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Cerebral hypometabolism measured with intravascular T2-prepared tissue relaxation with inversion recovery (T2-TRIR) and pCASL in adults with sickle cell disease
Lena Vaclavu1,2, Esben Thade Petersen3, Henri JMM Mutsaerts1, Jan Petr4, Charles BLM Majoie1, John C Wood5, Ed T VanBavel6, Bart J Biemond7, and Aart J Nederveen1

1Department of Radiology & Nuclear Medicine, Amsterdam UMC, Amsterdam, Netherlands, 2C.J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands, 3Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark, 4Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany, 5Department of Cardiology and Radiology, Children’s Hospital of Los Angeles, Los Angeles, CA, United States, 6Department of Biomedical Engineering & Physics, Amsterdam UMC, Amsterdam, Netherlands, 7Department of Hematology, Amsterdam UMC, Amsterdam, Netherlands

Synopsis

Cerebral metabolic rate of oxygen (CMRO2) quantifies the amount of oxygen consumed by the brain, and relies on continuous delivery of nutrients and oxygen via cerebral blood flow (CBF). In sickle cell disease (SCD), CBF is elevated to compensate for chronic anaemia. This study investigates CMRO2 in adults with SCD using T2-prepared tissue relaxation with inversion recovery (T2-TRIR). CBF increased after acetazolamide-induced vasodilation in both groups but CMRO2 reduced even further in SCD patients while it remained stable in controls. Our results suggest that cerebral shunting is exacerbated by high flow conditions.

Introduction

Cerebral metabolic rate of oxygen (CMRO2) quantifies the amount of oxygen consumed by the brain, and relies on continuous cerebral blood flow (CBF) for nutrients and oxygen. In sickle cell disease (SCD), CBF is elevated to compensate chronic anaemia (low haemoglobin), but is associated with reduced flow reserve capacity and increased vessel dilation(1,2), potentially exhausting autoregulation. Inadequate CBF can result in ischaemic lesions(3), particularly in borderzone regions(4,5). We tested the hypothesis that adults with SCD have impaired cerebral oxygenation under various flow conditions, by measuring the CMRO2 response to acetazolamide, an isometabolic vasodilator.

Methods

Participants: 38 adults with sickle cell disease (SCD) and 11 matched controls were included after IRB approval and informed consent, and underwent a venous blood draw to measure haemoglobin. After baseline scans, 16mg/kg acetazolamide (dissolved in 20 mL saline) was administered intravenously and scans were repeated after 15 min.

Imaging: Images were acquired at 3T (Philips Ingenia) using a 32-channel receive head-coil. Venous T1 and T2 was measured by T2- prepared tissue relaxation with inversion recovery (T2-TRIR)(6,7), consisting of a slab-selective frequency offset corrected inversion (FOCI) pulse, a T2 preparation, and 2D single slice single-shot FFE EPI Look-locker read-out, and the following parameters: FOV 202x243mm, 1.69x1.69x4mm voxels, TR/TE 150/24ms, four T2 weightings resulting in eTEs of 0, 40, 80, and 160ms, corresponding to 0, 4, 8 and 16 refocusing pulses in the MLEV T2-preparation, interpulse spacing of tCPMG=10ms, TI1 10ms, ∆TI 130ms, 4 dynamic scans, flip angle 95°, and total scan duration of 50sec. For lesions we acquired a 3D FLAIR sequence (FOV 250x250x180 mm, 1mm isotropic voxels, TR/TE 4800/356ms). For CBF, we acquired a 2D gradient-echo single-shot EPI pCASL and M0 with the following parameters: FOV 240x240x133mm, 3x3x7mm voxels, 19 slices, TR/TE 4400/14ms, background suppression, flip angle 90°, PLD 1800ms, labelling duration 1800ms, and total scan duration 20min, where the first 5min and last 5min (each 35 dynamics) were used for pre and post-acetazolamide conditions.

Analysis: A region-of-interest was automatically detected in the sagittal sinus of T2-TRIR images and masked to all time-points (Figure 1). T2 was converted to venous saturation (Yv) using a recently developed calibration plot describing the relationship between T2, haematocrit and Yv for human SCD blood(9). Lesions were manually delineated on FLAIR and co-registered to CBF using SPM in ExploreASL(8). Whole-brain CBF was quantified with a dual compartment model(10) incorporating subject-specific T1 values, velocity-corrected labelling efficiency(11), and arterial transit time(12). Oxygen extraction fraction (OEF%) was calculated by (Ya-Yv)/Yv x 100. Arterial saturation (Ya) was assumed (98%). Oxygen delivery (mL O2/min) was calculated by CBF x CaO2, where the oxygen carrying capacity (CaO2) was calculated by (Hb x 1.34 x SaO2) + (0.003 x pO2). Using Fick’s principle, we calculated CMRO2 (μmol O2/100g/min) = CBF x OEF x CaO2, where CaO2 was converted to molar units. Parametric tests were used to assess changes from pre to post-acetazolamide conditions (Tables 1 and 2).

Results

Baseline: CaO2 was lower in patients with SCD compared to controls (453±71 vs 707±65 μmol O2/100ml blood, P<0.001) due to low haemoglobin. We found no difference in oxygen delivery between patients with SCD and controls (7.7±1.4 vs 7.5±0.7 mL O2/min, P=0.62) due to appropriately elevated whole brain CBF in patients with SCD compared to controls (68.5±15.7 vs 41.9±4.0 mL/100g/min, P<0.001). CMRO2 was however lower in patients with SCD compared to controls (87.8±3.0 vs 105.8±3.8 μmol O2/100g/min, P<0.001). WM lesions were located in regions of low CBF and/or low CMRO2 (Figure 3). Acetazolamide(Figure 2): As expected, CBF increased in both groups after acetazolamide. CMRO2 reduced even further in patients with SCD (87.8±3.0 to 80.7±3.6 μmol O2/100g/min, P<0.001), but in controls remained stable (105.8±3.8 to 103.0±9.3 μmol O2/100g/min, P=0.436), indicating sufficient autoregulation in controls but not in patients. Indeed, the increase in CBF was accompanied by a significant drop in OEF in SCD patients (27.1±4.4 to 19.0±5.8%, P<0.001) and controls (35.3±3.6 to 19.7±7.1%, P=0.003), demonstrating that reductions in OEF are associated with increased CBF.

Discussion

We found normal oxygen delivery and reduced CMRO2 in adults with SCD. Cerebral metabolism in SCD may have adapted to chronic low oxygen levels or autoregulation was unable to compensate the mismatch between CBF and OEF. Interestingly, the reduced CMRO2 in adults with SCD(9) declined further after acetazolamide, which may suggest that cerebral shunting is present in SCD(9,13) and is exacerbated by high flow conditions(14). CMRO2 could be useful to monitor response to new drugs in clinical trials targeting oxygen affinity or for clinical assessments to identify patients at risk for ischaemia.

Acknowledgements

No acknowledgement found.

References

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Figures

Table 1. Baseline characteristics

Table 2. MR oximetry and haemodynamics

Figure 1. Simultaneous T1 and T2 of blood measurement in the sagittal sinus. Exponential fit of the data from voxels in the region of interest in the sagittal sinus vein as shown in red (bottom right). Essentially, the T2 decay curve can be obtained from any of the timepoints on the x-axis. Four inversion recovery curves were fitted to the effective echo times (eTE) of 0, 40, 80, and 160 ms, which provided a very robust overall fit. The combination of voxels providing the lowest residual error was chosen to be the final result.

Figure 2. Acetazolamide and baseline results. A) T2 of blood was higher in patients with SCD at baseline and increased after acetazolamide in both groups. B) Venous saturation (Yv) was elevated in SCD patients and increased after acetazolamide. C) Oxygen extraction fraction (OEF) was lower in patients with SCD and declined after acetazolamide in response to the increase in D) cerebral blood flow (CBF). E) Oxygen delivery was the same in SCD patients as in controls, and increased after acetazolamide due to increased CBF. F) CMRO2 was lower at baseline and further declined in SCD, but remained stable in controls.

Figure 3. Co-registered and group-averaged axial MRI images of cerebral blood flow scaled to Cerebral Metabolic Rate of Oxygen (CMRO2). The white contours show an overlay of lesions from the same cohort of patients and controls, indicating co-localization with regions of lower perfusion in deep white matter relative to cortical grey matter.

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