Assessment of Cerebrovascular Reactivity Using Emerging MR Technologies

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4 Assessment of Cerebrovascular Reactivity Using Emerging MR Technologies

Extracranial-intracranial (EC-IC) arterial bypass is a potential therapy for the prevention of ischemic stroke in patients with high internal carotid or middle cerebral artery (MCA) steno-occlusive disease. This procedure was popular until the EC-IC Bypass Study ¹ was published in 1985. This study of patients with ischemic symptoms and atherosclerotic stenosis or occlusion of the high internal carotid artery or MCA found no difference in stroke incidence between patients randomized to medical therapy versus surgical bypass. A critique of the EC-IC Bypass Study was that patients were included based on angiographic stenosis, without specifically selecting the subset of patients who had cerebral hemodynamic compromise. Subsequent advances in brain imaging have made it possible to better identify this subset.

The most widely studied imaging markers of cerebral hemodynamic compromise are increased oxygen extraction fraction (OEF) and decreased cerebrovascular reactivity (CVR). A major trial currently under way, the North American Carotid Occlusion Surgery Study (COSS),² uses increased OEF on positron emission tomography (PET) to select patients for EC-IC bypass. PET measurement of OEF is accurate and the results of this trial are highly anticipated, yet clinical translation of PET OEF may remain a challenge due to limited availability, high cost, and the requirement for an on-site cyclotron to produce the very short-lived radiopharmaceutical oxygen-15 (half-life 2 minutes). This chapter will focus on CVR measurement using MRI.

Cerebrovascular reactivity

Severe stenosis or occlusion of a major cerebral artery does not usually result in a blood flow deficit. The cerebral autoregulatory mechanism maintains flow by compensatory dilatation of downstream arterial vessels and corresponding reduction of flow resistance. The presence of collateral flow pathways, including the circle of Willis and pial collaterals, also play an important compensatory role. However, increasing severity of steno-occlusive disease, with limited collateral flow, can lead to exhaustion of vasodilatory capacity. In this setting, blood flow becomes dependent on systemic blood pressure. One can assess cerebrovascular reserve by applying a vasodilatory stimulus, and measuring the resulting augmentation of cerebral blood flow (CBF). Cerebrovascular reactivity (CVR) is defined as the change in CBF per unit change in vasodilatory stimulus.

Existing techniques for measuring CVR

Assessment of CVR requires a vasodilatory stimulus and a technique for measuring the resulting change in CBF. The commonly used vasodilatory stimuli used are intravenous administration of acetazolamide and induction of hypercapnia through breath holding or inhalation of carbon dioxide (CO₂). Acetazolamide is widely available and administration does not require special equipment, but the technique does have limitations. After baseline CBF measurement and then acetazolamide injection, one must wait 10 to 15 minutes for peak change in CBF before imaging again. Differences in pharmacokinetics and pharmacodynamics between sessions for a given patient, and among patients, result in unmeasured variation in magnitude of the vasodilatory stimulus. Induction of hypercapnia through breath holding suffers from a constantly changing blood CO₂ level and it is therefore extremely difficult to quantify the magnitude of vasodilatory stimulus. Our preferred technique uses a re-breathing device called the RespirAct™ developed by one of our collaborators. This device is capable of controlling end-tidal CO₂ and O₂ precisely and independently with transitions between a stable baseline state and stable hypercapnic state occurring within three breaths.³ End-tidal PCO₂ measured with this device is as accurate a measurement of arterial PCO₂ as actual arterial blood sampling.⁴

Techniques for measuring the acetazolamide or hypercapnia-induced changes in CBF have traditionally included transcranial Doppler ultrasound (TCD), single-photon emission tomography (SPECT), and stable-xenon inhalation computed tomography (Xe-CT). TCD is inexpensive, noninvasive, and free of ionizing radiation. However, the technique yields only a single measurement of CVR for each MCA territory rather than a spatial map of reactivity for the brain, it is technically not feasible in about 10% of patients due to lack of an acoustic window, and it is highly operator dependent. SPECT has had relatively widespread use for mapping CVR. A major limitation of SPECT is that the study is typically performed over 2 days due to radiopharmaceutical kinetics. It is possible to perform the study over a single day, but this requires much higher activity for the second scan, increasing the radiation dose to the patient.⁵ Xe-CT is an excellent imaging technique, but it not widely available and inhalation of stable xenon can have undesirable side effects.

Clinical significance of impaired CVR

CVR is typically categorized into three patterns: normal, reduced, and paradoxical (negative). The paradoxical pattern refers to vasodilatory stimulus–induced reduction of CBF. This “steal phenomenon”⁶ develops because flow is diverted away from tissue that can no longer vasodilate toward tissues that retain this ability. Blood simply follows the path of least resistance. Consider a patient with severe stenosis of the right middle cerebral artery (MCA), and a normal right internal carotid artery (ICA) and right anterior cerebral artery (ACA). A vasodilatory stimulus will result in dilatation of the arterial vessels of the right ACA territory, and a corresponding decrease in vascular resistance in this territory. The right MCA territory arterial vessels are already maximally dilated at rest, and will not dilate any further. Following application of a vasodilatory stimulus, the decrease in vascular resistance in the ACA territory relative to the MCA territory results in redistribution of blood flow from the MCA to the ACA. In this way, the ACA territory “steals” from the MCA territory. Reduced CVR indicates impairment of cerebral hemodynamics, and paradoxical CVR indicates particularly severe impairment.^7,⁸

CVR Impairment is a strong and independent predictor of future ischemic events. Ogasawara et al.⁹ studied 70 patients with symptomatic unilateral ICA or MCA occlusion. Patients were categorized as having normal versus impaired CVR using acetazolamide and Xe-133 SPECT, and were followed prospectively for 2 years. The recurrent stroke rate was 6% in patients with normal CVR at entry, compared with 35% in patients with impaired CVR (significant difference, p = 0.03). Silvestrini et al.¹⁰ studied 94 patients with asymptomatic carotid artery stenosis of at least 70%. Patients were categorized as having normal versus impaired CVR using CO₂ and TCD, and were followed prospectively for a median of 2.4 years. The annual rate of ipsilateral ischemic events was 4% in patients with normal CVR at entry, compared with 14% in patients with impaired CVR. Markus et al.¹¹ studied 107 patients with symptomatic carotid artery stenosis or carotid occlusion. Patients were categorized as having normal versus impaired CVR using CO₂ and TCD, and were prospectively followed for a mean of 4.4 years. Controlling for patient demographics, vascular risk factors, prior infarct, and degree of stenosis, impaired reactivity was an independent predictor of ipsilateral TIA or stroke (odds ratio 14.4, 95% CI 2.63–78.74, p = 0.002). From these studies, and others with similar results,^12,¹³ it is well known that CVR can identify a subgroup of steno-occlusive disease patients at higher risk of stroke. The Japanese Extracranial to Intracranial Bypass Trial (JET),¹⁴ is an ongoing surgical study using acetazolamide SPECT CVR and acetazolamide Xe-CT CVR to identify this high-risk subgroup.

Other important uses of CVR in the context of EC-IC bypass are follow-up of those patients who do not initially meet criteria for bypass, and long-term follow-up of patients who do undergo bypass. A recent acetazolamide SPECT CVR study ¹⁵ of 77 patients with Moyamoya disease demonstrated that CVR performed 6 to 12 months following bypass is a strong predictor of long-term post-operative clinical course.

Emerging MR techniques for measuring CVR

Emerging MRI techniques for measuring CVR offer major advantages over the traditional techniques. We have had particular success applying blood oxygen level–dependent (BOLD) MRI measurement of CVR in a clinical cerebrovascular disease population. We will also briefly discuss dynamic susceptibility contrast (DSC) and arterial spin–labeling (ASL) MRI techniques for measuring CVR.

I BOLD CO₂ MR Measurement of CVR

Blood oxygen level–dependent (BOLD) MRI refers to a MRI acquisition that is sensitive to the concentration of deoxyhemoglobin in blood. Arterial blood is normally 95% to 100% saturated with oxygen, and venous blood is approximately 60% to 70% saturated. An increase in CBF during stable neuronal activity (i.e., a stable number of deoxyhemoglobin molecules produced per unit time) results in dilution or “wash-out” of deoxyhemoglobin in the cerebral microcirculation. Deoxyhemoglobin is a paramagnetic substance. Paramagnetic substances constrained by boundaries such as red cell membranes or blood vessel walls yield magnetic field inhomogeneities that act to reduce the MRI signal. Therefore, an increase in CBF in the setting of constant neural activity results in a decrease in deoxyhemoglobin concentration in the microcirculation, yielding an increase in MR signal. Furthermore, % BOLD MRI signal is linearly related to % CBF over the range of CBF changes that occur in a CVR study,¹⁶ enabling the use BOLD MRI to measure CVR.

Advantages of the BOLD MRI technique are the use of an MR pulse sequence that is standard on modern clinical MR systems, short duration of study (acquisition time less than 10 minutes, and real-time data analysis), no requirement for intravenous injection, no ionizing radiation, and the ability to acquire routine MRI and magnetic resonance angiography (MRA) of the brain in the same imaging session. This technique has particular potential when one uses CO₂ as the vasodilatory stimulus: unlike the sustained effect of acetazolamide, arterial pCO₂ is rapidly responsive to changes in the inhaled concentration of CO₂. The BOLD MRI pulse sequence, which is based on rapid echoplanar imaging, can acquire a complete data set covering the entire brain in 2 seconds. The sequence is repeated several hundred times over the course of several minutes in order to provide statistical power for the data analysis while correcting for imaging system instabilities.

The greatest concern with BOLD CVR has been that BOLD MRI signal depends on CBF, but also (and to an unknown extent) on other factors: cerebral blood volume (CBV), cerebral metabolic rate of oxygen consumption (CMRO₂), arterial partial pressure of oxygen (PaO₂), and hematocrit. However, we now have empirical evidence that these other factors are not major issues. Goode et al.¹⁷ and Kassner et al.¹⁸ have demonstrated between-session reproducibility of BOLD CO₂ CVR, and Shiino et al.¹⁹ and our group²⁰ have demonstrated the accuracy of BOLD CO₂ CVR in patients with severe cerebrovascular disease. Shiino et al. compared BOLD CO₂ CVR with SPECT acetazolamide CVR in 10 patients with severe carotid stenosis or occlusion. They found that the degree of impairment and distribution of impaired areas detected by BOLD MRI correlated with the results of SPECT. Our group studied 38 patients with steno-occlusive disease by both BOLD CO₂ CVR and arterial spin labeling (ASL) MRI. The latter technique does not have the CBV and CMRO₂ dependencies of BOLD MRI. Hemispheric CVR measured by BOLD MRI was significantly correlated with that measured by ASL MRI for both gray matter (r = 0.83, p < 0.0001) and white matter (r = 0.80, p < 0.0001). Diagnostic accuracy (area under receiver operating characteristic curve) for BOLD MRI discrimination between normal and abnormal hemispheric CVR was 0.90 (95% CI = 0.81 to 0.98; p < 0.001) for gray matter and 0.82 (95% CI = 0.70 to 0.94; P