Blood flow distribution in cerebral arteries

High-resolution phase–contrast magnetic resonance imaging can now assess flow in proximal and distal cerebral arteries. The aim of this study was to describe how total cerebral blood flow (tCBF) is distributed into the vascular tree with regard to age, sex and anatomic variations. Forty-nine healthy young (mean 25 years) and 45 elderly (mean 71 years) individuals were included. Blood flow rate (BFR) in 21 intra- and extracerebral arteries was measured. Total cerebral blood flow was defined as BFR in the internal carotid plus vertebral arteries and mean cerebral perfusion as tCBF/brain volume. Carotid/vertebral distribution was 72%/28% and was not related to age, sex, or brain volume. Total cerebral blood flow (717±123 mL/min) was distributed to each side as follows: middle cerebral artery (MCA), 21% distal MCA, 6% anterior cerebral artery (ACA), 12%, distal ACA, 4% ophthalmic artery, 2% posterior cerebral artery (PCA), 8% and 20% to basilar artery. Deviating distributions were observed in subjects with ‘fetal'' PCA. Blood flow rate in cerebral arteries decreased with increasing age (P<0.05) but not in extracerebral arteries. Mean cerebral perfusion was higher in women (women: 61±8; men: 55±6 mL/min/100 mL, P<0.001). The study describes a new method to outline the flow profile of the cerebral vascular tree, including reference values, and should be used for grading the collateral flow system.     

Calibrated MRI to evaluate cerebral hemodynamics in patients with an internal carotid artery occlusion

The purpose of this study was to assess whether calibrated magnetic resonance imaging (MRI) can identify regional variances in cerebral hemodynamics caused by vascular disease. For this, arterial spin labeling (ASL)/blood oxygen level-dependent (BOLD) MRI was performed in 11 patients (65±7 years) and 14 controls (66±4 years). Cerebral blood flow (CBF), ASL cerebrovascular reactivity (CVR), BOLD CVR, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO₂) were evaluated. The CBF was 34±5 and 36±11 mL/100 g per minute in the ipsilateral middle cerebral artery (MCA) territory of the patients and the controls. Arterial spin labeling CVR was 44±20 and 53±10% per 10 mm Hg ▵EtCO₂ in patients and controls. The BOLD CVR was lower in the patients compared with the controls (1.3±0.8 versus 2.2±0.4% per 10 mm Hg ▵EtCO₂, P<0.01). The OEF was 41±8% and 38±6%, and the CMRO₂ was 116±39 and 111±40 μmol/100 g per minute in the patients and the controls. The BOLD CVR was lower in the ipsilateral than in the contralateral MCA territory of the patients (1.2±0.6 versus 1.6±0.5% per 10 mmHg ▵EtCO₂, P<0.01). Analysis was hampered in three patients due to delayed arrival time. Thus, regional hemodynamic impairment was identified with calibrated MRI. Delayed arrival artifacts limited the interpretation of the images in some patients.     

Cerebral arterial bolus arrival time is prolonged in multiple sclerosis and associated with disability

Alterations in the overall cerebral hemodynamics have been reported in multiple sclerosis (MS); however, their cause and significance is unknown. While potential venous causes have been examined, arterial causes have not. In this study, a multiple delay time arterial spin labeling magnetic resonance imaging sequence at 3T was used to quantify the arterial hemodynamic parameter bolus arrival time (BAT) and cerebral blood flow (CBF) in normal-appearing white matter (NAWM) and deep gray matter in 33 controls and 35 patients with relapsing–remitting MS. Bolus arrival time was prolonged in MS in NAWM (1.0±0.2 versus 0.9±0.2 seconds, P=0.031) and deep gray matter (0.90±0.18 versus 0.80±0.14 seconds, P=0.001) and CBF was increased in NAWM (14±4 versus 10±2 mL/100 g/min, P=0.001). Prolonged BAT in NAWM (P=0.042) and deep gray matter (P=0.01) were associated with higher expanded disability status score. This study demonstrates alteration in cerebral arterial hemodynamics in MS. One possible cause may be widespread inflammation. Bolus arrival time was longer in patients with greater disability independent of atrophy and T₂ lesion load, suggesting alterations in cerebral arterial hemodynamics may be a marker of clinically relevant pathology.     

Cerebral blood flow and metabolism of hyperperfusion after cerebral revascularization in patients with moyamoya disease

In moyamoya disease (MMD), surgical revascularization may be complicated with postoperative hyperperfusion. We analyzed cerebral perfusion and metabolism using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) before and after bypass surgery on 42 sides of 34 adult patients with MMD. In seven cases (16.7%) with symptomatic hyperperfusion, diagnosed by qualitative ¹²³I-iodoamphetamine (IMP) SPECT, a subsequent PET study during postoperative subacute stages revealed significantly increased cerebral blood flow (CBF) from 34.1±8.2 to 74.3±12.8 mL/100 g per minute (P<0.01), a persistent increase in cerebral blood volume (CBV) from 5.77±1.67 to 7.01±1.44 mL/100 g and a significant decrease in oxygen extraction fraction (OEF) from 0.61±0.09 to 0.40±0.08 (P<0.01). Mean absolute CBF values during symptomatic hyperperfusion were more than the normal control +2 standard deviations, the predefined criteria of PET. Interestingly, two patients with markedly increased cerebral metabolic rate of oxygen (CMRO₂) at hyperperfusion were complicated with postoperative seizure. Among preoperative PET parameters, increased OEF was the only significant risk factor for symptomatic hyperperfusion (P<0.05). This study revealed that symptomatic hyperperfusion in MMD is characterized by temporary increases in CBF >100% over preoperative values caused by prolonged recovery of increased CBV.     

Blood pressure reduction does not reduce perihematoma oxygenation: a CT perfusion study

Blood pressure (BP) reduction after intracerebral hemorrhage (ICH) is controversial, because of concerns that this may cause critical reductions in perihematoma perfusion and thereby precipitate tissue damage. We tested the hypothesis that BP reduction reduces perihematoma tissue oxygenation.Acute ICH patients were randomized to a systolic BP target of <150 or <180 mm Hg. Patients underwent CT perfusion (CTP) imaging 2 hours after randomization. Maps of cerebral blood flow (CBF), maximum oxygen extraction fraction (OEF^max), and the resulting maximum cerebral metabolic rate of oxygen (CMRO₂^max) permitted by local hemodynamics, were calculated from raw CTP data.Sixty-five patients (median (interquartile range) age 70 (20)) were imaged at a median (interquartile range) time from onset to CTP of 9.8 (13.6) hours. Mean OEF^max was elevated in the perihematoma region (0.44±0.12) relative to contralateral tissue (0.36±0.11; P<0.001). Perihematoma CMRO₂^max (3.40±1.67 mL/100 g per minute) was slightly lower relative to contralateral tissue (3.63±1.66 mL/100 g per minute; P=0.025). Despite a significant difference in systolic BP between the aggressive (140.5±18.7 mm Hg) and conservative (163.0±10.6 mm Hg; P<0.001) treatment groups, perihematoma CBF was unaffected (37.2±11.9 versus 35.8±9.6 mL/100 g per minute; P=0.307). Similarly, aggressive BP treatment did not affect perihematoma OEF^max (0.43±0.12 versus 0.45±0.11; P=0.232) or CMRO₂^max (3.16±1.66 versus 3.68±1.85 mL/100 g per minute; P=0.857). Blood pressure reduction does not affect perihematoma oxygen delivery. These data support the safety of early aggressive BP treatment in ICH.     

Blood flow distribution during heat stress: cerebral and systemic blood flow

The purpose of the present study was to assess the effect of heat stress-induced changes in systemic circulation on intra- and extracranial blood flows and its distribution. Twelve healthy subjects with a mean age of 22±2 (s.d.) years dressed in a tube-lined suit and rested in a supine position. Cardiac output (Q), internal carotid artery (ICA), external carotid artery (ECA), and vertebral artery (VA) blood flows were measured by ultrasonography before and during whole body heating. Esophageal temperature increased from 37.0±0.2°C to 38.4±0.2°C during whole body heating. Despite an increase in Q (59±31%, P<0.001), ICA and VA decreased to 83±15% (P=0.001) and 87±8% (P=0.002), respectively, whereas ECA blood flow gradually increased from 188±72 to 422±189 mL/minute (+135%, P<0.001). These findings indicate that heat stress modified the effect of Q on blood flows at each artery; the increased Q due to heat stress was redistributed to extracranial vascular beds.     

Polynitroxylated-pegylated hemoglobin attenuates fluid requirements and brain edema in combined traumatic brain injury plus hemorrhagic shock in mice

Polynitroxylated-pegylated hemoglobin (PNPH), a bovine hemoglobin decorated with nitroxide and polyethylene glycol moieties, showed neuroprotection vs. lactated Ringer''s (LR) in experimental traumatic brain injury plus hemorrhagic shock (TBI+HS). Hypothesis: Resuscitation with PNPH will reduce intracranial pressure (ICP) and brain edema and improve cerebral perfusion pressure (CPP) vs. LR in experimental TBI+HS. C57/BL6 mice (n=20) underwent controlled cortical impact followed by severe HS to mean arterial pressure (MAP) of 25 to 27 mm Hg for 35 minutes. Mice (n=10/group) were then resuscitated with a 20 mL/kg bolus of 4% PNPH or LR followed by 10 mL/kg boluses targeting MAP>70 mm Hg for 90 minutes. Shed blood was then reinfused. Intracranial pressure was monitored. Mice were killed and %brain water (%BW) was measured (wet/dry weight). Mice resuscitated with PNPH vs. LR required less fluid (26.0±0.0 vs. 167.0±10.7 mL/kg, P<0.001) and had a higher MAP (79.4±0.40 vs. 59.7±0.83 mm Hg, P<0.001). The PNPH-treated mice required only 20 mL/kg while LR-resuscitated mice required multiple boluses. The PNPH-treated mice had a lower peak ICP (14.5±0.97 vs. 19.7±1.12 mm Hg, P=0.002), higher CPP during resuscitation (69.2±0.46 vs. 45.5±0.68 mm Hg, P<0.001), and lower %BW vs. LR (80.3±0.12 vs. 80.9±0.12%, P=0.003). After TBI+HS, resuscitation with PNPH lowers fluid requirements, improves ICP and CPP, and reduces brain edema vs. LR, supporting its development.     

Real-time ultrasound brain perfusion imaging with analysis of microbubble replenishment in acute MCA stroke

Real-time ultrasound perfusion imaging (rt-UPI) allows visualization of microbubbles flowing through the cerebral microvasculature. We hypothesized that analysis of microbubble tissue replenishment would enable for characterization of perfusion deficits in acute middle cerebral artery (MCA) territory stroke. Twenty-three patients (mean age 70.2±13.2 years, 9 weeks) were included. Sequential images of bubble replenishment were acquired by transcranial rt-UPI at low mechanical index immediately after microbubble destruction. Different parameters were calculated from regions of interest (ROIs): real-time time to peak (rt-TTP), rise rate (β), and plateau (A) of acoustic intensity, and A × β was used as an index of blood flow. Results were compared with diffusion-weighted and perfusion magnetic resonance imaging. Parameters of rt-UPI had lower values in ROIs of ischemic as compared with normal tissue (β=0.58±0.40 versus 1.25±0.83; P=0.001; A=1.44±1.75 versus 2.63±2.31; P=0.05; A × β=1.14±2.25 versus 2.98±2.70; P=0.01). Real-time time to peak was delayed in ischemic tissue (11.43±2.67 versus 8.88±1.66 seconds; P<0.001). From the analysis of receiver operating characteristic curves, β and A × β had the largest areas under the curve with optimal cutoff values of β<0.76 and A × β<1.91. We conclude that rt-UPI with analysis of microbubble replenishment correctly identifies ischemic brain tissue in acute MCA stroke.     

Cerebral metabolic rate of oxygen in obstructive sleep apnea at rest and in response to breath-hold challenge

Obstructive sleep apnea (OSA) is associated with extensive neurologic comorbidities. It is hypothesized that the repeated nocturnal apneas experienced in patients with OSA may inhibit the normal apneic response, resulting in hypoxic brain injury and subsequent neurologic dysfunction. In this study, we applied the recently developed OxFlow MRI method for rapid quantification of cerebral metabolic rate of oxygen (CMRO₂) during a volitional apnea paradigm. MRI data were analyzed in 11 OSA subjects and 10 controls (mean ± SD apnea-hypopnea index (AHI): 43.9 ± 18.1 vs. 2.9 ± 1.6 events/hour, P < 0.0001; age: 53.8 ± 8.2 vs. 45.3 ± 8.5 years, P = 0.027; BMI: 36.6 ± 4.4 vs. 31.9 ± 2.2 kg/m², P = 0.0064). Although total cerebral blood flow and arteriovenous oxygen difference were not significantly different between apneics and controls (P > 0.05), apneics displayed reduced baseline CMRO₂ (117.4 ± 37.5 vs. 151.6 ± 29.4 µmol/100 g/min, P = 0.013). In response to apnea, CMRO₂ decreased more in apneics than controls (−10.9 ± 8.8 % vs. −4.0 ± 6.7 %, P = 0.036). In contrast, group differences in flow-based cerebrovascular reactivity were not significant. Results should be interpreted with caution given the small sample size, and future studies with larger independent samples should examine the observed associations, including potential independent effects of age or BMI. Overall, these data suggest that dysregulation of the apneic response may be a mechanism for OSA-associated neuropathology.     

Regional neurovascular coupling and cognitive performance in those with low blood pressure secondary to high-level spinal cord injury: improved by alpha-1 agonist midodrine hydrochloride

Individuals with high-level spinal cord injury (SCI) experience low blood pressure (BP) and cognitive impairments. Such dysfunction may be mediated in part by impaired neurovascular coupling (NVC) (i.e., cerebral blood flow responses to neurologic demand). Ten individuals with SCI >T6 spinal segment, and 10 age- and sex-matched controls were assessed for beat-by-beat BP, as well as middle and posterior cerebral artery blood flow velocity (MCAv, PCAv) in response to a NVC test. Tests were repeated in SCI after 10 mg midodrine (alpha₁-agonist). Verbal fluency was measured before and after midodrine in SCI, and in the control group as an index of cognitive function. At rest, mean BP was lower in SCI (70±10 versus 92±14 mm Hg; P<0.05); however, PCAv conductance was higher (0.56±0.13 versus 0.39±0.15 cm/second/mm Hg; P<0.05). Controls exhibited a 20% increase in PCAv during cognition; however, the response in SCI was completely absent (P<0.01). When BP was increased with midodrine, NVC was improved 70% in SCI, which was reflected by a 13% improved cognitive function (P<0.05). Improvements in BP were related to improved cognitive function in those with SCI (r²=0.52; P<0.05). Impaired NVC, secondary to low BP, may partially mediate reduced cognitive function in individuals with high-level SCI.     

Absolute arterial cerebral blood volume quantification using inflow vascular-space-occupancy with dynamic subtraction magnetic resonance imaging

In patients with steno-occlusive disease of the internal carotid artery (ICA), cerebral blood flow may be maintained by autoregulatory increases in arterial cerebral blood volume (aCBV). Therefore, characterizing aCBV may be useful for understanding hemodynamic compensation strategies. A new ‘inflow vascular-space-occupancy with dynamic subtraction (iVASO-DS)'' MRI approach is presented where aCBV (mL blood/100 mL parenchyma) is quantified without contrast agents using the difference between images with and without inflowing blood water signal. The iVASO-DS contrast mechanism is investigated (3.0 T, spatial resolution=2.4 × 2.4 × 5 mm³) in healthy volunteers (n=8; age=29±5 years), and patients with mild (n=7; age=72±8 years) and severe (n=10; age=73±8 years) ICA stenoses. aCBV was quantified in right and left hemispheres in controls, and, alongside industry standard dynamic susceptibility contrast (DSC), contralateral (cont), and ipsilateral (ips) to maximum stenosis in patients. iVASO contrast significantly correlated (R=0.67, P<0.01) with DSC-CBV after accounting for transit time discrepancies. Gray matter aCBV (mL/100 mL) was 1.60±0.10 (right) versus 1.61±0.20 (left) in controls, 1.59±0.38 (cont) and 1.65±0.37 (ips) in mild stenosis patients, and 1.72±0.18 (cont) and 1.58±0.20 (ips) in severe stenosis patients. aCBV was asymmetric (P<0.01) in 41% of patients whereas no asymmetry was found in any control. The potential of iVASO-DS for autoregulation studies is discussed in the context of existing hemodynamic literature.     

Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis

Vitamin E consists of tocopherols and tocotrienols, in which α-tocotrienol is the most potent neuroprotective form that is also effective in protecting against stroke in rodents. As neuroprotective agents alone are insufficient to protect against stroke, we sought to test the effects of tocotrienol on the cerebrovascular circulation during ischemic stroke using a preclinical model that enables fluoroscopy-guided angiography. Mongrel canines (mean weight=26.3±3.2 kg) were supplemented with tocotrienol-enriched (TE) supplement (200 mg b.i.d, n=11) or vehicle placebo (n=9) for 10 weeks before inducing transient middle cerebral artery (MCA) occlusion. Magnetic resonance imaging was performed 1 hour and 24 hours post reperfusion to assess stroke-induced lesion volume. Tocotrienol-enriched supplementation significantly attenuated ischemic stroke-induced lesion volume (P<0.005). Furthermore, TE prevented loss of white matter fiber tract connectivity after stroke as evident by probabilistic tractography. Post hoc analysis of cerebral angiograms during MCA occlusion revealed that TE-supplemented canines had improved cerebrovascular collateral circulation to the ischemic MCA territory (P<0.05). Tocotrienol-enriched supplementation induced arteriogenic tissue inhibitor of metalloprotease 1 and subsequently attenuated the activity of matrix metalloproteinase-2. Outcomes of the current preclinical trial set the stage for a clinical trial testing the effects of TE in patients who have suffered from transient ischemic attack and are therefore at a high risk for stroke.     

Angiographic circulation time and cerebral blood flow during balloon test occlusion of the internal carotid artery

Angiography-based balloon test occlusion (BTO) has been empirically used to predict tolerance to permanent carotid artery occlusion. We tested the hypothesis that the laterality of the hemispheric circulation time (HCT) of the contrast medium at cerebral angiography would reflect bilateral asymmetry of the cerebral blood flow (CBF) during BTO. Thirty-one consecutive patients who underwent BTO of the internal carotid artery were retrospectively analyzed. HCT was defined as the interval between the time-to-peak in the middle cerebral artery and the cortical veins calculated using time-density curve. The difference in HCT between the occluded and nonoccluded side was calculated at the carotid or dominant vertebral angiograms obtained during BTO. We estimated the correlation between the difference in HCT and bilateral asymmetry of the CBF, which was quantitatively determined by single-photon emission computed tomography. The HCT was 5.3±1.5 seconds and regional CBF was 41.3±11.3 mL/100 g per minute in the occluded side, compared with 3.6±0.9 seconds and 48.4±14.9 mL/100 g per minute in the nonoccluded side, respectively. The difference in HCT was strongly correlated with the asymmetry ratio of the CBF (r²=0.89, P<0.0001). Angiographically based measurement of the cerebral circulation time can provide valuable information concerning cerebral hemodynamics.     

DSC perfusion-based collateral imaging and quantitative T2 mapping to assess regional recruitment of leptomeningeal collaterals and microstructural cortical tissue damage in unilateral steno-occlusive vasculopathy

Leptomeningeal collateral supply is considered pivotal in steno-occlusive vasculopathy to prevent chronic microstructural ischaemic tissue damage. The aim of this study was to assess the alleged protective role of leptomeningeal collaterals in patients with unilateral high-grade steno-occlusive vasculopathy using quantitative (q)T2 mapping and perfusion-weighted imaging (PWI)-based collateral abundance. High-resolution qT2 was used to estimate microstructural damage of the segmented normal-appearing cortex. Volumetric abundance of collaterals was assessed based on PWI source data. The ratio relative cerebral blood flow/relative cerebral blood volume (rCBF/rCBV) as a surrogate of relative cerebral perfusion pressure (rCPP) was used to investigate the intravascular hemodynamic competency of pial collateral vessels and the hemodynamic state of brain parenchyma. Within the dependent vascular territory with increased cortical qT2 values (P = 0.0001) compared to the contralateral side, parenchymal rCPP was decreased (P = 0.0001) and correlated negatively with increase of qT2 (P  < 0.05). Furthermore, volumetric abundance of adjacent leptomeningeal collaterals was significantly increased (P < 0.01) and negatively correlated with changes of parenchymal rCPP (P = 0.01). Microstructural cortical damage is closely related to restrictions of antegrade blood flow despite increased pial collateral vessel abundance. Therefore, increased leptomeningeal collateral supply cannot necessarily be regarded as a sign of effective compensation in patients with high-grade steno-occlusive vasculopathy.     

Combined arterial spin labeling and diffusion-weighted imaging for noninvasive estimation of capillary volume fraction and permeability-surface product in the human brain

A number of two-compartment models have been developed for the analysis of arterial spin labeling (ASL) data, from which both cerebral blood flow (CBF) and capillary permeability-surface product (PS) can be estimated. To derive values of PS, the volume fraction of the ASL signal arising from the intravascular space (v_bw) must be known a priori. We examined the use of diffusion-weighted imaging (DWI) and subsequent analysis using the intravoxel incoherent motion model to determine v_bw in the human brain. These data were then used in a two-compartment ASL model to estimate PS. Imaging was performed in 10 healthy adult subjects, and repeated in five subjects to test reproducibility. In gray matter (excluding large arteries), mean voxel-wise v_bw was 2.3±0.2 mL blood/100 g tissue (all subjects mean±s.d.), and CBF and PS were 44±5 and 108±2 mL per 100 g per minute, respectively. After spatial smoothing using a 6-mm full width at half maximum Gaussian kernel, the coefficient of repeatability of CBF, v_bw and PS were 8 mL per 100 g per minute, 0.4 mL blood/100 g tissue, and 13 mL per 100 g per minute, respectively. Our results show that the combined use of ASL and DWI can provide a new, noninvasive methodology for estimating v_bw and PS directly, with reproducibility that is sufficient for clinical use.     

Cerebral metabolic rate of oxygen during transition from wakefulness to sleep measured with high temporal resolution OxFlow MRI with concurrent EEG

During slow-wave sleep, synaptic transmissions are reduced with a concomitant reduction in brain energy consumption. We used 3 Tesla MRI to noninvasively quantify changes in the cerebral metabolic rate of O₂ (CMRO₂) during wakefulness and sleep, leveraging the ‘OxFlow’ method, which provides venous O₂ saturation (SvO₂) along with cerebral blood flow (CBF). Twelve healthy subjects (31.3 ± 5.6 years, eight males) underwent 45–60 min of continuous scanning during wakefulness and sleep, yielding one image set every 3.4 s. Concurrent electroencephalography (EEG) data were available in eight subjects. Mean values of the metabolic parameters measured during wakefulness were stable, with coefficients of variation below 7% (average values: CMRO₂ = 118 ± 12 µmol O₂/min/100 g, SvO₂ = 67.0 ± 3.7% HbO₂, CBF = 50.6 ±4.3 ml/min/100 g). During sleep, on average, CMRO₂ decreased 21% (range: 14%–32%; average nadir = 98 ± 16 µmol O₂/min/100 g), while EEG slow-wave activity, expressed in terms of δ-power, increased commensurately. Following sleep onset, CMRO₂ was found to correlate negatively with relative δ-power (r = −0.6 to −0.8, P < 0.005), and positively with heart rate (r = 0.5 to 0.8, P < 0.0005). The data demonstrate that OxFlow MRI can noninvasively measure dynamic changes in cerebral metabolism associated with sleep, which should open new opportunities to study sleep physiology in health and disease.     

Evaluation of cerebrovascular impedance and wave reflection in mouse by ultrasound

Genetic and surgical mouse models are commonly used to study cerebrovascular disease, but their size makes invasive hemodynamic testing technically challenging. The purpose of this study was to demonstrate a noninvasive measurement of cerebrovascular impedance and wave reflection in mice using high-frequency ultrasound in the left common carotid artery (LCCA), and to examine whether microvascular changes associated with hypercapnia could be detected with such an approach. Ten mice (C57BL/6J) were studied using a high-frequency ultrasound system (40 MHz). Lumen area and blood flow waveforms were obtained from the LCCA and used to calculate pulse-wave velocity, input impedance, and reflection amplitude and transit time under both normocapnic and hypercapnic (5% CO₂) ventilation. With hypercapnia, vascular resistance was observed to decrease by 87%±12%. Although the modulus of input impedance was unchanged with hypercapnia, a phase decrease indicative of increased total arterial compliance was observed at low harmonics together with an increased reflection coefficient in both the time (0.57±0.08 versus 0.68±0.08, P=0.04) and frequency domains (0.62±0.08 versus 0.73±0.06, P=0.02). Interestingly, the majority of LCCA blood flow was found to pass into the internal carotid artery (range=76% to 90%, N=3), suggesting that hemodynamic measurements in this vessel are a good metric for intracerebral reactivity in mouse.     

Cerebral vasomotor reactivity during hypo- and hypercapnia in sedentary elderly and Masters athletes

Physical activity may influence cerebrovascular function. The objective of this study was to determine the impact of life-long aerobic exercise training on cerebral vasomotor reactivity (CVMR) to changes in end-tidal CO2 (EtCO2) in older adults. Eleven sedentary young (SY, 27±5 years), 10 sedentary elderly (SE, 72±4 years), and 11 Masters athletes (MA, 72±6 years) underwent the measurements of cerebral blood flow velocity (CBFV), arterial blood pressure, and EtCO2 during hypocapnic hyperventilation and hypercapnic rebreathing. Baseline CBFV was lower in SE and MA than in SY while no difference was observed between SE and MA. During hypocapnia, CVMR was lower in SE and MA compared with SY (1.87±0.42 and 1.47±0.21 vs. 2.18±0.28 CBFV%/mm Hg, P<0.05) while being lowest in MA among all groups (P<0.05). In response to hypercapnia, SE and MA exhibited greater CVMR than SY (6.00±0.94 and 6.67±1.09 vs. 3.70±1.08 CBFV1%/mm Hg, P<0.05) while no difference was observed between SE and MA. A negative linear correlation between hypo- and hypercapnic CVMR (R²=0.37, P<0.001) was observed across all groups. Advanced age was associated with lower resting CBFV and lower hypocapnic but greater hypercapnic CVMR. However, life-long aerobic exercise training appears to have minimal effects on these age-related differences in cerebral hemodynamics.     

Cerebral oxygen metabolism of rats using injectable 15O-oxygen with a steady-state method

To develop a less-stressful and simple method for measurement of the cerebral metabolic rate of oxygen (CMRO₂) in small animals, the steady-state method was applied to injectable ¹⁵O₂-PET (¹⁵O₂-positron emission tomography) using hemoglobin-containing vesicles (¹⁵O₂-HbV). Ten normal rats and 10 with middle cerebral arterial occlusion (MCAO) were studied using a small animal PET scanner. A series of ¹⁵O-PET scans with C¹⁵O-labeled HbV, H₂¹⁵O, and ¹⁵O₂-HbV were performed with 10 to 15 minutes intervals to measure cerebral blood volume (CBV), cerebral blood flow (CBF), and CMRO₂. Positron emission tomography scans were started with a tracer injection using a multiprogramming syringe pump, which provides a slowly increasing injection volume to achieve steady-state radioactivity for H₂¹⁵O and ¹⁵O₂-HbV scans. The radioactivity concentration of ¹⁵O rapidly achieved equilibrium in the blood and whole brain at about 2 minutes after H₂¹⁵O and ¹⁵O₂-HbV administration, which was stable during the scans. The whole brain mean values of CBF, CBV, and CMRO₂ were 54.3±2.0 mL per 100 g per minute, 4.9±0.4 mL/100 g, and 2.8±0.2 μmoL per g per minute (6.2±0.4 mL per 100 g per minute) in the normal rats, respectively. In the MCAO model rats, all hemodynamic parameters of the infarction area on the occlusion side significantly decreased. The steady-state method with ¹⁵O-labeled HbV is simple and useful to analyze hemodynamic changes in studies with model animals.     

Evolution of intracerebral hemorrhage after intravenous tPA: reversal of harmful effects with mast cell stabilization

Thrombolysis with tissue plasminogen activator (tPA) traditionally demands baseline imaging to rule out intracerebral hemorrhage (ICH), which causes delays in treatment. Preventing possible adverse effects of tPA on ICH would allow rapid on-site thrombolysis in patients with presumed acute ischemic stroke, reducing onset-to-treatment times. We examined how intravenous tPA alters ICH evolution during an extended follow-up, and how mast cell stabilization affects this process. Intracerebral hemorrhage was induced in rats by collagenase injection. Rats received either saline (n=10), tPA (n=13), tPA+low-dose cromoglycate (n=10), or tPA+high-dose cromoglycate (n=10). Magnetic resonance imaging was performed at 24, 48, and 72 hours after ICH induction, together with neurologic evaluations. During 72 hours of follow-up, tPA administration did not significantly increase hematoma volume (mean±s.d. 83.5±14.3 versus 66.7±14.7 μL; P=0.256) or hemispheric expansion (14.5±5.0 versus 11.5±5.0% P=0.457) compared with saline. However, tPA-treated animals had worse neurologic outcomes (P<0.05), and mortality (8/13 versus 3/10). Combining tPA with high-dose cromoglycate mitigated hemispheric expansion (7.4±1.7 versus 14.5±5.0% P=0.01), improved neurologic outcome (P<0.001) and decreased mortality (1/10; P<0.05) compared with tPA alone. Our results suggest tPA increases neurologic deficit in ICH, an effect that was abolished by concomitant mast cell stabilization. Further studies are needed to establish the clinical relevance of these findings.