Fumio Shishido

A System for Cerebral Blood Flow Measurement Using an H215O Autoradiographic Method and Positron Emission Tomography

A system for CBF measurement using an H215O autoradiographic method and positron emission tomography (PET) has been designed and installed as a clinical tool. Following an intravenous injection of H215O, a radioactivity accumulation in the brain tissue for 60 s and a continuous record of radioactivity in arterial blood were measured by a high counting speed PET device and a beta-ray detector, respectively, and CBF was calculated by a table-lookup procedure. First, this method was compared with the C15O2 inhalation steady-state method on 17 cerebrovascular disease patients and four normal subjects. The two values for CBF agreed with each other when H215O autoradiographic method was applied by correction for the dispersion in the measured arterial radioactivity–time curve. However, without the correction, the CBF by the H215O autoradiographic method revealed substantial overestimation by 30.6 ± 17.5%. A reduced gray/white ratio of CBF was also observed in the H215O autoradiographic method. Second, simulation was performed in order to determine optimal accumulation time by PET scan; the result was that errors due to dispersion and time mismatch became critical as the accumulation time was shortened to <60 s.

Evaluation of regional differences of tracer appearance time in cerebral tissues using [15O] water and dynamic positron emission tomography.

The tracer appearance time relative to the radial artery–sampling site has been evaluated in six brain locations in five human subjects using dynamic positron emission tomography (PET) following the bolus injection of H215O. There was a maximum difference of ± 2 s from the average in each location. T o globally adjust the timing difference between the measured arterial curve and the PET scan, a correction method was developed based on a nonlinear least-squares fitting procedure. This new technique determined the global time delay with an accuracy of ± 0.5 s. On the other hand, the linear backward extrapolation method resulted in a systematic error of 4 s.

Clinical Value of Pet with 18F-Fluorodeoxyglucose and L-Methyl-11C-Methionine for Diagnosis of Recurrent Brain Tumor and Radiation Injury

We studied 15 patients clinically suspected to have recurrent brain tumor or radiation injury, using positron emission tomography (PET) with 18F-fluorodeoxyglucose (18FDG) and L-methyl-11C-methionine (11C-Met). PET with 11C-Met (Met-PET) clearly delineated the extent of recurrent brain tumor as focal areas of increased accumulation of 11C-Met, and was useful for early detection of recurrent brain tumor. PET with 18FDG (FDG-PET) showed focal 18FDG-hypermetabolism in one patient with malignant transformation of low grade glioma, and demonstrated its usefulness for evaluation of malignant transformation. 18FDG-hypometabolism was observed in all patients with radiation injury, but was also found in one patient with recurrent malignant brain tumor. 11C-Met uptake in 3 patients with radiation injury was similar to that of the normal cortical tissue. FDG-PET can be used to initially exclude recurrent brain tumor which is seen as 18FDG-hypermetabolism. The combined use of Met-PET in addition to FDG-PET can improve the accuracy of differentiation of recurrent brain tumor with 18FDG-hypometabolism from radiation injury.

Oxygen Extraction Fraction at Maximally Vasodilated Tissue in the Ischemic Brain Estimated from the Regional CO2 Responsiveness Measured by Positron Emission Tomography

The oxygen extraction fraction (OEF) at maximally vasodilated tissue in patients with chronic cerebrovascular disease was evaluated using positron emission tomography. The vascular responsiveness to changes in PaCO2 was measured by the H215O autoradiographic method. It was correlated with the resting-state OEF, as estimated using the 15O steady-state method. The subjects comprised 15 patients with unilateral or bilateral occlusion and stenosis of the internal carotid artery or middle cerebral artery or moyamoya disease. In hypercapnia, the scattergram between the OEF and the vascular responsiveness to changes in PaCO2 revealed a significant negative correlation in 11 of 19 studies on these patients, and the OEF at the zero cross point of the regression line with a vascular responsiveness of 0 was 0.53 ± 0.08 (n = 11). This OEF in the resting state corresponds to exhaustion of the capacity for vasodilation. The vasodilatory capacity is discussed in relation to the lower limit of autoregulation.

Electroencephalographic correlates of blood flow and oxygen metabolism provided by positron emission tomography in patients with cerebral infarction

Quantitative EEG data were analyzed statistically with respect to cortical cerebral blood flow (CBF) and oxygen metabolism (CMRO2) measured by positron emission tomography in 47 patients with unilateral cerebral infarction. Relative value of the square root of average power was used as a percentage power fraction (PPF) for each frequency category. Power ratio index (PRI) was calculated by dividing the combined delta-PPF and theta-PPF by the combined alpha-PPF and beta-PPF. Delta-PPF, theta-PPF and PRI correlated negatively with regional CBF (rCBF) and CMRO2 (rCMRO2) whereas alpha-PPF and beta-PPF correlated positively. In the acute stage, delta-PPF, alpha-PPF and PRI correlated with rCBF at all but the frontopolar region whereas the correlation with rCMRO2 was poor. Alpha-PPF and PRI correlated also with rCMRO2 in the frontal, central, parietal and occipital regions while delta-PPF correlated with rCBF only in the parietal and occipital regions in the subacute stage. In the chronic stage, all EEG quotients correlated significantly with both rCBF and CMRO2 in the central and parietal regions. In the frontopolar region, only the theta-PPF correlated with rCBF throughout. In the comparison of hemispheric mean values, the correlations were always closer for the affected hemisphere than for the contralateral hemisphere. Although hemispheric mean CBF and CMRO2 were significantly lower in patients with cortical infarcts on CT than in those with small subcortical infarcts, there was no significant difference in the EEG data between the 2 groups.

Changes of cerebral blood flow, and oxygen and glucose metabolism following radiochemotherapy of gliomas: a PET study.

The effects of radiochemotherapy on blood flow, blood volume, and consumption of oxygen and glucose in tumor tissue and normal brain were studied by positron emission tomography. Thirteen patients with cerebral gliomas were included, and they were examined before, during, and within approximately 1 month after the therapy. The 15O-labeled gas steady state inhalation and the 18F-fluorodeoxyglucose methods were used. After the therapy, glucose consumption and blood volume decreased (p less than 0.03) in the tumoral tissue. In the structurally (CT) normal gray matter, blood flow, blood volume, and oxygen consumption did not show any significant changes; oxygen extraction fraction, glucose consumption, and glucose extraction fraction, however, decreased significantly (p less than 0.05, less than 0.02, and less than 0.03, respectively).

Linearization Correction of 99mTc-Labeled Hexamethyl-Propylene Amine Oxime (HM-PAO) Image in Terms of Regional CBF Distribution: Comparison to C15O2 Inhalation Steady-State Method Measured by Positron Emission Tomography:

The radioisotope distribution following intravenous injection of 99mTc-labeled hexamethylpropyleneamine oxime (HM-PAO) in the brain was measured by single photon emission computed tomography (SPECT) and corrected for the nonlinearity caused by differences in net extraction. The “linearization” correction was based on a three compartment model, and it required a region of reference to normalize the SPECT image in terms of regional cerebral blood flow distribution. Two different regions of reference, the cerebellum and the whole brain, were tested. The uncorrected and corrected HM-PAO images were compared with cerebral blood flow (CBF) image measured by the C15O2 inhalation steady state method and positron emission tomography (PET). The relationship between uncorrected HM-PAO and PET–CBF showed a correlation coefficient of 0.85 but tended to saturate at high CBF values, whereas it was improved to 0.93 after the “linearization” correction. The whole-brain normalization worked just as well as normalization using the cerebellum. This study constitutes a validation of the “linearization” correction and it suggests that after linearization the HM-PAO image may be scaled to absolute CBF by employing a global hemispheric CBF value as measured by the nontomographic 133Xe clearance method.

Positron emission tomographic evaluation of histological malignancy in gliomas using oxygen-15 and fluorine-18-fluorodeoxyglucose.

HEADTOME III, a high resolution PET, has been employed using 15O and 18F labelled pharmaceuticals to evaluate histological malignancy of gliomas preoperatively. PET study was applied on eighteen preoperative gliomas including two recurrent cases. Haemocirculatory and metabolic indices of regional cerebral blood flow (rCBF), cerebral blood volume (rCBV), oxygen extraction fraction (rOEF), cerebral metabolic rates for oxygen (rCMRO2) and glucose (rCMRGI) were measured in the viable portion of the tumour, and the contralateral grey and white matter. In the tumour region, rCBF and rCBV were variable and unrelated to grades of tumour malignancy. rCMRO2 and rOEF values reduced significantly (p less than 0.01) relative to the contralateral brain tissue. The average rCMRGI values was 3.00 +/- 1.06 mg 100 ml-1 min-1 (mean +/- SD) for 7 low grade gliomas (grade II), and 5.91 +/- 3.61 mg 100 ml-1 min-1 for 11 high grade gliomas (grade III and IV). These results would support that anaerobic glycolysis increased in the metabolism of gliomas with malignancy. In comparison with normal volunteers, rCBF, rCMRO2, and rCMRGI values in the contralateral grey matter of gliomas were markedly reduced (p less than 0.01, p less than 0.05, p less than 0.01, respectively) possibly due in part to raised intracranial pressure and depressed cerebral functional activity, so that rOEF was increased to a level of approximately 0.5.(ABSTRACT TRUNCATED AT 250 WORDS)

Tomographic Mapping of Kinetic Rate Constants in the Fluorodeoxyglucose Model Using Dynamic Positron Emission Tomography

A quick computing algorithm to calculate the rate constants (k*1, k*2, k*3) in the [18F]2-fluoro-2-deoxy-d-glucose (FDG) model was developed. The algorithm solved for the rate constants pixel by pixel using a conventional least-squares method and two tables consisting of a set of various rate constants, to shorten the computing time. Five planes of rate constant images were obtained. A combined study using the dynamic FDG method and the 15O-labeled gas continuous inhalation method was performed on seven healthy male volunteers aged 26–35 years. Results indicated an apparent discrepancy between CMRglu and CMRO2 in the cerebellum, where the low glucose utilization was correlated with a low FDG phosphorylation rate (k*3) despite a sufficient FDG transportation rate (k*1) from plasma to tissue.

Positron emission tomographic evaluation of radiochemotherapeutic effect on regional cerebral hemocirculation and metabolism in patients with gliomas.

SummaryHemocirculatory and metabolic changes in tumor regions and the remote brain structure were analyzed using oxygen-15 and fluorine-18 positron emission tomography (PET) in eight patients with gliomas after radiation and chemotherapy of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and N-(2-tetrahydrofuryl)-5-fluorouracil (FT 207).In the tumor regions after the radiochemotherapy, regional cerebral blood flow (rCBF) and cerebral blood volume (rCBV) varied widely and there was a tendency for oxygen consumption (rCMRO2) to fall. The change in glucose consumption (rCMRGI) was especially noteworthy with regard to clinical correlations. Six patients with decreased rCMRGI values had 16010 to 29010 regressions in tumor size measured by X-ray computerized tomography (CT), and showed some period of clinical relief. In contrast, one patient with an increased rCMRGI value had some progression of tumor growth, and there were no clinical amelioration. The hemocirculation and metabolism of the contralateral gray matter seem to fluctuate by various factors as intracranial pressure and the effectiveness of the therapy.In gliomas therapy, tumor rCMRGI values can be a good indicator of therapeutic effectiveness.