Local Cerebral Metabolic Rates For Glucose Research Articles

Changes in glucose metabolism in dementia of the Alzheimer type compared with depression: A preliminary report

We evaluated positron emission tomography (PET) in the differential diagnosis of depression and Alzheimer's disease. The local cerebral metabolic rate for glucose (LCMRGlc) in the parahippocampal gyrus-hippocampus and the dorsolateral prefrontal cortex were determined. The ratio of the LCMRGlc in those two regions was examined in patients with unipolar depression, bipolar depression, and Alzheimer's dementia. An analysis of variance revealed significant overall intergroup differences in values for both hemispheres. Student's t test showed significant differences in LCMRGlc for both unipolar and bipolar depression as compared with Alzheimer's dementia. These data indicate that PET may be useful in the differential diagnosis of dementia vs. depression.

Changes in glucose metabolism in dementia of the Alzheimer type compared with depression: A preliminary report

We evaluated positron emission tomography (PET) in the differential diagnosis of depression and Alzheimer's disease. The local cerebral metabolic rate for glucose (LCMRGlc) in the parahippocampal gyrus-hippocampus and the dorsolateral prefrontal cortex were determined. The ratio of the LCMRGlc in those two regions was examined in patients with unipolar depression, bipolar depression, and Alzheimer's dementia. An analysis of variance revealed significant overall intergroup differences in values for both hemispheres. Student's t test showed significant differences in LCMRGlc for both unipolar and bipolar depression as compared with Alzheimer's dementia. These data indicate that PET may be useful in the differential diagnosis of dementia vs. depression.

The Marinesco-Sjogren Syndrome Examined by Computed Tomography, Magnetic Resonance, and 18F-2-Fluoro-2-Deoxy-d-Glucose and Positron Emission Tomography

The Marinesco-Sjögren syndrome is an autosomal recessive degenerative disorder characterized by congenital cataracts, cerebellar ataxia, spasticity, mental deficiency, and skeletal abnormalities. We studied two adult siblings with Marinesco-Sjögren syndrome using anatomic and metabolic brain imaging techniques to characterize the pattern and nature of abnormalities in the brain. Computed tomographic and magnetic resonance imaging showed diffuse brain atrophy of mild to moderate degree, involving primarily the white matter of the cerebrum, cerebellum, brain stem, and cervical spinal cord. The pattern of atrophy resembled that seen in diffuse leukoencephalopathies. Measurements of local cerebral glucose metabolic rates with positron emission tomography revealed no statistically significant differences from normal control subjects in most regions, but metabolic rate was decreased in the thalamus in one patient. The findings support a diffuse white matter disorder in Marinesco-Sjögren syndrome.

Local Cerebral Glucose Metabolic Rates in Obsessive-Compulsive Disorder

In a recent study, we reported abnormal local cerebral glucose metabolic rates in the orbital frontal cortex of patients with obsessive-compulsive disorder. Eight patients with obsessive-compulsive disorder scanned previously were scanned again during treatment with the tricyclic antidepressant clomipramine hydrochloride. Comparisons of local cerebral glucose metabolic rates for both groups showed a relative decrease in regions of the orbital frontal cortex and the left caudate, and an increase in other areas of the basal ganglia, including the right anterior putamen. When comparing patients who responded well to clomipramine with those who were either poor or partial responders, we found significant decreases only in the left caudate of patients who responded well to the drug. The present study suggests that clomipramine-induced improvement in obsessive-compulsive symptoms is associated with a return of regional brain metabolism to a more normal level in regions of the orbital frontal cortex and the caudate nucleus.

Local cerebral glucose metabolism after global ischemia

The local cerebral metabolic rate for glucose (LCMRg) was measured in cats subjected to global cerebral ischemia (GCI). Control (nonperfused) cats showed decreased LCMRg (P less than 0.01) in the frontal, temporal, parietal, and occipital cortex 9.5 hours after a 10-minute exposure to GCI. Cats perfused ventriculocisternally with oxygenated nutrient solution (ONS) for 8 hours showed significant increases in the LCMRg (p less than 0.05) at 9.5 hours postischemia in the parietal and occipital areas over the levels found in untreated ischemic cats. Supplementing the ONS perfusion medium with fluorocarbon (OFNS) increased the LCMRg (P less than 0.05) in the frontal, as well as the parietal and occipital areas, over that seen in untreated ischemic brains. The increase of LCMRg in three (rather than only two) cortical areas may be a result of the ability of the fluorocarbon in OFNS to deliver greater quantities of oxygen to the brain than ONS without fluorocarbon. Perfusion with OFNS without glucose, or with low (50 mg%) glucose, was more effective than OFNS with high (200 mg%) glucose in restoring LCMRg to normal in all four cortical areas affected by GCI. In five brain areas not affected by GCI, perfusion with OFNS having no glucose significantly increased LCMRg as compared to normal animals. This study demonstrates that OFNS perfused by the ventriculocisternal route can restore toward normal the LCMRg following GCI and that different concentrations of glucose in the perfusing fluid will have variable effects on LCMRg in certain brain areas.

Local Cerebral Glucose Metabolism after Global Ischemia: Treatment by Ventriculocisternal Perfusion with a Fluorocarbon Emulsion

The local cerebral metabolic rate for glucose (LCMRg) was measured in cats subjected to global cerebral ischemia (GCI). Control (nonperfused) cats showed decreased LCMRg (P less than 0.01) in the frontal, temporal, parietal, and occipital cortex 9.5 hours after a 10-minute exposure to GCI. Cats perfused ventriculocisternally with oxygenated nutrient solution (ONS) for 8 hours showed significant increases in the LCMRg (p less than 0.05) at 9.5 hours postischemia in the parietal and occipital areas over the levels found in untreated ischemic cats. Supplementing the ONS perfusion medium with fluorocarbon (OFNS) increased the LCMRg (P less than 0.05) in the frontal, as well as the parietal and occipital areas, over that seen in untreated ischemic brains. The increase of LCMRg in three (rather than only two) cortical areas may be a result of the ability of the fluorocarbon in OFNS to deliver greater quantities of oxygen to the brain than ONS without fluorocarbon. Perfusion with OFNS without glucose, or with low (50 mg%) glucose, was more effective than OFNS with high (200 mg%) glucose in restoring LCMRg to normal in all four cortical areas affected by GCI. In five brain areas not affected by GCI, perfusion with OFNS having no glucose significantly increased LCMRg as compared to normal animals. This study demonstrates that OFNS perfused by the ventriculocisternal route can restore toward normal the LCMRg following GCI and that different concentrations of glucose in the perfusing fluid will have variable effects on LCMRg in certain brain areas.

The effect of focal cerebral atrophy in positron emission tomographic studies of aging and dementia

We used x-ray computed tomographic (XCT) scans to measure the degree of cerebral atrophy in brain regions defined by a region of interest (ROI) anatomy atlas. The same atlas was employed for quantitation of local cerebral glucose metabolic rates (LCMRglc) by PET. PET data were obtained from 9 young controls, 7 healthy elderly controls, and 10 patients with dementia. Cerebrospinal fluid (CSF) in atrophic brain regions was assumed to be metabolically inert, and LCMRglc measurements were corrected for the degree of atrophy. Significantly greater atrophy was seen for 7 of 8 regions in comparisons between demented patients and age-matched controls. This atrophy was most pronounced in superior parietal (SP) regions. Decreases in parietal LCMRglc in dementia patients and SP LCMRglc in old controls were no longer significant after correction for atrophy. These results emphasize the need to consider focal atrophy effects in regional quantitative analyses of emission tomographic data.

Local cerebral glucose abnormalities in mild closed head injured patients with cognitive impairments.

Mild-moderate closed head injury (CHI) can be followed by neuropsychological impairments in recent memory and attention, despite the absence of discernible structural abnormalities in a significant number of patients. To determine whether CHI may result in cerebral glucose metabolic abnormalities, we used fluorodeoxyglucose (FDG) technique with PET imaging to measure local cerebral metabolic rates for glucose (LCMRGlu) in three CHI patients and three matched normal controls. The CHI patients were between 3-12 months post-injury. All had deficits in attention and recent memory shown by neuropsychological testing. CT, MRI, EEG and drug screens were negative at the time of PET scanning. Subjects were engaged in a vigilance task throughout the initial 30 min following FDG administration. Group comparisons were made using t tests. There were no significant group differences found in global glucose metabolic rate. Nevertheless, the CHI group exhibited significantly decreased LCMRGLu in medial temporal, posterior temporal, and posterior frontal cortices, as well as in the left caudate nucleus. LCMRGlu was significantly increased, relative to controls, in anterior temporal and anterior frontal cortices. These results suggest that CHI patients can have regional glucose metabolic abnormalities, indicative of altered neuronal function, despite the absence of discernible anatomic abnormalities.

Cerebral metabolism of Parkinsonian primates 21 days after MPTP

This study evaluates the changes in the local cerebral metabolic rate for glucose (LCMRg) in primates exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The LCMRg was evaluated 21 days following the last dose of MPTP. At this time, all MPTP-injected animals demonstrated parkinsonism and striatal dopamine was reduced to less than 3% of control values. The structures whose LCMRg was most affected were the motor cortex, the intermediate zone of the putamen, the external segment of the globus pallidus, the medial part of the ventrolateral nucleus of the thalamus (VL m), visual cortex, locus ceruleus, and the dorsolateral segment of the substantia nigra pars compacta. The structure whose increase in LCMRg correlated most closely to the clinical severity of parkinsonism was the external segment of the globus pallidus.

Single vibrissal cortical column in SI cortex of rat and its alterations in neonatal and adult vibrissa-deafferented animals: a quantitative 2DG study.

1. A quantitative 2-[14C]deoxy-D-glucose (2DG) autoradiographic study was undertaken to determine the functional (metabolic) organization of an individual column in the first somatosensory cortex (SI) of the awake restrained rat. Manual or mechanically controlled brush stroking of a single vibrissa (typically C3) was used in order to evoke neural activity and increase glucose utilization in a single cortical barrel in lamina IV and in adjacent supra- and infragranular layers in register with the single cortical barrel labeling in lamina IV. 2. The single activated vibrissal column was found to extend from layer I to the superficial half of layer VI of the contralateral SI cortex and was fusiform in shape, being of largest diameter (650-micron) in layer IV and smallest diameter (200 micron) in layer VI. 3. This single metabolic column was not uniform in its density of labeling. The greatest local cerebral metabolic rate of glucose (LCMRG) was found in layer IV (170 mumol.100 g-1.min-1), layers II-III, and V had, on the average, similar LCMRG values (115 mumol.100 g-1.min-1), which decreased with distance from layer IV. 4. The functional (metabolic) columnar activity center situated in layer IV corresponded in size to the appropriate anatomical barrel as determined from thionin-stained sections. Increased metabolic activity was not strictly confined to the candle-pin-shaped column but extended tangentially as radiating fingerlike projections toward the neighboring barrels. 5. In cortical layers other than IV, the metabolic column was less prominently labeled, and the metabolic activity also branched in the tangential plane. The labeling pattern profile in upper layers was characterized by numerous lateral spreading fingerlike projections of increased glucose metabolism. 6. Neonatal follicle lesions sparing only C3 vibrissa caused a great increase (125%) in cortical territory driven by the spared whisker with a concomitant loss of columnar shape and decrease in intensity of metabolic activity in response to its stimulation. 7. Similar lesions in adult rats produced a significant increase (40%) in dimensions of the spared C3 cortical column, which was, however, smaller than that produced after neonatal lesions. The metabolic activation of layer Vb in the spared C3 column was increased (17%) compared with that of the control column.(ABSTRACT TRUNCATED AT 400 WORDS)

Quantitative autoradiographic maps of local cerebral glucose metabolism in awake rats: I. Septal region and anterior hypothalamus.

Quantitative 14C-2-deoxyglucose autoradiography was used to determine the local cerebral glucose metabolic rate (lCMRG) of nuclei in the septal region and anterior hypothalamus of awake, unanesthetized rats. The lCMRG of the medial and lateral septal areas, preoptic areas, medial preoptic nuclei, suprachiasmatic nuclei, supraoptic nuclei, anterior hypothalamic nuclei, and paraventricular nuclei were measured. The lCMRG of each nucleus was mapped at successive rostral-caudal levels to determine significant internuclear and intranuclear variations. These data provide a detailed neuroanatomic map of cerebral energy metabolism of the septal and anterior hypothalamic regions in animals under standardized conditions.

Simultaneous double-isotope autoradiographic measurement of local cerebral glucose metabolic rate and acid-base status in rat brain.

We developed a double-isotope autoradiographic method for the simultaneous measurement of the local cerebral metabolic rate for glucose (1CMRG) and index of regional acid-base status (rABI) in single brain slices using [2-14C]deoxy-D-glucose (DG) and 5,5-dimethyl-[2-14C]oxazolidine-2,4,dione (DMO). After iv isotope administration, paper chromatography separates plasma DMO from DG activity using a methanol-methylene chloride solvent system. Initial tissue autoradiograms depict regional DMO plus DG and DG metabolite distribution. After 14 days in a well-ventilated hood, 97.5 +/- 0.5% of all DMO is lost from tissue sections by sublimation, and a second autoradiogram depicts DG plus DG metabolite distribution. Retention of brain lipids does not alter beta-particle self-absorption, avoiding problems associated with isotope extraction with solvents. Autoradiograms are digitized and converted to isotope-content images. The second autoradiogram is used for 1CMRG computation. After subtracting the second regional isotope-content value from the first, the DMO content is obtained and used to compute rABI. Application of this method to normal animals yields expected values for 1CMRG and rABI. This method is amenable to whole-slice digitization and creation of functional images of 1CMRG and ABI followed by pixel-by-pixel correlations of the two variables, making this a potentially valuable tool for the investigation of the relationships between glucose metabolism and brain acid-base balance.

Trazodone treatment response in obsessive-compulsive disorder--correlated with shifts in glucose metabolism in the caudate nuclei.

Obsessive-compulsive disorder (OCD) is a severe psychiatric illness that is difficult to treat. The effects of trazodone hydrochloride treatment were studied, both with and without the addition of a monoamine oxidase inhibitor, in OCD patients. Changes in symptoms correlated with changes in local cerebral metabolic rates for glucose (LCMRGlc), as measured by positron emission tomography and the 18F-fluorodeoxyglucose method. All patients whose OCD responded favorably to drug treatment showed a relative increase in glucose metabolism in the heads of the caudate nuclei compared with the metabolic rate in the ipsilateral hemisphere as a whole (ratio LCMRGlc caudate/LCMRGlc hemisphere). Patients who did not respond to treatment did not show an increase in this ratio, and the difference between responders and nonresponders was significant (p less than 0.03). Changes in the ratio LCMRGlc caudate/LCMRGlc hemisphere correlated with changes on OCD and depression rating scales.

Cortical Metabolism, Acetylcholinesterase Staining and Pathological Changes in Alzheimers Disease

The local cerebral metabolic rate for glucose (LCMRgl) was determined by positron emission tomography (PET) using the 18F-fluorodeoxyglucose method in a series of Alzheimer patients and normal controls. The LCMRgl declined in the cerebral cortex with age, but the decrement was significantly greater in the clinically diagnosed Alzheimer's cases. Comparison of PET and psychological data indicated that, as the disease progressed clinically, the reduction in cortical LCMRgl and the number of cortical regions involved also increased. Variable regions of cortex were involved in the early stages but the temporal, parietal and frontal regions were most typically affected. One case coming to autopsy showed that the severity of the LCMRgl decline paralleled loss of neurons in the cortex and their replacement with astroglia. A case of Pick's disease coming to autopsy had shown a different and highly characteristic pattern of cortical metabolic defect. In this case also a poor metabolic rate was associated with extensive gliosis. Acetylcholinesterase (AChE) staining of the cerebral cortex in elderly normals and Alzheimer's disease cases with a new, highly sensitive method showed that in Alzheimer's disease there was an extensive loss of AChE-positive fibers with senile plaques frequently incorporating AChE-positive fiber debris. AChE staining of the substantia innominata area, where the cells giving rise to these neocortical fibers are presumably located, also showed evidence of degenerating cells and fibers.

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 μmol/100 g/min, the values in gray matter structures of the posterior fossa were 25–30 μmol/100 g/min, the lowest LCMRGl was found in the white matter (15–20 μmol/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.

Cerebral glucose metabolism as a function of age in man: influence of the rate constants in the fluorodeoxyglucose method.

Measurement of the local cerebral metabolic rate of glucose (LCMRGlc) with the fluorodeoxyglucose (FDG) method requires the utilization of appropriate values for the rate constants of the transport and phosphorylation processes. We measured these rate constants as a function of age to determine whether a decline in LCMRGlc as a function of age, in prior studies with the FDG method, actually represents changes in the rate constants. We found that measurements of LCMRGlc are not significantly affected by changes in rate constants as a function of aging, and that LCMRGlc did not change significantly with age.

Error sensitivity of fluorodeoxyglucose method for measurement of cerebral metabolic rate of glucose.

The fluorodeoxyglucose (FDG) method for the measurement of local cerebral metabolic rate of glucose (LCMRGlc) employs typical values of the FDG transport rate constants that have been obtained by kinetic measurements on an appropriate control group. Discrepancies between the true values of the rate constants in tissue and the typical values used in the operational equation of the FDG method will introduce error in the estimate of LCMRGlc. Computer simulations were used to evaluate the accuracy of the FDG method in cases where (1) the tissue LCMRGlc deviates greatly from the normal values (e.g., stroke) or (2) the tissue LCMRGlc changes during the experiment (e.g., epileptic seizure). The effects of the magnitude and duration of metabolic changes were studied. The results indicate that if tissue LCMRGlc differs greatly from the normal value, the error in the estimated LCMRGlc at a scan time of 60 min is less than 20% of the difference between the true and normal values. In the non-steady-state cases, the estimated LCMRGlc was found to be a weighted average of the metabolic rates during the experiments, with the weightings approximately proportional to the plasma FDG concentration at the corresponding times. For example, if LCMRGlc in tissue was 5 times the normal values for the first 10 min but then returned to normal state, the LCMRGlc measured by the FDG method at a scan time of 60 min would be about only 2-3 times the normal value. The results of this study provide a better understanding of the accuracy of the FDG method under various tissue metabolic conditions and is useful for interpreting metabolic values obtained with the FDG method.

TOMOGRAPHIC MAPPING OF HUMAN CEREBRAL METABOLISM

Positron computed tomography was used to investigate changes in the local cerebral metabolic rate for glucose (LCMRGlc) of the visual cortex. Progressive increases in LCMRGlc were found from eyes-closed control to stimulation with white light, alternating black/white checkerboard pattern, and a complex visual scene of a park, with the associative visual cortex increasing at a faster rate than the primary visual cortex as the visual scene complexity increased. A graded decrease in LCMRGlc of the visual cortex was found with a stepwise deletion of spontaneous cell firing at the retinal, geniculate and cortical level due to lesions. Left/right metabolic symmetry of the visual cortex during monocular stimulation confirms 50% crossing of the human visual system. Neonatal blindness showed no apparent degeneration of the visual cortex and was equivalent to eyes-closed controls. The interictal state of a patient with visual seizures demonstrated a hypometabolic visual cortex with a 2.5-fold increase in metabolism during an ictal visual hallucination.

Use of 123I and 14C in a double radionuclide autoradiographic technique for simultaneous measurement of LCBF and LCMRgl. Theory and method.

We have developed an autoradiographic technique for the simultaneous measurement of local cerebral blood flow (LCBF) and local cerebral metabolic rate for glucose (LCMRgl) using 123I-iodoantipyrine and 14C-2-deoxyglucose respectively. By exploiting the different half-lives of 123I and 14C, 13.0 hours versus 5730 years, we produce 2 autoradiographic images. The first is predominantly a result of the 123I and the second is predominantly from the 14C. Because of the impracticality of making 123I standards, it was necessary to determine the constant which relates the ability of 123I, with respect to 14C, to expose Kodak SB-54 film, so that the 123I exposure could be quantified using 14C standards. Subtraction equations can then be used to solve for the local 123I and 14C concentrations. The technique was validated in conditions simulating a 12-fold decoupling of flow and metabolism and the standard deviation of error in measuring tracer concentrations was less than 6%. It was then used to measure these parameters in the normal awake rats and values obtained agreed well with published values from single radionuclide studies. The technique is expected to be useful in the simultaneous measurement of LCBF and LCMRgl in various physiologic or pathologic states, including those with significant decoupling of flow and metabolism. In addition, by using other tracers labelled with 123I and 14C, other parameters can be measured concurrently.

Tomographic mapping of human cerebral metabolism visual stimulation and deprivation.

Positron computed tomography was used to investigate changes in the local cerebral metabolic rate for glucose (LCMRGlc) of the visual cortex. Progressive increases in LCMRGlc were found from eyes-closed control to stimulation with white light, alternating black/white checkerboard pattern, and a complex visual scene of a park, with the associative visual cortex increasing at a faster rate than the primary visual cortex as the visual scene complexity increased. A graded decrease in LCMRGlc of the visual cortex was found with a stepwise deletion of spontaneous cell firing at the retinal, geniculate and cortical level due to lesions. Left/right metabolic symmetry of the visual cortex during monocular stimulation confirms 50% crossing of the human visual system. Neonatal blindness showed no apparent degeneration of the visual cortex and was equivalent to eyes-closed controls. The interictal state of a patient with visual seizures demonstrated a hypometabolic visual cortex with a 2.5-fold increase in metabolism during an ictal visual hallucination.