Non-invasive imaging of oxygen extraction fraction in adults with sickle cell anaemia

Abstract

Sickle cell anaemia is a monogenetic disorder with a high incidence of stroke. While stroke screening procedures exist for children with sickle cell anaemia, no accepted screening procedures exist for assessing stroke risk in adults. The purpose of this study is to use novel magnetic resonance imaging methods to evaluate physiological relationships between oxygen extraction fraction, cerebral blood flow, and clinical markers of cerebrovascular impairment in adults with sickle cell anaemia. The specific goal is to determine to what extent elevated oxygen extraction fraction may be uniquely present in patients with higher levels of clinical impairment and therefore may represent a candidate biomarker of stroke risk. Neurological evaluation, structural imaging, and the non-invasive T2-relaxation-under-spin-tagging magnetic resonance imaging method were applied in sickle cell anaemia (n = 34) and healthy race-matched control (n = 11) volunteers without sickle cell trait to assess whole-brain oxygen extraction fraction, cerebral blood flow, degree of vasculopathy, severity of anaemia, and presence of prior infarct; findings were interpreted in the context of physiological models. Cerebral blood flow and oxygen extraction fraction were elevated (P < 0.05) in participants with sickle cell anaemia (n = 27) not receiving monthly blood transfusions (interquartile range cerebral blood flow = 46.2-56.8 ml/100 g/min; oxygen extraction fraction = 0.39-0.50) relative to controls (interquartile range cerebral blood flow = 40.8-46.3 ml/100 g/min; oxygen extraction fraction = 0.33-0.38). Oxygen extraction fraction (P < 0.0001) but not cerebral blood flow was increased in participants with higher levels of clinical impairment. These data provide support for T2-relaxation-under-spin-tagging being able to quickly and non-invasively detect elevated oxygen extraction fraction in individuals with sickle cell anaemia with higher levels of clinical impairment. Our results support the premise that magnetic resonance imaging-based assessment of elevated oxygen extraction fraction might be a viable screening tool for evaluating stroke risk in adults with sickle cell anaemia.

Keywords: arterial spin labelling; brain ischaemia; cerebral haemodynamics; oxygen extraction fraction; sickle cell anaemia.

Adults with sickle cell anaemia are at high risk of stroke but, unlike in children, no screening procedures are available to stratify this risk. Using the MRI method ‘T2-relaxation-under-spin-tagging’, Jordan et al. show that elevated oxygen extraction fraction and cerebral blood flow are potential markers of stroke risk in adults.

Figure 1

Mechanistic model for increasing stages of haemo-metabolic impairment in SCA. (A) Cerebral metabolic rate of oxygen consumption remains constant until severe impairment. (B) Large arteriole CBV may increase on average in moderate stages via vasodilation to maintain CBF. (C) CBF increases sharply in moderate stages to maintain adequate delivery of oxygen to tissue. (D) Once autoregulatory capacity is reached, or vasculopathy becomes severe, CBF plateaus or declines and OEF increases. When oxygen can no longer be supplied by these mechanisms, a stroke occurs. We postulate that in adults with SCA, elevated oxygen extraction fraction (D) can be used to identify those at increased risk of having new ischaemic events.

Figure 2

The TRUST MRI approach for quantifying whole-brain OEF. The pulse-sequence is shown in A and a conceptual representation of the method is shown in B. Briefly, the method consists of a presaturation pulse followed by an inversion pulse and corresponding gradient for labelling venous blood water in a label condition or inversion pulse with no gradient for a control condition. Following the venous blood water labelling (B; red), a post-labelling delay (PLD = 1022 ms) is prescribed during which a T₂-preparation module with varying duration (duration = effective echo time) allows for variable T₂-weighting. An image (B; white) is acquired at the level of the supratentorial sagittal sinus, ∼ 20 mm above the foramen magnum. The difference in signal between control (C) and label (D) acquisitions yields only venous signal in the superior sagittal sinus (E), which allows for venous T₂ and corresponding oxygenation level to be determined upon application of appropriate models.

Figure 3

Non-invasive CBF using pseudocontinuous arterial spin labelling imaging in patients with SCA and controls. (A) Central slices of a T₁-weighted atlas, along with (B) regions analysed for CBF quantification. The flow territories were calculated from vessel-encoded arterial spin labelling data obtained from 92 subjects. CBF maps in (C) controls (n = 11) and (D) participants with SCA (n = 27) demonstrate increased CBF in participants with SCA.

Figure 4

Volumetric, CBF, and OEF analysis in SCA participants and control volunteers. Controls (n = 11), SCA participants not on blood transfusion and without a history of prior overt stroke (n = 27) and SCA participants on blood transfusion (n = 7) are shown, however to reduce confounds from patient heterogeneity only non-transfusion patients were used for testing the primary hypothesis of the study. Tissue volumes (A) are significantly reduced in non-transfusion patients versus control volunteers. CBF (B) is elevated (P < 0.05) in the cortical mask (Fig. 3) of non-transfusion patient versus controls and did not differ significantly between flow territories. OEF (C) is also elevated (P < 0.05) in non-transfusion patients relative to controls. The central black line on the box plot depicts the median of the data, top and bottom solid lines depict 25th and 75th percentile of the data, and whiskers extend to all data points not determined to be outliers. Actual data points are overlaid on boxplots as red circles (black circles for outliers).

Figure 5

Results of the secondary study aim, which was to assess how OEF and CBF varied for SCA participants with less or more impairment as defined by clinical criteria. OEF (A) was elevated in more impaired patients (P < 0.001), whereas CBF (B) was not different (P = 0.088) between SCA groups with different levels of impairment, likely due to multiple competing effects related to reduced oxygen carrying capacity and steno-occlusion.

Figure 6

Individual case examples of structural and haemo-metabolic imaging. (A) Control: A healthy 25-year-old male control with no vasculopathy or prior infarcts. Mean CBF in the grey matter mask (Fig. 3) is 40.6 ml/100 g/min and whole-brain OEF is 0.325, consistent with normal values. (B) Adult with SCA and silent strokes: A 29-year-old male with SCA on regular blood transfusion therapy for recurrent pain crises. His baseline haemoglobin is 7.7 g/dl, and his pulse oximetry shows an oxygen saturation of 95%. Magnetic resonance angiography of the brain does not reveal any vasculopathy, but prior silent strokes without overt neurological symptoms are apparent on FLAIR imaging (white arrows). The CBF is elevated relative to the control at 60.5 ml/100 g/min, as is the OEF = 0.393. (C) Adult with SCA and progressive infarcts: 25-year-old female with SCA with no history of overt stroke but silent cerebral infarcts apparent on MRI and elevated OEF on her study MRI with recurrent infarcts after this MRI. Her baseline haemoglobin was 7.7 g/dl, and pulse oximetry oxygen saturation of 92.5%. MRI shows a silent cerebral infarct (white arrow, axial and coronal views). Normal magnetic resonance angiography head and neck but CBF and OEF were elevated relative to controls at 51.3 ml/100 g/min and 0.48, respectively. Approximately 1 week after this study MRI, she presented with a typical pain crisis and developed a persistent headache. Clinical MRI showed two punctate foci of restricted diffusion consistent with new, tiny infarcts. Colour bar on right denotes CBF in units of ml/100 g/min.