0291
A comparison of Gadolinium- and water-based blood-brain barrier dysfunction measures in patients with small vessel disease1Centre for Clinical Brain Sciences and UK Dementia Research Institute, University of Edinburgh, Edinburgh, United Kingdom, 2Laboratory of FMRI Technology (LOFT), USC Mark & Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States, 3Department of Anesthesiology, Yale School of Medicine, Yale University, New Haven, CT, United States, 4Glasgow Experimental MRI Centre, School of Psychology and Neuroscience, University of Glasgow, Glasgow, United Kingdom, 5Department of Biomedical Engineering, Yale School of Medicine, Yale University, New Haven, CT, United States
Synopsis
Clinically relevant non-invasive blood-brain barrier (BBB) function imaging techniques are needed to monitor the role of neuroinflammation and endothelial cell dysfunction, particularly in small vessel disease (SVD). Diffusion-weighted ASL measures water exchange rate (kw), a promising endogenous BBB function metric, but has not been assessed in sporadic SVD. We measured kw in SVD patients to explore associations with established Gadolinium-based contrast agent (GBCA) BBB permeability measures and SVD severity. We found only limited associations between kw and GBCA metrics, although patients with more severe SVD tended to have higher kw, reflecting that the methods may probe different mechanisms.
Introduction
Perivascular neuroinflammation has been documented in SVD for >100 years but its role in SVD pathogenesis remains poorly understood.1,2 Subtle blood-brain barrier (BBB) disruption is well reported in SVD, BBB permeability is higher in patients with more severe disease3,4 and linked to inflammation and endothelial cell dysfunction.2 Accurate in-vivo BBB dysfunction measurements are therefore highly relevant to understanding the role of neuroinflammation in SVD and potential causes of progression.5 Dynamic-contrast enhanced MRI (DCE-MRI) can detect BBB dysfunction, however contrast agent molecular size limits sensitivity, compromised kidney function is a contraindication, and retention limits repeated scanning.3,6 Several techniques using water as an endogenous contrast agent have been developed, including diffusion-weighted arterial spin labelling (DW-ASL), but have not been widely applied in patients.7 We compared DW-ASL and DCE-MRI measures of BBB function in patients with symptomatic SVD and assessed associations with age and SVD burden.Methods
We recruited patients with minor stroke due to SVD in an on-going longitudinal study (ISRCTN:12113543).8 We scanned patients within 1-3 months of symptom onset on a 3 T Siemens Prisma MRI scanner.The imaging protocol included:
- Structural images8 (T1-weighted, T2-weighted, and FLAIR)
- Quantitative T1 mapping (two inversion recovery (IR-) spoiled gradient recalled echo (SPGR): TR/TE/TI=1040/1.82/600 and 1940/1.82/1500 ms, FA=5°; three SPGR: TR/TE = 5.4/1.82 ms, FA = 2/5/12°, acquisition matrix 160×200×160, 1.2-mm isotropic)
- DCE-MRI (32 consecutive SPGR volumes during intravenous injection of 0.1 mmol/kg body weight gadobutrol (1M Gadovist, Bayer AG, Leverkusen, Germany) using a power injector; TR/TE = 3.4/1.7 ms, FA = 15°, acquisition matrix size 120×96×96, 2-mm isotropic)
We segmented subcortical grey (SGM), whole-brain normal-appearing white matter (NAWM) and WMH masks, using validated methods, checked and manually corrected as necessary.8 We calculated percentage white matter volume normalised to intracranial volume (ICV).
We measured pre-contrast T1 maps using the DESPOT1-HIFI method,9 correcting flip angle error voxelwise.10 We processed the DCE-MRI data using consensus recommendations3 as described:11 we determined a patient-specific venous input function and calculated signal enhancement timecourses relative to the mean pre-contrast signal using the median signal within each tissue mask.11 We estimated the GBCA concentration using the SPGR signal equation assuming a linear dependence of 1/T1 on concentration, and calculated concentration in blood plasma using patient-specific haematocrits. We calculated permeability surface area product (PS) and blood plasma volume (vP) from the tissue concentration timecourses using the Patlak model.11,12
We used a two-stage approach to measure arterial transit time (ATT) and water exchange rate (kw) as previously described.13 We calculated kw using a total-generalized variation regularized single-pass-approximation model from scans acquired at PLD=1,800 ms with b=0 and 50 s/mm2, to separate the intra- and extra-vascular compartments, respectively.6
We investigated associations between kw and PS, vP and kGad (PS/vP) in separate models using univariate and multiple variable linear regression adjusting for age and SVD burden (percentage WMH volume).
Results
We recruited 26 patients, 2 scans failed, and the remaining 24 patients had a mean age of 61±10 years, mean percentage WMH volume of 0.72±0.66 % and 17 (71%) were male (Table 1). Figure 1 shows representative BBB function parameter maps. Table 2 and Figure 2 show mean values and distribution of the imaging variables.In univariate analyses (Figure 3), patients with higher SGM kw tended to have lower vP (B=-34.65, 95% confidence interval (95%CI)=-60.37,-8.93, p=0.01) and marginally higher kGad (B=4.17, 95%CI=-2.23,10.57, p=0.19). Patients with higher NAWM kw tended to have lower vP (B=-42.15, 95%CI=-102.77,18.48, p=0.16), but we found no clear associations with PS or kGad. Patients with higher WMH kw had lower PS (B=-17.34, 95%CI=-29.78,-4.91, p=0.009), and tended to have lower vP (B=-54.15, 95%CI=-116.22, 7.93, p=0.08) and kGad (B=-3.56, 95%CI=-8.73, 1.60, p=0.16). After correcting for WMH volume and age, all associations were attenuated, though the direction of effect was unchanged.
Patients with higher kw in SGM, NAWM and WMH tended to have higher WMH volumes (e.g. SGM: B=12.90, 95%CI=-1.53,27.33, p=0.08).
Discussion
We found SVD patients with higher kw tended to have higher kGad in SGM and lower vP in SGM and NAWM. Limited associations between water and GBCA exchange metrics reflect previous findings that the two approaches may probe different BBB transport mechanisms,14 while reduced vP may reflect inflammation-induced vascular changes15 and/or vessel loss in patients with greater BBB dysfunction.4 Lastly, we found patients with higher WMH volumes, a key marker of SVD,1 had higher kw which may be consistent with worse neuroinflammation as documented in SVD histologically.Conclusion
In this small study we found evidence of associations between DW-ASL and GBCA BBB function metrics. kw was sensitive to disease severity, consistent with previous studies using GBCA, suggesting DW-ASL is a promising imaging marker of subtle BBB dysfunction. Further studies are required to validate these findings in a larger cohort, in comparison with positron emission tomography markers of inflammation, explore longitudinal changes in kw and associations with other disease burden metrics.Acknowledgements
The authors acknowledge the contribution of the Laboratory of Functional MRI Technology (LOFT) and the University of Southern California’s Stevens Neuroimaging and Informatics Institute to this study though provision of the diffusion prepared pseudocontinuous ASL sequence used for acquisition and the BBB water exchange mapping software (http://www.loft-lab.org/index-5.html) used for image reconstruction and processing. We also thank the Edinburgh Imaging Facility (Royal Infirmary of Edinburgh) radiographers for their work and patients for participating in this study.References
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