Rates Of Cerebral Glucose Utilization Research Articles

Neurochemical effects of pyritinol and their relevance for the treatment of brain function deficits in old age

AbstractThis article reviews the neurochemical results obtained in rats treated with pyritinol, a drug used clinically in the treatment of brain function deficits in old age. Pyritinol can be characterized as an indirectly acting cholinergic drug in the CNS, although its precise mechanism and its primary site of action remains to be elucidated. Direct interactions with muscarinic receptors and influences on catecholaminergic or indolaminergic systems are unlikely. Other actions of pyritinol, i.e., increases in cerebral glucose utilization in rats and cerebral blood flow in man might be secondary to its activating actions on cholinergic neurons. Since pyritinol is reported to significantly improve memory and cognitive functions in patients, the results are considered as evidence that neurochemical measurements of cholinergic functions in animals provide useful and relevant information for these indications although, similar to other cholinergic drugs, the magnitude of its therapeutic effect remains limited.

Local cerebral glucose utilization following unilateral and bilateral lesions of the nucleus basalis magnocellularis in the rat

To investigate to what extent the loss of cholinergic projections to the neocortex results in functional impairment in the target areas, local rates of cerebral glucose utilization were measured following excitotoxin lesions of the nucleus basalis magnocellularis (NBM) in the rat. Both unilateral and bilateral of NBM resutled in reversible depression of cerebral metabolism. The effects of unilateral lesion were limited to the cortical areas which receive most of the cholinergic projections from NBM. The metabolic defect produced by bilateral lesions was spread to the whole brain. Within 4 months, however, normal metabolic values coexisted with marked changes of the presynaptic cholinergic markers and impairment of conditioned behavior.

Cerebral Glucose Utilization in Rats is Not Altered by Hindlimb Restraint or by Femoral Artery and Vein Cannulation

The effects of immobilization and femoral artery and vein cannulation on resting rates of local cerebral glucose utilization (LCGU) were measured in 35 brain regions of awake rats by using the quantitative, autoradiographic [14C]2-deoxy-D-glucose [( 14C]DG) technique. Three groups of rats were cannulated on the previous day, and LCGU was measured under conditions of no restraint, 4 h of hindlimb restraint, or acute, four-limb immobilization. A fourth group represented the conventional preparation for [14C]DG experiments, with same-day cannulation followed immediately by 4 h of hindlimb restraint. Plasma catecholamines, corticosterone, and glucose concentrations were measured in all groups; all were elevated significantly above values in unrestrained animals only during four-limb immobilization. LCGU was unchanged by same-day surgery, hindlimb restraint, or both. During four-limb immobilization, LCGU was reduced by 25% in the dorsal hippocampus, and to a lesser extent in the anteroventral thalamic nucleus. It was increased only in the lateral habenula (42%). We conclude that two stressors of the experimental preparation (same-day surgery and hindlimb restraint) do not influence LCGU measurements by the [14C]DG method. More severe, acute stress selectively alters LCGU in a few rat brain regions.

Regional cerebral glucose utilization transiently increases during mild hypoxia.

Regional cerebral glucose utilization (rCMRglu) was studied during mild hypoxic hypoxia in awake free-ranging rats. Rats were prepared with chronic arterial and venous catheters and placed in individual chambers for 4 days to recover from surgery before the experiments. The catheters were accessible by passing them through the top of the chambers. Hypoxia was induced by filling the chambers with a gas mixture consisting of 11% O2 in a balance of N2. Regional CMRglu and physiological parameters were measured in normoxic controls and in rats that had been hypoxic for 2 and 17 min before beginning the measurements. Regional CMRglu was measured in 17 brain regions using [6-14C]glucose. PaO2 decreased from 88 mm Hg in the controls to approximately 40 mm Hg during hypoxia. In the early stages of hypoxia (2-12 min), rCMRglu increased approximately 10-25% above the control rates. In later stages of hypoxia (17-27 min), rCMRglu was not different from that in the normoxic controls. The increase in rCMRglu in the early hypoxia was not blocked by propranolol (1.4 mg/kg), indicating that beta-adrenergic receptors were not involved with the increase in rCMRglu. It was concluded that mild hypoxia is associated with an increased rate of cerebral glucose utilization; however, the increase is transitory, with glucose utilization returning to control rates before 17 min.

Anatomical-functional correlation using an adjustable MRI-based region of interest atlas with positron emission tomography.

A procedure is described for combining anatomical information from magnetic resonance imaging (MRI) or computerized tomography (CT) and functional information from positron emission tomography (PET) in a rapid fashion. MRI data are combined with a procedure for the definition, storage, and recall of anatomically based regions of interest. An atlas of standard regions of interest, defined for a set of 18 parallel planes spaced at 6-mm intervals, provides an initial region of interest template for each patient slice. Global adjustments to scale, orientation, and position are applied to obtain an initial match. Individual regions of interest may then be moved, deleted, or redrawn as needed. The ability to store region of interest templates ensures reproducibility of analysis over long periods and introduces a standardization of analysis technique. In 25 brain structures, the mean coefficient of variation in cerebral glucose utilization rate (CMRGlc) measurements among five neuroanatomically trained observers was reduced from 8.1% for manual region of interest definition to 4.0% using the template approach with MRI. Template analysis for space-occupying lesions such as tumors or infarcts is illustrated with PET data from a stroke study, emphasizing the facility for rapid, reproducible analysis of multifunctional studies. MRI-PET matching for a structurally intact caudate nucleus having reduced CMRGlc in Huntington's disease emphasizes the accuracy of anatomical localization required to quantify small structures.

Local Cerebral Glucose Utilization in Controlled Graded Levels of Hyperglycemia in the Conscious Rat

Local cerebral glucose utilization assayed by the [14C]deoxyglucose ([14C]DG) method and calculated by means of its operational equation with values for the rate constants and lumped constant determined in rats under physiological conditions remains relatively stable with variations in arterial plasma glucose concentration within the normoglycemic range. Large changes in arterial plasma glucose level may, however, significantly alter the values of these constants and lead to artifactual results. Values for the lumped constant have been measured and reported for a wide range of arterial plasma glucose concentrations ranging from hypoglycemia to hyperglycemia in the rat (Schuier et al., 1981; Suda et al., 1981; Pettigrew et al., 1983). In the present study we have redetermined the rate constants in rats with arterial plasma glucose levels clamped at approximately 350, 450, and 550 mg/dl (i.e., 19, 25, and 31 mM) by a glucose clamp technique. The rate constants for the transport of DG from plasma to brain, K1*, and its phosphorylation in tissue, k3*, were found to decline with increasing plasma glucose levels, while the rate constant for its transport back from brain to plasma, k*2, remained relatively unchanged from its value in normoglycemia. These rate constants were used together with the previously determined values for the lumped constants to calculate local rates of cerebral glucose utilization in three groups of rats in which arterial plasma glucose levels were clamped at approximately 350, 450, and 550 mg/dl (i.e., 19, 25, and 31 mM). Average glucose utilization in the brain as a whole was unchanged in hyperglycemia from the values calculated in normoglycemic rats with the standard normal set of constants. Changes in the rate of glucose utilization were found, however, in the hypothalamus, globus pallidus, and amygdala during hyperglycemia.

Selective alterations in cerebral metabolism within the mesocorticolimbic dopaminergic system produced by acute cocaine administration in rats

The 2-[14C]deoxyglucose method was used to examine the effects of acute intravenous administration of cocaine on local cerebral glucose utilization in rats. These effects were correlated with the effects of cocaine on locomotor activity assessed simultaneously in the same animals. At the lowest dose of cocaine, 0.5 mg/kg (1.47 mumol/kg), alterations in glucose utilization were restricted to the medial prefrontal cortex and nucleus accumbens. Metabolic activity at 1.0 mg/kg (2.9 mumol/kg) was altered in these structures, but in the substantia nigra reticulata and lateral habenula as well. The selectivity of cocaine's effects at low doses demonstrates the particular sensitivity of these structures to cocaine's actions in the brain. In contrast, 5.0 mg/kg (14.7 mumol/kg) produced widespread changes in glucose utilization, particularly in the extrapyramidal system. Only this dose significantly increased locomotor activity above levels in vehicle-treated controls. Rates of glucose utilization were positively correlated with locomotor activity in the globus pallidus, substantia nigra reticulata, and subthalamic nucleus, and negatively correlated in the lateral habenula.

The evaluation of quantitative autoradiogram processing systems for cerebrovascular research

The development of an image processing system for quantitative autoradiography (QAR) is described, with emphasis on the evaluation of image digitization systems independent of hardware or software design. Each step of converting the autoradiographic image to a functional image of a physiological variable such as local cerebral blood flow (LCBF) or local cerebral glucose utilization rate (LCGU) is evaluated. The autoradiograms are digitized, aligned, transformed to a tissue tracer concentration image based on the gray value (GV) of calibrated 14C standards, subtracted from each other as required in double tracer QAR, and converted to an LCBF or LCGU image using the proper tracer kinetic model. Geometric size, mean and standard deviation of the LCBF, LCGU, and tracer concentration can be measured in regions of interest. These steps are evaluated separately for their contribution to the accuracy and precision of the final, functional image. The qualities important in the final image are spatial resolution, intensity linearity, and intensity sensitivity, as well as the noise level. Techniques for evaluating the LCBF image include: (1) optimization of the input linearity and dynamic range of the video camera to maximize relative intensity sensitivity of the final functional image; (2) visual inspection of the curves used to fit various functions that are important in the conversion of the GV image to an image of physiological interest; (3) consideration of the noise introduced by the input devices and during the image conversion; and (4) above all, the integration of the various parts of the system to produce an accurate image useful in cerebrovascular research.

Effects of leukocytic pyrogen (interleukin-1) on local cerebral glucose utilization in rats with and without premedication with indomethacin or dexamethasone.

Changes in body temperature were recorded in freely moving rats given phosphate-buffered saline or leukocytic pyrogen (interleukin-1) while the animals were in an infant incubator maintained at 25.5 +/- 0.5 degrees C. The leukocytic pyrogen increased body temperature by at least 1 degree C within 1 h. This rise in temperature was prevented by premedication with indomethacin (10 mg/kg) but not dexamethasone (0.5 mg/kg) given 15 min before the leukocytic pyrogen. Local rates of glucose utilization were measured in 47 regions of the central nervous system. In none of the regions previously reported to have an increased rate of glucose utilization associated with an ambient temperature of 32.5 degrees C (McCulloch et al., 1982b) was an increase found in the present experiments. It was concluded that the intensity of the changes in local cerebral glucose utilization in response to the fever caused by the leukocytic pyrogen was insufficient to be measured. Neither indomethacin nor dexamethasone caused remarkable changes in rates of local glucose utilization.

Concomitant in Vivo Measurement of Lumped and Rate Constants for F-18 FDG in Cat Brain

External coincidence counting was used for simultaneous estimation, in the 2-fluoro-2-deoxy-D-glucose (2-FDG) model, of the lumped and apparent rate constants (i.e., for a white/gray matter mixture). Eleven normal cats were studied. During a programmed 2-[18F]FDG infusion that kept a constant arterial plasma concentration of 2-[18F]FDG [Cp*(t)] for 45 minutes, the time course of cerebral tissue activity [Ci*(t)] was monitored by external coincidence counting. The apparent rate constants were estimated from Ci*(t) and Cp*(t) by a nonlinear least squares optimization method. The lumped constant (LC) estimate was obtained by fitting the ratio of extraction fractions of glucose and 2-[18F] FDG by use of a nonweighted, nonlinear least squares fitting method. The estimated apparent rate constants, k1*, k2*, k3*, and the LC were 0.074 ± 0.005 min-1, 0.129 ± 0.007 min-1, 0.021 ± 0.001 min-1, and 0.395 ± 0.016, respectively (mean ± SEM). The focal cerebral metabolic rate for glucose detected in the brain was 28.7 ± 1.5 μmol/100 gm/min (mean ± SEM). The influence of arterial plasma glucose (CP), the LC, and the metabolic index [MI = k1*k3*/(k2* + k3*)] on the stability of the cerebral glucose utilization rate was examined. Negative correlations between CP and LC, and CP and MI were observed. However, there was a positive correlation between the LC and the MI. The method applied in this study should be very useful in the detection of changes in the kinetics of 2-[18F]FDG under pathophysiological conditions in animals. Because of the short half-life of this isotope, repeated measurements are possible.

Diurnal rhythmicity and hypothalamic deficits in glucose utilization in aged ovariectomized rats

Aging is associated with a loss of cyclic gonadotropin release in female animals. This deficit may reflect dampened circadian rhythmicity of neuroendocrine events and/or altered function in hypothalamic nuclei important to regulation of cyclic female reproduction. The purpose of this study was to determine if diurnal periodicity and glucose metabolism in the hypothalamus are altered with age and whether such changes could help to explain the age-related deficits in gonadotropin release. Young (3-4-month-old) and old (18-21-month-old) rats were ovariectomized and subjected to the 2-deoxy-D-1-14C-glucose technique to measure rates of cerebral glucose utilization (GU), an index of neural function (Sokoloff et al., 1977) in various brain areas and in the pineal gland. We measured GU during the light (1400 hours) and the dark (2200 hours) in 17 anatomical regions including the following hypothalamic areas: medial preoptic nucleus, suprachiasmatic preoptic nucleus, suprachiasmatic nucleus, paraventricular nucleus, arcuate nucleus, and median eminence. Serum concentrations of luteinizing hormone (LH) and prolactin were measured in the same rats to determine the effect of age on both of these hormones. Diurnal periodicity of GU was observed in the suprachiasmatic nucleus and the pineal gland in young and old rats. Although there was no age difference in GU of the pineal gland, GU was reduced during the light and dark in the suprachiasmatic nucleus and all other hypothalamic areas examined except the suprachiasmatic preoptic nucleus and the median eminence. Ovariectomy induced an attenuated increase in concentrations of LH in old, compared to young rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of single and repeated electroconvulsive shock on local cerebral glucose utilization in the conscious rat

Local rates of cerebral glucose utilization (LCGU) were determined in adult rats submitted to electroconvulsive shock (ECS) treatment. One group of rats ( n = 5) received a single ECS, a second group ( n = 5) was treated once daily for 7 days. A third group ( n = 5) of unshocked rats served as control. LCGU measurements were performed one day after either the single or the last ECS. Following a single ECS, most of the 45 brain regions examined exhibited lower rates of LCGU than controls, in contrast after repeated ECS treatment the metabolic activity results increased in segments of the hippocampus. The results indicate that repeated ECS treatment selectively increases metabolic rates within the hippocampus, a structure of the limbic system thought to be related to affective disorders and memory.

The effects of mazindol on local cerebral glucose utilization in rats.

The effects of mazindol (1 mg or 10 mg/animal, p.o.) on local cerebral utilization of glucose were studied by the quantitative autoradiographic [14C]2-deoxyglucose method in conscious adult male rats. Significant increases in local cerebral utilization of glucose were observed 2 hr after administration of 10 mg of mazindol in 10 out of 37 anatomically discrete regions examined. These 10 areas included regions rich in dopaminergic receptors (substantia nigra, globus pallidus), and also regions with few dopaminergic receptors (cerebral cortex, thalamus, cerebellum). Only the habenular nucleus showed a significant decrease in utilization of glucose induced by the administration of 10 mg of mazindol. No significant changes in local cerebral utilization of glucose were observed following the administration of 1 mg of mazindol. The fact that the pattern of utilization of glucose observed in this study resembled that produced by apomorphine, a putative dopaminergic agonist, indicates that the pharmacological effects of mazindol are related to the dopaminergic system.

Human cerebral glucose metabolism determined by positron emission tomography: a revisit.

The cerebral glucose utilization rate was studied for 27 normal volunteers with 18F-deoxyglucose positron emission tomography (PET). The scanner has a spatial resolution of 6-7 mm and contains corrections for scatter, attenuation, and random coincidences. The lumped constant (tracer-to-glucose dynamic uptake ratio) was determined by comparing the average global uptake of tracer in representative slices with average glucose utilization rates measured by the Kety-Schmidt method as reported in the literature. The resulting value of 0.50 is in excellent agreement with a recent direct determination done by arterial and jugular bulb blood sampling. Gray and white matter values of glucose utilization in various areas of the brain were determined by placing small regions of interest over various cortical, basal, and white matter structures. These values are within 20% of published autoradiographic data on the macaque monkey. The average ratio of gray to white glucose utilization was 2.9, compared with a range of 3-5 for the monkey study and 1.6-2.2 reported in previous PET studies. The effect of instrumental errors on the results is analyzed and discussed.

ALLOCATION OF SYSTEMIC GLUCOSE PRODUCTION TO CEREBRAL GLUCOSE UTILIZATION AS A FUNCTION OF INTRAUTERINE CANINE GROWTH

Hypoglycemia in intrauterine growth retardation may be due to an imbalance between glucose production (GP) and cerebral glucose needs. We investigated relationships between GP, cerebral glucose uptake (CMRG), brain and body weight in 16 fasted 3 hr old term pups weighing 263 g (170-345 g). Brain wt 6.1±0.3 g was 2.3% of body wt, while liver wt 11.8±1.5 g was 4.4% of body wt. Brain wt:liver wt ratio was 0.66 for the entire group. Mean pH 7.23, pCO2 48.4, pO2 90.0, blood glucose 3.36 mM (1.45-10.77mM), steady state GP 49.6 umol/kg/min, cerebral blood flow (CBF) 0.83 ml/g/min, CMRC 0.60 umol/g/min, and cerebral O2 uptake (CMRO2) 1.76 umol/g/min. The brain utilized 36.6±7.9% of total body GP. To test the effect of growth status at term upon brain glucose utilization, we analyzed these data as a function of birth wt. Both brain and liver wt increased as a function of body wt. However, brain:liver (r=-0.6, p<0.02) and brainibody (r= -0.63, p<0.01) ratios were greatest in smaller pups. Although CBF increased, CMRO2, CMRG, and GP did not correlate with body wt. However, the % of GP used by the brain increased exponentially with body wt (r=0.50, p<0.05).CONCLUSION: In small pups a smaller % of GP was used by brain despite the fact that the brain represents a larger % of body wt. These data suggest that smaller pups do not use a disproportionately larger % of GP to maintain their normal rates of cerebral glucose utilization. Within the range of wt there was no imbalance between GP and CMRG.

Changes in local cerebral glucose utilization after chronic ethanol in rats

Local rates of cerebral glucose utilization were investigated in ethanol-treated rats using the 2-deoxy[ 14C]glucose method. Rats received ethanol in drinking water for 3 h each day. After 4 days of exposure to 2 or 4% ethanol ( v v ), there was a general tendency toward increased local cerebral glucose utilization. In contrast, after 28 days of exposure to concentrations to 10% ethanol a general depression of cerebral glucose metabolism was observed. Brain regions showing significantly reduced glucose utilization rates in the 28-day group included components of the extrapyramidal system, several thalamic and hypothalamic nuclei, and forebrain limbic structures. A group of animals tested 7 days after discontinuation of ethanol showed essentially normal rates of local cerebral glucose utilization, indicating that alterations in regional brain glucose metabolism induced by this particular regimen and duration of ethanol administration were largely reversible.

Correlation between behavioral status and cerebral glucose utilization in rats following freezing lesion

Standard small, superficial freezing lesions placed along the anterior-posterior plane of the left cortex produced behavioral changes in rats. One to 3 days following the lesion, rats showed asymmetries in somatosensory responsiveness decreases in running wheel activity and difficulty with limb coordination. No changes in spontaneous circling activity were seen. At the completion of the behavioral testing on day 3 the [ 14C]2-deoxyglucose method confirmed the presence of widespread depression in local cerebral glucose utilization with cortical areas ipsilateral to the lesion being most affected. At this time the degree of the somatosensory deficit was significantly correlated with the extent of the depression of glucose utilization in the cortical areas of the lesioned hemisphere. At 6 days following the lesion only deficits in limbs coordination remained, while local cerebral glucose utilization had returned to within normal limits. It is concluded that the demonstrated behavioral changes were a manifestation of widespread functional depression, as reflected by decreased cortical glucose utilization throughout the lesioned hemisphere.

The effects of l-DOPA on regional cerebral glucose utilization in rats with unilateral lesions of the substantia nigra

Using [ 14C]2-deoxyglucose autoradiography, we have studied the effects of systemically administered l-DOPA (10, 25 and 50 mg/kg s.c.) on regional cerebral glucose utilization (RCGU) in rats with unilateral substantia nigra lesions. In comparison with lesioned rats treated with saline, the lesioned-DOPA treated rats demonstrated contralateral turning and RCGU changes in both ipsilateral and contralateral brain regions. l-DOPA treatment markedly increased RCGU in the ipsilateral entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), cell groups that receive direct striatal input and function as major outflow pathways of corpus striatal activity. In contrast, l-DOPA did not alter RCGU in the globus pallidus (GP), supporting the thesis that dopamine (DA) has different effects on striatal outflow to the GP compared with outflow to both the EP and SNr. Moderate RCGU increases were observed in the ipsilateral subthalamic nucleus (STN), lateral midbrain reticular formation (LMRF), and deep layers of the superior colliculus (DLSC), all regions which receive direct projections from the GP, EP or SNr. l-DOPA decreased RCGU in the ipsilateral lateral habenular nucleus (LHN) and increased RCGU in the contralateral LHN, changes that we suggest are mediated via altered neuronal activity in the striatum and EP. The results suggest that systemically administered l-DOPA, after conversion to DA in the brain, interacts with supersensitive DA receptors in the DA-depleted striatum to selectively activate efferent pathways. Furthermore, the data suggest that the LMRF and DLSC are functionally activated during l-DOPA induced turning and support the hypothesis that nigroreticular and nigrocollicular projections are of physiologic significance in the expression of striatal activity.

Local cerebral glucose utilization in the adult cretinous rat

Local rates of cerebral glucose utilization were determined in 5-month-old neonatally radiothyroidectomized and control (littermate) rats. Virtually all 48 brain regions examined in the thyroidectomized rats exhibited lower rates of glucose utilization than those of the controls with differences ranging from −24 to −58%. The decreases were particularly large in the cerebral cortex and throughout the auditory system. Altered patterns in the intrastructural distribution of rates of glucose utilization were seen in a number of regions and were particularly prominent in the hippocampus and inferior colliculus. Lesser changes were seen in hypothalamic regions involved in the synthesis of thyrotropin releasing hormone (TRH). The results indicate that the many structural, functional and biochemical abnormalities of cretinism are associated with widespread reductions in energy metabolism throughout the brain.

Brain glucose metabolism and memory functions: age decrease in factor scores.

The F-18 fluorodeoxyglucose (FDG) scan method with positron emission tomography was used to determine age differences in factors underlying both the performances on 18 multivariate memory tests and the rates of cerebral glucose utilization in nine left and nine right hemispheric regions of 23 healthy adults aged 27 to 78 years. Two of the five derived factors separated persons below age 42 from those above age 48 years, one reflecting secondary memory for material verbally processed together with Broca's metabolic ratio, the other defined by tests requiring sequential or organizational coding of information and metabolic measures of thalamic regions. Education did not override their parallel age decrease. Several regional metabolic measures covaried with distinct memory measures. Persons with high superior frontal and low caudate-thalamic metabolic measures were those who performed well in tests of memory for sentences, story, designs, and complex patterns, suggesting a frontal-subcortical interaction in age-dependent memory processing.