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Hemodynamic impairments in asymptomatic unilateral carotid artery stenosis are increased within individual watershed areas

Stephan Kaczmarz^1,2, Jens Goettler^1,2,3, Jan Petr⁴, Mikkel Bo Hansen⁵, Jan Kufer¹, Andreas Hock⁶, Christian Sorg¹, Claus Zimmer¹, Kim Mouridsen⁵, Fahmeed Hyder², and Christine Preibisch^1,7

¹Department of Neuroradiology, Technical University of Munich, Munich, Germany, ²MRRC, Yale University, New Haven, CT, United States, ³Clinic for Radiology, Technical University of Munich, Munich, Germany, ⁴PET center, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany, ⁵Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark, ⁶Philips Healthcare, Hamburg, Germany, ⁷Clinic for Neurology, Technical University of Munich, Munich, Germany

Synopsis

Internal carotid-artery stenosis (ICAS) causes complex and not yet well understood physiological impairments, which currently limits treatment decisions. We present multimodal perfusion and oxygenation-related MRI-data from unilateral asymptomatic ICAS-patients and age-matched healthy controls. The major aim was to investigate hemodynamic impairments in ICAS within individually defined watershed areas (iWSA’s) to account for individual vascular configurations. We found statistically significant lateralization of hemodynamic parameters within iWSA’s - strongest in WM of iWSA’s. Therefore, our iWSA-based approach facilitates detection of even subtle hemodynamic changes in ICAS. Furthermore, we detected spatially widespread capillary flow heterogeneity increases which are promising future treatment indicators.

Purpose

Severe internal carotid-artery stenosis (ICAS) is a major public health issue, as it accounts for approximately 10% of all strokes.¹ Hemodynamic impairments in ICAS have been investigated intensively,^2-6 but treatment guidelines for asymptomatic patients are still insufficient⁷, not accounting for hemodynamic changes. Improve the currently lacking detection of subtle hemodynamic changes in asymptomatic ICAS^7,8 is crucial to better identify patients at high stroke risk who could benefit from the invasive treatment^8,9.¹⁰ It is known that perfusion impairments arise first in border zones between perfusion territories,¹¹ while ICAS significantly increases the spatial variability of those watershed areas (WSA), e.g. by collateral flow.¹² We therefore hypothesize that we can improve sensitivity to hemodynamic impairments of ICAS by using subject-specific iWSA's.¹²Furthermore, we propose an easily applicable multimodal imaging protocol (Fig.1) to gain deeper insights into the complex interplay of hemodynamic impairments.

Methods

Fifty-nine participants (29 asymptomatic, unilateral ICAS-patients, age=70.1±4.8y and 30 age-matched healthy controls [HC], age=70.3±7.3y) underwent MRI on a Philips 3T Ingenia (Philips Healthcare, Best, Netherlands) using a 16-channel head-neck-coil. The imaging protocol and derived hemodynamic parameters are summarized in Fig.1. Imaging yielded maps of cerebrovascular reactivity (CVR),¹⁴ cerebral blood flow (CBF),¹⁶ relative oxygen extraction fraction (rOEF) following the multiparametric-quantitative BOLD approach (mq-BOLD)²⁰ and relative cerebral blood volume (rCBV), capillary transit-time heterogeneity (CTH) and oxygen extraction capacity (OEC) by parametric modeling¹⁹of dynamic susceptibility contrast (DSC) data (Fig.2C-H). Processing was performed with SPM12²²and custom Matlab²³programs. Artefact-affected parameter-maps were excluded based on visual ratings (CP, SK, JG).

Individual watershed areas (iWSA's) of each participant were defined based on DSC-derived time-to-peak (TTP) maps (Fig.2A).¹²For comparisons, additional masks outside iWSA’s were generated (Fig.2B). Mean hemodynamic parameters within each hemisphere were compared between ICAS-patients vs. HC and inside vs. outside iWSA’s with additional GM and WM masks. For ICAS-patients, mean values were evaluated within hemispheres ipsilateral and contralateral to the stenosis.

Results

Exemplary data of an ICAS-patient is shown in Fig.2. Statistically significant lateralization of CBF, CVR, rCBV, CTH and OEC within GM-iWSA were found in ICAS-patients. For the HC group, all parameters were symmetrical between hemispheres (Fig.3). Regarding rOEF in ICAS, no significant lateralization was found on group level (Fig.3D), however, lateralization standard deviations were increased by +127% compared to HC (data not shown). Furthermore, focal rOEF increases of single subjects corresponded to elevated OEC and CTH (Fig.2E-G). Lateralization inside iWSA’s was statistically significantly enhanced for CBF and CVR, with a strong trend for rCBV (Fig.4). Overall, lateralization was stronger within WM than GM. Contrary, OEC and CTH were also lateralized, but show comparable values inside/outside iWSA's (Fig.4). Comparison of parameter's relationship reveals a clear trend, ordered from strongest to weakest lateralization (Fig.5): CTH(increased), CBF(decreased), OEC(increased), CVR(decreased), rCBV(increased) to rOEF(unaffected).

Discussion

The multimodal MRI protocol was found to be sensitive to hemodynamic impairments in unilateral-ICAS and affirmed by symmetrical HC results (Fig.3). As hypothesized, impairments of CBF, CVR and rCBV were increased within iWSA’s (Fig.4). Thus, individual WSA definition can contribute to detect subtle hemodynamic changes. Stronger effects in WM-iWSA coincide with the different blood supply in GM/WM. Ipsilaterally decreased CBF agrees with recent studies²and decreased CVR, along with increased rCBV, indicates chronic vasodilation.²⁵Consistent with current literature,²no rOEF lateralization was found on group level. However, detailed analysis revealed increased rOEF variability and individual focal increases – which is suspected to relate to increasing and decreasing OEF²⁶at different disease stages. Observed CBF vs. OEF mismatch could imply variable oxygen diffusivity²⁷– potentially moderated by CTH^19,28,29.

Increased capillary flow heterogeneity (CTH) has been previously demonstrated in ICAS.³⁰ Interestingly, we found CTH and OEC lateralization independent of iWSA-locations – which suits previous findings regarding CTH and T_max^31,32. Those CTH increases beyond iWSA-locations might be due to different sensitivities of CTH and TTP to macrovascular effects and microcapillary flow heterogeneity.³⁰Regarding potential early indicators for harmful cerebral hemodynamics, CTH and OEC are highly promising^30,33,34 and imply straightforward impairment detection, as they showed strong lateralization independent of iWSA-locations (Fig.4).

Conclusion

In the presented study, we successfully analyzed hemodynamic impairments of ICAS within iWSA's. Our results are in accordance with current literature and offer a substantial perspective with regard to the relationship of involved parameters. Results of ∆CBF, ∆CVR and ∆rCBV suggest increased sensitivity for subtle changes when applying iWSA's. Interestingly, CTH and OEC increases are independent of iWSA-locations which implies representation of different hemodynamic changes. For the next step, we currently evaluate already acquired follow-up data after ICAS-treatment with additional cognitive testing^34,35 to investigate whether hemodynamic impairments are reversible and possible positive effects on clinical outcome.

Acknowledgements

The authors acknowledge support by the Friedrich-Ebert-Stiftung, Dr.-Ing. Leonhard-Lorenz-Stiftung and the German research Foundation (DFG, grant PR 1039/6-1).

References

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Figures

Figure 1: Overview of MRI protocol and derived parameters. FLAIR was applied for lesion detection and MP-RAGE for white matter (WM) and grey matter (GM) masks. Breathhold-fMRI (BH-fMRI) was performed to measure cerebral vascular reactivity (CVR)¹³by data-driven analysis¹⁴, and pseudo-continuous arterial spin labelling (pCASL) for cerebral blood flow (CBF)^15,16. By dynamic susceptibility contrast (DSC),¹⁷ individual watershed areas (iWSA) were generated for each subject¹² and additionally GM/WM masked. By parametric modelling, relative cerebral blood volume (rCBV), NAWM=2.5% normalised,^17,18 oxygen extraction capacity (OEC) and capillary transit-time heterogeneity (CTH) were calculated.¹⁹ By mq-BOLD, rOEF was calculated from rCBV, T2* and T2.^{20, 21}

Figure 2: Exemplary parameter maps of a right-sided ICAS-patient in an axial slice. Individually defined watershed areas (iWSA) (A) and outside-iWSA (B), CVR (C), CBF (D), rOEF (E), OEC (F), CTH (G) and rCBV (H). CVR and CBF are decreased ipsilateral to the stenosis (white arrows). Focal ipsilateral rOEF increases correspond to elevated OEC and CTH (red arrows). However, OEC and CTH elevations are spatially more extended. For group analyses, each hemisphere’s subject specific iWSA (A) and outside-iWSA masks (B) with additional GM/WM-masks were applied to all parameter-maps (C-H) and mean values within hemispheres calculated. Images were generated with Vinci.²⁵

Figure 3: Paired scatterplots comparing parameter’s lateralization between hemispheres within iWSA in GM. CBF (A), CVR (B), rCBV (C), rOEF (D), CTH (E) and OEC (F) are compared for ICAS-patients (orange captions) and healthy controls (green captions). Dots show mean parameter values within GM-iWSA for each hemisphere and subject - lines connect hemispheres mean values of the same subject. Red dashed lines indicate parameter’s mean values within each hemisphere. In ICAS-patients, all parameters, except rOEF, show statistically significant differences (p<0.05) between hemispheres (asterisks) and their lateralization is significantly different from HC (double asterisks). All parameters are symmetrical between HC’s hemispheres.

Figure 4: Hemodynamic lateralization within iWSA of ICAS-patients. Lateralization was calculated between mean values of ipsilateral and contralateral hemispheres normalised by average bilateral VOI parameter-values. Four VOI’s were compared (see exemplary inlay): inside iWSA in WM (red) & GM (orange) and outside iWSA in WM (dark blue) & GM (light blue). Negative ∆CBF and ∆CVR correspond to decreased values ipsilateral to the stenosis while ∆rCBV, ∆OEC and ∆CTH are increased. Lateralization of ∆CBF, ∆CVR and ∆rCBV is enhanced within iWSA and strongest in WM (asterisks indicate significant differences inside/outside iWSA). Contrary, ∆OEC and ∆CTH are indeed lateralized, but independent of iWSA locations.

Figure 5: Parameter lateralization relationship in ICAS-patients. Parameter lateralization between ipsilateral and contralateral hemispheres within GM-iWSA (normalised by average bilateral VOI-values) are shown. Dots correspond to each parameter’s lateralization per subject - lines connect the same subject’s values. Subjects with good quality of all parameter-maps are shown. Note that stronger lateralization of ∆CBF and ∆CVR correspond to decreased values ipsilateral to the stenosis - while ∆CTH, ∆OEC, ∆rCBV and ∆rOEF are ipsilaterally decreased (inverted scaling). On group level (dashed red lines), a clear trend is apparent from strongest to weakest lateralization in the order ∆CTH, ∆CBF, ∆OEC, ∆CVR, ∆rCBV, ∆rOEF.

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)

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