Neuroimaging of vascular reserve in patients with cerebrovascular diseases

Abstract

Cerebrovascular reactivity, defined broadly as the ability of brain parenchyma to adjust cerebral blood flow in response to altered metabolic demand or a vasoactive stimulus, is being measured with increasing frequency and may have a use for portending new or recurrent stroke risk in patients with cerebrovascular disease. The purpose of this review is to outline (i) the physiological basis of variations in cerebrovascular reactivity, (ii) available approaches for measuring cerebrovascular reactivity in research and clinical settings, and (iii) clinically-relevant cerebrovascular reactivity findings in the context of patients with cerebrovascular disease, including atherosclerotic arterial steno-occlusion, non-atherosclerotic arterial steno-occlusion, anemia, and aging. Literature references summarizing safety considerations for these procedures and future directions for standardizing protocols and post-processing procedures across centers are presented in the specific context of major unmet needs in the setting of cerebrovascular disease.

Keywords: Cerebral blood flow; Cerebrovascular reactivity; Hemodynamics; Hypercapnia; Ischemia; Stroke.

Figure 1

Healthy cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) patterns. (A) Major neck and head vessels as visualized from 3.0 Tesla time-of-flight magnetic resonance angiography. (B) Tissue atlas (Montreal Neurological Institute; 2 mm isotropic) and (C) corresponding flow territories averaged from healthy adults overlaid on the atlas, as quantified from vessel-encoded arterial spin labeling MRI (red=basilar artery; green=left ICA; blue= right ICA). (D) Normocapnic normoxic CBF, (E) Hypercapnic (5% CO₂) normoxic CBF, and corresponding (F) CVR quantified as the fractional CBF change normalized by the end-tidal change in CO₂ (EtCO₂) in 10 healthy subjects. CBF was determined using arterial spin labeling and thresholded to show gray matter only, as white matter CBF values are less reliable using ASL at 3.0T. Additional information can be found in (Donahue et al., 2014b)

Figure 2

Relationships between vessel diameter and intravascular pressure (A) and flow velocity (B); data are adapted from data summarized in Piechnik et al. (Piechnik et al., 2008), and based on human and animal literature reports of PaCO₂-manipulated perfusion over a range of 25–70 mmHg.

Figure 3

Physiological changes in early stages of cerebrovascular disease. For increasing levels of impairment and cerebral perfusion pressure (CPP) reduction, cerebral hemodynamics adjust in a manner that depends on the adequacy of tissue-level compensation mechanisms. (A) Cerebral blood volume (CBV) can be maintained in mild stages of disease through microvascular autoregulation, which in turn (B) reduces cerebrovascular reactivity (CVR), or the further abilities of vessels to respond to a vasoactive stimulus. (C) When CVR is exhausted, cerebral blood flow (CBF) reduces if CPP reduces further. (D) Throughout these stages, microvascular atherosclerotic burden and/or damage to arteriolar smooth muscle may lead to increases in CVR_DELAY, or the time required for microvessels to vasodilate. (E) When these mechanisms become collectively inadequate to maintain sufficient oxygen delivery to tissue, the oxygen extraction fraction (OEF; ratio of oxygen consumed to oxygen delivered) will begin to increase.

Figure 4

Blood oxygenation level-dependent (BOLD) MR images acquired for cerebrovascular reactivity (CVR) imaging may be analyzed using either a conventional approach where the stimulus paradigm or EtCO₂ change is applied as the regressor, or in a time-regression approach where the regressor is progressed in time, and maximum correlation and time to maximum correlation (delay) are separately quantified. Representative cases of (A) uncorrected CVR using a pre-defined regressor from the stimulus timing (CVR_Uncorrected), (B) maximum CVR (CVR_Max) from when the time-progressed regressor maximally corresponds with the timecourse, and (C) time-to-maximum CVR (CVR_Delay) maps are shown here for a 52-year old Caucasian male with primary moyamoya disease acquired with hypercapnic stimulus. CVR_Uncorrected images show reduced CVR-weighted signal in the left anterior and posterior flow territories compared to the contralateral flow territories. While the CVR_Max is marginally reduced in the affected region, a greater difference is observed in the CVR_Delay of the affected region compared to the non-affected region. BOLD signal time courses, normalized to baseline, are shown for the affected region and contralateral region across two baseline blocks and one stimulus block. In the affected region, the signal ultimately reaches a similar level compared to the contralateral region but takes longer to achieve this maximum response, potentially indicating delayed blood arrival times and impaired smooth muscle or endothelial response to vasoactive stimuli.

Figure 5

Blood oxygenation level-dependent (BOLD) MRI may be utilized to monitor treatment response in patients with moyamoya disease. (A, B) Representative examples of pre- and post-surgery digital subtraction angiography (DSA), (C, D) uncorrected CVR (CVR_Uncorrected), and (E, F) time-to-maximum CVR (CVR_Delay) maps are shown for two patients: 1) a 28-year old Asian female with primary moyamoya disease and successful right-sided EDAS and 2) a 53-year old Caucasian female with secondary moyamoya disease and unsuccessful left-sided EDAS. Surgical success was determined based on whether 2/3 or more of the MCA territory was perfused following surgery as determined from DSA. For the first patient, success of the revascularization procedure is demonstrated by DSA, and corresponding increases in CVR_Uncorrected (C) and decreases in CVR_Delay (E) can be seen. For the second patient, the revascularization procedure was unsuccessful based on the post-surgery DSA (B), and this is indicated by the lack of change seen in the CVR_Uncorrected (D) and CVR_Delay (F) images. This example illustrates the potential of CVR imaging as a marker of treatment response to revascularization surgery in patients with moyamoya disease.

Figure 6

Cerebrovascular reserve in sickle cell disease (SCD). (Above) Intracranial magnetic resonance angiography (MRA) and corresponding cerebral blood flow (CBF) maps at baseline and 10 minutes following intravenous acetazolamide (dose=16 mg/kg) infusion in a 24 year old healthy male without a history of cerebrovascular disease or hemoglobinopathy. CVR, defined as the fractional change in CBF in response to acetazolamide, is approximately 80% and largely symmetric throughout gray matter parenchyma. (Below) A 29 year old male with SCD and moyamoya syndrome. MRA shows hypervascularity and baseline CBF is elevated in response to anemia and reduced oxygen carrying capacity. Upon acetazolamide administration, the CBF response is blunted compared to the healthy control, translating to low-to-negligible CVR. These data are consistent with the SCD patient operating at or near cerebrovascular reserve capacity and such patients may be at elevated risk of future ischemic events. Images provided by Lena Vaclavu and additional information can be found in Vaclavu L et al. (Vaclavu et al., 2017).

Figure 7

Reactivity in white matter, acquired using 7.0T MRI and adapted from Bhogal et al. (Bhogal et al., 2015). (A) Normalized BOLD-CVR response curves comparing gray matter with white matter of increasing depth averaged across nine subjects. BOLD signal magnitude is reduced at increasing white matter depth. Also, the shape of the response curve shifts to the right at increasing white matter depth. (B) Regions of interest for a single subject are shown in top right inset. Return to baseline decaying exponential curves averaged across nine subjects.