Evaluation of MRI models in the measurement of CMRO2 and its relationship with CBF

The aim of this study was to investigate the various MRI biophysical models in the measurements of local cerebral metabolic rate of oxygen (CMRO₂) and the corresponding relationship with cerebral blood flow (CBF) during brain activation. This aim was addressed by simultaneously measuring the relative changes in CBF, cerebral blood volume (CBV), and blood oxygen level dependent (BOLD) MRI signals in the human visual cortex during visual stimulation. A radial checkerboard delivered flash stimulation at five different frequencies. Two MRI models, the single‐compartment model (SCM) and the multicompartment model (MCM), were used to determine the relative changes in CMRO₂ using three methods: [1] SCM with parameters identical to those used in a prior MRI study (M = 0.22; α = 0.38); [2] SCM with directly measured parameters (M from hypercapnia and α from measured δCBV and δCBF); and [3] MCM. The magnitude of relative changes in CMRO₂ and the nonlinear relationship between CBF and CMRO₂ obtained with Methods [2] and [3] were not in agreement with those obtained using Method [1]. However, the results of Methods [2] and [3] were aligned with positron emission tomography findings from the literature. Our results indicate that if appropriate parameters are used, the SCM and MCM models are equivalent for quantifying the values of CMRO₂ and determining the flow‐metabolism relationship. Magn Reson Med 60:380–389, 2008. © 2008 Wiley‐Liss, Inc.     

Database of normal human cerebral blood flow, cerebral blood volume, cerebral oxygen extraction fraction and cerebral metabolic rate of oxygen measured by positron emission tomography with 15O-labelled carbon dioxide or water, carbon monoxide and oxygen: a multicentre study in Japan

Measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO₂) by positron emission tomography (PET) with oxygen-15 labelled carbon dioxide (C¹⁵O₂) or ¹⁵O-labelled water (H₂ ¹⁵O), ¹⁵O-labelled carbon monoxide (C¹⁵O) and ¹⁵O-labelled oxygen (¹⁵O₂) is useful for diagnosis and treatment planning in cases of cerebrovascular disease. The measured values theoretically depend on various factors, which may differ between PET centres. This study explored the applicability of a database of ¹⁵O-PET by examining between-centre and within-centre variation in values. Eleven PET centres participated in this multicentre study; seven used the steady-state inhalation method, one used build-up inhalation and three used bolus administration of C¹⁵O₂ (or H₂ ¹⁵O) and ¹⁵O₂. All used C¹⁵O for measurement of CBV. Subjects comprised 70 healthy volunteers (43 men and 27 women; mean age 51.8±15.1 years). Overall mean±SD values for cerebral cortical regions were: CBF=44.4±6.5 ml 100 ml^–1 min^–1; CBV=3.8±0.7 ml 100 ml^–1; OEF=0.44±0.06; CMRO₂=3.3±0.5 ml 100 ml^–1 min^–1. Significant between-centre variation was observed in CBV, OEF and CMRO₂ by one-way analysis of variance. However, the overall inter-individual variation in CBF, CBV, OEF and CMRO₂ was acceptably small. Building a database of normal cerebral haemodynamics obtained by the¹⁵O-PET methods may be practicable.     

Cerebral muscarinic acetylcholinergic receptor measurement in Alzheimer’s disease patients on11C-N-methyl-4-piperidyl benzilate — Comparison with cerebral blood flow and cerebral glucose metabolism—

We studied the cerebral muscarinic acetylcholinergic receptor (mACh-R) by means of¹¹C-N- methyl-4-piperidyl benzilate (¹¹C-NMPB) and positron emission tomography (PET) in Alzheimer’s disease (AD) cases, and the findings were compared with the cerebral blood flow (CBF) and the glucose metabolism (CMRGlc) to evaluate the relationship between the mACh-R and the CBF or the CMRGlc. The subjects consisted of 18 patients with AD and 18 age and sex matched normal volunteers. The patients were clinically diagnosed according to the criteria of the NINDS-ADRDA as having “probable AD” and were thus classified into two groups (mild and moderate AD) according to the severity of dementia determined by DSM-III-R. The CBF was measured by^99mTc-HMPAO SPECT, and the CMRGlc was measured by¹⁸FDG PET. The¹¹C-NMPB uptake was evaluated by the graphical method and the ratio method (ROIs/Cerebellum). A significant mACh-R decrease and more severe CMRGlc decrease in the cortical region was seen in mild and moderate AD. The decrease in the CBF was not as obvious as that in the mACh-R and the CMRGlc. Our study thus suggested that the mACh-R decreased in patients with AD, and that the¹⁸FDG PET was the most sensitive method for detecting the degenerative regions in patients with AD.     

Evaluation of the default-mode network by quantitative <Superscript>15</Superscript>O-PET: comparative study between cerebral blood flow and oxygen consumption

Objective

Resting-state functional MRI (rs-fMRI) has revealed the existence of a default-mode network (DMN) based on spontaneous oscillations of the blood oxygenation level-dependent (BOLD) signal. The BOLD signal reflects the deoxyhemoglobin concentration, which depends on the relationship between the regional cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO₂). However, these two factors cannot be separated in BOLD rs-fMRI. In this study, we attempted to estimate the functional correlations in the DMN by means of quantitative ¹⁵O-labeled gases and water PET, and to compare the contribution of the CBF and CMRO₂ to the DMN.

Methods

Nine healthy volunteers (5 men and 4 women; mean age, 47.0?±?1.2 years) were studied by means of ¹⁵O-O₂, ¹⁵O-CO gases and ¹⁵O-water PET. Quantitative CBF and CMRO₂ images were generated by an autoradiographic method and transformed into MNI standardized brain template. Regions of interest were placed on normalized PET images according to the previous rs-fMRI study. For the functional correlation analysis, the intersubject Pearson’s correlation coefficients (r) were calculated for all pairs in the brain regions and correlation matrices were obtained for CBF and CMRO₂, respectively. We defined r?>?0.7 as a significant positive correlation and compared the correlation matrices of CBF and CMRO₂.

Results

Significant positive correlations (r?>?0.7) were observed in 24 pairs of brain regions for the CBF and 22 pairs of brain regions for the CMRO₂. Among them, 12 overlapping networks were observed between CBF and CMRO₂. Correlation analysis of CBF led to the detection of more brain networks as compared to that of CMRO₂, indicating that the CBF can capture the state of the spontaneous activity with a higher sensitivity.

Conclusions

We estimated the functional correlations in the DMN by means of quantitative PET using ¹⁵O-labeled gases and water. The correlation matrix derived from the CBF revealed a larger number of brain networks as compared to that derived from the CMRO₂, indicating that contribution to the functional correlation in the DMN is higher in the blood flow more than the oxygen consumption.

     

Cerebral blood flow in temporal lobe epilepsy: a partial volume correction study

Purpose Previous studies in temporal lobe epilepsy (TLE) have shown that, owing to brain atrophy, positron emission tomography (PET) can overestimate deficits in measures of cerebral function such as glucose metabolism (CMR_glu) and neuroreceptor binding. The magnitude of this effect on cerebral blood flow (CBF) is unexplored. The aim of this study was to assess CBF deficits in TLE before and after magnetic resonance imaging-based partial volume correction (PVC). Methods Absolute values of CBF for 21 TLE patients and nine controls were computed before and after PVC. In TLE patients, quantitative CMR_glu measurements also were obtained. Results Before PVC, regional values of CBF were significantly (p<0.05) lower in TLE patients than in controls in all regions, except the fusiform gyrus contralateral to the epileptic focus. After PVC, statistical significance was maintained in only four regions: ipsilateral inferior temporal cortex, bilateral insula and contralateral amygdala. There was no significant difference between patients and controls in CBF asymmetry indices (AIs) in any region before or after PVC. In TLE patients, AIs for CBF were significantly smaller than for CMR_glu in middle and inferior temporal cortex, fusiform gyrus and hippocampus both before and after PVC. A significant positive relationship between disease duration and AIs for CMR_glu, but not CBF, was detected in hippocampus and amygdala, before but not after PVC. Conclusion PVC should be used for PET CBF measurements in patients with TLE. Reduced blood flow, in contrast to glucose metabolism, is mainly due to structural changes.     

Automatic labeling method for injectable 15O-oxygen using hemoglobin-containing liposome vesicles and its application for measurement of brain oxygen consumption by PET

IntroductionThe aim of this study was to develop an injectable ¹⁵O-O₂ system using hemoglobin-containing vesicles (HbV), a type of artificial red blood cell, and to investigate the feasibility of ¹⁵O₂-labeled HbV (¹⁵O₂-HbV) to measure cerebral metabolic rate of oxygen (CMRO₂) in rats.MethodsThe direct bubbling method was combined with vortexing to enhance labeling efficiency of HbV with ¹⁵O-O₂ gas. l-Cysteine was added as a reductant to protect hemoglobin molecules in HbV from oxidation at different concentrations, and labeling efficiencies were also compared. Measurement of cerebral blood flow (CBF) and CMRO₂ in five normal rats was performed using a small animal PET scanner after the injection of H₂¹⁵O and ¹⁵O₂-HbV to evaluate the precision of hemodynamic parameters quantitatively.ResultsThe labeling efficiency of HbV was significantly increased when vortexing and bubbling were combined compared with the simple bubbling method (P<.05). The most efficient method for labeling was bubbling of ¹⁵O-O₂ combined with vortexing and the addition of 2.8 mM l-cysteine in HbV solution. The mean radioactivity of 214.4±7.8 MBq/mL HbV was obtained using this method. PET scans using ¹⁵O₂-HbV and H₂¹⁵O yielded a mean CMRO₂ value of 6.8±1.4 (mL/min per 100 g) in rats with normal CBF of 51.4±7.9 (mL/min per 100 g).ConclusionAddition of l-cysteine to HbV and simple direct bubbling of ¹⁵O-O₂ gas combined with vortexing was the most efficient method for preparation of ¹⁵O₂-HbV. The present injectable system using ¹⁵O₂-HbV was successfully utilized to measure CMRO₂ in rats, indicating that this new method could be useful for animal models to measure oxygen metabolism in the brain.     

Cerebral blood flow and oxygen metabolism in senile dementia of Alzheimer's type and vascular dementia with deep white matter changes

Regional cerebral blood flow (rCBF), cerebral metabolic rate of oxygen (rCMRO₂), oxygen extraction fraction (rOEF), and cerebral blood volume (rCBV) were investigated using positron emission tomography (PET) in 16 patients with senile dementia of Alzheimer's type (SDAT), and compared with those of 6 nondemented and 3 demented patients with deep white matter high signal (DWMH) on T2-weighted MRI and 6 controls. rCBF, rCMRO₂ and rCBV were determined using C¹⁵O₂, ¹⁵O₂ and C¹⁵O, respectively. rCBF and CMRO₂ were significantly decreased in the frontal, parietal and temporal cortex (P < 0.05) in patients with SDAT, and showed a significant correlation with the severity of dementia (P < 0.05). In patients with DWMH rCBF was significantly decreased in the parietal cortex and in the frontal white matter in nondemented patients, and in the cerebral cortex and white matter of most regions studied in demented patients (P < 0.05), whereas rCMRO₂ was significantly reduced in only the frontal and temporal cortex of demented patients (P < 0.05). rOEF was significantly increased in the parietal cortex of patients with SDAT and in the white matter of patients with SDAT or DWMH (P < 0.05), and the increase in the frontal white matter significantly paralleled the progression of dementia in patients with SDAT (P < 0.05). rCBV was significantly decreased in the parietal and temporal cortex of patients with SDAT (P < 0.05), but not in any areas of those with DWMH. These results suggest that rOEF is increased in both SDAT and patients with DWMH. The increase in rOEF in patients with SDAT may be accounted for by reduction in rCBV resulting from decreased activity in the vasodilatory cholinergic system, impairment of glucose metabolism and white matter changes; the rOEF increase in patients with DWMH suggests relative preservation of oxidative metabolism compared to disturbed perfusion. Received: 24 October 1996 Accepted: 30 June 1997     

Cortical Cerebral Blood Flow,Oxygen Extraction Fraction,and Metabolic Rate in Patients with Middle Cerebral Artery Stenosis or Acute Stroke

BACKGROUND AND PURPOSE:With the advances of magnetic resonance technology, the CBF, oxygen extraction fraction, and cerebral metabolic rate of oxygen can be measured in MRI. Our aim was to measure the CBF, oxygen extraction fraction, and cerebral metabolic rate of oxygen use in patients with different severities of middle cerebral artery stenosis or acute stroke by using the arterial spin-labeling and susceptibility-weighted imaging techniques.MATERIALS AND METHODS:Fifty-seven patients with MCA stenosis or acute stroke were recruited and classified into 4 groups: mild MCA stenosis (group 1), severe MCA stenosis (group 2), occluded MCA (group 3), and acute stroke (group 4). Arterial spin-labeling and SWI sequences were used to acquire CBF, oxygen extraction fraction, and cerebral metabolic rate of oxygen.RESULTS:The oxygen extraction fraction in hemispheres with mild MCA stenosis (group 1) was remarkably higher than that in the contralateral hemisphere. In addition, hemispheres with severe MCA stenosis (group 2) had significantly lower CBF and a significantly higher oxygen extraction fraction than the contralateral hemisphere. Hemispheres with occluded MCA (group 3) or acute stroke (group 4) had a significantly lower CBF and cerebral metabolic rate of oxygen and a significantly higher oxygen extraction fraction than the contralateral hemisphere.CONCLUSIONS:The oxygen extraction fraction gradually increased in groups 1–3. When this offset a decrease in CBF, the cerebral metabolic rate of oxygen remained at a normal level. An occluded MCA led to reduction in both the CBF and cerebral metabolic rate of oxygen. Moreover, the oxygen extraction fraction and cerebral metabolic rate of oxygen significantly increased and decreased, respectively, in the occluded MCA region during acute stroke.

A reduction in cerebral blood flow in brain tissue is typically accompanied by a compensatory increase in the oxygen extraction fraction (OEF) to maintain normal neuronal function.¹ However, the risk of stroke is greatly increased once the maximum OEF is achieved.² The presence of increased OEF in stroke is an independent predictor of subsequent stroke in patients.^3,4 Consequently, both CBF and OEF are important indicators for stroke; however, neither parameter sufficiently predicts the risk of this condition. It is possible to use both parameters and the arterial oxygen content to derive cerebral metabolic rate of oxygen (CMRO₂) use, which is of critical importance in the occurrence of stroke.¹Positron-emission tomography provides the most accurate in vivo OEF and CMRO₂ measurements; however, it is expensive and requires administration of radioactive isotopes. Both OEF and CBF can be determined using MR susceptometry and arterial spin-labeling (ASL).^5,6 MR susceptometry uses gradient-echo phase maps to estimate oxygen saturation in segments of the jugular and gray matter veins.^7,8 This technique requires blood vessels to have a substantially greater length than the diameter.^7,8 Susceptibility-weighted imaging is a type of MR susceptometry that can obtain measurements of venous oxygen saturation by using the phase difference between the venous blood and surrounding tissue.^9,10 ASL is a noninvasive technique that can measure CBF.^11,12 The gray matter CMRO₂ can be obtained from local CBF and OEF measurements.Most previous PET studies have focused on OEF and CMRO₂ in patients with an occluded carotid artery; few studies have investigated the stenotic or occluded middle cerebral artery.^13,14 To the best of our knowledge, no studies have assessed CBF, OEF, and CMRO₂ relative to the degree of MCA stenosis. To address this question, we measured CBF, OEF, and CMRO₂ in patients with different degrees of MCA stenosis or stroke via ASL and susceptibility-weighted phase imaging.     

Regional cerebral blood flow,blood volume,oxygen extraction fraction,and oxygen utilization rate in normal volunteers measured by the autoradiographic technique and the single breath inhalation method

By means of a high resolution PET scanner, the regional cerebral blood flow (rCBF), cerebral blood volume (rCBV), oxygen extraction fraction (rOEF), and metabolic rate of oxygen (rCMRO₂) for major cerebral gyri and deep brain structures were studied in eleven normal volunteers during an eye-covered and ear-unplugged resting condition. Regional CBF was measured by the auto-radiographic method after intravenous administration of H₂ ¹⁵O. Regional OEF and rCMRO₂ were measured by the single inhalation of¹⁵O₂. With MR T₁-weighted images as an anatomical reference, thirteen major cerebral gyri, caudate nucleus, lentiform nucleus, thalamus, midbrain, pons, cerebellum and vermis were defined on the CMRO₂ images. Values were read by using circular regions of interest 16 mm in diameter. The posterior part of the cingulate gyri had the highest rCBF and rCMRO₂ values among brain structures, followed by the lentiform nucleus, the cerebellum, the caudate nucleus, and the thalamus. Parahippocampal gyri had the lowest rCBF and rCMRO₂ values amongthe cortical gyri.RegionalOEFforthepontinenuclei (0.34 ± 0.04), the midbrain (0.35 ± 0.05), the parahippocampal gyri (0.35 ± 0.04 for the right and 0.37 ± 0.05 for the left), and the thalami (0.37 ± 0.05 for the right and 0.36 ± 0.04 for the left) were significantly lower than the mean OEF for the cerebral cortices (0.42 ± 0.04) (p < 0.05 or less). The global CBF and CMRO₂ were consistent with those obtained by the Kety-Schmidt method. Although several limitations to the quantification derived from an inadequate spacial resolution remain unsolved, the performance of the present PET scanner and the method for the quantification employed provide regional estimates of brain circulation and oxygen metabolism more acurately than the PET system and the steady state method previously used.     

Evaluation of critically perfused area in acute ischemic stroke for therapeutic reperfusion: A clinical PET study

To evaluate critically perfused areas in the acute ischemic brain, 9 patients were studied by positron emission tomography (PET) within 7–32 hours after the onset. The cerebral blood flow (CBF) and oxygen metabolic rate (CMRO₂) were evaluated and compared with sequential change in CT findings. In all the regions developing subsequent necrosis on CT, CBF dropped below 17 ml/100 g/min. But in some of these lesions, CMRO₂ remained above the minimum value for regions in which infarction did not develop, and the tissue density on CT obviously remained normal for several hours after PET scan. The mean CBF in these lesions (14.0 ml/100 g/min, range: 9.9–17.3 ml/100 g/min) was significantly higher than that in ischemic areas with low density on CT before or just after PET study (～10 ml/100 g/min, range: 7.7–14.1 ml/100 g/min). These findings suggest that a part of the tissue with CBF between 10–17 ml/100 g/min is still viable at least 7 hours after the onset of ischemia, but becomes non-viable in a longer period of ischemia. These lesions should respond to effective treatment, including therapeutic reperfusion.