Finally, the interpretation of APT imaging in the subacute phase is not straightforward, and several factors can significantly increase APT asymmetry (i.e., proteolysis and inflammation are likely to increase the amount of mobile proteins) (22). This increase opposes the reduction in APT asymmetry caused by a reduced pH, thus limiting the interval window for APT imaging and interpretation in the subacute stage.…”

“…Therefore, pulsed saturation approaches are commonly used in clinical MRI scanners, wherein a train of saturation RF pulses is used with crusher gradients. Alternatively, one or multiple short saturation RF pulses are inserted into the two-dimensional or three-dimensional (3D) gradient-echo (22,23), segmented echo-planar imaging (24,25), turbo spin-echo (19,26,27) or gradient-and spin-echo image readout (12,18). This leads to accumulation of the saturation effect for slowly exchanging species, e.g., amide protons, due to a relatively short imaging TR, which is much less than the relaxation time (T1) of tissue.…”

Novel Magnetic Resonance Imaging Techniques in Brain Tumors

“…Amide proton transfer was then applied in human brain tumors by Jones et al 95 showing increased contrast in regions of tumor, which were again attributed to increased protein and peptide content. Since then, additional studies have implemented APT imaging in human gliomas at 3 T. 96,97 In addition, APT has been applied in cases of ischemia, 98,99 stroke, 100,101 and multiple sclerosis, 102 as well as imaging of the breast 103 and prostate 104 in humans and in a lung cancer mouse model. 105 The APTeffects in healthy brain tissue have also been characterized at 7 T, 106 where the effects of nuclear Overhauser enhancement are more prevalent.…”

Depiction of Acute Stroke Using 3-Tesla Clinical Amide Proton Transfer Imaging: Saturation Time Optimization Using an in vivo Rat Stroke Model, and a Preliminary Study in Human

“…This new imaging biomarker may have the potential to be incorporated into stroke imaging protocols, since depicting ischemic penumbra remains a challenge using computed tomography or diffusion-or perfusion-weighted magnetic resonance imaging (MRI) (4)(5)(6). However, to date, clinical studies have been sparse for APT imaging in stroke (3).…”