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Biomedical subjects

M Diksic

Publications and source records attributed to M Diksic.

At least 109 records · Page 6Linked to original sources
PubMed1989

Transvenous perfusion of the brain with verapamil during focal cerebral ischemia in rats.

We report on the effect of calcium channel blocker verapamil administered into the inferior cerebral vein in rats 1 hour after occlusion of the middle cerebral artery. Twenty-four rats were divided into four groups of six rats each. Group A rats received no medication. The other three groups received 0.1 mg verapamil/kg/2 hr. Group B rats received verapamil intravenously. Group C and D rats received verapamil and autologous arterial blood by transvenous perfusion of the brain, Group C rats at 100 mm Hg perfusion pressure and Group D rats at 150 mm Hg perfusion pressure. The administration of verapamil started 1 hour after middle cerebral artery occlusion and lasted for 2 hours. Three hours after occlusion, we used double- or single-tracer autoradiography with 4-[18F]fluoroantipyrine or [14C]iodoantipyrine and [14C]alpha-aminoisobutyric acid as tracers to study the brains for local cerebral blood flow and blood-brain barrier permeability changes. Group C showed a significant increase of local cerebral blood flow in the parietal cortex (89%, p less than 0.01) and sensorimotor cortex (64%, p less than 0.05) compared with Group A. Group D showed an extensive and striking increase in local cerebral blood flow of the ischemic cortical and subcortical areas (57-100%, p less than 0.05). Group B showed no significant changes but exhibited further reduction of local cerebral blood flow in the ischemic cerebral hemisphere associated with slightly increased local cerebral blood flow in the nonischemic cerebral hemisphere compared with Group A. There was no change of blood-brain barrier permeability in any group.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1989

Hemodynamic and metabolic effects of cerebral arteriovenous malformations studied by positron emission tomography.

Seventeen patients with an intracranial arteriovenous malformation were studied with positron emission tomography. Cerebral blood flow, cerebral blood volume, oxygen extraction fraction, and glucose and oxygen metabolism were evaluated in both hemispheres, excluding the area of the malformation itself. Patients were divided into three groups according to the size of their malformation, and results obtained were compared with studies in healthy volunteers. The glucose metabolism was significantly (p less than 0.01) decreased in the ipsilateral hemisphere in all patients. The cerebral blood volume was significantly increased (p less than 0.001) ipsilaterally in the three groups, and contralaterally in patients with medium- and large-sized arteriovenous malformations. The cerebral blood volume to cerebral blood flow ration, an index of vascular mean transit time, was significantly increased (p less than 0.005) ipsilaterally in patients with medium- and large-sized malformations and contralaterally in patients with large ones. Cerebral blood flow, oxygen extraction fraction, and oxygen metabolism were within the normal range bilaterally in all three groups, but oxygen extraction fraction tended to be higher in patients with larger lesions. The lack of significant change in oxygen metabolism suggests that oxygen metabolism in cortical areas remote from the arteriovenous malformation has been maintained by compensatory hemodynamic mechanisms. These data reveal widespread metabolic and hemodynamic consequences of arteriovenous malformations and suggest that they are associated with impairment of glucose metabolism, both in ipsilateral regions remote from the lesion and in the contralateral hemisphere in patients with large lesions.

Adult↗
PubMed1988

Influx of a choline analog to dog brain measured by positron emission tomography.

The influx of the 11C-labeled choline analog pyrrolidinocholine into tissue was measured in the brain of three dogs by positron emission tomography (PET). During the first 90 s after the intravenous bolus injection of the tracer, transfer of tracer from plasma to tissue was unidirectional. The influx constant for pyrrolidinocholine into intracranial tissue, Kin, was 0.017 ml/g/min (0.008 SD), and the initial volume of distribution, V0, was 0.08 ml/g (0.03 SD). The influx constant was at least five times larger than the value expected if simple diffusion were to account for tissue uptake. The method presented in this paper can be used to investigate the availability of plasma choline and its analogs to the living human brain and other tissue in degenerative diseases affecting the cholinergic system, and to provide in vivo information on a choline transport system.

Animals↗
PubMed1988

The transfer coefficients for L-valine and the rate of incorporation of L-[1-14C] valine into proteins in normal adult rat brain.

An autoradiographic method for the measurement of the rate of valine incorporation into brain proteins is described. The transfer coefficients for valine into and out of the brain and the rate of valine incorporation into normal rat brain proteins are given. The valine incorporation and the transfer constants of valine between different biological compartments are provided for 14 gray matter and 2 white matter structures of an adult rat brain. The rate of valine incorporation varies between 0.52 +/- 0.19 nmol/g/min in white matter and 1.94 +/- 0.47 in inferior colliculus (gray matter). Generally, the rate of valine incorporation is about three to four times higher in the gray matter than in the white matter structures.

Animals↗
PubMed1988

Workshop on schizophrenia, PET, and dopamine D2 receptors in the human neostriatum.

Recently, two research groups published numbers for D2 receptor sites in the neostriatum of drug-naive schizophrenic patients, obtained in vivo by positron emission tomography (PET). One study appeared to confirm the increase of D2 receptor numbers, while the other study did not. A workshop was convened in Montreal to examine the reasons for the discrepancy between the results obtained by the two groups. The workshop considered patient populations, PET instrumentation and scanning methods, pharmacology, and modeling. The workshop identified differences between the approaches of the two groups that could contribute to the divergent results, including age and chronicity of the patient samples, brain region selected for study, metabolism of the different radioligands in blood and brain, reversibility of binding, PET instrumentation, and complexity of data analysis. The workshop concluded that these initial efforts had made considerable progress in establishing the role of PET in the understanding of the biochemical processes underlying mental illness. In particular, the unique ability to quantify regional neuroreceptor density at different stages in the evolution of the disease has been implemented. At the same time, the work so far and this conference served to identify the main sources contributing to the different findings from the two centers. This information will be important in designing the next phase of the research which will build upon and reconcile these apparent discrepancies.

Adult↗
PubMed1988

Validation of the triple-tracer autoradiographic method in rats.

We have developed a quantitative autoradiographic technique to measure simultaneously local cerebral blood flow, tissue pH, and local cerebral glucose utilization using 4-[18F]fluoroantipyrine, [14C]dimethyloxazolidine-2,5-dione, and 2-[3H]deoxyglucose as radioactive tracers. Our technique was validated by measurements of local cerebral blood flow, tissue pH, and local cerebral glucose utilization in the brains of sham-operated rats. Sham-operated rats showed a 14% reduction in local cerebral blood flow and a 10% reduction in local cerebral glucose utilization in the most affected piriform and entorhinal cortical regions compared with the contralateral homologous regions. There was no difference in tissue pH measured in the sham-operated side compared with normal rats or with the contralateral region.

Animals↗
PubMed1988

Triple-tracer autoradiography demonstrates effects of hyperglycemia on cerebral blood flow, pH, and glucose utilization in cerebral ischemia of rats.

Triple-tracer autoradiography was used to measure topographic changes in local cerebral blood flow, cerebral tissue pH, and local cerebral glucose utilization in hyperglycemic and normoglycemic rats, all of which had undergone occlusion of the middle cerebral artery. More severe and extensive reduction of all three variables was observed in the hyperglycemic than in the normoglycemic rats. In seven normoglycemic rats, significant reduction in local cerebral blood flow (p less than 0.025) was observed in the ischemic but not in the contralateral nonischemic side at the lateral portion of the caudate nucleus and the neocortex. Tissue pH was significantly lower (p less than 0.025) only at the lateral portion of the caudate nucleus in the ischemic side. No significant differences in local cerebral glucose utilization were observed when the two hemispheres were compared. In the ischemic hemisphere of five hyperglycemic rats, the caudate nucleus and the neocortex exhibited significant reduction (p less than 0.025) in local cerebral blood flow, tissue pH, and local cerebral glucose utilization. Even in the nonischemic hemisphere of the hyperglycemic rats, local cerebral blood flow in the caudate nucleus and the neocortex was significantly reduced (p less than 0.025) compared with the normoglycemic rats. No significant change in tissue pH or local cerebral glucose utilization was observed throughout the nonischemic hemisphere of the hyperglycemic compared with the normoglycemic rats. Tissue pH was systematically lower in the hyperglycemic than in the normoglycemic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Synthesis of "no-carrier-added" carbon-11 SarCNU: the sarcosinamide analog of the chemotherapeutic agent BCNU.

Carbon-11-labeled SarCNU [N-(2-chloroethyl)-N-nitroso-N'-(carboxamidomethylene)-N'-(methyl) - [11C]-urea], a potential chemotherapeutic agent, has been prepared by the nitrosation of the corresponding urea, N-(2-chloroethyl)-N'-(carboxamidomethylene)-N'-(methyl) [11C]urea (SarCU). SarCU was prepared by reacting sarcosinamide with [11C]-2-chloroethylisocyanate, which was itself prepared by reacting [11C]-phosgene with 2-chloroethylamine hydrochloride suspended in dioxane. The synthesis yielded [11C]SarCNU with an average radiochemical purity of 95% in an average overall radiochemical yield of 18% relative to the activity measured at the end of [11C]phosgene introduction.

Antineoplastic Agents↗
PubMed1988

Stability of regional cerebral glucose metabolism in the normal brain measured by positron emission tomography.

Cerebral glucose utilization (LCMRGI) was measured using the [18F]fluorodeoxyglucose method with PET in two groups of ten healthy young volunteers, each scanned in a resting state under different methodological conditions. In addition, five subjects had a second scan within 48 hr. Mean hemispheric values averaged 45.8 +/- 3.3 mumol/100 g/min in the right cerebral hemisphere and 47.0 +/- 3.7 mumol/100 g/min in the left hemisphere. A four-way analysis of variance (group, sex, region, hemisphere) was carried out on the results using three different methods of data manipulation: (a) the raw values of glucose utilization, (b) LCMRGI values "normalized" by the mean hemispheric gray matter LCMRGI value, and (c) log transformed LCMRGI values. For all analysis techniques, significantly higher LCMRGI values were consistently seen in the left mid and posterior temporal area and caudate nucleus relative to the right, and in the right occipital region relative to the left. The coefficient of variation of intrasubject regional differences (9.9%) was significantly smaller than the coefficient of variation for regions between subjects (16.5%). No differences were noted between the sexes and no effect of repeat procedures was seen in subjects having multiple scans. In addition, inter-regional LCMRGI correlations were examined both in values from the 20 normal subjects, as well as in a set of hypothetical "abnormal" values. Results were compared with those reported from other PET centers; despite certain methodological differences, the intersubject and inter-regional variation of LCMRGI is fairly constant.

Adult↗
PubMed1988

Synthesis of "no-carrier-added" alpha-[11C]methyl-L-tryptophan.

Described here is a synthesis of "no-carrier-added" alpha-[11C]methyl-L-tryptophan based on alkylation with 11CH3I of an anion generated by reacting the Schiff base of L-tryptophan methyl ester with di-isopropylamine. The synthesis requires approximately 30 min after the end of 11CO2 collection and gives alpha-[11C]methyl-L-tryptophan in a 20-25% radiochemical yield calculated at the end of the synthesis and without correction for radioactive decay. The specific activity of the final radiopharmaceutical, measured at the end of the synthesis, was around 2,000 Ci/mmol. Data confirming the stereospecificity of the synthesis are also presented.

Carbon Radioisotopes↗
PubMed1987

The effect of spontaneous reperfusion on metabolic function in early human cerebral infarcts.

Twelve patients were studied within 48 hours of stroke using positron emission tomography to determine cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO2), oxygen extraction fraction, cerebral blood volume, cerebral pH (CpH), and cerebral metabolic rate for glucose (CMRGlc), the last calculated using published normal rate constants (CMRGlc[N]) and those for severe ischemia. In these studies, a cortical region of severe ischemia (I) was outlined, its metabolic and perfusion properties evaluated, and its length measured. The contralateral uninvolved cortical rim (C) in these patients and the cortical rim in 5 older normal patients were used for comparison. The length of region I correlated with the neurological deficit measured independently by a clinical scoring method. The 12 patients fell into two groups: Group I (8 patients), whose CBF in I was 9.3 +/- 2.5 ml/100 gm/min (mean +/- SEM) and was in every patient lower than that in C (33.1 +/- 2.2), and Group 2 (4 patients), whose CBF in I was 42.1 +/- 8.5 ml/100 gm/min and was in every case higher than that in C (28.2 +/- 1.5). In Group I, region I showed a CMRGlc(N)/CMRO2 ratio of 0.22 +/- 0.06 and a CpH of 6.83 +/- 0.06. In Group 2, the same ratio in the region I was 0.58 +/- 0.09 and the CpH was 7.12 +/- 0.05. The CMRGlc (N)/CMRO2 ratio for the contralateral hemisphere was comparable in the two groups. Our data suggest that, within 48 hours of the clinical onset of stroke, the ischemic cortex is already reperfused in one third of patients. Those ischemic regions with persistent hypoperfusion appear acidotic, whereas in the reperfused regions, despite evidence of an increased CMRGlc/CMRO2 ratio, acidosis is not evident. The implications of these findings for therapies proposed in acute human cerebral ischemia are discussed.

Acute Disease↗
PubMed1987

Effect of generalized spike-and-wave discharge on glucose metabolism measured by positron emission tomography.

Positron emission tomography was used to study the cerebral metabolic rate for glucose (CMRGlc) in 7 adult patients with generalized spike-and-wave activity in the electroencephalogram. No consistent changes were seen in the CMRGlc. There was a slight trend toward an increased CMRGlc in 2 patients with primary generalized epilepsy, while in the 5 other patients with minor deviations from this condition or with secondary generalized epilepsy, the CMRGlc was unaffected by spike-and-wave activity or was below the normal range. Neither the amount of spike-and-wave activity in the EEG nor the presence of clinically evident absence seizures appeared to influence the CMRGlc. Therefore, we conclude that neuronal activity underlying spike-and-wave discharge does not seem to require increased glucose utilization.

Adolescent↗
PubMed1987

Borderzone ischemia.

Positron emission tomography was used to measure cerebral perfusion and metabolism in 7 patients with severe carotid stenosis. None of the patients had sustained a major stroke, and all had a normal neurological examination except 1 patient with a mild neurological deficit from a capsular lacuna. Cerebral blood flow (CBF), cerebral blood volume, the cerebral blood flow/cerebral blood volume ratio, oxygen metabolism, and the fractional extraction of oxygen by the brain were measured in the cerebral cortex of both hemispheres in the anterior and middle cerebral artery distributions, in the borderzone regions between the anterior and middle cerebral arteries (anterior borderzone), and between the middle cerebral and posterior cerebral arteries (posterior borderzone). Results obtained in patients were compared, using Student's t test, to those obtained in 6 neurologically normal, elderly volunteers. Cerebral blood flow and the cerebral blood flow/cerebral blood volume ratio were both significantly decreased (p less than 0.025 and p less than 0.05, respectively) in the anterior borderzone ipsilateral to the carotid stenosis. In the same region there was a tendency toward a rising fractional extraction of oxygen with the oxygen metabolism maintained in the low-normal range. Cerebral blood flow was also significantly decreased (p less than 0.05) in the contralateral anterior borderzone. Hemodynamic and metabolic variables in other vascular territories were not significantly different from values obtained in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1987

In vivo measurement of [18F]fluorodeoxyglucose rate constants in rat brain by external coincidence counting.

The operational equation for the double-label deoxyglucose method described in the following paper requires the knowledge of the rate constants for transfer of fluorodeoxyglucose across the blood-brain barrier (K1* and K2*), and those for phosphorylation of fluorodeoxyglucose (K3*) and dephosphorylation of fluorodeoxyglucose-6-phosphate (k4*). These rate constants were determined in anesthetized rats by external coincidence counting. Radioactivity in parietal brain was measured for a 110 min experimental period after a bolus injection of 18F-labeled fluorodeoxyglucose. Apparent rate constants were obtained by fitting the resulting tissue radioactivity curves to the tissue radioactivity function of the deoxyglucose model modified to take into account the dephosphorylation of fluorodeoxyglucose-6-phosphate. The apparent fluorodeoxyglucose rate constants in rat brain are K1* = 0.195 ml g-1 min-1, k2* = 0.379 min-1, k3* = 0.088 min-1, and k4* = 0.009 min-1.

Animals↗
PubMed1987

Double-label autoradiographic deoxyglucose method for sequential measurement of regional cerebral glucose utilization.

A new double-label autoradiographic glucose analog method for the sequential measurement of altered regional cerebral metabolic rates for glucose in the same animal is presented. This method is based on the sequential injection of two boluses of glucose tracer labeled with two different isotopes (short-lived 18F and long-lived 3H, respectively). An operational equation is derived which allows the determination of glucose utilization for the time period before the injection of the second tracer; this equation corrects for accumulation and loss of the first tracer from the metabolic pool occurring after the injection of the second tracer. An error analysis of this operational equation is performed. The double-label deoxyglucose method is validated in the primary somatosensory ("barrel") cortex of the anesthetized rat. Two different rows of whiskers were stimulated sequentially in each rat; the two periods of stimulation were each preceded by an injection of glucose tracer. After decapitation, dried brain slices were first exposed, in direct contact, to standard X-ray film and then to uncoated, "tritium-sensitive" film. Results show that the double-label deoxyglucose method proposed in this paper allows the quantification and complete separation of glucose utilization patterns elicited by two different stimulations sequentially applied in the same animal. The double-label deoxyglucose is of potential usefulness in sensory physiology since it makes possible the separate mapping of regional cerebral glucose utilization patterns elicited by two sequentially applied sensory stimulations in the same animal. The method allows the quantification of a step-like change in regional cerebral glucose utilization in the same animal. It could be used to study the cerebral metabolic effects induced by neuropharmacological agents or surgical interventions applied during the experiment. Using each animal as its own control eliminates intersubject variability. Thus experimental cost and effort can be saved, and the reliability of the results obtained can be increased.

Animals↗
PubMed1987

Time-dependent changes of lumped and rate constants in the deoxyglucose method in experimental cerebral ischemia.

Time-dependent changes in the lumped and rate constants in a bilateral middle cerebral artery (MCA) occlusion in cats were evaluated. These variables were measured in 11 cats after a sham operation, in five after a 1-h occlusion, in two after a 2-h occlusion, in five after a 4-h occlusion, and in four after a 16-h occlusion. The time course of the cerebral tissue radioactivity [Ci* (t)] was monitored by external coincidence counting during a programmed infusion of [18F]2-fluorodeoxyglucose (FDG). Arterial plasma concentration [Cp* (t)] of tracer was kept constant during the first 45 min. Comparison of k2* and k3* in the sham-operated group, estimated by external coincidence counting, and by the ratio of extraction fractions of glucose and [18F]2-FDG, demonstrated no significant difference between these rate constants in these two groups of animals. The rate and lumped constants were also estimated from Ci* (t) and Cp* (t), as well as from the ratio of extraction fractions of glucose and [18F]2-FDG, respectively, in the MCA occlusion group. Significant decrease in k3* was observed after 1 h of occlusion (20% lower than in the sham operation, p less than 0.05); in k1* decrease occurred within 4 h of occlusion (21% lower than in the sham operation, p less than 0.05). However, decrease in k2* was observed only after 16 h of occlusion (26% lower than in the sham operation, p less than 0.05). Namely, decrease of rate constants occurred first in k3* then in k1* and k2*.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗