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M Diksic

Publications and source records attributed to M Diksic.

At least 91 records · Page 5Linked to original sources
PubMed1990

Biological model for the in vivo measurement of rate of serotonin synthesis in the brain.

A biological model for the measurement of the rate of serotonin synthesis in rat brain with alpha-[14C]methyl-L-tryptophan is described. The rate of serotonin synthesis in several grossly dissected brain structures is reported. The half-life of the precursor pool, estimated from kinetic data, is between 20 and 25 min. The method allows, for the first time, measurement of the brain serotonin synthesis rate without any pharmacological manipulation and does not require separation of metabolites. Autoradiographic data are also presented to demonstrate anatomical resolution of this method. The synthesis rate can be estimated in a large number of discrete structures when autoradiography is applied. Long retention of the tracer in brain is also demonstrated.

Animals↗
PubMed1990

A new method to measure brain serotonin synthesis in vivo. I. Theory and basic data for a biological model.

We describe here an autoradiographic method to measure the in vivo rate of serotonin synthesis in rat brain. The method is based on the use of the L-tryptophan analogue alpha-methyl-L-tryptophan (alpha-MTrp), which is converted in vivo into alpha-methylserotonin (alpha-M5HT). Since alpha-M5HT is not a substrate for monoamine oxidase, it is accumulated in the brain tissue. Data are presented to confirm time-dependent conversion of alpha-MTrp into alpha-M5HT in the dorsal raphe nucleus and also in the pineal body, an organ outside the blood-brain barrier. It has also been shown that washing brain slices in 10% trichloroacetic acid results in less than 3% incorporation of alpha-MTrp into brain proteins. The rates of synthesis are calculated in several grossly dissected brain structures by using tracer kinetics and a three-compartment biological model. The half-life of the precursor pool is estimated to be approximately 20 min. The rate of serotonin synthesis is highest in the pineal body.

Animals↗
PubMed1990

Blood-brain transfer and metabolism of 6-[18F]fluoro-L-dopa in rat.

In a study designed to reveal the rates of blood-brain transfer and decarboxylation of fluoro-L-3,4-dihydroxyphenylalanine (FDOPA), we discovered a major discrepancy between the DOPA decarboxylase activity reported in the literature and the rate of FDOPA decarboxylation measured in the study. "Donor" rats received intravenous injections of 6 mCi fluorine-18-labeled FDOPA. The donor rats synthesized methyl-FDOPA. Arterial plasma, containing both FDOPA and methyl-FDOPA, was sampled from the donor rats at different times and reinjected into "recipient" rats in which it circulated for 20 s. The blood-brain clearance of the mixture of labeled tracers in the plasma was determined by an integral method. The individual permeabilities were determined by linear regression analysis, according to which the average methyl-FDOPA permeability in the blood-brain barrier was twice that of FDOPA, which averaged 0.037 ml g-1 min-1. The permeability ratio was used to determine the fractional clearance from the brain of FDOPA (and hence of methyl-FDOPA), which averaged 0.081 min-1. In the striatum, the measured average FDOPA decarboxylation rate constant (kD3) was 0.010 min-1, or no more than 1% of the rate of striatal decarboxylation of DOPA measured in vitro and in vivo. We interpreted this finding as further evidence in favor of the hypothesis that striatum has two dopamine (DA) pools, of which only DA in the large pool is protected from metabolism. Hence, no more than 1% of the quantity of fluoro-DA theoretically synthesized was actually retained in striatum.

Animals↗
PubMed1990

A new method to measure brain serotonin synthesis in vivo. II. A practical autoradiographic method tested in normal and lithium-treated rats.

We describe here a practical autoradiographic method to estimate the rate of serotonin synthesis in brain. A two-time point method (60 and 150 min after injection of alpha-[14C]methyl-L-tryptophan) was first evaluated in 14 normal rats (7 at each time point). After this the method was tested in lithium-treated rats. In normal rats the rate of serotonin synthesis measured by the two-time point method generally correlated with known concentrations of tryptophan hydroxylase. The rate of synthesis in lithium-treated rats was compared with that in sham-treated rats (NaCl treatment). The results showed a significant increase in the synthesis rate in some cerebral structures. The greatest increases in the serotonin synthesis rate, attributable to the lithium treatment, were observed in the parietal cortex (52%) and caudate nucleus (47%). This is the first investigation to demonstrate, with autoradiographic resolution (approximately 100 microns), the differential changes in the rate of serotonin synthesis in the brain. Lithium had no significant effect on the rate of synthesis in the pineal gland.

Animals↗
PubMed1990

Measurement of cerebral blood flow and volume with positron emission tomography during isoflurane administration in the hypocapnic baboon.

Using positron emission tomography, cerebral blood flow (CBF) and cerebral blood volume (CBV) were measured after the addition of isoflurane (1.3 vols %, end-tidal concentration) to neuroleptanesthesia (fentanyl/droperidol) in hypocapnic baboons. The study was designed to determine whether isoflurane, when administered during hypocapnia, acted as a cerebral vasodilator to increase either CBF or CBV. Mean arterial pressure was maintained within 10% of preisoflurane levels with an angiotensin infusion. In the first protocol (A), CBF and CBV were measured as close together in time as possible in order to detect divergent effects of isoflurane on these variables. When PaCO2 was reduced from 40 mmHg to 25 mmHg, CBF decreased from 44 +/- 4 to 31 +/- 4 ml.100 g-1.min-1 (P less than 0.05) and CBV decreased from 3.1 +/- 0.3 to 2.6 +/- 0.3 ml/100 g (P less than .05). Neither CBF nor CBV was significantly changed by the addition of isoflurane. In the second protocol (B), serial CBV scans were performed frequently during the addition of isoflurane in a fashion designed to detect transient changes in CBV at the time isoflurane was first added to the breathing circuit. Induction of hypocapnia again reduced CBV from 3.1 +/- .3 to 2.7 +/- .2 ml/100 g, (P less than .05) and addition of isoflurane did not change CBV. From these results the authors conclude that in the normal hypocapnic baboon the addition of 1.3% isoflurane does not significantly change cerebral blood flow or volume.

Animals↗
PubMed1990

Functional organization in the ferret visual cortex: a double-label 2-deoxyglucose study.

The functional organization of visual cortical area 17/18 of the ferret was studied using a double-label 2-deoxyglucose (2-DG) method. Animals were stimulated sequentially with moving gratings of 2 different orientations. Elongated orientational patches running roughly at a right angle into the area 17/18 border were seen. The orientation maps were similar in areas 17 and 18. When animals were stimulated with 2 orthogonally oriented gratings, activation patterns were not fully complementary but did not overlap. A complex pattern of partial overlap was observed, with orientations differing by 45 degrees. More gradual and more abrupt changes alternated frequently on a scale smaller than the average periodicity in the patterns. A cortical patch representing a given orientation was regularly surrounded by both neighboring and orthogonal orientations. The direction of the orientational changes reversed frequently in the immediate vicinity of any orientational patch. Orientation maps were compared with complete maps of retino-cortical projections obtained by transneuronal labeling with intravitreally injected tritiated proline. Ocular dominance in the binocular segment of both areas 17 and 18 was found to be organized into elongated ipsilateral islands in an almost contiguous contralateral projection. In area 18, the patches were wider than in area 17, and the ipsilateral islands were smaller in the regions representing the upper and central visual field than in those representing the lower visual field.

Animals↗
PubMed1989

In vivo quantification of blood-brain transfer and binding of [125I]HEAT, an alpha 1-adrenoceptor antagonist.

The uptake and binding constants of [125I]iodo-2-[beta-(4-hydroxyphenyl)-ethyl-amino-methyl]tetralone ( [125I]HEAT) in rat brain were determined in vivo. The initial clearance of the radioligand from blood to brain, K1, was calculated from the initial uptake of the radioligand; it averaged 0.21 +/- 0.01 (SD) ml g-1 min -1, consistent with an initial extraction of 25% (i.e., one-quarter of the blood flow). The most strongly binding regions included the olfactory bulb, thalamic nuclei, medial geniculate body, and cerebral cortical layers. We identified saturable, specific binding in frontal cortex layers 1, 5a, and 5c (motor region), frontal cortex layers 3+4, ventral thalamic nuclei, medial geniculate body, striatum, cerebellum, and olfactory bulb. Addition of unlabeled ligand depressed binding in all regions to the same low level (partition coefficient) of 0.8 ml g-1. Displacement of [125 I]HEAT binding by unlabeled HEAT yielded a global affinity constant (KDVd) of 34 +/- 8 pmol g-1 and receptor densities (Bmax) that varied from 50 pmol g-1 in cerebellar cortex and caudate nucleus to 200 pmol g-1 in the region of highest specific binding, the medial geniculate body.

Adrenergic alpha-Antagonists↗
PubMed1989

Synthesis of 6-[18F]fluoropyridoxal and radioactivity distribution in rat at 60 min.

6-[18F]Fluoropyridoxal was synthesized by the flourination of a propylamine derivative of pyridoxal (pyridoxal Schiff base) with 18F-labelled acetylhypofluorite. Two different fluorinating agents, 5% F2 in N2 and acetylhypofluorite, were investigated with nonradioactive material. The evaluation of reactions in CH3CN and chloroform showed CH3CN to be the better solvent and CH3COOF to be the better fluorinating reagent. The synthesis gave a radiochemical yield of about 18% (expressed at the end of synthesis) and required 35-40 min to complete. The specific activity of the final radiopharmaceutical at the end of the synthesis was about 25.9 GBq/mmol (700 mCi/mmol). The tissue distribution of 6-fluoropyridoxal in rat at 60 min is also reported. A large concentration in liver and kidney indicates that this radiopharmaceutical could be of special interest in the imaging of liver functions. The concentration in the brain might also allow in vivo PET imaging of the 6-(fluoropyridoxal) uptake if a high efficiency PET scanner is used.

Animals↗
PubMed1989

Quantitative measurements of regional glucose utilization and rate of valine incorporation into proteins by double-tracer autoradiography in the rat brain tumor model.

We examined the rate of glucose utilization and the rate of valine incorporation into proteins using 2-[18F]fluoro-2-deoxyglucose and L-[1-14C]-valine in a rat brain tumor model by quantitative double-tracer autoradiography. We found that in the implanted tumor the rate of valine incorporation into proteins was about 22 times and the rate of glucose utilization was about 1.5 times that in the contralateral cortex. (In the ipsilateral cortex, the tumor had a profound effect on glucose utilization but no effect on the rate of valine incorporation into proteins.) Our findings suggest that it is more useful to measure protein synthesis than glucose utilization to assess the effectiveness of antitumor agents and their toxicity to normal brain tissue. We compared two methods to estimate the rate of valine incorporation: "kinetic" (quantitation done using an operational equation and the average brain rate coefficients) and "washed slices" (unbound labeled valine removed by washing brain slices in 10% trichloroacetic acid). The results were the same using either method. It would seem that the kinetic method can thus be used for quantitative measurement of protein synthesis in brain tumors and normal brain tissue using [11C]-valine with positron emission tomography.

Animals↗
PubMed1989

The deoxyglucose method in the ferret brain. I. Methodological considerations.

In the brain of the anesthetized ferret, the 2-deoxyglucose (2-DG) transfer rate constants required to determine cerebral glucose utilization by the deoxyglucose method were calculated from regional gray matter time-radioactivity curves measured for 180 min after tracer injection. Results suggest that loss of metabolized tracer from brain occurs at a rate of about 1%/min for the first 180 min after injection if the rate constant of the rate-limiting step for loss of metabolized tracer (k4*) represents a first-order kinetic process. A simulation experiment shows that, whether k4* is assumed to be 0 or 0.01 min-1, has a negligible influence on glucose utilization rates obtained in conventional 45 min autoradiographic experiments provided that the entire analysis, including lumped constant determination, is carried out in a consistent way. The 2-DG lumped constant for k4* = 0 is 0.54, and 0.68 for k4* = 0.01 min-1.

Animals↗
PubMed1989

The deoxyglucose method in the ferret brain. II. Glucose utilization images and normal values.

To measure cerebral glucose utilization with the autoradiographic deoxyglucose method, the tracer transfer rate constants and lumped constants must be known. 2-Deoxyglucose (2-DG) and fluorodeoxyglucose (FDG) constants were determined in 18 gray and white matter brain structures of the anesthetized ferret. The ferret is a domestic carnivore particularly suitable for deoxyglucose studies because of its small brain size and low body weight. The average gray matter rate constants for tracer transfer across the blood-brain barrier are similar for 2-DG and FDG in the ferret brain (K*1 = 0.21 ml/g/min and k*2 = 0.39 min-1). The rate constant for the rate-limiting step of tracer phosphorylation, k*3, is 1.6 times higher for FDG than for 2-DG (0.21 vs. 0.13 min-1). Loss of metabolized tracer is about 1-1.5%/min throughout the ferret brain for both tracers as estimated for a 180 min experimental period. Taking into account this loss, the lumped constant is 0.92 for FDG and 0.68 for 2-DG. Glucose utilization values in the brain of the anesthesized ferret range from 33 mumol/100 g/min in the corpus callosum to 104 mumol/100 g/min in the caudate nucleus. Representative glucose utilization images of coronal sections of the ferret brain are shown. Brain structures are identified on the same slices counterstained with thionin.

Animals↗
PubMed1989

The effect of nimodipine on the evolution of human cerebral infarction studied by PET.

Fourteen patients were studied by positron emission tomography (PET) within 48 h of onset of a hemispheric ischemic stroke and again 7 days later. After the first set of PET scans, the patients were randomized to receive either nimodipine (n = 7) or a carrier solution (n = 7) by intravenous infusion. The infusions were maintained until the end of the second PET studies. CBF, cerebral blood volume (CBV), oxygen extraction ratio (OER), CMRO2, and CMRglc were measured each time. These metabolic and perfusion measurements were performed by standard methods. A surface map of each metabolic and perfusion measurement in the cortical mantle was generated by interpolating between the available slices. The various surface maps representing the physiological characteristics determined in the same or subsequent studies were aligned so that all data sets could be analyzed identically using an array of square regions of interest (ROIs). The functional status of each ROI was recorded at the two intervals following the cerebrovascular accident to characterize the evolution of the infarct, penumbra, and normal brain regions. We presumed the ischemic penumbra to be cortical regions in the proximity of the infarct and perfused at CBF values between 12 and 18 ml/100 g/min on the first PET scan, while densely ischemic regions had CBF of less than 12 nl/100 g/min and normally perfused brain greater than 18 ml/100 g/min. In the densely ischemic zone, CBF increased more in the nimodipine-treated group than in the carrier group. As well, in this region nimodipine reversed the decline in CMRO2 noted in the carrier group, the difference in the changes being significant. In the penumbra zone, comparable trends were noted in OER and CMRO2 but the difference in the changes between the two groups did not reach statistical significance. Changes in CMRglc and CBV were comparable between the two groups in both cortical regions.

Adult↗
PubMed1989

Minimisation of parameter estimation errors in dynamic PET: choice of scanning schedules.

We addressed the general problem of finding an optimal scan schedule in positron emission tomography (PET) dynamic studies which minimises the errors in estimating the transfer constants between a set of compartments. As an example, the influence of scan intervals in PET on the accuracy of estimation of the rate constants and vascular component in the deoxyglucose method was examined using an empirical noise model. The simulated noisy curves used in the analysis were compared with patient data to validate the noise model. A series of scan schedules were compared for accuracy of fit by evaluating the determinant of the variance-covariance matrix of the fitted parameters as an index of parameter accuracy. For realistic noise levels there is a monotonic improvement in the index of parameter accuracy with increasing sampling frequency, particularly over the initial minutes after the tracer injection. However, since faster schedules are more susceptible to errors introduced by time mismatches between plasma and tissue curves and impose greater computational and memory overhead, an initial scan duration of 30 s provide a practical trade-off for dynamic PET 18F-fluoro-deoxyglucose studies.

Models, Biological↗
PubMed1989

Myoclonus epilepsy and ragged-red fibres (MERRF). 1. A clinical, pathological, biochemical, magnetic resonance spectrographic and positron emission tomographic study.

Thirteen patients, including 6 from one family, with the syndrome of myoclonus epilepsy and ragged-red fibres (MERRF) were studied. There was considerable heterogeneity in the age of onset, severity and associated clinical features. Postmortem studies in 3 patients from the one family showed a particular system degeneration. In addition, the youngest and most severely affected family member showed the pathological changes of Leigh's syndrome. Cortical dysfunction is a prominent clinical feature in MERRF, but postmortem examination failed to reveal cortical abnormalities. Positron emission tomographic studies, however, showed decreased cortical metabolic rates for glucose and oxygen utilization, with normal cortical blood flow and cerebral pH. Analyses of kinetic rate constants for uptake and phosphorylation of the glucose analogue, fluorodeoxyglucose showed decreased hexokinase-mediated phosphorylation: normal K1 and k2 values but reduced k3. Phosphorus magnetic resonance spectroscopy studies suggested a normal cerebral intracellular pH. Biochemical studies on muscle homogenates in 6 patients showed partial deficiencies of the activities of certain mitochondrial enzymes in 4 cases, whereas in 2 patients no abnormality was found. Our data, combined with previous reports, show that MERRF is biochemically and genetically heterogeneous. Our experience, and analysis of the literature, suggests that many cases previously described as the Ramsay Hunt syndrome, as well as other hitherto unclassified system degenerations associated with myoclonus epilepsy, are examples of MERRF. These data permit the formulation of a hypothesis to explain the clinical, biochemical and genetic heterogeneity of MERRF, and its overlap with Leigh's syndrome. We suggest that different biochemical defects of the mitochondrial respiratory chain may cause similar cerebral metabolic effects, as measured by positron emission tomography, resulting in similar phenotypes. Reduced activity of one enzyme, however, may result in different phenotypes, depending on the severity of the defect and its tissue distribution. Moreover, the phenotypic expression of certain biochemical defects may be influenced by randomly occurring factors such as fever, which may increase metabolic demand and result in more deleterious cellular metabolic effects.

Adolescent↗
PubMed1989

Generalized decrease in brain glucose metabolism during fasting in humans studied by PET.

In prolonged fasting, the brain derives a large portion of its oxidative energy from the ketone bodies, beta-hydroxybutyrate and acetoacetate, thereby reducing whole body glucose consumption. Energy substrate utilization differs regionally in the brain of fasting rat, but comparable information has hitherto been unavailable in humans. We used positron emission tomography (PET) to study regional brain glucose and oxygen metabolism, blood flow, and blood volume in four obese subjects before and after a 3-wk total fast. Whole brain glucose utilization fell to 54% of control (postabsorptive) values (P less than 0.002). The whole brain rate constant for glucose tracer phosphorylation fell to 51% of control values (P less than 0.002). Both parameters decreased uniformly throughout the brain. The 2-fluoro-2-deoxy-D-glucose lumped constant decreased from a control value of 0.57 to 0.43 (P less than 0.01). Regional blood-brain barrier transfer coefficients for glucose tracer, regional oxygen utilization, blood flow, and blood volume were unchanged.

Adult↗
PubMed1989

Tolerance of the cerebral venous system to retrograde perfusion pressure in focal cerebral ischemia in rats.

Using quantitative double-tracer autoradiography, we examined the tolerance of the rat cerebral venous system in focal cerebral ischemia to retrograde perfusion pressure into the inferior cerebral vein. At perfusion pressures of less than 150 mm Hg, there was no significant change in local cerebral blood flow (LCBF) and blood-brain barrier (BBB) permeability. At pressures of greater than 170 mm Hg, significant changes occurred in BBB permeability in the superficial cortical layers and there was a mild reduction of LCBF. In the group of rats subjected to 200 mm Hg perfusion pressure, the change in BBB permeability extended to the entire cortical zone and significant reduction of LCBF occurred. Our results indicate for the first time that during conditions of focal cerebral ischemia, the rat cerebral venous system can tolerate up to 150 mm Hg of retrograde perfusion pressure into the cerebral venous system without any change in BBB permeability or in LCBF. However, progressive change in BBB permeability and reduction in LCBF occur once the perfusion pressure exceeds 170 mm Hg. This finding may permit more efficient delivery of cytoprotective agents into ischemic tissue.

Animals↗