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Biomedical subjects

Thomas J Ruth

Publications and source records attributed to Thomas J Ruth.

18 recordsLinked to original sources
PubMed2006

Sequential versus nonsequential measurement of density and affinity of dopamine D2 receptors with [11C]raclopride: 2: effects of DAT inhibitors.

The multiple ligand concentration receptor assays (MLCRA) method allows, in a stable condition, reliable and reproducible measurements of the density and affinity of the dopamine (DA) D2 receptors with [11C]raclopride, using either a sequential method (two or more scans in one day) or a nonsequential method (two or more scans over days or weeks). We have shown that measurement of receptor density and affinity is also possible after an acute pharmacological challenge with methamphetamine and that both scanning protocols yield similar values. However, our attempts to measure receptor density and affinity after a pharmacological challenge with another class of drugs that lead to the same outcome, increase in synaptic DA concentrations, revealed opposite results with the two scanning methods: a decrease in receptor density with the sequential method and an increase in affinity with a nonsequential method. These results show the impact of the time-dependency of the effects of an 'acute' pharmacological challenge on MLCRA studies. A theoretical simulation is presented to account for the discrepancy in the sequential and nonsequential data. A possible alternate scanning paradigm is proposed to avoid the confounding effect of time variability of the endogenous ligand synaptic concentrations in the sequential condition.

Animals↗
PubMed2005

The influence of measurement uncertainties on the evaluation of the distribution volume ratio and binding potential in rat studies on a microPET R4: a phantom study.

In small animal positron emission tomography (PET) imaging, the injectable radiotracer dose is often limited by the tracer mass which, together with the tracer kinetics and scanner sensitivity, dictates the statistical quality of the time activity curves (TACs) used to extract biological parameters. We investigated the effect of measurement uncertainty on the determination of the distribution volume ratio (DVR) and binding potential (BP) as estimated using the tissue input Logan (DVR(L), BP(L)) and the ratio (DVRr, BPr) methods for two tracers, with the Concorde microPET R4 camera. Parameters' coefficients of variation (COV) were estimated from a combination of rat and phantom data. For 11C-dihydrotetrabenazine, the COV was 11% for the BP(L) and 13.4% for the BPr when using TACs obtained from individual regions of interest (ROIs) and segmented attenuation correction. The COVs were reduced to 7.5% (BP(L)) and 8.6% (BPr) when the striatal and cerebellar TACs were estimated as averages of 3 and 2 ROIs respectively. Results obtained for 11C-methylphenidate (MP) yielded approximately 30% higher COVs. With measured attenuation correction, the COVs were on average 100% higher. The presented method can be used to examine the contribution of a variety of imaging conditions to the uncertainty of biologically meaningful parameters.

Affinity Labels↗
PubMed2004

Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias.

Peak-dose dyskinesias are abnormal movements that usually occur 1 h after oral administration of levodopa, and often complicate chronic treatment of Parkinson's disease. We investigated by PET with [11C]raclopride whether Parkinson's disease progression modifies the striatal changes in synaptic dopamine levels induced by levodopa administration, and whether this modification, if present, could have an impact on the emergence of dyskinesias. We found that, 1 h after oral administration of standard-release 250/25 mg of levodopa/carbidopa, levodopa-induced increases in synaptic dopamine levels (as estimated by striatal changes in [11C]raclopride binding potential) correlated positively with duration of Parkinson's disease symptoms (for the caudate nucleus, r = 0.79, P < 0.001; for the putamen, r = 0.88, P < 0.0001). Patients with peak-dose dyskinesias had larger 1-h increases in synaptic dopamine levels than stable responders, but there were no between-group differences in [11C]raclopride binding 4 h post-levodopa. The corresponding (time x group) interaction term in the repeated measures analysis of covariance was significant, even after adjusting for between-group differences in duration of Parkinson's disease symptoms (for the caudate nucleus, P = 0.030; for the putamen, P = 0.021). Our results indicate that, at the synaptic level, an identical dose of levodopa induces increasingly larger 1-h changes in dopamine levels as Parkinson's disease progresses. Large levodopa-induced increases in synaptic dopamine concentration can lead to dramatic changes in receptor occupancy, which may be responsible for the emergence of peak-dose dyskinesias in Parkinson's disease.

Aged↗
PubMed2004

Lack of regional selectivity during the progression of Parkinson disease: implications for pathogenesis.

BACKGROUND: Dopamine terminal loss in the putamen of patients with Parkinson disease (PD) shows a regional heterogeneity, reflecting selective vulnerability of degenerating neurons to mechanisms of cell death. HYPOTHESIS: If the same pathogenic mechanisms are responsible for the onset and progression of PD, the regional selectivity of dopamine cell loss will be the same throughout the course of the disorder. OBJECTIVE: To investigate the regional selectivity of dopamine terminal loss during the progression of PD. PARTICIPANTS: We studied 67 patients with PD and 20 healthy subjects using positron emission tomography with [(11)C](+/-)dihydrotetrabenazine (DTBZ). RESULTS: Regional values of DTBZ binding potential (calculated as maximum specific binding [B(max)] divided by the equilibrium dissociation constant K(d)) against disease duration in the putamen of PD patients were best described by a multivariate exponential model with distinct parallel asymptotic values that were significantly (P<.001) different across 4 regions of the putamen. The extent of loss of DTBZ binding potential with disease progression during the clinical stage of PD (early vs late PD) was similar between the anterior (-33%, using early PD as the baseline) and posterior (-29%) putamen. In contrast, the extent of loss of DTBZ binding potential in early PD, which reflects the cumulated loss of DTBZ binding potential from the onset of the disorder (in healthy subjects vs those with early PD), was significantly (P<.001) lower in the posterior (-58%, using healthy subjects as the baseline) than the anterior (-42%) putamen. CONCLUSION: To the extent that DTBZ positron emission tomography provides an accurate estimate of loss of dopamine neurons, our findings suggest that the mechanisms responsible for the progression of PD may not be the same as those responsible for its onset.

Aged↗
PubMed2004

Studies of the mechanism of the in-loop synthesis of radiopharmaceuticals.

A series of experiments were performed to better understand the mechanism of the In-loop [11C]CH3I-methylation. The timing of [11C]CH3I delivery is critical for the high yield of radiolabeling since in-loop radioactivity trapping is reversible. Trapped radioactivity escapes faster from a Tefzel loop compared to a PEEK- or stainless steel loop. Up to 50% of delivered radioactivity may be concentrated at the loop origin (representing 8.1% of the total loop volume). A five-fold reduction of the reaction solvent volume and/or precursor amount may lead to a decrease of the product radiochemical yield either by lowering the in-loop radioactivity trapping or by diminishing conversion of [11C]CH3I into the product.

Carbon Radioisotopes↗
PubMed2004

Changes of dopamine turnover in the progression of Parkinson's disease as measured by positron emission tomography: their relation to disease-compensatory mechanisms.

An increase in dopamine turnover has been shown to occur early in Parkinson's disease (PD). This study investigated changes of dopamine turnover as a function of PD duration using the effective distribution volume (EDV) for dopamine, determined by positron emission tomography with 6-[18F]-fluoro-L-dopa, and compared them with changes in dopamine synthesis and storage ability, quantified with the fluorodopa uptake rate constant Ki. Six healthy subjects, 9 early PD patients (PD1), and 13 advanced PD patients (PD2) participated in the study. In the caudate, the Ki and EDV for PD1 were not significantly different from the normal values, whereas in the putamen Ki was 63% of normal and EDV was only 35%. Between PDI and PD2 the decline in EDV was higher than that for Ki (caudate 44% and putamen 46% for EDV vs. 21% and 34%, respectively, for Ki). Turnover was higher in the caudate than the putamen in controls, whereas the PD patients exhibited the reverse pattern. This comparison of changes in Ki and EDV as a function of disease progression indicates that a relatively slower decrease in dopamine synthesis and a relatively faster increase in turnover in early disease likely act as compensatory mechanisms, and that the clinical onset of PD reflects a global failure of dopaminergic compensatory mechanisms.

Brain↗
PubMed2003

Cellular and whole-plant chloride dynamics in barley: insights into chloride-nitrogen interactions and salinity responses.

The first analysis of chloride fluxes and compartmentation in a non-excised plant system is presented, examining ten ecologically pertinent conditions. The short-lived radiotracer couple (38)Cl/(39)Cl was used as a Cl(-) tracer in intact barley ( Hordeum vulgare L. cv. Klondike) seedlings, which were cultured and investigated under four external [Cl(-)], from abundant (0.1 mM) to potentially toxic (100 mM). Chloride-nitrogen interactions were investigated by varying N source (NO(3)(-) or NH(4)(+)) and strength (0.1 or 10 mM), in order to examine, at the subcellular compartmentation level, the antagonism, previously documented at the influx level, between Cl(-) and NO(3)(-), and the potential role of Cl(-) as a counterion for NH(4)(+) under conditions in which cytosolic [NH(4)(+)] is excessive. Cytosolic [Cl(-)] increased with external [Cl(-)] from 6 mM to 360 mM. Cl(-) influx, fluxes to vacuole and shoot, and, in particular, efflux to the external medium, also increased along this gradient. Efflux reached 90% of influx at the highest external [Cl(-)]. Half-times of cytosolic Cl(-) exchange decreased between high-affinity and low-affinity influx conditions. The relationship between cytosolic [Cl(-)] and shoot flux indicated the presence of a saturable low-affinity transport system ("SLATS") responsible for xylem loading of Cl(-). N source strongly influenced Cl(-) flux to the vacuole, and moderately influenced Cl(-) influx and shoot flux, whereas efflux and half-time were insensitive to N source. Cytosolic pool sizes were not strongly or consistently influenced by N source, indicating the low potential for Cl(-) to act as a counterion to hyperaccumulating NH(4)(+). We discuss our results in relation to salinity responses in cereals.

Chlorides↗
PubMed2003

[11C]DTBZ-PET correlates of levodopa responses in asymmetric Parkinson's disease.

Levodopa effectively improves motor symptoms of Parkinson's disease. However, the beneficial effects of levodopa often erode over time with the emergence of response fluctuations. Although these response changes have been recognized from the early levodopa era, their mechanisms remain poorly understood. We investigated the role of dopamine (DA) terminal loss in the development of motor fluctuations by employing PET with [11C](+/-)dihydrotetrabenazine ([11C]DTBZ) as an in vivo marker for DA nerve terminals. Levodopa response was characterized by analysing the time-response curve to a single dose of levodopa with a finger-tapping test. PET scans were performed in 11 patients with asymmetric Parkinson's disease (age: 61.12 +/- 7.97 years; duration of Parkinson's disease: 10.55 +/- 4.53 years; mean +/- SD). Each patient performed finger-tapping tests for up to 5 h after taking a therapeutic dose of levodopa. Results showed significantly lower [11C]DTBZ binding potential (BP; Bmax/Kd) and baseline tapping rates on the more affected putamen and corresponding body side, respectively, than on the other (P = 0.003 for the former, P = 0.013 for the latter). Among the variables describing the time-response curve, the duration and early decay time were significantly shorter on the more affected side (P = 0.051 and P = 0.021, respectively). Latency to the onset and latency to 50% Emax (the magnitude of the levodopa response) were significantly longer on the more-affected side (P = 0.013 and P = 0.004, respectively). Emax was not significantly different between the two sides. The asymmetry (difference from the more affected to less affected side) of [11C]DTBZ BP in the putamen showed a highly significant correlation with the corresponding asymmetry of the estimated EC50 (levodopa concentration producing 50% of the maximal response; P = 0.022; r = -0.727), a marginally significant correlation with that of latency to the onset (P = 0.065; r = -0.583) and no significant correlation with that of the magnitude, duration or early decay time. This pattern of changes in levodopa response from the less affected to more affected side was similar to that from stable to fluctuating responders except for the latency to onset. These findings suggest a pathogenetic role for DA terminal loss in the development of motor fluctuations. However, the absence of a significant correlation between the early decay of levodopa response and DA terminal density suggests that DA terminal loss alone cannot account for the development of motor fluctuations. Therefore, our study suggests that both levodopa treatment and DA terminal loss contribute to the pathogenesis of motor fluctuations.

Aged↗
PubMed2003

Age and severity of nigrostriatal damage at onset of Parkinson's disease.

The clinical evolution of Parkinson's disease (PD) is known to be partly dependent on the age of onset. For example, motor complications associated with chronic dopaminomimetic treatment occur more often in younger patients. However, few attempts have been made to characterize the functional pathological differences underlying this age effect. We investigated the relationship between age and severity of nigrostriatal damage at onset of PD. Twenty patients with early PD (symptom duration <or=5 years) with onset before age 50 (n = 10) and with onset after age 50 (n = 10) were studied. The two groups were compared with respect to severity of nigrostriatal damage as evaluated by positron emission tomography (PET) scanning with 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ), and d-threo-[(11)C]methylphenidate ([(11)C]MP). We found no significant differences between younger- and older-onset PD patients with regard to any of the three presynaptic markers. For putamen, the P-values corresponding to the different PET measurements ranged from P = 0.34 ([(18)F]-dopa) to P = 0.79 ([(11)C]DTBZ). However, after adjusting for treatment and PD duration, regression analysis showed that [(18)F]-dopa uptake correlated positively with age of onset (r = 0.59; P = 0.010). No correlation was found between [(11)C]DTBZ and [(11)C]MP binding potentials and age of onset (P = 0.26 and P = 0.90, respectively). These data suggest that age-of-onset-dependent differences in clinical evolution are not likely to reflect early differences in nigrostriatal pathology in PD. Age-related differences in [(18)F]-dopa uptake may be related to changes in dopamine turnover.

Age of Onset↗
PubMed2003

VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET.

Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[(11)C]methylphenidate ([(11)C]MP) and 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), and [(11)C]raclopride were also used in the study. We found increased [(11)C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [(11)C]MP binding potential or [(18)F]-dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [(11)C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [(11)C]DTBZ binding likely reflects the dramatic decrease in the intravesicular concentration of dopamine that occurs in DRD; upregulation of vesicular monoamine transporter type 2 (VMAT2) expression may also contribute. Our findings suggest that the striatal expression of VMAT2 (as estimated by [(11)C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes (i.e., sequestration and release from the cell of potential toxic products), in addition to its importance for the quantal release of monoamines.

Adolescent↗
PubMed2002

Dopamine release in human ventral striatum and expectation of reward.

Using the ability of [11C]raclopride to compete with dopamine for D(2)/D(3) receptors, we investigated by positron emission tomography the effect of placebo (saline) injection on dopamine release in the ventral striatum of patients with Parkinson's disease. We found evidence for placebo-induced dopamine release of similar magnitude to that reported in healthy volunteers after amphetamine administration. However, in contrast to the dorsal striatum, there were no differences in [11C]raclopride binding potential changes between patients who experienced the reward (those who reported placebo-induced clinical benefit) and those who did not. We conclude that the release of dopamine in the ventral striatum (nucleus accumbens) is related to the expectation of reward and not to the reward itself. These observations have potential implications for the treatment of drug addiction.

Antiparkinson Agents↗
PubMed2002

In vivo receptor assay with multiple ligand concentrations: an equilibrium approach.

The ligand-receptor binding potential determined by PET studies at high ligand-specific radioactivity reflects both the receptor density and ligand-receptor affinity. This ambiguity has been resolved by various methods based on the administration of multiple unlabeled ligand concentrations. The authors aimed to implement and refine an approach to multiple ligand concentration receptor assay that combined maximum simplicity and a minimum of assumptions and model dependence that would nonetheless reliably distinguish density from affinity effects. The approach uses administration by bolus followed by infusion to obtain a true equilibrium between bound ligand and the other components of the ligand concentration, and does not require measurements of ligand in blood plasma. Four approaches to the optimization of the desired density and affinity parameters from the measured equilibrium data were implemented and compared in the analysis of raclopride studies performed in both normal control and MPTP-lesioned nonhuman primates. The authors conclude that the method is simple enough for routine use and yet reliable enough to apply in ongoing studies of both chronic and acute drug effects in the dopamine system.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Assessment of cancer-associated biomarkers by positron emission tomography: advances and challenges.

Positron emission tomography (PET) provides a powerful means to non-invasively image and quantify protein expression and biochemical changes in living subjects at nano- and picomolar levels. As the field of molecular imaging develops, and as advances in the biochemistry, pharmacology, therapeutics, and molecular biology of disease are made, there is a corresponding increase in the number of clinically relevant, novel disease-associated biomarkers that are brought to the attention of those developing imaging probes for PET. In addition, due to the high specificity of the PET radiotracers being developed, there is a demand for PET cameras with higher sensitivity and resolution. This manuscript reviews advances over the past five years in clinical and pre-clinical PET instrumentation and in new PET probes and imaging methods associated with the latest trends in the molecular imaging of cancer. Included in the PET tracer review is a description of new radioligands for steroid receptors, growth factor receptors, receptor tyrosine kinases, sigma receptors, tumor-associated enzymes, gene reporter probes, markers for tumor hypoxia and metabolism, and sites associated with angiogenesis and cellular proliferation. The use of PET imaging in drug development, including the monitoring of cancer chemotherapy, also is discussed.

Biomarkers, Tumor↗
PubMed2002

PET study of the effects of valproate on dopamine D(2) receptors in neuroleptic- and mood-stabilizer-naive patients with nonpsychotic mania.

OBJECTIVE: A previous study reported a higher than normal density of dopamine D(2) receptors in psychotic mania but not in nonpsychotic mania. The purpose of this study was to further examine D(2) receptor density in a larger sample of nonpsychotic manic patients by using positron emission tomography (PET) and [(11)C]raclopride. METHOD: Thirteen neuroleptic- and mood- stabilizer-naive patients with DSM-IV mania without psychotic features and 14 healthy comparison subjects underwent [(11)C]raclopride PET scans. Of the 13 patients, 10 were treated with divalproex sodium monotherapy. PET scans were repeated 2-6 weeks after commencement of divalproex sodium. D(2) receptor binding potential was calculated by using a ratio method with the cerebellum as the reference region. RESULTS: The [(11)C]raclopride D(2) binding potential was not significantly different in manic patients than in the comparison subjects in the striatum. Treatment with divalproex sodium had no significant effect on the [(11)C]raclopride D(2) binding potential in manic patients. There was no correlation between the D(2) binding potential and manic symptoms before or after treatment. CONCLUSIONS: These results suggest that D(2) receptor density is not altered in nonpsychotic mania and that divalproex sodium treatment does not affect D(2) receptor availability.

Adolescent↗
PubMed2002

PET study of [(18)F]6-fluoro-L-dopa uptake in neuroleptic- and mood-stabilizer-naive first-episode nonpsychotic mania: effects of treatment with divalproex sodium.

OBJECTIVE: Although dopaminergic hyperactivity has been implicated in mania, the precise location in the brain of the abnormality is unclear. This study assessed presynaptic dopamine function in neuroleptic- and mood-stabilizer-naive nonpsychotic first-episode manic patients before and after treatment with divalproex sodium by measuring [(18)F]6-fluoro-L-dopa ([(18)F]DOPA) uptake in the striatum with positron emission tomography (PET). METHOD: Thirteen patients with DSM-IV bipolar I disorder, manic episode, and 13 healthy comparison subjects underwent [(18)F]DOPA PET scans. Ten of the 13 patients had repeat PET scans 2-6 weeks after beginning treatment with divalproex sodium monotherapy. [(18)F]DOPA uptake rate constants (K(i) values) in the striatum were calculated by using graphical analysis with activity from the occipital cortex as the input function. RESULTS: No significant differences in [(18)F]DOPA uptake rate constants in the striatum were found between the manic patients and the comparison subjects. After treatment with divalproex sodium, [(18)F]DOPA rate constants were significantly reduced in the patients and were lower in the patients than in the comparison subjects. CONCLUSIONS: Although presynaptic dopamine function as reflected by [(18)F]DOPA uptake is not altered in mania, presynaptic dopamine function in manic patients was lower after treatment with divalproex sodium.

Adult↗