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Biomedical subjects

Thomas J Ruth

Publications and source records attributed to Thomas J Ruth.

At least 19 recordsLinked to original sources
PubMed2006

Quantitative micro positron emission tomography (PET) imaging for the in vivo determination of pancreatic islet graft survival.

Islet transplantation is an attractive approach for treating type-1 diabetes, but there is a massive loss of transplanted islets. It is currently only possible to estimate islet mass indirectly, through measurement of circulating C-peptide and insulin levels. This type of estimation, however, is not sufficiently sensitive or reproducible for follow-up of individuals who have undergone islet transplantation. Here we show that islet graft survival could be assessed for 1 month in diabetic NOD mice using 9-(4-[(18)F]-fluoro-3-hydroxymethylbutyl)guanine ([(18)F]FHBG)-positron emission tomography (PET) technology, the PET signal reflecting insulin secretory capacity of transplanted islets. Expression of the gene encoding viral interleukin-10 (vIL-10), was measurable in real time with PET scanning. Additionally, we addressed the clinical potential of this approach by visualizing transplanted islets in the liver, the preferred clinical transplantation site. We conclude that quantitative in vivo PET imaging is a valid method for facilitating the development of protocols for prolonging islet survival, with the potential for tracking human transplants.

Animals↗
PubMed2006

Oral methylphenidate fails to elicit significant changes in extracellular putaminal dopamine levels in Parkinson's disease patients: positron emission tomographic studies.

In this study, we assessed the changes of endogenous dopamine (DA) levels in response to methylphenidate in 5 patients with idiopathic Parkinson's disease (PD) and 6 healthy controls. Three-dimensional positron emission tomography was performed with the D2 receptor antagonist [11C]raclopride (RAC) at baseline and 1 hour following the administration of oral methylphenidate (0.8 mg/kg) to assess changes in dopamine levels indirectly. Oral methylphenidate produced no significant change in extracellular DA levels in the putamen, as estimated by comparing changes in RAC binding at baseline and 1 hour following its administration in PD subjects and healthy controls. However, there were small changes in RAC binding of opposite direction in caudate and ventral striatal regions compared between the two groups. Although there was no consistent improvement in motor function in the PD group, some patients did experience a subjective high in response to methylphenidate (MP). Failure of oral MP to alter extracellular DA levels in putamen could result from degeneration of presynaptic dopaminergic terminals, with consequent severe reductions in the levels of endogenous DA and dopamine transporter in PD subjects. Our data provide in vivo neurochemical support for the lack of clinical efficacy following MP in PD patients and are also in keeping with reduced DA release following amphetamine in PD subjects.

Administration, Oral↗
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

Effect of age on markers for monoaminergic neurons of normal and MPTP-lesioned rhesus monkeys: a multi-tracer PET study.

The binding of three tracers for monoaminergic terminals was mapped in the brain of healthy young (N=6) and healthy old rhesus monkeys (N=4), aged monkeys with mild unilateral intracarotid MPTP lesions (N=3), and monkeys of intermediate age with severe systemic MPTP lesions (N=6). The ligand for monoaminergic vesicles (+)-[(11)C]dihydrotetrabenazine (+DTBZ) had a mean binding potential (pB) of 1.4 in striatum of the healthy young monkeys, which was reduced by 20% in putamen of the old monkeys. The catecholamine transporter ligand (+)-[(11)C]methylphenidate (+MP) had a mean pB of 1.3 in striatum of the young monkeys, which was reduced by 40% in caudate and putamen of the old monkeys. The DOPA decarboxylase substrate [(18)F]fluoro-l-DOPA (FDOPA) had a mean decarboxylation coefficient (k(3)(S)) of 0.4 h(-1) in striatum of the young group, and was not significantly reduced in the aged group. Of the three ligands, only +DTBZ pB was significantly reduced in striatum of the small group of animals with mild unilateral lesions. In the group with systemic MPTP lesions, the mean reduction of the binding of the three ligands was 80% in the caudate and putamen. However, the decline in +MP pB in the ventral striatum (-75%) exceeded the declines of +DTBZ pB and FDOPA k(3)(S) in that region (-65%), suggesting that compensatory down-modulation of uptake sites may occur in the striatal regions with the least dopamine depletion. Binding of all three ligands was reduced by 50% in the anterior cingulate cortex and in the thalamus, suggesting toxicity of MPTP for extrastriatal catecholamine innervations. +DTBZ binding in the hypothalamus, presumably mainly in serotonin fibers, was unaffected by systemic MPTP treatment. Of the three tracers, +DTBZ was most sensitive for detecting MPTP-induced dopamine depletion in monkey striatum.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Arylfluoroborates and alkylfluorosilicates as potential PET imaging agents: high-yielding aqueous biomolecular 18F-labeling.

Organometalloid compositions of silicon and boron permit rapid, high-yielding, one-step radiolabeling of a covalently linked protein ligand (biotin) under aqueous conditions to give the corresponding alkyltetrafluorosilicates and aryltrifluoroborate salts. Biotin was chosen as a test ligand for protein targeting because of its quantitative interaction with avidin, which in turn allowed us to calculate fluoridation yields that approach 80-100%. The silicate was found to be moderately stable to hydrolysis, whereas the borate appears to be so stable that its hydrolytic decomposition was not readily measured. With the stability of both compounds ascertained, this work describes a novel and robust radiolabeling method that may find use in the development of positron emission tomography radiopharmaceuticals.

Boron↗
PubMed2005

PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation.

Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa (18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(+/-)-dihydrotetrabenazine (11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate (11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.

Adult↗
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↗
PubMed2005

A positron emission tomography study of the effects of treatment with valproate on brain 5-HT2A receptors in acute mania.

OBJECTIVE: To examine the effects of treatment with valproate on brain 5-HT2A receptors in acute manic patients using positron emission tomography (PET) and [18F]-setoperone. METHODS: Patients with DSM-IV bipolar I disorder-manic episode were recruited. Patients were drug free or drug naïve at the time of baseline PET scan. All patients were treated with valproate and one patient received lithium in addition to valproate for 3-5 weeks following which they had a post-treatment PET scan. The effect of treatment on brain 5-HT2A receptor binding was determined using statistical parametric mapping (SPM) and region of interest (ROI) analyses. Of the 12 manic patients recruited, seven patients had both baseline and post-treatment PET scans. RESULTS: All seven patients improved with treatment and were in remission at the time of the second PET scan. Both SPM and ROI analyses showed that treatment with mood stabilizers had no significant effect on brain 5-HT2A receptor binding in manic patients. CONCLUSION: This study suggests that changes in brain 5-HT2A receptors are not involved in the antimanic effects of mood stabilizers however, we cannot exclude the possibility of 5-HT2A receptor involvement in down-stream signaling pathways.

Acute Disease↗
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↗