Masanobu Ibaraki

Changes in Human Cerebral Blood Flow and Cerebral Blood Volume during Hypercapnia and Hypocapnia Measured by Positron Emission Tomography

Hypercapnia induces cerebral vasodilation and increases cerebral blood flow (CBF), and hypocapnia induces cerebral vasoconstriction and decreases CBF. The relation between changes in CBF and cerebral blood volume (CBV) during hypercapnia and hypocapnia in humans, however, is not clear. Both CBF and CBV were measured at rest and during hypercapnia and hypocapnia in nine healthy subjects by positron emission tomography. The vascular responses to hypercapnia in terms of CBF and CBV were 6.0 ± 2.6%/mm Hg and 1.8 ± 1.3%/mm Hg, respectively, and those to hypocapnia were −3.5 ± 0.6%/mm Hg and −1.3 ± 1.0%/mm Hg, respectively. The relation between CBF and CBV was CBV = 1.09 CBF0.29. The increase in CBF was greater than that in CBV during hypercapnia, indicating an increase in vascular blood velocity. The degree of decrease in CBF during hypocapnia was greater than that in CBV, indicating a decrease in vascular blood velocity. The relation between changes in CBF and CBV during hypercapnia was similar to that during neural activation; however, the relation during hypocapnia was different from that during neural deactivation observed in crossed cerebellar diaschisis. This suggests that augmentation of CBF and CBV might be governed by a similar microcirculatory mechanism between neural activation and hypercapnia, but diminution of CBF and CBV might be governed by a different mechanism between neural deactivation and hypocapnia.

Changes in the Arterial Fraction of Human Cerebral Blood Volume during Hypercapnia and Hypocapnia Measured by Positron Emission Tomography

Hypercapnia induces cerebral vasodilation and increases cerebral blood volume (CBV), and hypocapnia induces cerebral vasoconstriction and decreases CBV. Cerebral blood volume measured by positron emission tomography (PET) is the sum of three components, that is, arterial, capillary, and venous blood volumes. Changes in arterial blood volume (Va) and CBV during hypercapnia and hypocapnia were investigated in humans using PET with H215O and 11CO. Arterial blood volume was determined from H215O PET data by means of a two-compartment model that takes Va into account. Baseline CBV and values during hypercapnia and hypocapnia in the cerebral cortex were 0.034 ± 0.003, 0.038 ± 0.003, and 0.031 ± 0.003 mL/mL (mean ± s.d.), respectively. Baseline Va and values during hypercapnia and hypocapnia were 0.015 ± 0.003, 0.025 ± 0.011, and 0.007 ± 0.003 mL/mL, respectively. Cerebral blood volume changed significantly owing to changes in PaCO2, and Va changed significantly in the direction of CBV changes. However, no significant change was observed in venous plus capillary blood volume (= CBV-Va). This indicates that changes in CBV during hypercapnia and hypocapnia are caused by changes in arterial blood volume without changes in venous and capillary blood volume.

Quantification of Cerebral Blood Flow and Oxygen Metabolism with 3-Dimensional PET and 15O: Validation by Comparison with 2-Dimensional PET

Quantitative PET with 15O provides absolute values for cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO2), and oxygen extraction fraction (OEF), which are used for assessment of brain pathophysiology. Absolute quantification relies on physically accurate measurement, which, thus far, has been achieved by 2-dimensional PET (2D PET), the current gold standard for measurement of CBF and oxygen metabolism. We investigated whether quantitative 15O study with 3-dimensional PET (3D PET) shows the same degree of accuracy as 2D PET. Methods: 2D PET and 3D PET measurements were obtained on the same day on 8 healthy men (age, 21–24 y). 2D PET was performed using a PET scanner with bismuth germanate (BGO) detectors and a 150-mm axial field of view (FOV). For 3D PET, a 3D-only tomograph with gadolinium oxyorthosilicate (GSO) detectors and a 156-mm axial FOV was used. A hybrid scatter-correction method based on acquisition in the dual-energy window (hybrid dual-energy window [HDE] method) was applied in the 3D PET study. Each PET study included 3 sequential PET scans for C15O, 15O2, and \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{H}_{2}^{15}\mathrm{O}\) \end{document} (3-step method). The inhaled (or injected) dose for 3D PET was approximately one fourth of that for 2D PET. Results: In the 2D PET study, average gray matter values (mean ± SD) of CBF, CBV, CMRO2, and OEF were 53 ± 12 (mL/100 mL/min), 3.6 ± 0.3 (mL/100 mL), 3.5 ± 0.5 (mL/100 mL/min), and 0.35 ± 0.06, respectively. In the 3D PET study, scatter correction strongly affected the results. Without scatter correction, average values were 44 ± 6 (mL/100 mL/min), 5.2 ± 0.6 (mL/100 mL), 3.3 ± 0.4 (mL/100 mL/min), and 0.39 ± 0.05, respectively. With the exception of OEF, values differed between 2D PET and 3D PET. However, average gray matter values of scatter-corrected 3D PET were comparable to those of 2D PET: 55 ± 11 (mL/100 mL/min), 3.7 ± 0.5 (mL/100 mL), 3.8 ± 0.7 (mL/100 mL/min), and 0.36 ± 0.06, respectively. Even though the 2 PET scanners with different crystal materials, data acquisition systems, spatial resolution, and attenuation-correction methods were used, the agreement of the results between 2D PET and scatter-corrected 3D PET was excellent. Conclusion: Scatter coincidence is a problem in 3D PET for quantitative 15O study. The combination of both the present PET/CT device and the HDE scatter correction permits quantitative 3D PET with the same degree of accuracy as 2D PET and with a lower radiation dose. The present scanner is also applicable to conventional steady-state 15O gas inhalation if inhaled doses are adjusted appropriately.

Changes in Cerebral Blood Flow and Cerebral Oxygen Metabolism during Neural Activation Measured by Positron Emission Tomography: Comparison with Blood Oxygenation Level-Dependent Contrast Measured by Functional Magnetic Resonance Imaging

The discrepancy between the increases in cerebral blood flow (CBF) and CMRO2 during neural activation causes an increase in venous blood oxygenation and, therefore, a decrease in paramagnetic deoxyhemoglobin concentration in venous blood. This can be detected by functional magnetic resonance imaging (fMRI) as blood oxygenation level-dependent (BOLD) contrast. In the present study, changes in the cerebral oxygen extraction fraction (OEF) that corresponds to the ratio of CMRO2 to CBF, and in the BOLD signal during neural activation, were measured by both positron emission tomography (PET) and fMRI in the same human subjects. C15O, 15O2, and H215O PET studies were performed in each subject at rest (baseline) and during performance of a right-hand motor task. Functional magnetic resonance imaging studies were then performed to measure the BOLD signal under the two conditions. During performance of the motor task, a significant increase in CBF and a significant decrease in OEF were observed in the left precentral gyrus, left superior frontal gyrus, right precentral gyrus, right cingulate gyrus, and right cerebellum. A significant positive correlation was observed between changes in the CBF and the BOLD signal, and a significant negative correlation was observed between changes in the OEF and the BOLD signal. This supports the assumption on which BOLD contrast studies during neural activation are based.

Cerebral vascular mean transit time in healthy humans : a comparative study with PET and dynamic susceptibility contrast-enhanced MRI

Cerebral vascular mean transit time (MTT), defined as the ratio of cerebral blood volume to cerebral blood flow (CBV/CBF), is a valuable indicator of the cerebral circulation. Positron emission tomography (PET) and dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI) are useful for the quantitative determination of MTT in the clinical setting. The aim of this study was to establish a normal value set of MTT as determined by PET and by DSC-MRI and to identify differences between these methods. Seven healthy volunteers were studied with 15O-PET (H215O and C15O) and gradient-echo echo-planar DSC-MRI at 1.5 T. In the DSC-MRI study with bolus injection of contrast agent, deconvolution analysis was performed. Comparison of gray-to-white matter ratios showed fairly good agreement between PET and DSC-MRI for all parameters (relative CBV, relative CBF, and relative MTT), confirming the validity of relative measurements with DSC-MRI. However, quantitative MTT measured by DSC-MRI was significantly shorter than that measured by PET in cerebral cortical regions (2.8 to 3.0 secs for DSC-MRI versus 3.9 to 4.3 secs for PET) and the centrum semiovale (3.5secs for DSC-MRI versus 4.8secs for PET). These discrepancies may be because of the differences in the intrinsic sensitivity of each imaging modality to vascular components; whereas PET measurement of CBV is equally sensitive to all vascular components, measurement with DSC-MRI originates from the microvasculature in the vicinity of the brain parenchyma. This underlying difference may influence interpretation of MTT determined by PET or by DSC-MRI for patients with cerebrovascular disease.

Effect of Aging on Cerebral Vascular Response to Paco2 Changes in Humans as Measured by Positron Emission Tomography

Vascular responses to changes in Paco2 are used widely to estimate cerebral perfusion reserve, and they can also be used to assess the degree of arteriosclerosis. In the present study, the effect of aging on cerebral vascular responses to both hypercapnia and hypocapnia was investigated. Cerebral blood flow was measured with positron emission tomography at rest, during hypercapnia, and during hypocapnia in 11 young men and 12 older men. The vascular response to change in Paco2 was calculated as the percent change in cerebral blood flow per absolute change in Paco2 in response to hypercapnia and hypocapnia. The total vascular response to change in Paco2 from hypocapnia to hypercapnia was also calculated. To evaluate age-related changes in regional cerebral vascular responses on a pixel-by-pixel basis, an anatomic standardization technique was also used. Although no significant differences between young and old subjects was observed for vascular responses to both hypercapnia and hypocapnia, a significant decrease in total vascular response was observed with aging, indicating progression of sclerotic changes in the cerebral perforating and medullary arteries with normal aging. According to anatomic standardization analysis, relative capacities for vasodilatation in the cerebellum and insular cortex, and relative capacity for vasoconstriction in the frontal cortex were greater in the younger subjects. Such aging effects should be considered when estimating cerebral perfusion reserve.

Metabolic penumbra of acute brain infarction: A correlation with infarct growth

Volume expansion associated with brain infarction occurs in perfusion–diffusion mismatch of magnetic resonance imaging. We aimed at elucidating the metabolic impairment of this phenomenon with 15O positron emission tomography and perfusion and diffusion magnetic resonance imaging. Eleven patients with acute unilateral embolic occlusion of the internal carotid or middle cerebral artery were studied within 6 hours of onset. Regional cerebral blood flow and cerebral metabolic rate of oxygen (CMRO2) were compared with those in the contralateral cerebral hemisphere. The relative apparent diffusion coefficient of water was estimated as a marker of cytotoxic edema. Relative cerebral blood flow and relative CMRO2 in an evolving infarct (normal diffusion initially, but abnormal on day 3) were significantly (p < 0.05) less than those in the periinfarct area (normal diffusion initially and on day 3). The relative apparent diffusion coefficient between the evolving infarct and periinfarct showed no significant difference. These findings indicated that the initial 3‐day volume expansion of an embolic brain infarction was associated with disturbed CMRD2 but not with cytotoxic edema as early as 6 hours after onset. The “metabolic penumbra” defined as normal water diffusion with depressed CMRO2 is a target to reduce the volume expansion of brain infarction. Ann Neurol 2005;57:495–504

Interindividual Variations of Cerebral Blood Flow, Oxygen Delivery, and Metabolism in Relation to Hemoglobin Concentration Measured by Positron Emission Tomography in Humans

Regional cerebral blood flow (CBF) and oxygen metabolism can be measured by positron emission tomography (PET) with 15O-labeled compounds. Hemoglobin (Hb) concentration of blood, a primary determinant of arterial oxygen content (CaO2), influences cerebral circulation. We investigated interindividual variations of CBF, cerebral blood volume (CBV), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) in relation to Hb concentration in healthy human volunteers (n=17) and in patients with unilateral steno-occlusive disease (n=44). For the patients, data obtained only from the contralateral hemisphere (normal side) were analyzed. The CBF and OEF were inversely correlated with Hb concentration, but CMRO2 was independent of Hb concentration. Oxygen delivery defined as a product of CaO2 and CBF (CaO2 CBF) increased with a rise of Hb concentration. The analysis with a simple oxygen model showed that oxygen diffusion parameter (L) was constant over the range of Hb concentration, indicating that a homeostatic mechanism controlling CBF is necessary to maintain CMRO2. The current findings provide important knowledge to understand the control mechanism of cerebral circulation and to interpret the 15O PET data in clinical practice.

Tracer delay correction of cerebral blood flow with dynamic susceptibility contrast-enhanced MRI.

Cerebral blood flow (CBF) and vascular mean transit time (MTT) can be determined by dynamic susceptibility contrast-enhanced magnetic resonance imaging and deconvolution with an arterial input function. However, deconvolution by a singular value decomposition (SVD) method is sensitive to the tracer delay that often occurs in patients with cerebrovascular disease. We investigated the effect of tracer delay on CBF determined by SVD deconvolution. Simulation study showed that underestimation of CBF due to tracer delay was larger for shorter MTTs. We developed a delay correction method that determines tracer delay by means of least-squares fitting pixel-by-pixel. The corrected CBF was determined by SVD deconvolution after time-shifting of the measured concentration curve. The simulations showed that the corrected CBF was insensitive to tracer delay irrespective of the vascular model, although CBF fluctuation increased slightly. We applied the delay correction to the CBF and MTT images acquired for nine patients with hyperacute stroke and unilateral occlusion of the middle cerebral artery. We found in some patients that the delay correction modulated the contrast of CBF and MTT images. For hyperacute stroke patients, tracer delay correction is essential to obtain reliable perfusion image when SVD deconvolution is used.

18F-FDG accumulation in atherosclerosis: use of CT and MR co-registration of thoracic and carotid arteries

PurposeThe purpose of this study was to depict 18F-fluoro-2-deoxy-D-glucose (FDG) accumulation in atherosclerotic lesions of the thoracic and carotid arteries on CT and MR images by means of automatic co-registration software.MethodsFifteen hospitalised men suffering cerebral infarction or severe carotid stenosis requiring surgical treatment participated in this study. Automatic co-registration of neck MR images and FDG-PET images and of contrast-enhanced CT images and FDG-PET images was achieved with co-registration software. We calculated the count ratio, which was standardised to the blood pool count of the superior vena cava, for three arteries that branch from the aorta, i.e. the brachial artery, the left common carotid artery and the subclavian artery (n=15), for atherosclerotic plaques in the thoracic aorta (n=10) and for internal carotid arteries with and without plaque (n=13).ResultsFDG accumulated to a significantly higher level in the brachial artery, left common carotid artery and left subclavian artery at their sites of origin than in the superior vena cava (p=0.000, p=0.000 and p=0.002, respectively). Chest CT showed no atherosclerotic plaque at these sites. Furthermore, the average count ratio of thoracic aortic atherosclerotic plaques was not higher than that of the superior vena cava. The maximum count ratio of carotid atherosclerotic plaques was significantly higher than that of the superior vena cava but was not significantly different from that of the carotid artery without plaque.ConclusionThe results of our study suggest that not all atherosclerotic plaques show high FDG accumulation. FDG-PET studies of plaques with the use of fused images can potentially provide detailed information about atherosclerosis.