pH-sensitive MRI demarcates graded tissue acidification during acute stroke ― pH specificity enhancement with magnetization transfer and relaxation-normalized amide proton transfer (APT) MRI

Abstract

pH-sensitive amide proton transfer (APT) MRI provides a surrogate metabolic biomarker that complements the widely-used perfusion and diffusion imaging. However, the endogenous APT MRI is often calculated using the asymmetry analysis (MTRasym), which is susceptible to an inhomogeneous shift due to concomitant semisolid magnetization transfer (MT) and nuclear overhauser (NOE) effects. Although the intact brain tissue has little pH variation, white and gray matter appears distinct in the MTRasym image. Herein we showed that the heterogeneous MTRasym shift not related to pH highly correlates with MT ratio (MTR) and longitudinal relaxation rate (R1w), which can be reasonably corrected using the multiple regression analysis. Because there are relatively small MT and R1w changes during acute stroke, we postulate that magnetization transfer and relaxation-normalized APT (MRAPT) analysis increases MRI specificity to acidosis over the routine MTRasym image, hence facilitates ischemic lesion segmentation. We found significant differences in perfusion, pH and diffusion lesion volumes (P<0.001, ANOVA). Furthermore, MRAPT MRI depicted graded ischemic acidosis, with the most severe acidosis in the diffusion lesion (−1.05±0.29%/s), moderate acidification within the pH/diffusion mismatch (i.e., metabolic penumbra, −0.67±0.27%/s) and little pH change in the perfusion/pH mismatch (i.e., benign oligemia, −0.04±0.14%/s), providing refined stratification of ischemic tissue injury.

Improving the detection sensitivity of pH‐weighted amide proton transfer MRI in acute stroke patients using extrapolated semisolid magnetization transfer reference signals

“…However, when impaired perfusion is significant enough to affect metabolism, a systemic intracellular acidosis ensues propagating out from a central infarct core, sparing regions of oligemia that have not resulted in anaerobic metabolism. Our observations show that pH deficits are smaller than perfusion deficits and equal to or larger than diffusion deficits, in line with previous animal studies (26, 27, 48). The pH deficit may reflect the area of final infarction expected without reperfusion and thus, the acidosis-based penumbra.…”

“…All ischemic lesions in ADC, APT # , and rBTT images were automatically defined using a segmentation algorithm with K-means clustering technique (48). The hypoperfused area, showing a decrease in pH (APT # deficit) without an ADC abnormality, was defined as pH/diffusion mismatch, corresponding to the ischemic acidosis penumbra, while the hypoperfused area with normal pH (isointense APT # compared to the contralateral normal tissue) was defined as perfusion/pH mismatch, corresponding to the benign oligemia.…”

Enhancing sensitivity of pH-weighted MRI with combination of amide and guanidyl CEST

“…The difference between APTw values in gray and white matter can be as larger as ~2.5% at 9.4 T (Jin et al, 2013), and similar difference has been reported at 4.7 T (Guo et al, 2016). This background contrast is larger than the acidosis-induced change of APTw signals at the severely acidotic ischemic core (~1.5 %) where local tissue pH decreases by 0.5–1.0 unit (Back et al, 1994; Bereczki and Csiba, 1993; Rehncrona, 1985).…”

“…These amide protons exchange with water, leading to a decrease in MR imaging signal which is highly pH-sensitive. In the core of ischemic stroke, APT contrast can result in a decrease of about 1–2% of the water signal (i.e., ~1–2 M water protons) (Guo et al, 2016; Zhou et al, 2003; Zong et al, 2014), two orders of magnitude higher than the increase of lactate content reported in stroke studies (Jokivarsi et al, 2007; Rehncrona et al, 1981; Wagner et al, 1992; Zong et al, 2014). …”

Translational MR Neuroimaging of Stroke and Recovery

“…Additionally, several MRI research techniques under development may contribute to delineation of penumbrae and assessment of viability. pH-sensitive MRI offers the possibility to determine graded levels of ischemic acidosis [21], and diffusion kurtosis is a marker of local water restriction that may be more sensitive than mean diffusion to early structural damage [22]. …”