Carlos C Faraco

Routine Clinical Evaluation of Cerebrovascular Reserve Capacity Using Carbogen in Patients With Intracranial Stenosis

Background and Purpose— A promising method for identifying hemodynamic impairment that may serve as a biomarker for stroke risk in patients with intracranial stenosis is cerebrovascular reactivity (CVR) mapping using noninvasive MRI. Here, abilities to measure CVR safely in the clinic using hypercarbic hyperoxic (carbogen) gas challenges, which increase oxygen delivery to tissue, are investigated. Methods— In sequence with structural and angiographic imaging, blood oxygenation level–dependent carbogen-induced CVR scans were performed in patients with symptomatic intracranial stenosis (n=92) and control (n=10) volunteers, with a subgroup of patients (n=57) undergoing cerebral blood flow–weighted pseudocontinuous arterial spin labeling CVR. Subjects were stratified for 4 substudies to evaluate relationships between (1) carbogen and hypercarbic normoxic CVR in healthy tissue (n=10), (2) carbogen cerebral blood flow CVR and blood oxygenation level–dependent CVR in intracranial stenosis patients (n=57), (3) carbogen CVR and clinical measures of disease in patients with asymmetrical intracranial atherosclerotic (n=31) and moyamoya (n=29) disease, and (4) the CVR scan and immediate and longer-term complications (n=92). Results— Noninvasive blood oxygenation level–dependent carbogen-induced CVR values correlate with (1) lobar hypercarbic normoxic gas stimuli in healthy tissue (R=0.92; P<0.001), (2) carbogen-induced cerebral blood flow CVR in patients with intracranial stenosis (R=0.30–0.33; P<0.012), and (3) angiographic measures of disease severity both in atherosclerotic and moyamoya patients after appropriate processing. No immediate stroke-related complications were reported in response to carbogen administration; longer-term neurological events fell within the range for expected events in this patient population. Conclusions— Carbogen-induced CVR elicited no added adverse events and provided a surrogate marker of cerebrovascular reserve consistent with intracranial vasculopathy.

Bolus arrival time and cerebral blood flow responses to hypercarbia

The purpose of this study was to evaluate how cerebral blood flow and bolus arrival time (BAT) measures derived from arterial spin labeling (ASL) MRI data change for different hypercarbic gas stimuli. Pseudocontinuous ASL (pCASL) was applied (3.0T; spatial resolution = 4 × 4 × 7 mm 3 ; repetition time/echo time (TR/TE) = 3,600/11 ms) sequentially in healthy volunteers (n = 12; age = 30±4 years) for separate experiments in which (i) normocarbic normoxia (i.e., room air), hypercarbic normoxia (i.e., 5% CO2/21% O2/74% N2), and hypercarbic hyperoxia (i.e., carbogen: 5% CO2/95% O2) gas was administered (12 L/minute). Cerebral blood flow and BAT changes were quantified using models that account for macrovascular signal and partial volume effects in all gray matter and regionally in cerebellar, temporal, occipital, frontal, and parietal lobes. Regional reductions in BAT of 4.6% to 7.7% and 3.3% to 6.6% were found in response to hypercarbic normoxia and hypercarbic hyperoxia, respectively. Cerebral blood flow increased by 8.2% to 27.8% and 3.5% to 19.8% for hypercarbic normoxia and hypercarbic hyperoxia, respectively. These findings indicate that changes in BAT values may bias functional ASL data and thus should be considered when choosing appropriate experimental parameters in calibrated functional magnetic resonance imaging or ASL cerebrovascular reactivity experiments that use hypercarbic gas stimuli.

Dual echo vessel-encoded ASL for simultaneous BOLD and CBF reactivity assessment in patients with ischemic cerebrovascular disease

Blood oxygenation level‐dependent (BOLD)‐weighted and vessel‐encoded arterial spin labeling (VE‐ASL) MRI provide complementary information and can be used in sequence to gauge hemodynamic contributions to cerebrovascular reactivity. Here, cerebrovascular reactivity is assessed using dual echo VE‐ASL MRI to understand how VE labeling preparations influence BOLD and ASL contrast in flow‐limited and healthy perfusion territories.

The vascular steal phenomenon is an incomplete contributor to negative cerebrovascular reactivity in patients with symptomatic intracranial stenosis.

‘Vascular steal’ has been proposed as a compensatory mechanism in hemodynamically compromised ischemic parenchyma. Here, independent measures of cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) responses to a vascular stimulus in patients with ischemic cerebrovascular disease are recorded. Symptomatic intracranial stenosis patients (n = 40) underwent a multimodal 3.0T MRI protocol including structural (T1-weighted and T2-weighted fluid-attenuated inversion recovery) and hemodynamic (BOLD and CBF-weighted arterial spin labeling) functional MRI during room air and hypercarbic gas administration. CBF changes in regions demonstrating negative BOLD reactivity were recorded, as well as clinical correlates including symptomatic hemisphere by infarct and lateralizing symptoms. Fifteen out of forty participants exhibited negative BOLD reactivity. Of these, a positive relationship was found between BOLD and CBF reactivity in unaffected (stenosis degree <50%) cortex. In negative BOLD cerebrovascular reactivity regions, three patients exhibited significant (P < 0.01) reductions in CBF consistent with vascular steal; six exhibited increases in CBF; and the remaining exhibited no statistical change in CBF. Secondary findings were that negative BOLD reactivity correlated with symptomatic hemisphere by lateralizing clinical symptoms and prior infarcts(s). These data support the conclusion that negative hypercarbia-induced BOLD responses, frequently assigned to vascular steal, are heterogeneous in origin with possible contributions from autoregulation and/or metabolism.

The Cumulative Influence of Hyperoxia and Hypercapnia on Blood Oxygenation and R2

Cerebrovascular reactivity (CVR)-weighted blood-oxygenation-level-dependent magnetic resonance imaging (BOLD-MRI) experiments are frequently used in conjunction with hyperoxia. Owing to complex interactions between hyperoxia and hypercapnia, quantitative effects of these gas mixtures on BOLD responses, blood and tissue R2∗, and blood oxygenation are incompletely understood. Here we performed BOLD imaging (3T; TE/TR = 35/2,000 ms; spatial resolution = 3×3×3.5 mm3) in healthy volunteers (n = 12; age = 29±4.1 years) breathing (i) room air (RA), (ii) normocapnic-hyperoxia (95% O2/5% N2, HO), (iii) hypercapnic-normoxia (5% CO2/21% O2/74% N2, HC-NO), and (iv) hypercapnic-hyperoxia (5% CO2/95% O2, HC-HO). For HC-HO, experiments were performed with separate RA and HO baselines to control for changes in O2. T2-relaxation-under-spin-tagging MRI was used to calculate basal venous oxygenation. Signal changes were quantified and established hemodynamic models were applied to quantify vasoactive blood oxygenation, blood–water R∗2, and tissue-water R∗2. In the cortex, fractional BOLD changes (stimulus/baseline) were HO/RA = 0.011 ± 0.007; HC-NO/RA = 0.014±0.004; HC-HO/HO = 0.020±0.008; and HC-HO/RA = 0.035 ±0.010; for the measured basal venous oxygenation level of 0.632, this led to venous blood oxygenation levels of 0.660 (HO), 0.665 (HC-NO), and 0.712 (HC-HO). Interleaving a HC-HO stimulus with HO baseline provided a smaller but significantly elevated BOLD response compared with a HC-NO stimulus. Results provide an outline for how blood oxygenation differs for several gas stimuli and provides quantitative information on how hypercapnic BOLD CVR and R∗2 are altered during hyperoxia.

Crossed cerebellar diaschisis after stroke identified noninvasively with cerebral blood flow-weighted arterial spin labeling MRI.

BACKGROUND AND PURPOSE Crossed cerebellar diaschisis (CCD) is most commonly investigated using hemodynamic PET and SPECT imaging. However, noninvasive MRI offers advantages of improved spatial resolution, allowing hemodynamic changes to be compared directly with structural findings and without concerns related to ionizing radiation exposure. The aim of this study was to evaluate relationships between CCD identified from cerebral blood flow (CBF)-weighted arterial spin labeling (ASL) MRI with cerebrovascular reactivity (CVR)-weighted blood oxygenation level dependent (BOLD) MRI, Wallerian degeneration, clinical motor impairment, and corticospinal tract involvement. METHODS Subjects (n=74) enrolled in an ongoing observational stroke trial underwent CBF-weighted ASL and hypercapnic CVR-weighted BOLD MRI. Hemispheric asymmetry indices for basal cerebellar CBF, cerebellar CVR, and cerebral peduncular area were compared between subjects with unilateral supratentorial infarcts (n=18) and control subjects without infarcts (n=16). CCD required (1) supratentorial infarct and (2) asymmetric cerebellar CBF (>95% confidence interval relative to controls). RESULTS In CCD subjects (n=9), CVR (p=0.04) and cerebral peduncular area (p<0.01) were significantly asymmetric compared to controls. Compared to infarct subjects not meeting CCD criteria (n=9), CCD subjects had no difference in corticospinal tract location for infarct (p=1.0) or motor impairment (p=0.08). CONCLUSIONS CCD correlated with cerebellar CVR asymmetry and Wallerian degeneration. These findings suggest that noninvasive MRI may be a useful alternative to PET or SPECT to study structural correlates and clinical consequences of CCD following supratentorial stroke.

In vivo quantification of hyperoxic arterial blood water T1.

Normocapnic hyperoxic and hypercapnic hyperoxic gas challenges are increasingly being used in cerebrovascular reactivity (CVR) and calibrated functional MRI experiments. The longitudinal arterial blood water relaxation time (T1a) change with hyperoxia will influence signal quantification through mechanisms relating to elevated partial pressure of plasma‐dissolved O2 (pO2) and increased oxygen bound to hemoglobin in arteries (Ya) and veins (Yv). The dependence of T1a on Ya and Yv has been elegantly characterized ex vivo; however, the combined influence of pO2, Ya and Yv on T1a in vivo under normal ventilation has not been reported. Here, T1a is calculated during hyperoxia in vivo by a heuristic approach that evaluates T1‐dependent arterial spin labeling (ASL) signal changes to varying gas stimuli. Healthy volunteers (n = 14; age, 31.5 ± 7.2 years) were scanned using pseudo‐continuous ASL in combination with room air (RA; 21% O2/79% N2), hypercapnic normoxic (HN; 5% CO2/21% O2/74% N2) and hypercapnic hyperoxic (HH; 5% CO2/95% O2) gas administration. HH T1a was calculated by requiring that the HN and HH cerebral blood flow (CBF) change be identical. The HH protocol was then repeated in patients (n = 10; age, 61.4 ± 13.3 years) with intracranial stenosis to assess whether an HH T1a decrease prohibited ASL from being performed in subjects with known delayed blood arrival times. Arterial blood T1a decreased from 1.65 s at baseline to 1.49 ± 0.07 s during HH. In patients, CBF values in the affected flow territory for the HH condition were increased relative to baseline CBF values and were within the physiological range (RA CBF = 36.6 ± 8.2 mL/100 g/min; HH CBF = 45.2 ± 13.9 mL/100 g/min). It can be concluded that hyperoxic (95% O2) 3‐T arterial blood T1aHH = 1.49 ± 0.07 s relative to a normoxic T1a of 1.65 s. Copyright

Planning-free cerebral blood flow territory mapping in patients with intracranial arterial stenosis

A noninvasive method for quantifying cerebral blood flow and simultaneously visualizing cerebral blood flow territories is vessel-encoded pseudocontinuous arterial spin labeling MRI. However, obstacles to acquiring such information include limited access to the methodology in clinical centers and limited work on how clinically acquired vessel-encoded pseudocontinuous arterial spin labeling data correlate with gold-standard methods. The purpose of this work is to develop and validate a semiautomated pipeline for the online quantification of cerebral blood flow maps and cerebral blood flow territories from planning-free vessel-encoded pseudocontinuous arterial spin labeling MRI with gold-standard digital subtraction angiography. Healthy controls (n = 10) and intracranial atherosclerotic disease patients (n = 34) underwent 3.0 T MRI imaging including vascular (MR angiography) and hemodynamic (cerebral blood flow-weighted arterial spin labeling) MRI. Patients additionally underwent catheter and/or CT angiography. Variations in cross-territorial filling were grouped according to diameters of circle of Willis vessels in controls. In patients, Cohen’s k-statistics were computed to quantify agreement in perfusion patterns between vessel-encoded pseudocontinuous arterial spin labeling and angiography. Cross-territorial filling patterns were consistent with circle of Willis anatomy. The intraobserver Cohens k-statistics for cerebral blood flow territory and digital subtraction angiography perfusion agreement were 0.730 (95% CI = 0.593–0.867; reader one) and 0.708 (95% CI = 0.561–0.855; reader two). These results support the feasibility of a semiautomated pipeline for evaluating major neurovascular cerebral blood flow territories in patients with intracranial atherosclerotic disease.

Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD): a scoring system for moyamoya severity based on multimodal hemodynamic imaging

OBJECTIVE Quantification of the severity of vasculopathy and its impact on parenchymal hemodynamics is a necessary prerequisite for informing management decisions and evaluating intervention response in patients with moyamoya. The authors performed digital subtraction angiography and noninvasive structural and hemodynamic MRI, and they outline a new classification system for patients with moyamoya that they have named Prior Infarcts, Reactivity, and Angiography in Moyamoya Disease (PIRAMD). METHODS Healthy control volunteers (n = 11; age 46 ± 12 years [mean ± SD]) and patients (n = 25; 42 ± 13.5 years) with angiographically confirmed moyamoya provided informed consent and underwent structural (T1-weighted, T2-weighted, FLAIR, MR angiography) and hemodynamic (T2*- and cerebral blood flow-weighted) 3-T MRI. Cerebrovascular reactivity (CVR) in the internal carotid artery territory was assessed using susceptibility-weighted MRI during a hypercapnic stimulus. Only hemispheres without prior revascularization were assessed. Each hemisphere was considered symptomatic if localizing signs were present on neurological examination and/or there was a history of transient ischemic attack with symptoms referable to that hemisphere. The PIRAMD factor weighting versus symptomatology was optimized using binary logistic regression and receiver operating characteristic curve analysis with bootstrapping. The PIRAMD finding was scored from 0 to 10. For each hemisphere, 1 point was assigned for prior infarct, 3 points for reduced CVR, 3 points for a modified Suzuki Score ≥ Grade II, and 3 points for flow impairment in ≥ 2 of 7 predefined vascular territories. Hemispheres were divided into 3 severity grades based on total PIRAMD score, as follows: Grade 1, 0-5 points; Grade 2, 6-9 points; and Grade 3, 10 points. RESULTS In 28 of 46 (60.9%) hemispheres the findings met clinical symptomatic criteria. With decreased CVR, the odds ratio of having a symptomatic hemisphere was 13 (95% CI 1.1-22.6, p = 0.002). The area under the curve for individual PIRAMD factors was 0.67-0.72, and for the PIRAMD grade it was 0.845. There were 0/8 (0%), 10/18 (55.6%), and 18/20 (90%) symptomatic PIRAMD Grade 1, 2, and 3 hemispheres, respectively. CONCLUSIONS A scoring system for total impairment is proposed that uses noninvasive MRI parameters. This scoring system correlates with symptomatology and may provide a measure of hemodynamic severity in moyamoya, which could be used for guiding management decisions and evaluating intervention response.

Interrogating the Functional Correlates of Collateralization in Patients with Intracranial Stenosis Using Multimodal Hemodynamic Imaging

The authors assessed correlations among baseline perfusion and arterial transit time artifacts, cerebrovascular reactivity, and the presence of collateral vessels on digital subtraction angiography. Arterial spin-labeling MRI and DSA were compared with BOLD MR imaging measures of hypercapnic cerebrovascular reactivity in 18 patients with symptomatic intracranial stenosis. In regions with normal-to-high signal on ASL, collateral vessel presence on DSA strongly correlated with declines in cerebrovascular reactivity (as measured on BOLD MRI). These data support the use of ASL MR imaging rather than invasive DSA to assess the presence of collateralization, even for patients with internal carotid stenosis from nonatherosclerotic etiologies. Also, collaterals identified on ASL with arterial transit artifacts correlated with decreased CVR compared with regions not perfused via collaterals. BACKGROUND AND PURPOSE: The importance of collateralization for maintaining adequate cerebral perfusion is increasingly recognized. However, measuring collateral flow noninvasively has proved elusive. The aim of this study was to assess correlations among baseline perfusion and arterial transit time artifacts, cerebrovascular reactivity, and the presence of collateral vessels on digital subtraction angiography. MATERIALS AND METHODS: The relationship between the presence of collateral vessels on arterial spin-labeling MR imaging and DSA was compared with blood oxygen level–dependent MR imaging measures of hypercapnic cerebrovascular reactivity in patients with symptomatic intracranial stenosis (n = 18). DSA maps were reviewed by a neuroradiologist and assigned the following scores: 1, collaterals to the periphery of the ischemic site; 2, complete irrigation of the ischemic bed via collateral flow; and 3, normal antegrade flow. Arterial spin-labeling maps were scored according to the following: 0, low signal; 1, moderate signal with arterial transit artifacts; 2, high signal with arterial transit artifacts; and 3, normal signal. RESULTS: In regions with normal-to-high signal on arterial spin-labeling, collateral vessel presence on DSA strongly correlated with declines in cerebrovascular reactivity (as measured on blood oxygen level–dependent MR imaging, P < .001), most notably in patients with nonatherosclerotic disease. There was a trend toward increasing cerebrovascular reactivity with increases in the degree of collateralization on DSA (P = .082). CONCLUSIONS: Collateral vessels may have fundamentally different vasoreactivity properties from healthy vessels, a finding that is observed most prominently in nonatherosclerotic disease and, to a lesser extent, in atherosclerotic disease.