Use of PET methods for measurement of cerebral energy metabolism and hemodynamics in cerebrovascular disease.
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Brain↗
Biomedical subjects
K Wienhard
Publications and source records attributed to K Wienhard.
Measurement of blood-brain hexose transport with dynamic PET: comparison of [18F]2-fluoro-2-deoxyglucose and [11C]O-methylglucose.
Blood-to-tissue transport of [18F]2-fluoro-2-deoxyglucose (FDG) and [11C]O-methylglucose (CMG) was compared by dynamic positron emission tomography in four patients with recent ischemic infarcts and in three patients with intracerebral tumors. Local blood volume, tracer transport from tissue to blood, and FDG phosphorylation rates were also determined. A regional analysis of parametric images showed a close correlation of FDG and CMG transport rate constants in pathological tissue. Transport rates of FDG and CMG showed correspondingly less asymmetric remote effects than FDG phosphorylation rates. Transport rate constants were consistently higher for FDG than for CMG in pathological and normal tissue, in accordance with the higher affinity of carrier enzymes to FDG. There was a significant correlation between fitted regional blood volume values and correspondence of average absolute values with both tracers. It is concluded that dynamic FDG PET for measurement of cerebral glucose metabolism is also useful to measure alterations of hexose transport and local blood volume in pathological tissue.
Aged↗
Regional cerebral blood flow measurement with intravenous [15O]water bolus and [18F]fluoromethane inhalation.
In 20 patients with ischemic cerebrovascular disease, classic migraine, or angiomas, we compared paired dynamic positron emission tomographic measurements of regional cerebral blood flow using both [15O]water and [18F]fluoromethane as tracers. Cerebral blood flow was also determined according to the autoradiographic technique with a bolus injection of [15O]water. There were reasonable overall correlations between dynamic [15O]water and [18F]fluoromethane values for cerebral blood flow (r = 0.82) and between dynamic and autoradiographic [15O]water values for cerebral blood flow (r = 0.83). We found a close correspondence between abnormal pathologic findings and visually evaluated cerebral blood flow tomograms obtained with the two tracers. On average, dynamic [15O]water cerebral blood flow was 6% lower than that measured with [18F]fluoromethane. There also was a general trend toward a greater underestimation with [15O]water in high-flow areas, particularly in hyperemic areas, probably due to incomplete first-pass extraction of [15O]water. Underestimation was not detected in low-flow areas or in the cerebellum. Absolute cerebral blood flow values were less closely correlated between tracers and techniques than cerebral blood flow patterns. The variability of the relation between absolute flow values was probably caused by confounding effects of the variation in the circulatory delay time. The autoradiographic technique was most sensitive to this type error.
Administration, Inhalation↗
Regional metabolic correlates of Token test results in cortical and subcortical left hemispheric infarction.
We investigated 26 right-handed patients who had aphasia caused by a single infarct in the territory of the left middle cerebral artery (MCA) with cranial CT, positron emission tomography, and a standard language test battery including the Token test. The patients represented an unselected sample of various infarct locations within the left MCA territory and showed a wide range of aphasia types and severity. Stepwise regression analysis revealed that Token test performance mainly depended on parietotemporal metabolism, irrespective of infarct location. Frontal and basal ganglia metabolism did not contribute significantly to Token test performance. These results suggest that disturbance of language comprehension is due to parietotemporal cortical dysfunction in all types of left MCA infarction. Infarcts restricted to basal ganglia or the anterior part of the MCA territory apparently do not disturb language comprehension directly, but via their remote effects on parietotemporal metabolism.
Adult↗
PET measurement of D2 and S2 receptor binding of 3-N-[( 2'-18F]fluoroethyl)spiperone in baboon brain.
The regional pharmacokinetic behavior in baboon brain of 18F-fluoroethyl- and 18F-fluoropropylspiperone (18FESP, 18FPSP) at specific activities greater than or equal to 1000 Ci/mmol was studied with PET. Four hours after injection of 5-10 mCi 18FESP, uptake in striatum was 0.048% +/- 0.005% of injected dose per cm3, which is almost the same as with 18F- and 11C-methylspiperone. While 18FPSP was taken up in much smaller amounts than 18FESP, striatum to cerebellum activity ratios were quite similar for both ligands (about 9 to 10 at 4 h p.i.). Because of its higher striatal uptake, 18FESP seems to be better suited for PET. Furthermore, relative binding to S2 receptors was much smaller for FESP: competing cold S2 antagonists (ritanserin, ketanserin) did not alter 18FESP binding to striatum, concurrently reducing uptake in frontal cortex by only 15%-20%. With coinjection of increasing amounts of cold FESP, saturation of 18FESP binding to striatum occurred at doses exceeding 10 micrograms per kg. Quantitative analysis of radiolabelled ligand in arterial plasma (decrease to 8% at 4 h p.i.) demonstrated identical metabolic turnover for both ligands. Direct use of binding fractions from the saturation curve resulted in overestimation of the receptor density in striatum. Using the 18FESP plasma concentration time curve and the dynamic uptake data, k3 of a three compartment model could be determined by non linear regression. However, dramatic changes of the dependence of k3 on the specifically bound ligand concentration were observed even at small loading doses of FESP. Estimation of Bmax yielded a D2 receptor density of only 6 pmol per cm3 in baboon striatum.
Animals↗
Uncoupling of hexose transport and phosphorylation in human gliomas demonstrated by PET.
Tumor uptake of [18F]2-fluoro-2-deoxy-glucose (FDG) was studied in 20 patients with histologically classified gliomas, using dynamic positron emission tomography (PET). Parametric images of local blood volume, glucose metabolic rate, transport and phosphorylation rate constants were generated by weighted non-linear least-squares fits on a pixel-by-pixel basis. Tumor metabolism, i.e. ratios of tumor peak metabolism to contralateral brain metabolism, corresponded with histological grade. Approximately half of the tumors showed considerable metabolic heterogeneity, and metabolically active areas were found in the periphery of seven tumors. Rate constants of FDG transport and phosphorylation were significantly correlated and were inversely coupled to plasma glucose levels in contralateral brain. In contrast, tumor transport and phosphorylation rate constants varied independently of each other and of plasma glucose concentration. In some tumors large alterations of FDG phosphorylation were observed in presence of nearly normal FDG transport.
Adolescent↗
3-N-(2-[18F]-fluoroethyl)-spiperone: a novel ligand for cerebral dopamine receptor studies with pet.
3-N-(2-[18F]-fluoroethyl)-spiperone [( 18F]-FESP) was synthesized at high specific activity by condensation with 2-[18F]-fluoroethyltosylate (35 TBq/mmol). In vivo binding studies in baboons by positron emission tomography exhibited regio-selective uptake in the striatum which was saturable with the cold ligand and prevented by pretreatment with (+)-butaclamol. The pharmacokinetic behaviour, i.e. the absolute uptake in tissue and the striatum-to-cerebellum ratio, was very similar to that of methylspiperone. Analysis of the radioactivity in mouse brain after administration of [18F]-FESP indicated a high in-vivo stability (greater than 90% after 210 min in the striatum). Comparative distribution studies of other N-fluoroalkylspiperones in mice suggest that FESP and the N-fluoropropyl analogue are the most potent D2 receptor ligands.
Animals↗
Regional cerebral glucose metabolism in anorexia nervosa measured by positron emission tomography.
Regional cerebral glucose metabolism was measured in five female anorectic patients, during the anorectic state and after weight gain, using the fluorodeoxyglucose method and positron emission tomography. In addition, these results were compared with those of 15 young male normals. During the anorectic state, significant caudate hypermetabolism was found bilaterally, unlike the finding in repeat measurements or in male normals. In some other brain structures (temporal cortex, lentiform nucleus, thalamus, and brainstem), significant hypermetabolism was also found during the anorectic state, but these results were not concordant for both sides and in both comparisons. There was no difference between patients after improvement and young male normals.
Adolescent↗
Regional cerebral pharmacokinetics of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as examined by positron emission tomography in a baboon is altered by tranylcypromine.
The selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has chemical and metabolic characteristics which allow its in vivo tissue distribution to be studied using positron emission tomography (PET). The cerebral pharmacokinetics of [11C]MPTP labelled at the N-methyl position was quantitatively traced in the living brain of an anesthetized baboon using PET, and the effect of administration of the monoamine oxidase (MAO) inhibitor tranylcypromine on this regional cerebral distribution was determined in the same animal. Following injection of [1C]MPTP, radioactivity rapidly concentrated in the basal ganglia of the primate's brain. This in vivo localization was prevented by prior administration of tranylcypromine, suggesting that it is oxidized metabolites of MPTP which are sequestered by dopaminergic neurons. Radioactivity rapidly localized preferentially in the basal ganglia of the primate brain, and this in vivo localization was blocked by prior administration of the MAO inhibitor tranylcypromine.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Evaluation of 75Br-labelled butyrophenone neuroleptics for imaging cerebral dopaminergic receptor areas using positron emission tomography.
A comparative evaluation of three radiobrominated butyrophenone neuroleptics--bromospiperone (BSP), brombenperidol (BBP), and bromperidol (BP)--was made to assess the applicability of these compounds as radiopharmaceuticals labelled with the positron emitter 75Br (T1/2 = 1.6 h) for mapping cerebral dopaminergic receptor areas non-invasively with positron emission tomography (PET). BSP, BBP, and BP were prepared in high specific activities with high radiochemical yields, using electrophilic reactions with no-carrier-added 77Br- or 75Br-. Screening tests in rats using 77Br-labelled compounds indicated D2-specific localization for 77Br-BSP and 77Br-BBP, whereas PET experiments in baboons showed that only 75Br-BSP preferentially localized in cerebral tissues rich in dopaminergic receptors. The data suggest an inverse relationship between cerebral uptake and receptor-specific localization, which was attributed to a complicated interplay between the D2 receptor binding affinity, lipophilicity, % ionization and molecular weight of the radioligand, and the binding capacity of the cerebral tissues. 75Br-BSP gave a striatum-to-cerebellum ratio of 3 in baboon brain 5 h post-injection, which allowed visualization of dopaminergic-receptor-containing areas of the living brain using PET.
Animals↗
Positron emission tomography in neuropsychology.
By positron emission tomography (PET) of 18F-2-fluoro-2-deoxy-D-glucose (FDG) local cerebral metabolic rate for glucose (LCMRGl) can be measured in man. Normal values in cerebral cortex and basal ganglia range from 35 to 50 mumol/100 g/min, the values in gray matter structures of the posterior fossa were 25-30 mumol/100 g/min, the lowest LCMRGl was found in the white matter (15-20 mumol/100 g/min). During sensory stimulation by various modalities functional activation increases LCMRGl in the respective special areas, while sleep decreases metabolic rate in all cortical and basal gray matter structures. In many neurological disorders CMRGl is altered in a disease-specific pattern. In dementia of the Alzheimer type CMRGl is impaired even in early stages with accentuation in the parieto-temporal cortex, while in multi-infarct dementia glucose uptake is mainly reduced in the multifocal small infarcts. In Huntington's chorea the most conspicuous changes are found in the caudate nucleus and putamen. In cases of focal lesions (e.g. ischemic infarcts) metabolic disturbances extend far beyond the site of the primary lesion and inactivation of metabolism is found in intact brain structures far away from the anatomical lesion. Additional applications of PET include determination of the metabolism of various substrates, of protein synthesis, of function and distribution of receptors, of tumor growth and of the distribution of drugs as well as the measurement of oxygen consumption, blood flow and blood volume.
Brain↗
[Cerebral glucose metabolism in presenile dementia of the Alzheimer type--follow-up of therapy with muscarinergic choline agonists].
In 8 patients who had clinically diagnosed presenile dementia (Alzheimer's disease) the cerebral glucose metabolism was repeatedly determined via FDG-PET under therapy with a muscarinergic choline agonist. The pattern of glucose metabolism disturbance characteristic of Alzheimer's disease, which had been determined previously by examining the metabolism, was confirmed. Whereas the total cortical glucose metabolism was significantly reduced, the regions of the parietal and the adjacent regions of the temporal and occipital association cortex were preferably affected. The primary somatosensory and visual cortex were largely excepted from the reduction in metabolism or showed slightly enhanced metabolic rates, as for example the cerebellum. The disturbance was not equilaterally pronounced and correlated with the neuropsychological deficiency. Despite biochemically "on target" therapy the glucose metabolism decreased progressively (mean value with large interindividual and intraindividual variations. No relationship between the degree of reduced metabolism and the clinical pattern was seen. Rather, it appears that the clinical pattern is much more strongly influenced by mutual adjustment of metabolic differences in various areas of the brain. Results obtained by the authors are communicated besides a review of update knowledge and interpretation of pathophysiological and biochemical linkups in Alzheimer's disease, taking into consideration the glucose metabolism studies published in the literature.
Alzheimer Disease↗
Positron emission tomography in depression research: principles--results--perspectives.
At present, PET is the only technology affording the quantitative, three-dimensional imaging of various aspects of brain function. In the few PET studies of mood disorders performed so far, usually cerebral glucose metabolism was investigated by the fluorodeoxyglucose method. Its largest individual diagnostic potential was demonstrated in certain forms of organic depression, while metabolic abnormalities in major unipolar and bipolar depression were more subtle--albeit significantly different. Other PET tracers for investigation of transmitter systems are available, but have not been systematically applied in depression research.
Adult↗
Regional cerebral glucose metabolism in man during wakefulness, sleep, and dreaming.
Regional cerebral glucose metabolism was measured by positron emission tomography in 4 healthy male volunteers, both during wakefulness and sleep, using the 2-deoxy-D-[2-18F]glucose method. While 3 of the subjects did not report dreaming and, during sleep stages I-IV of variable duration, exhibited a non-selective decrease in metabolic rates averaging 12.6 +/- 4.73% (mean +/- S.D.) for the entire brain, the fourth volunteer who experienced an extended nightmare during his sleep examination showed a generalized increase in cerebral glucose utilization ranging from 2.1% in lentiform nucleus to 30.0% in the superior frontal cortex, with a weighted whole brain average of 16.4%. These findings suggest that energy metabolism in the human brain is generally depressed during slow-wave sleep as opposed to a--possibly differential--activation during dreaming.
Adult↗
Estimation of local cerebral glucose utilization by positron emission tomography of [18F]2-fluoro-2-deoxy-D-glucose: a critical appraisal of optimization procedures.
Various approaches estimating local cerebral glucose utilization by positron emission tomography of labeled deoxyglucose are compared. Autoradiographic methods that predict the glucose utilization rate from a single scan are unreliable in pathologic tissue because of abnormal values of the model rate constants. A normalization procedure using the ratio of measured tissue activity to activity calculated with standard rate constants is proposed to readjust the values of the rate constants. Reliable estimates of metabolic rates can be obtained from dynamic recordings of tracer uptake. In the graphic approach, metabolic rate can be derived from the slope of a segment of a transformed uptake curve, which becomes linear at 15-20 min after intravenous tracer injection, with an accuracy comparable with that in complete dynamic studies. However, by recording and analyzing full-length uptake curves, in addition to metabolic rate, the model rate constants can be determined regionally. The physiological significance of those parameters is demonstrated in crossed cerebellar deactivation in 30 patients with supratentorial infarcts. Mild hypometabolism both within the ischemic lesion and in the morphologically intact cerebellum is accompanied by a reduction of the phosphorylation rate only. Severe metabolic depression, by contrast, affects both cerebellar transport and phosphorylation processes, whereas in the cerebrum, only the rate constant k1 is significantly correlated with the degree of metabolic disturbance.
Autoradiography↗
Comparative regional analysis of 2-fluorodeoxyglucose and methylglucose uptake in brain of four stroke patients. With special reference to the regional estimation of the lumped constant.
The glucose metabolic rate of the human brain can be measured with labeled deoxyglucose, using positron emission tomography, provided certain conditions are fulfilled. The original method assumed irreversible trapping of deoxyglucose metabolites in brain during the experimental period, and it further requires that a conversion factor between deoxyglucose and glucose, the "lumped constant," be known for the brain regions of interest. We examined the assumption of irreversible trapping of fluorodeoxyglucose metabolites in brain of four patients in 365 normal and 4 recently infarcted regions. The average net, steady-state rate of fluorodeoxyglucose (KD) accumulation in normal regions of the four patients was 0.025 ml g-1 min-1. We also examined the variability of the lumped constant. We first confirmed that methylglucose is not phosphorylated in the human brain. We then estimated the lumped constant from the regional distribution of labeled methylglucose in brain. The average (virtual) volume of distribution of labeled methylglucose in the normal regions was 0.46 ml g-1 and was the same in both gray and white matter structures. The average brain glucose content corresponding to this value was 1.3 mumol g-1, assuming a Michaelis constant (Kt) of 3.7 mM for glucose transport across the blood-brain barrier. The lumped constant varied insignificantly between 0.4 and 0.5 in most regions, with an overall average of 0.44. It did not vary significantly between the patients and was the same in gray and white matter structures, but was inversely related to the calculated metabolic rate. This observation indicates that metabolic rates calculated with a fixed lumped constant (e.g., 0.40) would be slightly underestimated at high metabolic rates and slightly overestimated at low metabolic rates. The average glucose metabolic rates of the 365 normal regions, in which gray matter regions prevailed by 20:1, was 32 mumol 100 g-1 min-1. The average glucose phosphorylation rate in white matter was 20 mumol 100 g-1 min-1 with a lumped constant of 0.45. In the recently infarcted areas, the lumped constants varied from 0.37 to 2.83, corresponding to glucose metabolic rates varying from 2 to 18 mumol 100 g-1 min-1. Two infarct types were identified. In one type, the phosphorylation-limited type, glucose content and the lumped constant were close to normal (1 mumol g-1 and 0.40, respectively). In the other, the transport/flow-limited type, the glucose content was low (0.2 mumol g-1), and the lumped constant in excess of unity. The evidence from the present study upholds the model of Sokoloff et al. in every detail.
3-O-Methylglucose↗
[Possibilities of tracer-kinetic image diagnosis using positron emission tomography].
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Blood Glucose↗
(68Ga)-EDTA positron emission tomography in the diagnosis of brain tumors.
Fifty-two patients with active brain tumors and 8 patients with brain lesions from surgical treatment and/or radio- and/or chemotherapy of their brain tumors were examined by positron emission tomography (PET) using (68Ga)-EDTA in addition to conventional X-ray computed tomography (XCT). All patients with active brain tumors showed abnormal uptake of radioactivity in the tumor region, while all treated patients had normal PET scans. Site and shape of abnormal radioactivity accumulation were in good agreement with the tumor as demonstrated by XCT. Small tumors had a tendency to appear larger in PET than in XCT, while tumors with a mean largest diameter of more than 50.7 mm in XCT usually appeared smaller in PET. Despite considerable overlap to tumor classes with respect to their degree of tracer uptake a highly significant decreasing order of tumor-sagittal sinus ratios of radioactivity (TSR) was found, malignant gliomas ranking highest (median TSR 0.634), followed by meningiomas (median TSR 0.522) and metastases (median TSR 0.391), benign gliomas showing the least uptake (median TSR 0.307). These findings suggest that PET with (68Ga)-EDTA has a high sensitivity supplementing XCT in the diagnosis of brain tumors, and may be helpful in early detection of recurrent tumor growth after therapy.
Adolescent↗