Measuring Subtle Leakage in Patients with Cerebrovascular Disease Using Dual Temporal Resolution DCE-MRI: Is it Reproducible?
Sau May Wong1, Jacobus F.A. Jansen1, C. Eleana Zhang2, Julie Staals2, Paul A.M. Hofman1, Joachim E. Wildberger1, Robert J. van Oostenbrugge2, C├ęcile R.L.P.N. Jeukens1, and Walter H. Backes1

1Radiology & Nuclear Medicine, Maastricht University Medical Centre, Maastricht, Netherlands, 2Neurology, Maastricht University Medical Centre, Maastricht, Netherlands

Synopsis

Measuring subtle leakage through the blood-brain barrier using DCE-MRI is challenging since their magnitude is lower than in high-grade tumors. To have a clinical application, this method has to be reproducible. The reproducibility of the transfer constant (Ki) and fractional plasma volume (vp) using dual temporal resolution DCE-MRI was investigated in 14 patients with cerebrovascular disease. Low CVs and moderate to high ICCs demonstrate that despite the noisy nature of the measurement, the method is moderately reproducible. Still, cautious interpretation of the Ki and vp in individual patients is needed. Day-to-day variations may be partly compensated by using session-averaged VIFs.

Introduction

DCE-MRI is widely used in the clinic to determine leakage of a contrast medium in tumors. Recently, this method is increasingly applied to estimate the rather subtle leakage through the blood-brain barrier (BBB) in cerebrovascular and neurodegenerative pathology (e.g. cerebral small vessel disease (cSVD) and Alzheimer’s disease)1,2. Several studies have shown that breakdown of the BBB might play a pivotal role in the pathophysiology of these diseases3,4.

Measuring subtle leakage is challenging as the magnitude is several orders lower than that found in high-grade tumors. To have a clinical application, the measurement of subtle leakage using DCE-MRI has to be reproducible. The aim is to determine the reproducibility of the pharmacokinetic measures, the transfer constant (Ki) and fractional plasma volume (vp), using dual temporal resolution DCE-MRI in patients with cerebrovascular disease. In addition, the effect of different vascular input functions (VIFs) on the reproducibility was investigated.

Methods

Patients: MR imaging was conducted twice in 14 patients with cSVD (n=10), cortical stroke (n=3) or intracerebral hemorrhage (n=1) (age 68.0±6.8y) to obtain a range of leakage values. Imaging was conducted on a 3.0 Tesla MR scanner (Philips Achieva TX) on two separate days with on average 2.1±2.3 days in between.

Data acquisition: Dual temporal resolution DCE-MRI was used for dynamic imaging to quantify the leakage rate through the BBB and the microvascular blood plasma space5. The acquisition compromises the combination of two dynamic sequences with different dynamic scan times (DST). The first sequence was applied during bolus injection (DST 3.2 s, TR/TE = 5.6/2.5 ms, FOV: 256x200x50 mm3, voxel size 2x2x5 mm3, 29 volumes). Subsequently, the second sequence was conducted (DST 30.5 s, TR/TE = 5.6/2.5 ms, FOV: 256x256x100 mm3, voxel size 1x1x2 mm3, 45 volumes). The contrast agent (Gadobutrol, dose 0.1 mmol/kg, 3 ml/s) was injected in the antecubital vein.

Data analysis: Voxel wise calculation of Ki and vp was performed by using the Patlak graphical approach6. Histogram analysis was performed to calculate the mean vp and the 75th percentile of Ki, to determine the strongest leakage region with respect to noise. The following regions of interest (ROIs) were analyzed: vascular lesion (VL), white matter (WM) and grey matter (GM) (both distant from the VL). The individual VIFs were taken from the sagittal sinus. To explore the influence of the VIF on the day-to-day variation, a session-averaged VIF per subject was also calculated over the two sessions.

Reproducibility was expressed by 2 measures: (i) the correlation coefficient (CV) to measure the relative within-subject variation and (ii) the intraclass correlation coefficient (ICC) that expresses the part of the total variance ascribed to biological variation rather than measurement error. Lower CV and higher ICC are indicative of good reproducibility. Bland-Altman plots and the 95% limits of agreement (LoA) were also depicted7.

Results

No correlation between the magnitude and difference between sessions was present for the Ki and vp in the WM and GM (Fig. 1,2).

Table 1 shows the reproducibility values. Fairly low CVs and high ICCs were found in the WM and GM for both measures. For the VLs, high ICC was observed for Ki, whereas for vp it was low (Fig. 3).

Using session-averaged VIFs instead of individual VIFs, higher CVs and lower ICCs were observed for Ki. In contrast, lower CVs and higher ICCs were seen for the vp .

Discussion and conclusion

The magnitude of Ki and vp are comparable to the inter-session variability (LoA) (Fig. 1,2). Moreover, low CVs and moderate to high ICCs observed for Ki and vp indicate a moderate reproducibility in the WM and GM. In the VLs, contradictory reproducibility values were observed for the Ki and vp, for which more patients need to be investigated.

Furthermore, the reproducibility of Ki in the more vascularized GM (more leakage) was lower than in the WM. This might be caused by stronger partial volume effects in the GM by CSF and macrovessels, which are likely stronger in the (cortical) GM than WM.

Day-to-day variation might be induced by variation in the tissue signal and the VIF. Using session-averaged VIFs, it was observed that the reproducibility of vp improved, whereas Ki did not show this effect.

These results demonstrate that despite the noisy nature of the measurement, determining subtle leakage in cerebrovascular patients using dual temporal DCE-MRI is moderately reproducible. Still, cautious interpretation of the Ki and vp in individual patients is needed. Day-to-day variations may be partly compensated by using session-averaged (or standardized) VIFs.

Acknowledgements

No acknowledgement found.

References

1. Larsson HBW et al., MRM, 2009;62:1270–81. 2. Taheri S et al., MRM, 2011;65:1036–42 3. Wardlaw JM et al., Annals of Neurology; 2009;65:194-202 4. Montagne A et al., Neuron; 2015;85:296-302 5. Wong SM et al. Proc. Intl. Soc. Mag. Reson. Med. 23 (2015):2362 6. Patlak CS et al., J Cereb Blood Flow Metab, 1985;5:584–590. 7. Bland JM et al., Lancet; 1986;1:307-10.

Figures

Table 1. Reproducibility values of Ki and vp with different VIFs.

Figure 2. Bland-Altman plot of Ki values in the white matter (WM) and grey matter (GM) showing the limit of agreements (mean±1.96SD) in blue (WM: dotted; GM: straight) and the mean between the two sessions in red (WM: dotted; GM: straight).

Figure 3. Bland-Altman plot of vp values in the white matter (WM) and grey matter (GM) showing the limit of agreements (mean±1.96SD) in blue (WM: dotted; GM: straight) and the mean between the two sessions in red (WM: dotted; GM: straight).

Figure 3. Example FLAIR image (A), Ki map (B) and vp map (C) from a patient with intracerebral hemorrhage. The lesion is marked with a white arrow.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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