Takahiro Igarashi

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

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.

Comparison of image sensitivity between conventional tensor‐based and fast diffusion kurtosis imaging protocols in a rodent model of acute ischemic stroke

Diffusion kurtosis imaging (DKI) can offer a useful complementary tool to routine diffusion MRI for improved stratification of heterogeneous tissue damage in acute ischemic stroke. However, its relatively long imaging time has hampered its clinical application in the emergency setting. A recently proposed fast DKI approach substantially shortens the imaging time, which may help to overcome the scan time limitation. However, to date, the sensitivity of the fast DKI protocol for the imaging of acute stroke has not been fully described. In this study, we performed routine and fast DKI scans in a rodent model of acute stroke, and compared the sensitivity of diffusivity and kurtosis indices (i.e. axial, radial and mean) in depicting acute ischemic lesions. In addition, we analyzed the contrast‐to‐noise ratio (CNR) between the ipsilateral ischemic and contralateral normal regions using both conventional and fast DKI methods. We found that the mean kurtosis shows a relative change of 47.1u2009±u20097.3% between the ischemic and contralateral normal regions, being the most sensitive parameter in revealing acute ischemic injury. The two DKI methods yielded highly correlated diffusivity and kurtosis measures and lesion volumes (R2u2009⩾u20090.90, pu2009< 0.01). Importantly, the fast DKI method exhibited significantly higher CNR of mean kurtosis (1.6u2009±u20090.2) compared with the routine tensor protocol (1.3u2009±u20090.2, pu2009< 0.05), with its CNR per unit time (CNR efficiency) approximately doubled when the scan time was taken into account. In conclusion, the fast DKI method provides excellent sensitivity and efficiency to image acute ischemic tissue damage, which is essential for image‐guided and individualized stroke treatment. Copyright

Fast diffusion kurtosis imaging (DKI) with Inherent COrrelation-based Normalization (ICON) enhances automatic segmentation of heterogeneous diffusion MRI lesion in acute stroke

Diffusion kurtosis imaging (DKI) has been shown to augment diffusion‐weighted imaging (DWI) for the definition of irreversible ischemic injury. However, the complexity of cerebral structure/composition makes the kurtosis map heterogeneous, limiting the specificity of kurtosis hyperintensity to acute ischemia. We propose an Inherent COrrelation‐based Normalization (ICON) analysis to suppress the intrinsic kurtosis heterogeneity for improved characterization of heterogeneous ischemic tissue injury. Fast DKI and relaxation measurements were performed on normal (n = 10) and stroke rats following middle cerebral artery occlusion (MCAO) (n = 20). We evaluated the correlations between mean kurtosis (MK), mean diffusivity (MD) and fractional anisotropy (FA) derived from the fast DKI sequence and relaxation rates R1 and R2, and found a highly significant correlation between MK and R1 (p < 0.001). We showed that ICON analysis suppressed the intrinsic kurtosis heterogeneity in normal cerebral tissue, enabling automated tissue segmentation in an animal stroke model. We found significantly different kurtosis and diffusivity lesion volumes: 147 ± 59 and 180 ± 66 mm3, respectively (p = 0.003, paired t‐test). The ratio of kurtosis to diffusivity lesion volume was 84% ± 19% (p < 0.001, one‐sample t‐test). We found that relaxation‐normalized MK (RNMK), but not MD, values were significantly different between kurtosis and diffusivity lesions (p < 0.001, analysis of variance). Our study showed that fast DKI with ICON analysis provides a promising means of demarcation of heterogeneous DWI stroke lesions.

A generalized ratiometric chemical exchange saturation transfer (CEST) MRI approach for mapping renal pH using iopamidol: Generalized Ratiometric CEST Renal pH Imaging

To extend the pH detection range of iopamidol‐based ratiometric chemical exchange saturation transfer (CEST) MRI at sub‐high magnetic field and establish quantitative renal pH MRI.

pH imaging reveals worsened tissue acidification in diffusion kurtosis lesion than the kurtosis/diffusion lesion mismatch in an animal model of acute stroke:

Diffusion weighted imaging (DWI) has been commonly used in acute stroke examination, yet a portion of DWI lesion may be salvageable. Recently, it has been shown that diffusion kurtosis imaging (DKI) defines the most severely damaged DWI lesion that does not renormalize following early reperfusion. We postulated that the diffusion and kurtosis lesion mismatch experience heterogeneous hemodynamic and/or metabolic injury. We investigated tissue perfusion, pH, diffusion, kurtosis and relaxation from regions of the contralateral normal area, diffusion lesion, kurtosis lesion and their mismatch in an animal model of acute stroke. Our study revealed significant kurtosis and diffusion lesion volume mismatch (19.7u2009±u200910.7%, Pu2009<u20090.01). Although there was no significant difference in perfusion and diffusion between the kurtosis lesion and kurtosis/diffusion lesion mismatch, we showed lower pH in the kurtosis lesion (pHu2009=u20096.64u2009±u20090.12) from that of the kurtosis/diffusion lesion mismatch (6.84u2009±u20090.11, Pu2009<u20090.05). Moreover, pH in the kurtosis lesion and kurtosis/diffusion mismatch agreed well with literature values for regions of ischemic core and penumbra, respectively. Our work documented initial evidence that DKI may reveal the heterogeneous metabolic derangement within the commonly used DWI lesion.

A generalized ratiometric chemical exchange saturation transfer (CEST) MRI approach for mapping renal pH using iopamidol

To extend the pH detection range of iopamidol‐based ratiometric chemical exchange saturation transfer (CEST) MRI at sub‐high magnetic field and establish quantitative renal pH MRI.

Susceptibility weighted imaging of stroke brain in response to normobaric oxygen (NBO) therapy

The neuroprotective effect of oxygen leads to recent interest in normobaric oxygen (NBO) therapy after acute ischemic stroke. However, the mechanism remains unclear and inconsistent outcomes were reported in human studies. Because NBO aims to improve brain tissue oxygenation by enhancing oxygen delivery to ischemic tissue, monitoring the oxygenation level changes in response to NBO becomes necessary to elucidate the mechanism and to assess the efficacy. Susceptibility weighted imaging (SWI) which provides a new MRI contrast by combining the magnitude and phase images is fit for purpose. SWI is sensitive to deoxyhemoglobin level changes and thus can be used to evaluate the cerebral metabolic rate of oxygen. In this study, SWI was used for in vivo monitoring of oxygenation changes in a rat model of permanent middle cerebral artery occlusion (MCAO) before, during and after 30 min of NBO treatment. Regions of interest in ischemic core, penumbra and contralateral normal area were generated based on diffusionweighted imaging and perfusion imaging. Significant differences in SWI indicating different oxygenation levels were generally found: contralateral normal > penumbra > ischemic core. Ischemic core showed insignificant increase in oxygenation during NBO and returned to pre-treatment level after termination of NBO. Meanwhile, the oxygenation levels slightly increased in contralateral normal and penumbra regions during NBO and significantly decreased to a level lower than pre-treatment after termination of NBO, indicating secondary metabolic disruption upon the termination of transient metabolic support from oxygen. Further investigation of NBO effect combined with reperfusion is necessary while SWI can be used to detect hemorrhagic transformation after reperfusion.

Simplified correction of B1 inhomogeneity for chemical exchange saturation transfer (CEST) MRI measurement with surface transceiver coil

Chemical exchange saturation transfer (CEST) MRI is sensitive to dilute exchangeable protons and local properties such as pH and temperate, yet its susceptibility to field inhomogeneity limits its in vivo applications. Particularly, CEST measurement varies with RF irradiation power, the dependence of which is complex due to concomitant direct RF saturation (RF spillover) effect. Because the volume transmitters provide relatively homogeneous RF field, they have been conventionally used for CEST imaging despite of their elevated specific absorption rate (SAR) and relatively low sensitivity than surface coils. To address this limitation, we developed an efficient B1 inhomogeneity correction algorithm that enables CEST MRI using surface transceiver coils. This is built on recent work that showed the inverse CEST asymmetry analysis (CESTRind) is not susceptible to confounding RF spillover effect. We here postulated that the linear relationship between RF power level and CESTRind can be extended for correcting B1 inhomogeneity induced CEST MRI artifacts. Briefly, we prepared a tissue-like Creatine gel pH phantom and collected multiparametric MRI including relaxation, field map and CEST MRI under multiple RF power levels, using a conventional surface transceiver coil. The raw CEST images showed substantial heterogeneity due to B1 inhomogeneity, with pH contrast to noise ratio (CNR) being 8.8. In comparison, pH MRI CNR of the fieldinhomogeneity corrected CEST MRI was found to be 17.2, substantially higher than that without correction. To summarize, our study validated an efficient field inhomogeneity correction that enables sensitive CEST MRI with surface transceiver, promising for in vivo translation.

Quantification of in vivo pH-weighted amide proton transfer (APT) MRI in acute ischemic stroke

Amide proton transfer (APT) imaging is a specific form of chemical exchange saturation transfer (CEST) MRI that probes the pH-dependent amide proton exchange.The endogenous APT MRI is sensitive to tissue acidosis, which may complement the commonly used perfusion and diffusion scans for characterizing heterogeneous ischemic tissue damage. Whereas the saturation transfer asymmetry analysis (MTRasym) may reasonably compensate for direct RF saturation, in vivo MTRasym is however, susceptible to an intrinsically asymmetric shift (MTR’asym). Specifically, the reference scan for the endogenous APT MRI is 7 ppm upfield from that of the label scan, and subjects to concomitant RF irradiation effects, including nuclear overhauser effect (NOE)-mediated saturation transfer and semisolid macromolecular magnetization transfer. As such, the commonly used asymmetry analysis could not fully compensate for such slightly asymmetric concomitant RF irradiation effects, and MTRasym has to be delineated in order to properly characterize the pH-weighted APT MRI contrast. Given that there is very little change in relaxation time immediately after ischemia and the concomitant RF irradiation effects only minimally depends on pH, the APT contrast can be obtained as the difference of MTRasym between the normal and ischemic regions. Thereby, the endogenous amide proton concentration and exchange rate can be solved using a dual 2-pool model, and the in vivo MTR’asym can be calculated by subtracting the solved APT contrast from asymmetry analysis (i.e., MTR’asym =MTRasym-APTR). In addition, MTR’asym can be quantified using the classical 2-pool exchange model. In sum, our study delineated the conventional in vivo pH-sensitive MTRasym contrast so that pHspecific contrast can be obtained for imaging ischemic tissue acidosis.