Biomedical subjects

T J Ruth

Publications and source records attributed to T J Ruth.

At least 55 records · Page 3Linked to original sources

PubMed1994

Age-dependent decline of nigrostriatal dopaminergic function: a positron emission tomographic study of grandparents and their grandchildren.

Despite postmortem evidence for an age-related decline in nigrostriatal dopaminergic function, position emission tomography (PET) studies have produced inconsistent results. This may be due to differences in methods or of subject selection. To investigate further the effect of age on dopaminergic function, we performed PET with 6-L-[18F]fluorodopa (FD) on 12 pairs of grandchildren and their grandparents. The FD uptake rate constant (Ki) was calculated using a graphical method for the whole striatum to avoid confounding of the results by striatal atrophy. The mean Ki was significantly lower in grandparents (p = 0.020). These PET observations represent in vivo confirmation of postmortem evidence that nigrostriatal dopaminergic function declines with aging.

Adult↗

PubMed1994

The performance of the single-slice rebinning technique for imaging the human striatum as evaluated by phantom studies.

The single-slice rebinning (SSRB) technique has been implemented on a ring-based tomograph with removable septa and its performance evaluated with phantom studies. The studies involved the determination of the plane efficiency profile and the mapping of the point spread function. The image quality obtained using the SSRB technique has been compared to that obtained using the standard 3D reconstruction method in terms of the following figures of merit: recovery as a function of source axial position and slice averaging, contrast recovery and contrast to background noise ratio as a function of source axial position. The effect of the region of interest (ROI) size on such a comparison has been evaluated. Finally the effects of different contrast conditions and ROI position on a striatal phantom image have been thoroughly explored.

Algorithms↗

PubMed1994

Reproducibility of fluorine-18-6-fluorodopa positron emission tomography in normal human subjects.

UNLABELLED: Fluorine-18-6-fluorodopa (FD) positron emission tomography (PET) is established for measuring nigrostriatal dopaminergic function. This is despite the absence of data on the reproducibility of results. METHODS: With an ECAT 953B/31 tomograph, we performed two or three repeated FD PET scans in 10 normal subjects to measure the scan-to-scan variation in the total striatal uptake rate constant (Ki). RESULTS: We found a scan-to-scan standard deviation (s.d.) of 8.7% of the mean. The between-subject s.d. was 26% of the mean, resulting in a reliability coefficient of 90%. Analysis of the variation in the components contributing to Ki showed a reliability varying from 77% to 86% (depending on the different time points analyzed) for emission data measured by the PET camera. The reliability of the blood radioactivity time course, as reflected by the stretch time, varied from 43% to 81%. The overall reliability for the correction of the blood time course for metabolites of FD was 71%. Variation in the blood radioactivity contributed to the variability of Ki by 50% more than the metabolite correction and by 200% more than the emission data. CONCLUSION: The striatal Ki is a reliable measurement; it has a 95% chance of lying within +/- 18% of its value for an individual normal subject.

Adult↗

PubMed1993

Correlation of striatal fluorodopa uptake in the MPTP monkey with dopaminergic indices.

Striatal 18F-6-fluorodopa (FD) uptake constants were measured by positron emission tomography in (1) normal cynomolgus monkeys and (2) a series of cynomolgus and rhesus monkeys that had received intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After the animals were killed, the number and average size of dopaminergic neurons in the substantia nigra pars compacta were measured. Striatal levels of dopamine and its metabolites, and the striatal activities of the dopaminergic synthetic enzymes, were also determined. The striatal FD uptake constants showed highly significant positive correlations with both number and size of dopaminergic neurons, indicating atrophy of surviving neurons in MPTP-treated animals. The uptake constants also showed significant positive correlations with striatal levels of dopamine, total catecholamines, and the activities of the synthetic enzymes. Both histochemical and biochemical data on tyrosine hydroxylase suggested some contralateral enzyme loss in these MPTP-treated monkeys, as well as decreased enzyme activity in surviving neurons on the lesioned side. However, residual enzyme activities were apparently not rate limiting to striatal FD uptake. It is concluded that PET-FD measurements by positron emission tomography provide a good index of the integrity of the nigrostriatal pathway.

Animals↗

PubMed1993

The transport of L-6-fluorodopa and its metabolites from blood to cerebrospinal fluid and brain.

The transport of L-6-fluorodopa and its major metabolites from the blood to the brain, cerebrospinal fluid (CSF), and muscle was studied in carbidopa-pretreated cynomolgus monkeys. A bolus intravenous injection of 18F-L-6-fluorodopa was followed by serial positron emission tomography scans and sampling of cisternal CSF and arterial blood. The relative concentrations of L-6-fluorodopa and its metabolites were determined in blood plasma and CSF by high-performance liquid chromatography. Raising the blood concentration of phenylalanine by intraperitoneal injection markedly reduced the accumulation of tracer in the brain. This indicates that L-6-fluorodopa and 3-O-methylfluorodopa, like native L-dopa and its O-methylated derivative, are transported at the brain capillary by the large neutral amino acid carrier-mediated system, which is subject to saturation and competition by other large neutral amino acids (such as phenylalanine) at physiological plasma concentrations. In contrast, administration of phenylalanine had no effect on the accumulation of tracer either in muscle, or as L-6-fluorodopa and 3-O-methylfluorodopa, in CSF. This suggests that the transport of L-dopa and its derivatives at the blood-CSF barrier differs from the transport at the blood-brain barrier and also that measurement of CSF L-dopa is not a good index of the transport and pharmacokinetics of L-dopa in the brain. However, the effect of phenylalanine administration in reducing the concentration of fluorohomovanillic acid in the CSF suggests that the concentration of homovanillic acid in the CSF is an accurate reflection of dopamine turnover in the brain.

Amino Acids↗

PubMed1993

Parametric imaging of the rate constant Ki using [18Fluoro]-L-dopa positron emission tomography in progressive supranuclear palsy.

Positron emission tomography (PET) studies using [18F]-L-dopa were carried out in 9 patients with supranuclear palsy and 13 controls. For quantification of PET data a rate constant Ki was calculated for the radiotracer using a graphical method. Corrections for nonspecific activity were performed in both arterial plasma and brain tissue. The purpose of this study was to test the hypothesis that parametric images of the rate constant K mapping can be obtained on a pixel-by-pixel basis using an appropriate mathematical algorithm. Ki values from these parametric images and the graphical approach were compared. Both correlated closely, with y = 0.013 + 0.947*x, r = 0.992 and y = -0.052 + 1.018*x, r = 0.965 in patients and controls, respectively. Contrast measurements were also performed and showed a striking increase in contrast on parametric images. K mapping offers several advantages over the graphical approach, since parametric images are time-independent, i.e. one image represents the quantitative result of the study. In addition, parametric images of the rate constant are normalized to arterial plasma radioactivity and corrected for tissue metabolites. Thus, parametric images of Ki in different individuals can be compared directly without further processing in order to assess the nigrostriatal integrity.

Aged↗

PubMed1993

Recovery of the human striatal signal in a slice oriented positron emission tomograph.

The human striatum is small enough for partial volume effects to be important when imaged in positron tomographs with slice widths 10 mm or greater. The combination of interslice distance and slice width in such tomographs results in an axial undersampling of the striatal activity which introduces the additional problem of variation of axial recovery as a function of position of the striatum along the tomograph axis. Using striatal phantoms, we have developed a method that corrects the recovered striatal signal to a maximum value equivalent to that measured when the object is centered with respect to a slice. This makes the recovery independent of the axial position of the striatum. The method also provides an estimate of the total striatal activity by integrating the axial image intensity distribution along the tomograph axis. The method is able to detect and correct for relative axial tilt of the left and right striatum. We applied it to 26 human [18F]-6-L-fluorodopa scans and obtained an average uptake rate constant k value of 0.25 +/- 0.05 ml/min/striatum and a left to right k value percentage asymmetry of 0.1% +/- 6.3%.

Adult↗

PubMed1992

Routine determination of [18F]-L-6-fluorodopa and its metabolites in blood plasma is essential for accurate positron emission tomography studies.

A batch-contact alumina-extraction method has been used to separate [18F]-L-6-fluorodopa (FD) from its principal metabolite, 3-O-methyl-[18F]-6-fluorodopa (3-OMe-FD), in arterial blood plasma samples collected from subjects pretreated with carbidopa during positron emission tomography (PET) scans. The time course of the metabolite-corrected blood plasma activity is then used as an input function for kinetic analysis of striatal FD uptake. Results obtained from using the batch-contact alumina-extraction method were compared with those from high performance liquid chromatography, and also with those from a chromatographic alumina cartridge technique developed in this laboratory. In 60 human subjects including normal healthy volunteers and patients diagnosed as having a movement disorder, arterial blood plasma samples were collected after FD injection during a two-hour PET scan and analyzed by the batch-contact alumina-extraction method. The activity ratio (metabolites/FD) increased linearly with time for all subjects. However, there was a wide variation in the slope of the plot of the activity ratio (metabolites/FD) versus time among the subjects. No significant linear or curved relationship was observed between the slope and the age of the subject. Separation of FD from its metabolites is therefore necessary for each PET-FD study conducted.

Adsorption↗

PubMed1992

Plasma L-[18F]6-fluorodopa input function: a simplified method.

This article describes a simplified method for the determination of the L-[18F]6-fluorodopa (FDOPA) fraction time course that takes advantage of the strong correlation between the radioactivity ratio (metabolites/FDOPA) and time. Serial arterial blood samples are collected for assay of plasma total radioactivities following an intravenous injection of FDOPA into carbidopapretreated subjects. In addition, a single plasma sample, collected late in the study and analyzed for FDOPA fraction, is sufficient to determine accurately the time course of the FDOPA concentration in plasma. The validated straight-line method greatly simplifies blood analysis for routine positron emission tomography FDOPA studies.

Dihydroxyphenylalanine↗

PubMed1991

Positron emission tomography suggests that the rate of progression of idiopathic parkinsonism is slow.

We performed sequential positron emission tomography scans with 6-[18F]fluoro-L-dopa in 9 patients with idiopathic parkinsonism and 7 age-matched normal control subjects to compare changes in the nigrostriatal dopaminergic pathway over time. The mean interval between the scans was 3.3 years for the group with idiopathic parkinsonism and 3.9 years for the control subjects. The scans were analyzed by calculating the ratio of striatal to background radioactivity. Both groups showed statistically significant reductions of striatal uptake over the interval. The rate of decrease was almost identical in each group (p = 0.6). We infer that the usual rate of loss of integrity of the dopaminergic nigrostriatal pathway in patients with idiopathic parkinsonism is slow and the rate of change between the two groups was comparable.

Adult↗

PubMed1991

The reproducibility of striatal uptake data obtained with positron emission tomography and fluorine-18-L-6-fluorodopa tracer in non-human primates.

Cynomolgus and rhesus monkeys have been studied via PET with [18F]-L-6 fluorodopa tracer. Striatal fluorodopa uptake rate constants have been derived by graphical analysis of transaxial slice images centered on the striata. The differences between pairs of values of the rate constant, obtained from two scans on the same monkey separated by two weeks or more, exhibited a relative standard deviation of 34.4%. If the two scans were conducted one immediately after the other, with the position of the monkey undisturbed, the standard deviation was reduced to 14.0%. The utility of this technique was demonstrated by comparing the effects on the scans of halothane and pentobarbital anesthesia and by the administration of NSD 1015, a peripheral and central inhibitor of L-aromatic amino-acid decarboxylase, between back-to-back scans. With NSD 1015, the fluorodopa uptake constant was reduced by an average of 76.0%.

Animals↗

PubMed1990

Studies of the Uptake of Nitrate in Barley: I. Kinetics of NO(3) Influx.

(13)NO(3) (-) was used to investigate patterns of NO(3) (-) influx into roots of barley plants (Hordeum vulgare L. cv Klondike) previously grown with (;induced') or without (;uninduced') a source of external NO(3) (-) ([NO(3) (-)](0)). In both induced and uninduced plants, (13)NO(3) (-) influx was biphasic in the range from 0.005 to 50 moles per cubic meter [NO(3) (-)](0). In the low concentration range (<1 mole per cubic meter for induced plants and <0.3 mole per cubic meter for uninduced plants), influx was saturable and V(max) and K(m) values for influx either increased or decreased according to NO(3) (-) pretreatment. By contrast, (13)NO(3) (-) influx in the high concentration range revealed a strictly linear concentration dependence. These fluxes appeared to be mediated by a constitutive, rather than an inducible, transport system.

Journal Article↗

PubMed1990

Studies of the Uptake of Nitrate in Barley : II. Energetics.

Q(10) values for (13)NO(3) (-) influx were determined in ;uninduced' (NO(3) (-)-starved) and ;induced' (NO(3) (-)-pretreated) roots of barley (Hordeum vulgare L.) plants at various concentrations of external NO(3) (-) ([NO(3) (-)](0)). At 0.02 mole per cubic meter [NO(3) (-)](0), Q(10) values for influx were from 3 to 4 between 5 and 10 degrees C. As [NO(3) (-)](0) increased Q(10) values decreased, reaching values of 1.2 and 2.0, respectively, at 20 moles per cubic meter in uninduced and induced plants. The metabolic dependence of (13)NO(3) (-) influx at low and high [NO(3) (-)](0) (0.1 and 20.0 moles per cubic meter, respectively) in uninduced and induced plants was probed by the use of various inhibitors. These experiments confirmed the findings of the Q(10) studies, demonstrating that at low [NO(3) (-)](0) (13)NO(3) (-) influx was extremely sensitive to metabolic inhibition. By contrast, at high [NO(3) (-)](0), influx was relatively insensitive to the presence of inhibitors.

Journal Article↗

PubMed1989

Positron emission tomography in manganese intoxication.

We employed 6-fluorodopa to study the integrity of the nigrostriatal dopaminergic projection by positron emission tomography in 4 subjects with clinical features of mild parkinsonism caused by exposure to manganese. The 6-fluorodopa scans were normal. This finding suggests that in early manganism sufficient to cause parkinsonian deficits, damage may occur in pathways postsynaptic to the nigrostriatal system, probably involving striatal or pallidal neurons. Fluorodeoxyglucose scans showed decreased cortical glucose metabolism, the significance of which is discussed.

Adult↗

PubMed1989

PET studies of parkinsonian patients treated with autologous adrenal implants.

Transplantation of autologous adrenal medulla tissue into the striatum has recently been proposed as a treatment for Parkinson's disease. We report the use of positron emission tomography (PET) to evaluate patients who had adrenal implants placed into the right caudate. 6-[18F] fluoro-L-dopa (6-FD) scans were performed to study the integrity and activity of the implant, and the nigrostriatal dopamine system before and six weeks after transplantation surgery. [68Ga] Gallium-ethylenediaminetetraacetate (Ga) scans were also performed to assess the blood brain barrier. The Ga scans performed on two patients showed increased permeability of the blood brain barrier at the surgical site. 6-FD PET scans in five patients did not show a consistent change in striatal uptake following adrenal medullary implantation after six weeks. Further assessment of implant viability with 6-FD PET scans after longer follow up may provide useful information if the blood-brain barrier becomes re-established with the passage of time.

Adrenal Medulla↗

PubMed1989

Studies of the Regulation of Nitrate Influx by Barley Seedlings Using NO(3).

Using (13)NO(3) (-), effects of various NO(3) (-) pretreatments upon NO(3) (-) influx were studied in intact roots of barley (Hordeum vulgare L. cv Klondike). Prior exposure of roots to NO(3) (-) increased NO(3) (-) influx and net NO(3) (-) uptake. This ;induction' of NO(3) (-) uptake was dependent both on time and external NO(3) (-) concentration ([NO(3) (-)]). During induction influx was positively correlated with root [NO(3) (-)]. In the postinduction period, however, NO(3) (-) influx declined as root [NO(3) (-)] increased. It is suggested that induction and negative feedback regulation are independent processes: Induction appears to depend upon some critical cytoplasmic [NO(3) (-)]; removal of external NO(3) (-) caused a reduction of (13)NO(3) (-) influx even though mean root [NO(3) (-)] remained high. It is proposed that cytoplasmic [NO(3) (-)] is depleted rapidly under these conditions resulting in ;deinduction' of the NO(3) (-) transport system. Beyond 50 micromoles per gram [NO(3) (-)], (13)NO(3) (-) influx was negatively correlated with root [NO(3) (-)]. However, it is unclear whether root [NO(3) (-)] per se or some product(s) of NO(3) (-) assimilation are responsible for the negative feedback effects.

Journal Article↗

PubMed1988

Kinetics of in vitro decarboxylation and the in vivo metabolism of 2-18F- and 6-18F-fluorodopa in the hooded rat.

The metabolisms of L-18F-2-fluoro-DOPA (L-2-18F-DOPA) and L-18F-6-fluoro-DOPA (L-6-18F-DOPA) were compared in vitro and in vivo in the carbidopa-pretreated male hooded rat. In vivo, the sole metabolites in plasma were O-methylated derivatives. The peripheral formation of the O-methylated derivative of L-2-18F-DOPA was approximately twice as great as that for the 6-isomer. Animals were killed at 10 and 60 min after administration of the 18F-DOPAs, and samples of striatum and vermis were analyzed by HPLC. L-2-18F-DOPA passed less readily into brain than did L-6-18F-DOPA. Whereas significant amounts of 6-18F-fluorodopamine and metabolites were formed in the striatum, no decarboxylated derivatives of L-2-18F-DOPA were found. Determination of the Michaelis-Menten kinetic constants for aromatic amino acid decarboxylase AADC, EC 4.1.1.26) indicated that the Km for L-2-18F-DOPA (982 +/- 115 microM) was considerably higher than that for L-6-18F-DOPA (101 +/- 22 microM). The low substrate affinity for AADC and the relatively more rapid rate of O-methylation in the periphery account for the lack of formation of 2-18F-fluorodopamine in vivo. The ratio of total radioactivity between striatum and other brain regions is related to the decarboxylation of radiolabeled tracer and the relative persistence of the decarboxylated derivatives in the striatum. Since L-2-18F-DOPA is not decarboxylated in rat striatum, it is not a promising agent for the study of cerebral DOPA metabolism in humans by means of positron emission tomography.

Animals↗

PubMed1988

Asymptomatic striatal dopamine depletion: PET scans in unilateral MPTP monkeys.

In cynomolgus monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces irreversible clinical, chemical, and pathological alterations that are similar to those found in Parkinson's disease. Unilateral carotid injections of this toxin produce ipsilateral nigrostriatal dopamine depletion while sparing the contralateral dopaminergic pathways. In order to study the damage to the nigrostriatal dopamine system in asymptomatic animals after unilateral MPTP administration, positron emission tomography (PET) scans were performed with [18F]fluoro-L-dopa (6-FD). This study demonstrates that clinically asymptomatic MPTP lesions may be assessed in vivo using 6-FD and PET.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗