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Low cerebral glucose extraction rates in the human medial temporal cortex and cerebellum
Journal of the Neurological Sciences 172 (2000) 41–48 www.elsevier.com / locate / jns
Low cerebral glucose extraction rates in the human medial temporal cortex and cerebellum Setsu Sakamoto
a,b ,
*, Kazunari Ishii b
a
b
Department of Radiology, Kobe University School of Medicine, 7 -5 -2 Kusunoki-Cho, Chuo-Ku, Kobe 650 -0017, Japan Division of Neuroimaging Research, Hyogo Institute for Aging Brain and Cognitive Disorders ( HI-ABCD), Himeji, Japan Received 5 April 1999; received in revised form 2 August 1999; accepted 11 October 1999
Abstract Previous studies have reported that there exist different regional sensitivities to acute hypoxia. To better understand these differences, we estimated regional differences of cerebral blood flow (CBF), cerebral glucose metabolism (CMRglc) and kinetic constants (K1 , k 2 , k 3 ) in the human cortex under resting conditions. CBF, CMRglc, kinetic rate constants and glucose extraction rate (GER) were measured in eight normal male subjects (mean age: 26.16 4.9 years) using the 15 O-water autoradiographic technique and subsequently the dynamic and the static [ 18 F]2-fluoro-2-deoxy-D-glucose technique with positron emission tomography (PET). Of all the brain structures investigated, the medial temporal lobe showed the lowest CBF (46.0 ml / 100 g / min) and lowest CMRglc (3.97 mg / 100 g / min). The medial temporal GER was lowest (8.9%), followed by the cerebellar GER (9.3%). While the cerebellar blood flow (64.0 ml / 100 g / min) was the highest, the cerebellar metabolic rate for glucose (5.79 mg / 100 g / min) was relatively low. The cerebellum showed the highest K1 value (0.13) and k 2 value (0.16), and the lowest k 3 value (0.05). In the medial temporal cortices and cerebellum, CMRglc and GER were lower than those in the neocortices. These results indicate that there are great perfusional / metabolic differences between the medial temporal lobe, cerebellum and other brain regions in the normal human brain under resting conditions. 2000 Elsevier Science B.V. All rights reserved. Keywords: Cerebral blood flow; Cerebral glucose metabolism; Glucose extraction rate (GER); Medial temporal lobe; Positron emission tomography (PET); Rate constant
1. Introduction It is widely accepted that regional cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO 2 ) and cerebral metabolic rate for glucose (CMRglc) are all linearly related to one another in the normal brain under resting conditions [1,2]. In this paper, these quantities also refer to the values in the cerebellum. Previously we reported regional differences in CBF and CMRO 2 (both are high in the visual cortex) and oxygen extraction fraction (OEF) (low in the sensorimotor cortex) under resting conditions in normal subjects [3]. Previous studies *Corresponding author. Tel.: 181-78-382-6104; fax: 181-78-3826129. E-mail address: [email protected] (S. Sakamoto)
with 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG) and PET [4– 10] have shown that cerebellar glucose metabolism is always lower than CMRglc in the neocortices in the normal human brain, while other studies have shown that blood flow in the cerebellum is always higher than that in the neocortex in the normal human brain [11–16], though the results were not statistically analyzed. The medial temporal CBF and CMRglc have not been well estimated either. It is well-known that, in the adult human brain, hypoxic episodes cause more severe damage to the older brain structures such as the hippocampus and cerebellum than to the neocortices [17]. The vulnerability of the hippocampus and cerebellum may indicate that the metabolism and perfusion of these regions are different from those of the neocortex. The aim of this study was to estimate regional differences in the glucose extraction ratio
0022-510X / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00286-5
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(GER) in normal subjects, especially between the medial temporal lobe, cerebellum and neocortices, in the resting state by sequential measurements of CBF and CMRglc using 15 O-labeled water (H 15 2 O) and FDG with PET.
2. Materials and methods
2.1. Subjects We studied eight healthy normal male subjects, who volunteered for this study. They showed no clinical evidence of cognitive deficits or neurological disease and were taking no acute or chronic medications at the time of the scan. They had no abnormal findings on magnetic resonance (MR) images. All the subjects were right handed. Average age6SD was 26.164.9 years (range: 23–38 years). Before the examination, written informed consent was obtained from all the subjects.
2.2. PET procedure Before the PET scans, all the subjects received MR images for anatomical reference, for PET positioning and to confirm that they had no abnormal conditions. MR was performed as described previously [3]. Immediately before the PET examination, sagittal gradient-echo images were obtained to determine the coordinates for positioning of the head on the PET table. The PET procedure was approved by our institution’s Ethical Committee. PET was performed with a PET scanner Headtome IV (Shimadzu Corp., Kyoto, Japan), which had four rings located 13 mm apart and yielded a transverse resolution of 4.5 mm full-width-half-maximum (FWHM) [18]. The slice thickness was 11 mm and the slice interval was 13 mm with non-z motion mode for a dynamic scan and 6.5 mm with z-motion mode for a static scan. The gantry and scanner table were adjusted according to the coordinates determined by MR imaging so that scans were taken parallel to the AC–PC plane from 32.5 mm below to 52.0 mm above the AC–PC plane at 13- or 6.5-mm intervals. The scans were taken parallel to the anterior commissure–posterior commissure (AC–PC) plane using the MR markings. A transmission scan was performed using a 68 Ga / 68 Ge pin source for absorption correction after each subject was positioned. PET studies were performed under resting conditions with the subject’s eyes closed and ears unplugged. All subjects had fasted for at least 4 h before PET scanning. First, CBF was measured using the H 15 2 O and autoradiographic technique [12]. In brief, 740–1110 MBq of H 15 2 O was administered intravenously as a bolus. Scanning was begun after the radioactivity was detected in the brain (10–20 s after injection). Each position was sequentially
scanned for 5 s and this was repeated a total of nine times. The arterial radioactivity concentration was monitored by detecting beta-rays with a plastic scintillator. Arterial blood was withdrawn at a constant rate of 5 ml / min. The dispersion was corrected by deconvolving the beta probe curve delay in comparison with the appearance of the radiotracer in the brain, adjusting the initial rise in radioactivity in the blood and brain. The regional CBF was calculated by using the tissue radioactivity and radioactivity of the blood input function and the model equations [12]. After an interval of 12 min, regional CMRglc was measured using FDG. A dynamic sequence was performed with the non-z motion mode for 40 min after administration of 185–346 MBq of FDG. The scan protocol consisted of 20 images each for 2 min. Arterial blood sampling was done from a catheter inserted into the left radial artery just after administration, and at 15, 30, 45, 60, 75, 90, 105, 120 s and at 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 40, and 50 min after administration. Plasma and whole blood radioactivities were measured. Arterial plasma glucose levels were determined using the plasma samples obtained through the scan. Then a static sequence for the autoradiographic method was started at 45 min after the injection and emission data were collected for 12 min using the z-motion mode. The static CMRglc image was calculated by Phelps’ autoradiographic method [19]. The incorporated metabolic rate constants were K1 50.080, k 2 50.126, k 3 50.068, and k 4 50.0055, and the lumped constant (LC) was 0.52 [20].
2.3. Data analysis PET and MR image data sets were directly transmitted to a workstation (Indigo2 Extreme, Silicon Graphics, Mountain View, CA) from the PET and MR imaging units, and analyzed using image analyzing software Dr. View (ver. 4.0, Asahi Joho System, Tokyo, Japan). A standard three-compartmental tracer kinetic model extending the original method of Sokoloff et al. [21] was used. Taguchi et al. [22] compared three- and four-parameter models for 45 min and 120 min of data acquisition after FDG administration and concluded that the three-parameter model was better suited for the 45-min data acquisition and the four-parameter model was better suited for the 120-min data acquisition. Therefore, we calculated the dynamic data with the three-compartmental, three-parameter model. In addition to the rate constant, the fractional cerebral blood volume (CBV) was estimated by a leastsquares fit in order to correct for blood-borne activity in the PET measurement. Kinetic CMRglc was calculated directly from the individually fitted rate constants, using the averaged plasma glucose concentration (Cp) and a LC of 0.52 as follows: CMRglc5Cp / LC3(K1 3 k 3 ) /(k 2 1k 3 ). MR 3D-SPGR images were reconstructed parallel to the AC–PC plane as references. Both PET and MR images
S. Sakamoto, K. Ishii / Journal of the Neurological Sciences 172 (2000) 41 – 48
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Fig. 1. CBF images of a normal subject with overlain ROIs.
Fig. 2. Representative images of cerebral blood flow (CBF), cerebral metabolic rate for glucose (CMRglc), and glucose extraction rate (GER) in a 38-year-old healthy man under resting conditions. Note the low level of GER in the medial temporal lobe and cerebellum.
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were displayed side by side on a display monitor and total of 50 circular regions of interest (ROIs, 16 mm diameter) were determined in eight regions on the CBF image (Fig. 1). These included 6 ROIs in the cerebellum, 4 ROIs in the medial temporal lobe, 12 ROIs in the lateral temporal lobe, 6 ROIs in the occipital lobe, 12 ROIs in the frontal lobe, 6 ROIs in the parietal lobe, 2 ROIs in the basal ganglia and 2 ROIs in the thalamus. The same ROIs were transferred to the kinetic CMRglc, static CMRglc and kinetic rate constant (K1 , k 2 , k 3 ) images, and each regional value was measured. To increase the reliability of the measurements, the CBF, the static CMRglc, the kinetic CMRglc, K1 , k 2 and k 3 values were averaged for each of the eight regions. These averages were used to calculate the static glucose extraction rate (static GER5static CMRglc /(Cp*CBF)), the kinetic GER (5kinetic CMRglc /(Cp*CBF)) [23,24] and K1 /(k 2 1k 3 ) values. GER is the fraction of the glucose transported by the blood that is metabolized.
3. Statistical analysis The calculated data were compared in order to determine whether there were regional differences among the temporal, visual, frontal, sensorimotor and parietal regions by repeated measures using one-way analysis of variance (ANOVA) with post hoc Tukey’s HSD tests. A probability value less than 0.05 was considered to indicate a significant difference. We also calculated the correlation coefficients among the CBF, CMRglc, and kinetic rate parameters in each of the 50 regions that ROIs were set in each subject.
4. Results Estimates of the regional CBF, kinetic CMRglc, static CMRglc, kinetic GER, static GER, K1 , k 2 , k 3 and K1 /(k 2 1 k 3 ) were estimated in the cerebellum, frontal, medial temporal, lateral temporal, occipital, parietal lobes, basal ganglia and thalamus (Table 1). • CBF: The cerebellar blood flow was the highest and was significantly higher than the CBF in the frontal, medial temporal, lateral temporal, occipital and parietal lobes (P,0.001) and basal ganglia (P,0.05). The CBF in the medial temporal lobe was the lowest among all the brain structures and was significantly lower than the CBF values in the lateral temporal lobe (P,0.02), cerebellum, basal ganglia and thalamus (P,0.001). • Static CMRglc: The cerebellar static CMRglc was significantly lower than the CMRglcs in the frontal lobe, parietal lobe and basal ganglia (P,0.001). The cerebellar static CMRglc was lower than the thalamic
CMRglc, but the difference was not significant. The lowest CMRglc was in the medial temporal lobe, followed by the cerebellum (P,0.001). • Kinetic CMRglc: The lowest kinetic CMRglc was in the medial temporal lobe, followed by the thalamus and cerebellum. The difference in kinetic CMRglc between the medial temporal lobe and each of the regions was significant (P,0.001). CMRglc in the cerebellum was significantly lower than that in the parietal lobe (P,0.05), and significantly higher than that in the medial temporal lobe (P,0.001). These results were similar to those of the static CMRglc calculated from fixed rate constants. Rate constants • K1 : The cerebellar K1 value was the largest among all the other regional K1 values (P,0.001), followed by the occipital and parietal K1 values. The medial temporal K1 value was the lowest (P,0.001), followed by the basal ganglia, frontal, and lateral temporal K1 . The K1 value in the lateral temporal lobe was significantly lower than the K1 values in the cerebellum (P,0.001) and the occipital lobe (P,0.02). • k 2 : The cerebellum showed the highest k 2 value (P, 0.001), followed by the occipital, and medial temporal lobes. The k 2 value was significantly higher in the medial temporal lobe than in the frontal, parietal lobes, and basal ganglia (P,0.001). • k 3 : The k 3 values of the cerebellum and medial temporal lobe were the lowest among all the regions. Distribution volume (K1 /(k 2 1k 3 )) The K1 /(k 2 1k 3 ) value of the medial temporal lobe was the lowest among all the regions (P,0.03 with respect to the lateral temporal and occipital lobes and P,0.001 for the other regions). The cerebellum showed a relatively high K1 /(k 2 1k 3 ) value, although it was less than that in the thalamus. sGER and kGER sGER was calculated from a fixed standard set of rate constants, and kGER was calculated from rate constants estimated from the dynamic study. Both sGER and kGER values in the cerebellum and medial temporal lobe were significantly lower than those in the frontal, lateral temporal, occipital, parietal lobes and the basal ganglia (P,0.001). sGER values in both the cerebellum and medial temporal lobe were also lower than those in the thalamus (P,0.001). These results were similar to the estimates of GER from both static and kinetic CMRglc.
S. Sakamoto, K. Ishii / Journal of the Neurological Sciences 172 (2000) 41 – 48 Table 1 Mean regional kinetic rate constants of the dynamic 2-[ 18 F]fluoro-2-deoxy-D-glucose method, CMRglc and CBF measured by the autoradiographic technique in eight normal subjects a
45
15
O-labeled water
CBF (ml / 100 g / min)
Static CMRglc (mg / 100 g / min)
Kinetic CMRglc (mg / 100 g / min)
Cerebellum Frontal lobe Lateral temporal lobe Medial temporal lobe Occipital lobe Parietal lobe Basal Ganglia Thalamus
64.0614.3 51.5612.2 53.7612.1 46.068.4 49.8610.1 52.7612.2 56.4615.7 59.9611.6
6.8361.03 8.3561.07 7.5560.85 4.7760.58 7.7161.24 8.3861.19 8.3161.23 7.7961.36
5.7961.06 6.7860.69 6.3260.51 3.9760.56 6.5260.33 6.8760.71 6.3861.29 5.9261.57
Cerebellum Frontal lobe Lateral temporal lobe Medial temporal lobe Occipital lobe Parietal lobe Basal Ganglia Thalamus
Static GER 0.11060.019 0.16860.024 0.14560.023 0.10760.018 0.15860.019 0.16460.024 0.15260.018 0.13460.025
Kinetic GER 0.09360.020 0.13860.030 0.12360.025 0.08960.019 0.13560.017 0.13660.027 0.11760.021 0.10160.028
K1 /(k 2 1k 3 ) 0.63960.073 0.60460.069 0.55760.085 0.45760.080 0.55460.076 0.60560.064 0.62660.093 0.64960.112
Cerebellum Frontal lobe Lateral temporal lobe Medial temporal lobe Occipital lobe Parietal lobe Basal Ganglia Thalamus
K1 (min 21 ) 0.12960.018 0.09660.010 0.09960.012 0.08360.012 0.11060.014 0.10160.012 0.09560.009 0.10760.014
k 2 (min 21 ) 0.15560.013 0.09860.014 0.11960.015 0.13660.014 0.13860.030 0.10560.016 0.09660.015 0.11660.021
k 3 (min 21 ) 0.04860.009 0.06260.011 0.06160.012 0.04860.008 0.06460.009 0.06260.010 0.05960.014 0.05360.015
a
Values are mean and standard deviation.
Representative images of CBF, CMRglc and GER are shown in Fig. 2.
Correlations between the parameters Table 2 shows the average correlation coefficients between CBF, kinetic CMRglc, and the kinetic rate constants in the eight subjects. There were good correlations between CBF and the K1 values and between CMRglc and the k 3 values. Table 2 Correlation coefficients between rate constants, CMRglc and CBF a
K1 k2 k3 CMRglc a
k2
k3
CMRglc
CBF
0.645(0.141) – – –
0.255(0.100) 0.314(0.191) – –
0.364(0.114) 0.110(0.153) 0.751(0.069) –
0.709(0.1) 0.234(0.181) 0.109(0.066) 0.415(0.086)
Values are mean correlation coefficients of eight normal subjects, which are based on measurements on CBF, kinetic CMRglc and kinetic rate constants in 50 regions of interest. K1 , k 2 , k 3 and CMRglc were measured by the dynamic 2-[ 18 F]fluoro-2-deoxy-D-glucose method. Values are mean and standard deviation.
5. Discussion The preceding results demonstrate that there are regional differences in the brain GER, and that the GER in the medial temporal lobe and cerebellum in the normal human brain under resting conditions is low. This is based on the findings that (1) of the brain structures examined, the cerebellum had the highest blood flow, but that CMRglc was relatively low, and (2) the medial temporal lobe had the lowest CBF and CMRglc among all the brain structures examined. In addition, the cerebellum showed the highest K1 and k 2 values and the lowest k 3 value of the regions examined. Medial temporal CBF and CMRglc: The medial temporal CMRglc values were previously reported to be the lowest among all brain regions, though the values were not statistically analyzed [9,25]. Moreover, 11 C-glucose PET studies [26,27] revealed that relative glucose metabolism is lower in the amygdala and hippocampus than in other regions. Our study confirmed that CMRglc and CBF in the medial temporal lobe including the hippocampus are the lowest among all brain regions, and were significantly lower than the values in the cerebellum, basal ganglia and thalamus. The reason for the low CMRglc in the medial
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temporal cortex including the hippocampus is discussed below. Cerebellar blood flow and glucose metabolism: Holash et al. [28] estimated the vascular volume in mice brain using a point counting method. There was no difference in intraparenchymal vascular volume between the cerebellum and the cerebrum. By including the pial vessel volume with the brain vascular volume, the vascular volumes in the cerebral cortex and cerebellum were increased by approximately 6% and 30%, respectively, suggesting that measurements using intravascular tracers caused the higher cerebellar vascular volume. A similar difference in the calculated vascular volume may be present in the human brain. However, as mentioned above, we calculated the fractional CBV to correct for blood-borne activity in the FDG-PET measurements, which eliminated the effects of the vascular volume and the pial vascular volume on the CMRglc measurement. H 15 2 O is not an intravascular tracer, and therefore in the H 15 O autoradiographic CBF measure2 ments in this study, we did not correct blood volume. By measuring CBF and CMRglc by H 15 2 O and FDG, we demonstrated an apparent discrepancy between CBF and CMRglc in the cerebellum, where the low glucose utilization was correlated with a low FDG phosphorylation rate (k 3 ) despite a sufficient FDG transportation rate (K1 ) from plasma to tissue. This result confirmed the results of Sasaki et al. [4], who measured CBF by the 15 O-labeled gas steady state method. Medial temporal and cerebellar GER: In agreement with our results, Sasaki et al. [4] found that cerebellar GER was lower than the GER of the cerebral cortices. However, they did not measure GER of the medial temporal lobe. By simultaneous estimation of 18 F-FDG and H 215 O PET, we revealed for the first time that among all brain structures in the normal human brain under resting conditions, the medial temporal lobe has the lowest GER, followed by the cerebellum. Static CMRglc vs. kinetic CMRglc: If compared with the kinetic CMRglc as a golden standard, the static measures overestimated CMRglc in all brain regions in the present study. These results are consistent with those of the previous report [29]. This suggests that the kinetic measurement provides a less biased estimate of the true CMRglc than static imaging, because individual rate constants are taken into account [29]. Distribution volume (K1 /(k 2 1k 3 )): The K1 /(k 2 1k 3 ) value was significantly lower in the medial temporal lobe than in the other regions. This result confirmed that of Sokoloff et al. [21], who measured local cerebral glucose utilization by the 14 C-labeled deoxyglucose method in the normal conscious albino rat. Regional difference in GER: Delivery of glucose from the blood to the brain involves transport of glucose across the endothelium of the blood brain barrier, and the plasma membrane of the individual brain cells. This process is mediated by at least two isoforms of the glucose transpor-
ter family, GLUT-1, and GLUT-3 [30,31]. GLUT-1 is mainly localized in the capillary endothelium of the brain [32] and is associated with local transport and utilization [33,34]. In contrast to GLUT-1, GLUT-3 is primarily expressed in neurons [35,36] but is not detected in the microvasculature in human or rat brains [37]. Olson and Pessin reported that GLUT-3 is responsible for maintaining an adequate glucose supply to neurons [30], while the local distribution of GLUT-3 in rat brain showed no correlation with the moderately heterogeneous GLUT-3 transporter density and no correlation with the strongly heterogeneous local cerebral glucose utilization [38]. The results show that the local density of GLUT-3 glucose transporter protein does not reflect the local level of glucose utilization in the brain. Hippocampal GLUT3 distribution was higher than that in the cerebral cortices [39]. These two reports [38,39] do not support our findings that the low GER in the medial temporal lobe and cerebellum is due to low glucose metabolism. This discrepancy might be due to a difference in glucose metabolism in rat and human brains. Glucose is converted into glucose-6-phosphate by hexokinase. Brain hexokinase (ATP: D-hexose 6-phosphotransferase) levels in rat brain including the hippocampus, cerebellar molecular layer, frontal cortex and parietal cortex were shown to be significantly correlated with the basal rate of glucose metabolism [40]. The observation that the hexokinase content of a region reflects its metabolic energy demands agrees with the strong correlation between CMRglc and k 3 in our study (Table 2). In the human brain, hexokinase activity in the neocortex may be larger than the activities in the medial temporal cortex and cerebellum. Thus, regional perfusional / metabolic differences exist between the medial temporal lobe, cerebellum and other brain regions. CMRglc in the human brain depends on k 3 (hexokinase activity), and the low GER in the medial temporal and cerebellum is due to low hexokinase activity. The perfusion and metabolism in the medial temporal lobe and cerebellum are quite different from those in the neocortices, and the low CBF, CMRglc and GER in the medial temporal lobe suggests that the medial temporal lobe is more sensitive to hypoglycemia and hypoxia due to its low cerebral perfusion compared with the perfusion in other cortical regions.
Acknowledgements We thank Prof. Chikako Tanaka (Director, Hyogo Institute for Aging Brain and Cognitive Disorders [HIABCD]) and Prof. Kazuro Sugimura (Dept. Radiology, Kobe University) for their encouragement and critical reviews of the manuscript. We also thank Dr Masahiro Sasaki, Dr Hajime Kitagaki and Dr Shigeru Yamaji (Div. Neuroimaging Research, HI-ABCD) for their PET drug synthesis and assistance in performing PET scans, and Mr
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Toru Kida and Mr Hiroto Sakai (Radiology Service, HIABCD) for their technical support. We thank Dr Hinako Toyama (Positron Medical Center, Tokyo Metropolitan Institute of Gerontology) for providing the kinetic CMRglc analyzing program.
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ters in the brains of patients with Alzheimer’s disease. Ann Neurol 1994;35:546–51. [40] Turek TJ, Hawkins RA, Wilson JE. Correlation of hexokinase content and basal energy metabolism in discrete regions of rat brain. J Neurochem 1986;46:983–5.
Low cerebral glucose extraction rates in the human medial temporal cortex and cerebellum Setsu Sakamoto
a,b ,
*, Kazunari Ishii b
a
b
Department of Radiology, Kobe University School of Medicine, 7 -5 -2 Kusunoki-Cho, Chuo-Ku, Kobe 650 -0017, Japan Division of Neuroimaging Research, Hyogo Institute for Aging Brain and Cognitive Disorders ( HI-ABCD), Himeji, Japan Received 5 April 1999; received in revised form 2 August 1999; accepted 11 October 1999
Abstract Previous studies have reported that there exist different regional sensitivities to acute hypoxia. To better understand these differences, we estimated regional differences of cerebral blood flow (CBF), cerebral glucose metabolism (CMRglc) and kinetic constants (K1 , k 2 , k 3 ) in the human cortex under resting conditions. CBF, CMRglc, kinetic rate constants and glucose extraction rate (GER) were measured in eight normal male subjects (mean age: 26.16 4.9 years) using the 15 O-water autoradiographic technique and subsequently the dynamic and the static [ 18 F]2-fluoro-2-deoxy-D-glucose technique with positron emission tomography (PET). Of all the brain structures investigated, the medial temporal lobe showed the lowest CBF (46.0 ml / 100 g / min) and lowest CMRglc (3.97 mg / 100 g / min). The medial temporal GER was lowest (8.9%), followed by the cerebellar GER (9.3%). While the cerebellar blood flow (64.0 ml / 100 g / min) was the highest, the cerebellar metabolic rate for glucose (5.79 mg / 100 g / min) was relatively low. The cerebellum showed the highest K1 value (0.13) and k 2 value (0.16), and the lowest k 3 value (0.05). In the medial temporal cortices and cerebellum, CMRglc and GER were lower than those in the neocortices. These results indicate that there are great perfusional / metabolic differences between the medial temporal lobe, cerebellum and other brain regions in the normal human brain under resting conditions. 2000 Elsevier Science B.V. All rights reserved. Keywords: Cerebral blood flow; Cerebral glucose metabolism; Glucose extraction rate (GER); Medial temporal lobe; Positron emission tomography (PET); Rate constant
1. Introduction It is widely accepted that regional cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO 2 ) and cerebral metabolic rate for glucose (CMRglc) are all linearly related to one another in the normal brain under resting conditions [1,2]. In this paper, these quantities also refer to the values in the cerebellum. Previously we reported regional differences in CBF and CMRO 2 (both are high in the visual cortex) and oxygen extraction fraction (OEF) (low in the sensorimotor cortex) under resting conditions in normal subjects [3]. Previous studies *Corresponding author. Tel.: 181-78-382-6104; fax: 181-78-3826129. E-mail address: [email protected] (S. Sakamoto)
with 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG) and PET [4– 10] have shown that cerebellar glucose metabolism is always lower than CMRglc in the neocortices in the normal human brain, while other studies have shown that blood flow in the cerebellum is always higher than that in the neocortex in the normal human brain [11–16], though the results were not statistically analyzed. The medial temporal CBF and CMRglc have not been well estimated either. It is well-known that, in the adult human brain, hypoxic episodes cause more severe damage to the older brain structures such as the hippocampus and cerebellum than to the neocortices [17]. The vulnerability of the hippocampus and cerebellum may indicate that the metabolism and perfusion of these regions are different from those of the neocortex. The aim of this study was to estimate regional differences in the glucose extraction ratio
0022-510X / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00286-5
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(GER) in normal subjects, especially between the medial temporal lobe, cerebellum and neocortices, in the resting state by sequential measurements of CBF and CMRglc using 15 O-labeled water (H 15 2 O) and FDG with PET.
2. Materials and methods
2.1. Subjects We studied eight healthy normal male subjects, who volunteered for this study. They showed no clinical evidence of cognitive deficits or neurological disease and were taking no acute or chronic medications at the time of the scan. They had no abnormal findings on magnetic resonance (MR) images. All the subjects were right handed. Average age6SD was 26.164.9 years (range: 23–38 years). Before the examination, written informed consent was obtained from all the subjects.
2.2. PET procedure Before the PET scans, all the subjects received MR images for anatomical reference, for PET positioning and to confirm that they had no abnormal conditions. MR was performed as described previously [3]. Immediately before the PET examination, sagittal gradient-echo images were obtained to determine the coordinates for positioning of the head on the PET table. The PET procedure was approved by our institution’s Ethical Committee. PET was performed with a PET scanner Headtome IV (Shimadzu Corp., Kyoto, Japan), which had four rings located 13 mm apart and yielded a transverse resolution of 4.5 mm full-width-half-maximum (FWHM) [18]. The slice thickness was 11 mm and the slice interval was 13 mm with non-z motion mode for a dynamic scan and 6.5 mm with z-motion mode for a static scan. The gantry and scanner table were adjusted according to the coordinates determined by MR imaging so that scans were taken parallel to the AC–PC plane from 32.5 mm below to 52.0 mm above the AC–PC plane at 13- or 6.5-mm intervals. The scans were taken parallel to the anterior commissure–posterior commissure (AC–PC) plane using the MR markings. A transmission scan was performed using a 68 Ga / 68 Ge pin source for absorption correction after each subject was positioned. PET studies were performed under resting conditions with the subject’s eyes closed and ears unplugged. All subjects had fasted for at least 4 h before PET scanning. First, CBF was measured using the H 15 2 O and autoradiographic technique [12]. In brief, 740–1110 MBq of H 15 2 O was administered intravenously as a bolus. Scanning was begun after the radioactivity was detected in the brain (10–20 s after injection). Each position was sequentially
scanned for 5 s and this was repeated a total of nine times. The arterial radioactivity concentration was monitored by detecting beta-rays with a plastic scintillator. Arterial blood was withdrawn at a constant rate of 5 ml / min. The dispersion was corrected by deconvolving the beta probe curve delay in comparison with the appearance of the radiotracer in the brain, adjusting the initial rise in radioactivity in the blood and brain. The regional CBF was calculated by using the tissue radioactivity and radioactivity of the blood input function and the model equations [12]. After an interval of 12 min, regional CMRglc was measured using FDG. A dynamic sequence was performed with the non-z motion mode for 40 min after administration of 185–346 MBq of FDG. The scan protocol consisted of 20 images each for 2 min. Arterial blood sampling was done from a catheter inserted into the left radial artery just after administration, and at 15, 30, 45, 60, 75, 90, 105, 120 s and at 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 40, and 50 min after administration. Plasma and whole blood radioactivities were measured. Arterial plasma glucose levels were determined using the plasma samples obtained through the scan. Then a static sequence for the autoradiographic method was started at 45 min after the injection and emission data were collected for 12 min using the z-motion mode. The static CMRglc image was calculated by Phelps’ autoradiographic method [19]. The incorporated metabolic rate constants were K1 50.080, k 2 50.126, k 3 50.068, and k 4 50.0055, and the lumped constant (LC) was 0.52 [20].
2.3. Data analysis PET and MR image data sets were directly transmitted to a workstation (Indigo2 Extreme, Silicon Graphics, Mountain View, CA) from the PET and MR imaging units, and analyzed using image analyzing software Dr. View (ver. 4.0, Asahi Joho System, Tokyo, Japan). A standard three-compartmental tracer kinetic model extending the original method of Sokoloff et al. [21] was used. Taguchi et al. [22] compared three- and four-parameter models for 45 min and 120 min of data acquisition after FDG administration and concluded that the three-parameter model was better suited for the 45-min data acquisition and the four-parameter model was better suited for the 120-min data acquisition. Therefore, we calculated the dynamic data with the three-compartmental, three-parameter model. In addition to the rate constant, the fractional cerebral blood volume (CBV) was estimated by a leastsquares fit in order to correct for blood-borne activity in the PET measurement. Kinetic CMRglc was calculated directly from the individually fitted rate constants, using the averaged plasma glucose concentration (Cp) and a LC of 0.52 as follows: CMRglc5Cp / LC3(K1 3 k 3 ) /(k 2 1k 3 ). MR 3D-SPGR images were reconstructed parallel to the AC–PC plane as references. Both PET and MR images
S. Sakamoto, K. Ishii / Journal of the Neurological Sciences 172 (2000) 41 – 48
43
Fig. 1. CBF images of a normal subject with overlain ROIs.
Fig. 2. Representative images of cerebral blood flow (CBF), cerebral metabolic rate for glucose (CMRglc), and glucose extraction rate (GER) in a 38-year-old healthy man under resting conditions. Note the low level of GER in the medial temporal lobe and cerebellum.
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were displayed side by side on a display monitor and total of 50 circular regions of interest (ROIs, 16 mm diameter) were determined in eight regions on the CBF image (Fig. 1). These included 6 ROIs in the cerebellum, 4 ROIs in the medial temporal lobe, 12 ROIs in the lateral temporal lobe, 6 ROIs in the occipital lobe, 12 ROIs in the frontal lobe, 6 ROIs in the parietal lobe, 2 ROIs in the basal ganglia and 2 ROIs in the thalamus. The same ROIs were transferred to the kinetic CMRglc, static CMRglc and kinetic rate constant (K1 , k 2 , k 3 ) images, and each regional value was measured. To increase the reliability of the measurements, the CBF, the static CMRglc, the kinetic CMRglc, K1 , k 2 and k 3 values were averaged for each of the eight regions. These averages were used to calculate the static glucose extraction rate (static GER5static CMRglc /(Cp*CBF)), the kinetic GER (5kinetic CMRglc /(Cp*CBF)) [23,24] and K1 /(k 2 1k 3 ) values. GER is the fraction of the glucose transported by the blood that is metabolized.
3. Statistical analysis The calculated data were compared in order to determine whether there were regional differences among the temporal, visual, frontal, sensorimotor and parietal regions by repeated measures using one-way analysis of variance (ANOVA) with post hoc Tukey’s HSD tests. A probability value less than 0.05 was considered to indicate a significant difference. We also calculated the correlation coefficients among the CBF, CMRglc, and kinetic rate parameters in each of the 50 regions that ROIs were set in each subject.
4. Results Estimates of the regional CBF, kinetic CMRglc, static CMRglc, kinetic GER, static GER, K1 , k 2 , k 3 and K1 /(k 2 1 k 3 ) were estimated in the cerebellum, frontal, medial temporal, lateral temporal, occipital, parietal lobes, basal ganglia and thalamus (Table 1). • CBF: The cerebellar blood flow was the highest and was significantly higher than the CBF in the frontal, medial temporal, lateral temporal, occipital and parietal lobes (P,0.001) and basal ganglia (P,0.05). The CBF in the medial temporal lobe was the lowest among all the brain structures and was significantly lower than the CBF values in the lateral temporal lobe (P,0.02), cerebellum, basal ganglia and thalamus (P,0.001). • Static CMRglc: The cerebellar static CMRglc was significantly lower than the CMRglcs in the frontal lobe, parietal lobe and basal ganglia (P,0.001). The cerebellar static CMRglc was lower than the thalamic
CMRglc, but the difference was not significant. The lowest CMRglc was in the medial temporal lobe, followed by the cerebellum (P,0.001). • Kinetic CMRglc: The lowest kinetic CMRglc was in the medial temporal lobe, followed by the thalamus and cerebellum. The difference in kinetic CMRglc between the medial temporal lobe and each of the regions was significant (P,0.001). CMRglc in the cerebellum was significantly lower than that in the parietal lobe (P,0.05), and significantly higher than that in the medial temporal lobe (P,0.001). These results were similar to those of the static CMRglc calculated from fixed rate constants. Rate constants • K1 : The cerebellar K1 value was the largest among all the other regional K1 values (P,0.001), followed by the occipital and parietal K1 values. The medial temporal K1 value was the lowest (P,0.001), followed by the basal ganglia, frontal, and lateral temporal K1 . The K1 value in the lateral temporal lobe was significantly lower than the K1 values in the cerebellum (P,0.001) and the occipital lobe (P,0.02). • k 2 : The cerebellum showed the highest k 2 value (P, 0.001), followed by the occipital, and medial temporal lobes. The k 2 value was significantly higher in the medial temporal lobe than in the frontal, parietal lobes, and basal ganglia (P,0.001). • k 3 : The k 3 values of the cerebellum and medial temporal lobe were the lowest among all the regions. Distribution volume (K1 /(k 2 1k 3 )) The K1 /(k 2 1k 3 ) value of the medial temporal lobe was the lowest among all the regions (P,0.03 with respect to the lateral temporal and occipital lobes and P,0.001 for the other regions). The cerebellum showed a relatively high K1 /(k 2 1k 3 ) value, although it was less than that in the thalamus. sGER and kGER sGER was calculated from a fixed standard set of rate constants, and kGER was calculated from rate constants estimated from the dynamic study. Both sGER and kGER values in the cerebellum and medial temporal lobe were significantly lower than those in the frontal, lateral temporal, occipital, parietal lobes and the basal ganglia (P,0.001). sGER values in both the cerebellum and medial temporal lobe were also lower than those in the thalamus (P,0.001). These results were similar to the estimates of GER from both static and kinetic CMRglc.
S. Sakamoto, K. Ishii / Journal of the Neurological Sciences 172 (2000) 41 – 48 Table 1 Mean regional kinetic rate constants of the dynamic 2-[ 18 F]fluoro-2-deoxy-D-glucose method, CMRglc and CBF measured by the autoradiographic technique in eight normal subjects a
45
15
O-labeled water
CBF (ml / 100 g / min)
Static CMRglc (mg / 100 g / min)
Kinetic CMRglc (mg / 100 g / min)
Cerebellum Frontal lobe Lateral temporal lobe Medial temporal lobe Occipital lobe Parietal lobe Basal Ganglia Thalamus
64.0614.3 51.5612.2 53.7612.1 46.068.4 49.8610.1 52.7612.2 56.4615.7 59.9611.6
6.8361.03 8.3561.07 7.5560.85 4.7760.58 7.7161.24 8.3861.19 8.3161.23 7.7961.36
5.7961.06 6.7860.69 6.3260.51 3.9760.56 6.5260.33 6.8760.71 6.3861.29 5.9261.57
Cerebellum Frontal lobe Lateral temporal lobe Medial temporal lobe Occipital lobe Parietal lobe Basal Ganglia Thalamus
Static GER 0.11060.019 0.16860.024 0.14560.023 0.10760.018 0.15860.019 0.16460.024 0.15260.018 0.13460.025
Kinetic GER 0.09360.020 0.13860.030 0.12360.025 0.08960.019 0.13560.017 0.13660.027 0.11760.021 0.10160.028
K1 /(k 2 1k 3 ) 0.63960.073 0.60460.069 0.55760.085 0.45760.080 0.55460.076 0.60560.064 0.62660.093 0.64960.112
Cerebellum Frontal lobe Lateral temporal lobe Medial temporal lobe Occipital lobe Parietal lobe Basal Ganglia Thalamus
K1 (min 21 ) 0.12960.018 0.09660.010 0.09960.012 0.08360.012 0.11060.014 0.10160.012 0.09560.009 0.10760.014
k 2 (min 21 ) 0.15560.013 0.09860.014 0.11960.015 0.13660.014 0.13860.030 0.10560.016 0.09660.015 0.11660.021
k 3 (min 21 ) 0.04860.009 0.06260.011 0.06160.012 0.04860.008 0.06460.009 0.06260.010 0.05960.014 0.05360.015
a
Values are mean and standard deviation.
Representative images of CBF, CMRglc and GER are shown in Fig. 2.
Correlations between the parameters Table 2 shows the average correlation coefficients between CBF, kinetic CMRglc, and the kinetic rate constants in the eight subjects. There were good correlations between CBF and the K1 values and between CMRglc and the k 3 values. Table 2 Correlation coefficients between rate constants, CMRglc and CBF a
K1 k2 k3 CMRglc a
k2
k3
CMRglc
CBF
0.645(0.141) – – –
0.255(0.100) 0.314(0.191) – –
0.364(0.114) 0.110(0.153) 0.751(0.069) –
0.709(0.1) 0.234(0.181) 0.109(0.066) 0.415(0.086)
Values are mean correlation coefficients of eight normal subjects, which are based on measurements on CBF, kinetic CMRglc and kinetic rate constants in 50 regions of interest. K1 , k 2 , k 3 and CMRglc were measured by the dynamic 2-[ 18 F]fluoro-2-deoxy-D-glucose method. Values are mean and standard deviation.
5. Discussion The preceding results demonstrate that there are regional differences in the brain GER, and that the GER in the medial temporal lobe and cerebellum in the normal human brain under resting conditions is low. This is based on the findings that (1) of the brain structures examined, the cerebellum had the highest blood flow, but that CMRglc was relatively low, and (2) the medial temporal lobe had the lowest CBF and CMRglc among all the brain structures examined. In addition, the cerebellum showed the highest K1 and k 2 values and the lowest k 3 value of the regions examined. Medial temporal CBF and CMRglc: The medial temporal CMRglc values were previously reported to be the lowest among all brain regions, though the values were not statistically analyzed [9,25]. Moreover, 11 C-glucose PET studies [26,27] revealed that relative glucose metabolism is lower in the amygdala and hippocampus than in other regions. Our study confirmed that CMRglc and CBF in the medial temporal lobe including the hippocampus are the lowest among all brain regions, and were significantly lower than the values in the cerebellum, basal ganglia and thalamus. The reason for the low CMRglc in the medial
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temporal cortex including the hippocampus is discussed below. Cerebellar blood flow and glucose metabolism: Holash et al. [28] estimated the vascular volume in mice brain using a point counting method. There was no difference in intraparenchymal vascular volume between the cerebellum and the cerebrum. By including the pial vessel volume with the brain vascular volume, the vascular volumes in the cerebral cortex and cerebellum were increased by approximately 6% and 30%, respectively, suggesting that measurements using intravascular tracers caused the higher cerebellar vascular volume. A similar difference in the calculated vascular volume may be present in the human brain. However, as mentioned above, we calculated the fractional CBV to correct for blood-borne activity in the FDG-PET measurements, which eliminated the effects of the vascular volume and the pial vascular volume on the CMRglc measurement. H 15 2 O is not an intravascular tracer, and therefore in the H 15 O autoradiographic CBF measure2 ments in this study, we did not correct blood volume. By measuring CBF and CMRglc by H 15 2 O and FDG, we demonstrated an apparent discrepancy between CBF and CMRglc in the cerebellum, where the low glucose utilization was correlated with a low FDG phosphorylation rate (k 3 ) despite a sufficient FDG transportation rate (K1 ) from plasma to tissue. This result confirmed the results of Sasaki et al. [4], who measured CBF by the 15 O-labeled gas steady state method. Medial temporal and cerebellar GER: In agreement with our results, Sasaki et al. [4] found that cerebellar GER was lower than the GER of the cerebral cortices. However, they did not measure GER of the medial temporal lobe. By simultaneous estimation of 18 F-FDG and H 215 O PET, we revealed for the first time that among all brain structures in the normal human brain under resting conditions, the medial temporal lobe has the lowest GER, followed by the cerebellum. Static CMRglc vs. kinetic CMRglc: If compared with the kinetic CMRglc as a golden standard, the static measures overestimated CMRglc in all brain regions in the present study. These results are consistent with those of the previous report [29]. This suggests that the kinetic measurement provides a less biased estimate of the true CMRglc than static imaging, because individual rate constants are taken into account [29]. Distribution volume (K1 /(k 2 1k 3 )): The K1 /(k 2 1k 3 ) value was significantly lower in the medial temporal lobe than in the other regions. This result confirmed that of Sokoloff et al. [21], who measured local cerebral glucose utilization by the 14 C-labeled deoxyglucose method in the normal conscious albino rat. Regional difference in GER: Delivery of glucose from the blood to the brain involves transport of glucose across the endothelium of the blood brain barrier, and the plasma membrane of the individual brain cells. This process is mediated by at least two isoforms of the glucose transpor-
ter family, GLUT-1, and GLUT-3 [30,31]. GLUT-1 is mainly localized in the capillary endothelium of the brain [32] and is associated with local transport and utilization [33,34]. In contrast to GLUT-1, GLUT-3 is primarily expressed in neurons [35,36] but is not detected in the microvasculature in human or rat brains [37]. Olson and Pessin reported that GLUT-3 is responsible for maintaining an adequate glucose supply to neurons [30], while the local distribution of GLUT-3 in rat brain showed no correlation with the moderately heterogeneous GLUT-3 transporter density and no correlation with the strongly heterogeneous local cerebral glucose utilization [38]. The results show that the local density of GLUT-3 glucose transporter protein does not reflect the local level of glucose utilization in the brain. Hippocampal GLUT3 distribution was higher than that in the cerebral cortices [39]. These two reports [38,39] do not support our findings that the low GER in the medial temporal lobe and cerebellum is due to low glucose metabolism. This discrepancy might be due to a difference in glucose metabolism in rat and human brains. Glucose is converted into glucose-6-phosphate by hexokinase. Brain hexokinase (ATP: D-hexose 6-phosphotransferase) levels in rat brain including the hippocampus, cerebellar molecular layer, frontal cortex and parietal cortex were shown to be significantly correlated with the basal rate of glucose metabolism [40]. The observation that the hexokinase content of a region reflects its metabolic energy demands agrees with the strong correlation between CMRglc and k 3 in our study (Table 2). In the human brain, hexokinase activity in the neocortex may be larger than the activities in the medial temporal cortex and cerebellum. Thus, regional perfusional / metabolic differences exist between the medial temporal lobe, cerebellum and other brain regions. CMRglc in the human brain depends on k 3 (hexokinase activity), and the low GER in the medial temporal and cerebellum is due to low hexokinase activity. The perfusion and metabolism in the medial temporal lobe and cerebellum are quite different from those in the neocortices, and the low CBF, CMRglc and GER in the medial temporal lobe suggests that the medial temporal lobe is more sensitive to hypoglycemia and hypoxia due to its low cerebral perfusion compared with the perfusion in other cortical regions.
Acknowledgements We thank Prof. Chikako Tanaka (Director, Hyogo Institute for Aging Brain and Cognitive Disorders [HIABCD]) and Prof. Kazuro Sugimura (Dept. Radiology, Kobe University) for their encouragement and critical reviews of the manuscript. We also thank Dr Masahiro Sasaki, Dr Hajime Kitagaki and Dr Shigeru Yamaji (Div. Neuroimaging Research, HI-ABCD) for their PET drug synthesis and assistance in performing PET scans, and Mr
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Toru Kida and Mr Hiroto Sakai (Radiology Service, HIABCD) for their technical support. We thank Dr Hinako Toyama (Positron Medical Center, Tokyo Metropolitan Institute of Gerontology) for providing the kinetic CMRglc analyzing program.
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