Abstract: Since the initial results of the DATATOP study, considerable effort has been devoted over the past 20 years to test neuroprotective therapies for Parkinson's disease (PD). Two trials (CALM-PD-CIT and REAL-PET studies) used neuroimaging dopamine changes as a surrogate marker for PD progression, and concluded that pramipexole and ropinirole could have a neuroprotective effect compared to levodopa. However, it should be recognized that all the presynaptic dopamine markers currently available for SPECT and PET studies are potentially subject to regulatory changes. Consequently, the results of these two trials can also be interpreted in terms of drug-related differences in dopamine regulation. More recently, the delayed-start design was applied to test whether rasagiline could have a neuroprotective effect in PD (ADAGIO study). Unfortunately, a major limitation of the delayed-start design is that, whenever the active treatment has a symptomatic effect, the blinding can be broken. This can lead to unequally-distributed placebo responses during phase 2, and is also a potential source of raters' biases. None of the trials on neuroprotective therapies for PD has yet provided solid evidence for neuroprotection.
Abstract: BACKGROUND: Brain serotonin(2) (5-hydroxytryptamine(2); 5-HT(2)) receptors were considered potential targets for therapeutic efficacy of electroconvulsive therapy (ECT), but pre-clinical studies showed that electroconvulsive shock up-regulates 5-HT(2) receptors in contrast to antidepressant medications, which down-regulate brain 5-HT(2) receptors. Positron emission tomography (PET) studies in individuals with depression confirmed that antidepressant medications reduce brain 5-HT(2) receptors, but the effects of ECT on these receptors in individuals with depression are unknown. AIMS: To determine if a course of ECT alters brain 5-HT(2) receptors in individuals with depression and whether such changes correlate with improvement in symptoms. METHOD: Fifteen people with major depression, refractory to antidepressant therapy and referred for a course of ECT, had an [18F]setoperone scan during baseline drug-free washout period and another after a course of ECT. We assessed changes in brain 5-HT(2) receptors with ECT and their relationship to therapeutic outcome. RESULTS: Widespread reduction in brain 5-HT(2) receptors was observed in all cortical areas with changes slightly more prominent in the right hemisphere. There was a trend for correlation between reduction in brain 5-HT(2) receptors in right parahippocampal gyrus, right lingual gyrus and right medial frontal gyrus, and improvement in depressive symptoms. CONCLUSIONS: Unlike in rodents, and similar to antidepressants, ECT reduces brain 5-HT(2) receptors in individuals with depression. The ability of ECT to further down-regulate brain 5-HT(2) receptors in antidepressant non-responsive individuals may explain its efficacy in those people with antidepressant refractory depression.
Abstract: CONTEXT: Expectations play a central role in the mechanism of the placebo effect. In Parkinson disease (PD), the placebo effect is associated with release of endogenous dopamine in both nigrostriatal and mesoaccumbens projections, yet the factors that control this dopamine release are undetermined. OBJECTIVE: To determine how the strength of expectation of clinical improvement influences the degree of striatal dopamine release in response to placebo in patients with moderate PD. DESIGN: Randomized, repeated-measures study with perceived expectation as the independent between-subjects variable. SETTING: University of British Columbia Hospital, Vancouver, British Columbia, Canada. Patients Thirty-five patients with mild to moderate PD undergoing levodopa treatment. Intervention Verbal manipulation was used to modulate the expectations of patients, who were told that they had a particular probability (25%, 50%, 75%, or 100%) of receiving active medication when they in fact received placebo. MAIN OUTCOME MEASURES: The dopaminergic response to placebo was measured using [11C]raclopride positron emission tomography. The clinical response was also measured (Unified Parkinson Disease Rating Scale) and subjective responses were ascertained using patient self-report. RESULTS: Significant dopamine release occurred when the declared probability of receiving active medication was 75%, but not at other probabilities. Placebo-induced dopamine release in all regions of the striatum was also highly correlated with the dopaminergic response to open administration of active medication. Whereas response to prior medication was the major determinant of placebo-induced dopamine release in the motor striatum, expectation of clinical improvement was additionally required to drive dopamine release in the ventral striatum. CONCLUSIONS: The strength of belief of improvement can directly modulate dopamine release in patients with PD. Our findings demonstrate the importance of uncertainty and/or salience over and above a patient's prior treatment response in regulating the placebo effect and have important implications for the interpretation and design of clinical trials.
Abstract: BACKGROUND: Although 5-hydroxytryptamine (5-HT) has been implicated in mania, the precise alterations in the 5-HT system remain elusive. AIMS: To assess brain 5-HT2 receptors in drug-free individuals experiencing a manic episode in comparison with healthy volunteers using positron emission tomography (PET). METHOD: Participants (n = 10) with DSM-IV bipolar I disorder-manic episode and healthy controls (n = 10) underwent [18F]-setoperone scans. The differences in 5-HT2 receptor binding potential between the two groups were determined using statistical parametric mapping (SPM) analysis. RESULTS: Age was a significant correlate with 5-HT2 receptor binding potential with a similar magnitude of correlation in both groups. The SPM analysis with age as a covariate showed that the individuals with current mania had significantly lower 5-HT2 receptor binding potential in frontal, temporal, parietal and occipital cortical regions, with changes more prominent in the right cortical regions compared with controls. CONCLUSIONS: This study suggests that brain 5-HT2 receptors are decreased in people with acute mania.
Abstract: Small animal positron emission tomography (PET) imaging allows in vivo quantification of lesion- or treatment-induced neurochemical changes in animal models of disease. Important for quantification are the kinetic modeling methods used to determine biologically-relevant parameters of tracer-tissue interaction. In this work, we evaluate modeling algorithms for the dopaminergic tracers (11)C-dihydrotetrabenazine (DTBZ), (11)C-methylphenidate (MP), and (11)C-raclopride (RAC), used to image the dopaminergic system in the unilateral 6-hydroxydopamine lesioned rat model of Parkinson's disease. For the presynaptic tracers, PET measures are compared with autoradiographic binding measurements using DTBZ and [(3)H]WIN 35,428 (WIN). We independently developed a new variant of the tissue-input Logan graphical modeling method, and compared its performance with the simplified Logan graphical method and the simplified reference tissue with basis functions method (SRTM), for region of interest (ROI) averaged time activity curves (TACs) and parametric imaging. The modified graphical method was found to be effectively unbiased by target tissue noise and has advantages for parametric imaging, while all tested methods were equivalent for ROI-averaged data.
Abstract: PURPOSE: Levodopa and dopamine (DA) agonist therapy are two common treatments for Parkinson's disease (PD). There is controversy about the effects of these treatments on disease progression and imaging markers. Here we used multi-tracer positron emission tomography imaging and a unilateral 6-hydroxydopamine (6-OHDA) rat model of PD to evaluate in vivo the effects of chronic levodopa and pramipexole treatments on measurements of vesicular monoamine transporter type 2 (VMAT2), dopamine transporter (DAT) levels, and on levodopa-induced changes in synaptic DA levels [Delta(DA)]. METHODS: Twenty-three unilaterally 6-OHDA lesioned rats underwent an (11)C-dihydrotetrabenazine (DTBZ, VMAT2 marker), an (11)C-methylphenidate (MP, DAT marker), and a double (11)C-raclopride (RAC, D(2)-type receptor marker) scan. They were assigned to three treatment groups: saline (N = 7), pramipexole (N = 8), and levodopa (N = 8). After 4 weeks of treatment, imaging was repeated. RESULTS: Results showed (1) a significant treatment effect on DTBZ, with pramipexole decreasing DTBZ binding compared to levodopa, (2) significant side and treatment-striatal side interaction effects for MP, indicating that levodopa tends to decrease MP binding compared to pramipexole, and (3) no treatment effect on Delta(DA). CONCLUSION: These data indicate that while chronic dopaminergic pharmacological treatment affects DTBZ and MP binding, it does not affect levodopa-induced changes in synaptic DA level.
Abstract: OBJECTIVES: To determine the impact of age-related decline in dopamine transporter (DAT) expression on motor function in the elderly. METHODS: About 33 normal individuals of a wide age range were scanned with PET employing d-threo-[(11)C]-methylphenidate (MP, a marker of DAT) and [(11)C]-dihydrotetrabenazine (DTBZ, that binds to the vesicular monoamine transporter Type 2). Motor function was assessed using the Purdue Pegboard Test (PPB). We analyzed the relationship between [(11)C]-MP and motor performance. RESULTS: Age ranged from 27- to 77-year old (mean +/- SD, 54.75 +/- 14.14). There was no age-related decline in binding potentials (BP) for [(11)C]-DTBZ. In contrast, [(11)C]-MP BP was inversely related to age in all striatal regions analyzed (caudate: reduction of 11.2% per decade, P < 0.0001, r = -0.86; putamen: reduction of 10.5% per decade, P < 0.0001, r = -0.80). A differential effect of [(11)C]-MP on PPB could be observed according to age group. There was a positive relation between the PPB and [(11)C]-MP in young individuals (coefficient = 13.56), whereas in individuals greater than 57 years this relationship was negative (coefficient = -19.53, P = 0.031). CONCLUSIONS: Our findings confirm prior observations of age-related DAT decline and suggest that this phenomenon is independent of changes in VMAT2. After the fifth decade of life, this reduction in DAT binding is associated with a motor performance comparable to mid-adult life. These findings imply that biochemical processes associated with healthy aging may offset the naturaldecline in motor function observed in the elderly.
Abstract: Studies showed that the dopamine (DA) transporter (DAT) modulates changes in levodopa-derived synaptic dopamine levels (Delta(DA)) in Parkinson's disease (PD). Here we evaluate the relationship between DAT and Delta(DA) in the 6-hydroxydopamine model of Parkinson's disease to investigate these mechanisms as a function of dopaminergic denervation and in relation to other denervation-induced regulatory changes. 27 rats with a unilateral 6-hydroxydopamine lesion (denervation approximately 20-97%) were imaged with (11)C-dihydrotetrabenazine (VMAT2 marker), (11)C-methylphenidate (DAT marker) and (11)C-raclopride (D2-type receptor marker). For denervation <75%Delta(DA) was significantly correlated with a combination of relatively preserved terminal density and lower DAT. For denervation <90%, Delta(DA) was significantly negatively correlated with DAT with a weaker dependence on VMAT2. For the entire data set, no dependence on pre-synaptic markers was observed; Delta(DA) was significantly positively correlated with (11)C-raclopride binding-derived estimates of DA loss. These findings parallel observations in humans, and show that (i) regulatory changes attempt to normalize synaptic DA levels (ii) a lesion-induced functional dependence of Delta(DA) on DAT occurs up to approximately 90% denervation (iii) for denervation < 75% relative lower DAT levels may relate to effective compensation; for higher denervation, lower DAT levels likely contribute to oscillations in synaptic DA associated with dyskinesias.
Abstract: Parkinson's disease is a heterogeneous disorder with multiple factors contributing to disease initiation and progression. Using serial, multi-tracer positron emission tomography imaging, we studied a cohort of 78 subjects with sporadic Parkinson's disease to understand the disease course better. Subjects were scanned with radiotracers of presynaptic dopaminergic integrity at baseline and again after 4 and 8 years of follow-up. Non-linear multivariate regression analyses, using random effects, of the form BP(ND)(t) or K(occ)(t) = a*e((-)(bt)(-d)(A) + c, where BP(ND) = tracer binding potential (nondispaceable), K(OCC) = tracer uptake constant a, b, c and d are regression parameters, t is the symptom duration and A is the age at onset, were utilized to model the longitudinal progression of radiotracer binding/uptake. We found that the initial tracer binding/uptake was significantly different in anterior versus posterior striatal subregions, indicating that the degree of denervation at disease onset was different between regions. However, the relative rate of decline in tracer binding/uptake was similar between the striatal subregions. While an antero-posterior gradient of severity was maintained for dopamine synthesis, storage and reuptake, the asymmetry between the more and less affected striatum became less prominent over the disease course. Our study suggests that the mechanisms underlying Parkinson's disease initiation and progression are probably different. Whereas factors responsible for disease initiation affect striatal subregions differently, those factors contributing to disease progression affect all striatal subregions to a similar degree and may therefore reflect non-specific mechanisms such as oxidative stress, inflammation or excitotoxicity.
Abstract: It has been suggested that dopamine derived from exogenous levodopa may not follow vesicular dynamics in Parkinson's disease (PD). Using a novel PET method based on the sensitivity of [(11)C]-dihydrotetrabenazine (DTBZ) binding to changes in vesicular dopamine levels, we show here that striatal [(11)C]-DTBZ binding decreases after levodopa administration in advanced PD, likely reflecting an increase in vesicular dopamine levels. Endogenous dopamine and exogenously derived dopamine seem to follow the same vesicular dynamics.
Abstract: OBJECTIVE: Dyskinesias are common in Parkinson disease (PD). Prior investigations suggest that dopamine (DA) terminals compensate for abnormal DA transmission. We verified whether similar adaptations could be related to the development of treatment-related complications. METHODS: Thirty-six patients with PD with motor fluctuations were assessed with PET using [(11)C]-d-threo-methylphenidate (MP) and [(11)C]-(+/-) dihydrotetrabenazine (DTBZ). The expression of DA transporter relative to DA nerve terminal density was estimated by determining the MP/DTBZ ratio. Age, treatment, and disease severity were also taken into account in the evaluation of our data. RESULTS: Twenty-seven of the 36 patients had dyskinesias. Nine individuals had motor fluctuations without dyskinesia. The two patient groups were comparable in terms of age, disease duration and severity, medication, and striatal MP and DTBZ binding potentials. The MP/DTBZ ratio in the caudate was not different between groups (nondyskinesia 1.54 +/- 0.36, dyskinesia 1.39 +/- 0.28; mean +/- SD, p = 0.23). Putaminal MP/DTBZ was decreased in individuals with dyskinesia (1.18 +/- 0.24), compared to those who had motor fluctuations without dyskinesia (1.52 +/- 0.24, p = 0.019). The relationship between putaminal MP/DTBZ ratio and the presence of dyskinesias was not altered after correcting for age, treatment, and measures of disease severity. CONCLUSIONS: This investigation supports the role of presynaptic alterations in the appearance of dyskinesias. Dopamine (DA) transporter downregulation may minimize symptoms by contributing to increased synaptic DA levels in early Parkinson disease, but at the expense of leading to increased extracellular DA catabolism and oscillating levels of DA. Such oscillations might ultimately facilitate the appearance of dyskinesias.
Abstract: In previous work, we described and validated a method of scatter correction for singles-mode transmission data using experimental preinjection data acquired with a dedicated rodent PET scanner. In the current work, we investigated the impact that our method has on the quantitative accuracy of small-animal PET. METHODS: This investigation had 3 stages. We first confirmed the general validity of our method by applying it to preinjection transmission data from a different imaging system (a larger dedicated primate scanner). For these data, we evaluated the accuracy of the reconstructed distributions of linear attenuation coefficients (mu-values). In the second stage, we applied our attenuation-map reconstruction and scatter correction procedure for postinjection transmission data acquired with the dedicated rodent scanner. For these studies, we investigated the quantitative accuracy of reconstructed emission images that use attenuation correction derived from postinjection transmission data. In the third stage, we compared our scatter correction method with 2 more commonly used alternatives (automated rescaling and segmentation of the attenuation-map images). RESULTS: For the primate scanner data, the average reconstructed mu-values with scatter correction were within 3% of the expected values for water and soft tissue, whereas uncorrected values were 19%-26% lower than their expected values. For the postinjection transmission studies, we found that the correct average mu-values and reconstructed activity concentrations consistent with well-counter measurements were obtained only when scatter correction and emission contamination correction were applied to the transmission data. We also found that our transmission scatter correction provides more accurate mu-values and better image quantification than either rescaling or segmentation. CONCLUSION: Using different imaging systems (primate and rodent) and different scanning protocols (before and after injection), we found that our transmission scatter correction is more accurate (for both reconstructed mu-values and activity concentrations) than the existing alternatives.
Abstract: OBJECTIVE: Little is known about the progression of dopaminergic dysfunction in LRRK2-associated Parkinson disease (PD). We sought to characterize the neurochemical progression with multitracer PET in asymptomatic members of parkinsonian kindred (family D, Western Nebraska) carrying LRRK2 (R1441C) mutation. METHOD: Thirteen family D subjects underwent PET scans of presynaptic dopaminergic integrity and five subjects were rescanned 2 to 3 years later. RESULTS: In subjects 8, 9 (mutation carriers), and 13 (genealogically at risk subject), there was a decline in PET markers over the course of the study that was significantly greater than the expected rate of decline in healthy controls. Reduced dopamine transporter binding was the earliest indication of subclinical dopaminergic dysfunction and progression to clinical disease was generally associated with the emergence of abnormal fluorodopa uptake. CONCLUSION: PET study of presymptomatic members of our LRRK2 kindred revealed dopaminergic dysfunction that progressed over time. This represents an ideal group to study the natural history of early disease and the potential effects of neuroprotective interventions.
Abstract: BACKGROUND AND AIM: In high-resolution emission tomography imaging, even small patient movements can considerably degrade image quality. The aim of this work was to develop a general approach to motion-corrected reconstruction of motion-contaminated data in the case of rigid motion (particularly brain imaging) which would be applicable to any PET scanner in the field, without specialized data-acquisition requirements. METHODS: Assuming the ability to externally track subject motion during scanning (e.g., using the Polaris camera), we proposed to incorporate the measured rigid motion information into the system matrix of the expectation maximization reconstruction algorithm. Furthermore, we noted and developed a framework to incorporate the additional effect of motion on modifying the attenuation factors. A new mathematical brain phantom was developed and used along with elaborate combined Simset/GATE simulations to compare the proposed framework with the cases of no motion correction. RESULTS AND CONCLUSION: Clear qualitative and quantitative improvements were observed when incorporating the proposed framework. The method is very practical to implement for any scanner in the field, not requiring any hardware modifications or access to the list-mode acquisition capability.
Abstract: With continuing improvements in spatial resolution of positron emission tomography (PET) scanners, small patient movements during PET imaging become a significant source of resolution degradation. This work develops and investigates a comprehensive formalism for accurate motion-compensated reconstruction which at the same time is very feasible in the context of high-resolution PET. In particular, this paper proposes an effective method to incorporate presence of scattered and random coincidences in the context of motion (which is similarly applicable to various other motion correction schemes). The overall reconstruction framework takes into consideration missing projection data which are not detected due to motion, and additionally, incorporates information from all detected events, including those which fall outside the field-of-view following motion correction. The proposed approach has been extensively validated using phantom experiments as well as realistic simulations of a new mathematical brain phantom developed in this work, and the results for a dynamic patient study are also presented.
Abstract: We present an analytical scatter correction, based upon the Klein-Nishina formula, for singles-mode transmission data in positron emission tomography (PET) and its implementation as part of an iterative image reconstruction algorithm. We compared our analytically-calculated scatter sinogram data with previously validated simulation data for a small animal PET scanner with 68 Ge (a positron emitter) and 57 Co (approximately 122-keV photon emitter) transmission sources using four different phantom configurations (three uniform water cylinders with radii of 25, 30, and 45 mm and a nonuniform phantom consisting of water, Teflon, and air). Our scatter calculation correctly predicts the contribution from single-scattered (one incoherent scatter interaction) photons to the simulated sinogram data and provides good agreement for the percent scatter fraction (SF) per sinogram for all phantoms and both transmission sources. We then applied our scatter correction as part of an iterative reconstruction algorithm for PET transmission data for simulated and experimental data using uniform and nonuniform phantoms. For both simulated and experimental data, the reconstructed linear attenuation coefficients (mu-values-values) agreed with expected values to within 4% when scatter corrections were applied, for both the 68 Ge and 57 Co transmission sources. We also tested our reconstruction and scatter correction procedure for two experimental rodent studies (a mouse and rat). For the rodent studies, we found that the average mu-values for soft-tissue regions of interest agreed with expected values to within 4%. Using a 2.2-GHz processor, each scatter correction iteration required between 6-27 min of CPU time (without any code optimization) depending on the phantom size and source used. This extra calculation time does not seem unreasonable considering that, without scatter corrections, errors in the reconstructed mu-values were between 18%-45% depending on the phantom size and transmission source used.
Abstract: This is the first in vivo determination of the vesicular monoamine transporter (VMAT2) density (B(max)) and ligand-transporter affinity (K(d)(app)) in six unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats using micro-positron emission tomography (PET) imaging with [(11)C]-(+)-alpha-dihydrotetrabenazine (DTBZ). A multiple ligand concentration transporter assay (MLCTA) was used to determine a B(max) value of 178+/-32 pmol/mL and a K(d)(app) of 47.7+/-9.3 pmol/mL for the non-lesioned side and 30.52+/-5.84 and 43.4+/-15.52 pmol/mL for the lesioned side, respectively. While B(max) was significantly different between the two sides, no significant difference was observed for the K(d)(app). In addition to demonstrating the feasibility of in vivo Scatchard analysis in rats, these data confirm the expectation that a 6-OHDA lesion does not affect the affinity; a much simpler binding potential (BP) measure can thus be used as a marker of lesion severity (LS) in this rat model of Parkinson's disease. A transporter occupancy curve demonstrated negligible transporter occupancy ( approximately 1%) at a specific activity (SA) of 1100 nCi/pmol (assuming an injected dose of 100 microCi/100 g), while 10% occupancy was estimated at 100 nCi/pmol. An indirect measurement indicated that the degree of occupancy as a function of SA is independent of LS. Finally, BP measurement reproducibility was assessed and found to be 11%+/-7% for the healthy and 8%+/-12% for the lesioned side. Quantitative PET results can thus be obtained even for severely lesioned animals with the striatum on one side not clearly visible provided accurate image analysis methods are used.
Abstract: AIMS/HYPOTHESIS: Insulin controls glucose metabolism via multiple signalling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway in muscle and adipose tissue. The protein/lipid phosphatase Pten (phosphatase and tensin homologue deleted on chromosome 10) attenuates PI3K signalling by dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate generated by PI3K. The current study was aimed at investigating the effect of haploinsufficiency for Pten on insulin-stimulated glucose uptake. MATERIALS AND METHODS: Insulin sensitivity in Pten heterozygous (Pten(+/-)) mice was investigated in i.p. insulin challenge and glucose tolerance tests. Glucose uptake was monitored in vitro in primary cultures of myocytes from Pten(+/-) mice, and in vivo by positron emission tomography. The phosphorylation status of protein kinase B (PKB/Akt), a downstream signalling protein in the PI3K pathway, and glycogen synthase kinase 3beta (GSK3beta), a substrate of PKB/Akt, was determined by western immunoblotting. RESULTS: Following i.p. insulin challenge, blood glucose levels in Pten(+/-) mice remained depressed for up to 120 min, whereas glucose levels in wild-type mice began to recover after approximately 30 min. After glucose challenge, blood glucose returned to normal about twice as rapidly in Pten(+/-) mice. Enhanced glucose uptake was observed both in Pten(+/-) myocytes and in skeletal muscle of Pten(+/-) mice by PET. PKB and GSK3beta phosphorylation was enhanced and prolonged in Pten(+/-) myocytes. CONCLUSIONS/INTERPRETATION: Pten is a key negative regulator of insulin-stimulated glucose uptake in vitro and in vivo. The partial reduction of Pten due to Pten haploinsufficiency is enough to elicit enhanced insulin sensitivity and glucose tolerance in Pten(+/-) mice.
Abstract: The attenuation corrections factors (ACFs), which are necessary for quantitatively accurate PET imaging, can be obtained using singles-mode transmission scanning. However, contamination from scatter is a largely unresolved problem for these data. We present an extension of the Monte Carlo simulation tool, GATE, for singles-mode transmission data and its validation using experimental data from the microPET R4 and Focus 120 scanners. We first validated our simulated PET scanner for coincidence-mode data where we found that experimental resolution and scatter fractions (SFs) agreed well for simulations that included positron interactions and scatter in the source material. After modifying GATE to model singles-mode data, we compared simulated and experimental ACFs and SFs for three different sized water cylinders using 57Co (122 keV photon emitter) and 68Ge (positron emitter) transmission sources. We also propose a simple correction for a large background contamination we identified in the 68Ge singles-mode data due to intrinsic 176Lu radioactivity present in the detector crystals. For simulation data, the SFs agreed to within 1.5% and 2.5% of experimental values for background-corrected 68Ge and 57Co transmission data, respectively. This new simulation tool accurately models the photon interactions and data acquisition for singles-mode transmission scans.
Abstract: We describe an ordinary Poisson list-mode expectation maximization (OP-LMEM) algorithm with a sinogram-based scatter correction method based on the single scatter simulation (SSS) technique and a random correction method based on the variance-reduced delayed-coincidence technique. We also describe a practical approximate scatter and random-estimation approach for dynamic PET studies based on a time-averaged scatter and random estimate followed by scaling according to the global numbers of true coincidences and randoms for each temporal frame. The quantitative accuracy achieved using OP-LMEM was compared to that obtained using the histogram-mode 3D ordinary Poisson ordered subset expectation maximization (3D-OP) algorithm with similar scatter and random correction methods, and they showed excellent agreement. The accuracy of the approximated scatter and random estimates was tested by comparing time activity curves (TACs) as well as the spatial scatter distribution from dynamic non-human primate studies obtained from the conventional (frame-based) approach and those obtained from the approximate approach. An excellent agreement was found, and the time required for the calculation of scatter and random estimates in the dynamic studies became much less dependent on the number of frames (we achieved a nearly four times faster performance on the scatter and random estimates by applying the proposed method). The precision of the scatter fraction was also demonstrated for the conventional and the approximate approach using phantom studies.
Abstract: An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.
Abstract: OBJECTIVE: To investigate the role of the dopamine transporter (DAT) in the regulation of synaptic dopamine (DA) levels in Parkinson's disease and its role in the preservation of DA in presynaptic terminals. METHODS: Ten Parkinson's disease patients (age, 62.9 +/- 9.5 years; Unified Parkinson's Disease Rating Scale motor score in "off" state, 28.5 +/- 8.2) underwent positron emission tomography with (11)C-methylphenidate (MP, a DAT marker), (11)C-dihydrotetrabenazine (a vesicular monoamine transporter 2 marker), and (18)F-fluorodopa, leading to the determination of the MP and (11)C-dihydrotetrabenazine binding potentials (BPs) and the effective distribution volume for (18)F-fluorodopa, the inverse of DA turnover. Seven patients also underwent positron emission tomography with (11)C-raclopride before and 1 hour after levodopa administration to estimate levodopa-induced changes in synaptic DA concentration. RESULTS: We found a significant positive correlation between effective distribution volume and BP(MP) (r = 0.93; p < 0.001) and a significant negative correlation between changes in synaptic DA concentration and BP(MP) (r = -0.93; p = 0.04), independent of disease severity and duration. INTERPRETATION: These data show that in Parkinson's disease, greater DAT levels are directly associated with lower DA turnover and lower changes in synaptic DA concentration. This implies that an important functional role of DAT is to maintain relatively constant synaptic DA levels and to preserve DA in nerve terminals. A decrease in DAT, although potentially serving as a compensatory mechanism in early disease, may ultimately result in increased DA turnover and higher oscillations in synaptic DA concentration, thereby possibly predisposing toward the occurrence of motor complications as disease progresses.
Abstract: A review of recent advances in brain imaging using positron emission tomography (PET) is presented in this article. Some properties of the high-resolution research tomograph are described as examples of state-of-the-art PET instrumentation. A summary of current research topics in image reconstruction and quantification is given, with emphasis on the requirements of brain dynamic imaging. A brief overview of image analysis methods is presented, together with some examples of the contributions of quantitative PET imaging to the current understanding of brain function and disease. PET findings must be evaluated in the context of clinical observations and complemented by other imaging modalities whenever possible to ensure a proper interpretation of the data.
Abstract: Treatment-related motor complications in Parkinson's disease have been previously linked to disease-induced pre-synaptic alterations: dopaminergic denervation and changes in dopamine (DA) release patterns. The occurrence of such complications is also known to be partly dependent on the age of disease onset, occurring more frequently in patients with disease onset at a younger age. Using positron emission tomography (PET) and 4-h-long 18F-fluorodopa (FD) scans we have investigated in vivo an age dependence of disease-induced changes in DA turnover as a possible contributing factor to the age-related differences in treatment-related motor complications. We evaluated the relative changes in DA turnover (measured by its direct inverse, effective DA distribution volume--EDV) and DA synthesis and vesicular storage capacity (quantified by the plasma input uptake rate constant Ki) in Parkinson's disease patients as a function of age (n = 27, age range 38-79 years). After correcting for disease severity, a significant negative correlation was found between age and magnitude of disease-induced decrease in EDV and in Ki in the putamen (P < 0.001, P = 0.02, respectively). However, the difference between the disease-induced decrease in EDV and that in Ki also exhibited an age dependence (P < 0.001), indicating a relatively higher disease-induced increase in DA turnover (inverse of EDV) compared with the decrease in DA synthesis and storage rate in patients of younger age compared with older patients. This finding implies that DA turnover in younger-onset patients undergoes a relatively greater alteration and thus likely contributes to a greater imbalance between DA synthesis, storage and release, which could lead to larger swings in synaptic DA levels. It has indeed been suggested on theoretical grounds that such imbalance may contribute to the greater propensity for motor fluctuations. These results provide one possible explanation for the age-dependent occurrence of complications and support the existence of a pre-synaptic contribution to the occurrence of motor complications.
Abstract: PURPOSE: In the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), it is important to determine lesion severity. This evaluation can be performed in vivo, through evaluation of dopamine (DA)-dependent motor function or with small animal positron emission tomography (microPET), or at postmortem, by examining markers for DA neurons. PROCEDURES: Rats were given mild or severe unilateral 6-OHDA lesions, scanned with the tracer [(11)C](+/-)dihydrotetrabenazine ([(11)C]DTBZ), and tested on a tapered/ledged beam-walking task. At postmortem, autoradiography was performed with [(11)C]DTBZ. RESULTS: Autoradiography was significantly correlated with microPET and behavioral scores, whereas the microPET and behavioral data were not significantly correlated. CONCLUSIONS: This study shows that behavioral analysis, microPET, and autoradiography are all good tools for measuring the integrity of the DA system, and demonstrates the utility of the tapered/ledged beam-walking test to screen for lesion severity, as well as the importance of including postmortem analysis after in vivo imaging studies.
Abstract: 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.
Abstract: 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.
Abstract: Huntington's disease (HD) is a progressive disorder with no known cure. We report two-year postoperative positron emission tomography (PET) data from 7 HD patients who underwent intrastriatal fetal transplantation. Patients showed widespread reductions in glucose uptake with no significant change over 2 years. Dopamine receptor binding was significantly reduced in HD striatum. D1 binding did not change significantly following transplantation, but there was a significant loss of D2 binding. These findings may reflect loss of graft viability and/or disease progression. There was no significant relationship between changes in PET and clinical function. In summary, there was no benefit from transplantation.
Abstract: Significant technological advancements required for imaging physiological function in small animals have been achieved in the last few years. Dedicated small animals PET scanners are now achieving resolutions that approach the one obtainable by autoradiographic methods, while still maintaining enough detection sensitivity to reliably measure biologically relevant parameters such as binding potentials or rate constants. Such developments have enabled researchers to explore in-vivo rodent models of human disease. The future in imaging now lies in the development of multi-modality imaging approaches, while the big challenge in the next few years will be for the chemists to develop tracers that are more specific and reflective of the functional condition under investigation, while miniaturizing the chemical synthesis related instrumentation.
Abstract: 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.
Abstract: Modern high-resolution PET is now more than ever in need of scrutiny into the nature and limitations of the imaging modality itself as well as image reconstruction techniques. In this work, we have reviewed, analysed and addressed the following three considerations within the particular context of state-of-the-art dynamic PET imaging: (i) the typical average numbers of events per line-of-response (LOR) are now (much) less than unity, (ii) due to the physical and biological decay of the activity distribution, one requires robust and efficient reconstruction algorithms applicable to a wide range of statistics and (iii) the computational considerations in dynamic imaging are much enhanced (i.e., more frames to be stored and reconstructed). Within the framework of statistical image reconstruction, we have argued theoretically and shown experimentally that the sinogram non-negativity constraint (when using the delayed-coincidence and/or scatter-subtraction techniques) is especially expected to result in an overestimation bias. Subsequently, two schemes are considered: (a) subtraction techniques in which an image non-negativity constraint has been imposed and (b) implementation of random and scatter estimates inside the reconstruction algorithms, thus enabling direct processing of Poisson-distributed prompts. Both techniques are able to remove the aforementioned bias, while the latter, being better conditioned theoretically, is able to exhibit superior noise characteristics. We have also elaborated upon and verified the applicability of the accelerated list-mode image reconstruction method as a powerful solution for accurate, robust and efficient dynamic reconstructions of high-resolution data (as well as a number of additional benefits in the context of state-of-the-art PET).
Abstract: 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.
Abstract: 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.
Abstract: We have investigated statistical list-mode reconstruction applicable to a depth-encoding high resolution research tomograph. An image non-negativity constraint has been employed in the reconstructions and is shown to effectively remove the overestimation bias introduced by the sinogram non-negativity constraint. We have furthermore implemented a convergent subsetized (CS) list-mode reconstruction algorithm, based on previous work (Hsiao et al 2002 Conf. Rec. SPIE Med. Imaging 4684 10-19; Hsiao et al 2002 Conf. Rec. IEEE Int. Symp. Biomed. Imaging 409-12) on convergent histogram OSEM reconstruction. We have demonstrated that the first step of the convergent algorithm is exactly equivalent (unlike the histogram-mode case) to the regular subsetized list-mode EM algorithm, while the second and final step takes the form of additive updates in image space. We have shown that in terms of contrast, noise as well as FWHM width behaviour, the CS algorithm is robust and does not result in limit cycles. A hybrid algorithm based on the ordinary and the convergent algorithms is also proposed, and is shown to combine the advantages of the two algorithms (i.e. it is able to reach a higher image quality in fewer iterations while maintaining the convergent behaviour), making the hybrid approach a good alternative to the ordinary subsetized list-mode EM algorithm.
Abstract: 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.
Abstract: Parkinson disease is characterized by the loss of dopaminergic neurons, thus decreasing the system's ability to produce and store dopamine (DA). Such ability is often investigated using 18F-fluorodopa (FD) positron emission tomography. A commonly used model to investigate the DA synthesis and storage rate is the modified Patlak graphical approach. This approach allows for both plasma and tissue input functions, yielding the respective uptake rate constants K(i) and K(occ). This method requires the presence of an irreversible compartment and the absence of any nontrapped tracer metabolite. In the case of K(occ), this last assumption is violated by the presence of the FD metabolite 3-O-methyl-[18F]fluoro-dopa (3OMFD), which makes the K(occ) evaluation susceptible to a downward bias. It was found that both K(i) and K(occ) are influenced by DA loss and thus are not pure measures of DA synthesis and storage. In the case of K(occ), the presence of 3OMFD exacerbates the effect of DA egress, thus introducing a disease-dependent bias in the K(occ) determination. These findings imply that K(i) and K(occ) provide different assessments of disease severity and that, as disease progresses, K(i) and especially K(occ) become more related to DA storage capacity and less to the DA synthesis rate.
Abstract: 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.
Abstract: 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.
Abstract: Thirty-four patients with advanced Parkinson's disease participated in a prospective 24-month double-blind, placebo-controlled trial of fetal nigral transplantation. Patients were randomized to receive bilateral transplantation with one or four donors per side or a placebo procedure. The primary end point was change between baseline and final visits in motor component of the Unified Parkinson's Disease Rating Scale in the practically defined off state. There was no significant overall treatment effect (p = 0.244). Patients in the placebo and one-donor groups deteriorated by 9.4 +/- 4.25 and 3.5 +/- 4.23 points, respectively, whereas those in the four-donor group improved by 0.72 +/- 4.05 points. Pairwise comparisons were not significant, although the four-donor versus placebo groups yielded a p value of 0.096. Stratification based on disease severity showed a treatment effect in milder patients (p = 0.006). Striatal fluorodopa uptake was significantly increased after transplantation in both groups and robust survival of dopamine neurons was observed at postmortem examination. Fifty-six percent of transplanted patients developed dyskinesia that persisted after overnight withdrawal of dopaminergic medication ("off"-medication dyskinesia). Fetal nigral transplantation currently cannot be recommended as a therapy for PD based on these results.
Abstract: BACKGROUND: Transplanted striatal cells have been demonstrated to survive, grow, establish afferent and efferent connections, and improve behavioral signs in animal models of Huntington's disease (HD). OBJECTIVE: To evaluate feasibility and safety and to provide preliminary information regarding the efficacy of bilateral human fetal striatal transplantation in HD. METHODS: Seven symptomatic patients with genetically confirmed HD underwent bilateral stereotactic transplantation of two to eight fetal striata per side in two staged procedures. Tissue was dissected from the lateral half of the lateral ventricular eminence of donors 8 to 9 weeks postconception. Subjects received cyclosporine for 6 months. RESULTS: Three subjects developed subdural hemorrhages (SDHs) and two required surgical drainage. One subject died 18 months after surgery from probable cardiac arrhythmia secondary to severe atherosclerotic cardiac disease. Autopsy demonstrated clearly demarcated grafts of typical developing striatal morphology, with host-derived dopaminergic fibers extending into the grafts and no evidence of immune rejection. Other adverse events were generally mild and transient. Mean Unified HD Rating Scale (UHDRS) motor scores were 32.9 plus minus 6.2 at baseline and 29.7 plus minus 7.5 12 months after surgery (p = 0.24). Post-hoc analysis, excluding one subject who experienced cognitive and motor deterioration after the development of symptomatic bilateral SDHs, found that UHDRS motor scores were 33.8 plus minus 6.2 at baseline and 27.5 plus minus 5.2 at 12 months (p = 0.03). CONCLUSIONS: Transplantation of human fetal striatal cells is feasible and survival of transplanted cells was demonstrated. Patients with moderately advanced HD are at risk for SDH after transplantation surgery.
Abstract: An increase in dopamine turnover has been hypothesized to occur early in Parkinson's disease (PD) as a compensatory mechanism for dopaminergic neuronal loss. A new approach to the determination of dopamine turnover was developed using 4-hour-long 18 F-fluorodopa (FD) positron emission tomography (PET) data. An effective dopamine turnover, an estimate of dopamine turnover, has been measured using its inverse, the effective dopamine distribution volume (EDV). This new method is based on a reversible tracer approach and determines the EDV using a graphical method. Six healthy subjects and 10 subjects with very early PD underwent a 4-hour-long FD scan. The EDV and the plasma uptake rate constant K(i), a marker of dopamine synthesis and storage, were compared according to their ability to separate the PD group from the healthy group. The EDV was the better discriminator (93.8% correct classification versus 81.3% for K(i)). Effective dopamine distribution volume decreased by 65% in the PD group relative to the healthy group, whereas the decrease in K(i) was 39%. These results show that changes in EDV are measurable with PET earlier than changes in the dopamine synthesis and storage rate, indicating that EDV is a sensitive marker for early PD and that a dopamine turnover increase likely serves as an early compensatory mechanism.
Abstract: 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.
Abstract: 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.
Abstract: The NU 2-1994 standard document for PET performance measurements has recently been updated. The updated document, NU 2-2001, includes revised measurements for spatial resolution, intrinsic scatter fraction, sensitivity, counting rate performance, and accuracy of count loss and randoms corrections. The revised measurements are designed to allow testing of dedicated PET systems in both 2-dimensional and 3-dimensional modes as well as coincidence gamma cameras, conditions not considered in the original NU 2-1994 standard. In addition, the updated measurements strive toward being more representative of clinical studies, in particular, whole-body imaging. METHODS: Performance measurements following the NU 2-1994 and NU 2-2001 standards were performed on several different PET scanners. Differences between the procedures and resulting performance characteristics, as well as the rationale for these changes, were noted. RESULTS: Spatial resolution is measured with a point source in all 3 directions, rather than a line source, as specified previously. For the measurements of intrinsic scatter fraction, sensitivity, and counting rate performance, a 70-cm line source is now specified, instead of a 19-cm-long cylindric phantom. The longer configuration permits measurement of these performance characteristics over the entire axial field of view of all current PET scanners and incorporates the effects of activity outside the scanner. A measurement of image quality has been added in an effort to measure overall image quality under clinically realistic conditions. This measurement replaces the individual measurements of uniformity and of the accuracy of corrections for attenuation and scatter. CONCLUSION: The changes from the NU 2-1994 standard to the NU 2-2001 standard strive toward establishing relevance with clinical studies. The tests in the updated standard also are, in general, simpler and less time-consuming to perform than those in the NU 2-1994 standard.
Abstract: 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.
Abstract: Motor fluctuations are a major disabling complication in the treatment of Parkinson's disease. To investigate whether such oscillations in mobility can be attributed to changes in the synaptic levels of dopamine, we studied prospectively patients in the early stages of Parkinson's disease with a follow-up after at least 3 years of levodopa treatment. At baseline, 3 positron emission tomography (PET) scans using [11C]raclopride before and after (1 hour and 4 hours) orally administered levodopa were performed on the same day for each patient. Patients who developed "wearing-off" fluctuations during the follow-up period had a different pattern of levodopa-induced changes in [11C]raclopride binding potential (BP) from that observed in patients who were still stable by the end of the follow-up. Thus, 1 hour post-levodopa the estimated increase in the synaptic level of dopamine was 3 times higher in fluctuators than in stable responders. By contrast, only stable responders maintained increased levels of synaptic dopamine in the PET scan performed after 4 hours. These results indicate that fluctuations in the synaptic concentration of dopamine precede clinically apparent "wearing-off" phenomena. The rapid increase in synaptic levels of dopamine observed in fluctuators suggests that increased dopamine turnover might play a relevant role in levodopa-related motor complications.
Abstract: Pallido-ponto-nigral degeneration (PPND) is a rapidly progressive disorder characterized by frontotemporal dementia with parkinsonism unresponsive to levodopa therapy. In this study, we have further characterized the regional abnormalities of cerebral function using PET with 6-[18F]fluoro-L-dopa (FD), [11C] raclopride (RAC), and 2-deoxy-2-fluoro-[18F]-D-glucose (FDG). FD and RAC scans were performed in 3 patients-2 new patients and a previously reported asymptomatic at-risk individual who became symptomatic 2years after the first FD scan. Cerebral glucose metabolism was studied by FDG in 2 other patients. In keeping with previous reports, there was a severe reduction of FD uptake, which affected both caudate and putamen to a similar degree in all 3 patients. RAC scans showed normal to elevated striatal D2-receptor binding in all patients. Cerebral glucose metabolism was globally reduced (>2 SD below control mean) in one patient, with maximal involvement of frontal regions, and to a lesser degree in the other patient. Our study showed severe presynaptic dopaminergic dysfunction with intact striatal D2 receptors in PPND patients, implying that the dopa unresponsiveness is probably a result of pathology downstream to the striatum. The pattern of presynaptic dysfunction contrasts with that seen in idiopathic parkinsonism, where the putamen is affected more than the caudate nucleus. The pattern of glucose hypometabolism correlates well with the presence of frontotemporal dementia.
Abstract: Autosomal recessive spinal muscular atrophy (SMA) is a common motor neuron disease caused by absence or mutation in the survival motor neuron (SMN1) gene. SNM1 and a nearly identical copy, SMN2, encode identical proteins, but SMN2 only produces a little full length protein due to alternative splicing. The level of functional SMN protein and the number of SMN2 genes correlate with the clinical phenotype ranging from severe to very mild. Here, we report on premature termination mutations in SMN1 exon 3 (425del5 and W102X) which induce skipping of the mutated exon. The novel nonsense mutation W102X was detected in two patients with a relatively mild phenotype who had only two copies of the SMN2 gene, a number that has previously been found associated with the severe form of SMA. We show that the shortened transcripts are translated into predicted in frame protein isoforms. Aminoglycoside treatment suppressed the nonsense mutation in cultured cells and abolished exon skipping. Fibroblasts from both patients show a high number of nuclear structures containing SMN protein (gems). These findings suggest that the protein isoform lacking the exon 3 encoded region contributes to the formation of the nuclear protein complex which may account for the milder clinical phenotype.
Abstract: Changes in dopamine turnover resulting from disease states such as Parkinson's disease may be reflected in corresponding changes in the kinetics of the positron emission tomographic tracer [(18)F]fluorodopa. The authors had previously refined the conventional irreversible-tracer graphical approach to determine both the uptake rate constant K(i) and the rate constant kloss that describes the slow loss of the trapped kinetic component. Because these parameters change in the opposite sense with disease, their ratios may be more powerfully discriminating than either one alone. The ratio k(loss)/K(i) is indicative of effective dopamine turnover. Its inverse, K(i)/k(loss), can be interpreted as the effective distribution volume (EDV) of the specific uptake compartment referred to the fluorodopa concentration in plasma. Here the authors present a new approach to the estimation of EDV based on reversible-tracer graphical methods. When implemented with a plasma input function, the method evaluates EDV directly. When implemented with a tissue input function, the outcome is proportional to the ratio of the distribution volumes of the specific uptake and precursor compartments. Comparison of the new and previous approaches strongly validates this alternative approach to the study of effective dopamine turnover.
Abstract: The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors.
Abstract: The power of placebos has long been recognized for improving numerous medical conditions such as Parkinson's disease (PD). Little is known, however, about the mechanism underlying the placebo effect. Using the ability of endogenous dopamine to compete for [11C]raclopride binding as measured by positron emission tomography, we provide in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo. Our findings indicate that the placebo effect in PD is powerful and is mediated through activation of the damaged nigrostriatal dopamine system.
Abstract: OBJECTIVES: To examine the distribution of striatal dopaminergic function in humans with parkinsonism induced by 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) to determine if there is a caudate-putamen gradient as is seen in idiopathic Parkinson's disease. METHODS: We scanned nine humans exposed to MPTP with parkinsonism ranging from minimal to severe using [(18)F]fluorodopa (FD) and high resolution PET. The results were compared with those of 10 patients with Parkinson's disease and six normal subjects. RESULTS: In the MPTP group there was an equal degree of reduction of dopaminergic function in the caudate and putamen. This was different from the greater putaminal than caudate loss in Parkinson's disease (p<0.001). CONCLUSIONS: Parkinson's disease is not caused by transient exposure to MPTP.
Abstract: The integrity of the dopaminergic system can be studied using positron emission tomography. The presynaptic tracers [11C]-methylphenidate and [11C]dihydrotetrabenazine (DTBZ) are used to investigate the dopamine transporter availability, the dopamine vesicular transporter integrity; the postsynaptic tracers [11C]-raclopride and [11C]-Schering 23990 (SCH) are used to probe the D2 and D1 receptors. These are reversible tracers, where the binding potential (BP) = Bmax/Kd often is used to quantify the amount of their specific binding to the sites of interest. The simplified tissue input methods to calculate BP are attractive, since they do not require a blood input function. The suitability and performance of two such methods were evaluated: the Logan graphical tissue method, and the Lammertsma reference tissue method (RTM). The BP estimates obtained with the two methods were nearly identical in most cases, with similar reliability and reproducibility indicating that all four tracers satisfy the assumptions required by each method. The correlations among the fitted parameters obtained from the RTM were estimated and were found not to introduce noticeable bias in the RTM BP and R1 estimates. R1 showed low intersubject and intrasubject variability. The k2 estimate showed good reliability for SCH with cerebellar input function and DTBZ with occipital input function.
Abstract: Clinical symptoms of Parkinson's disease (PD) do not manifest until dopamine (DA) neuronal loss reaches a symptomatic threshold. To explore the mechanisms of functional compensation that occur in presynaptic DA nerve terminals in PD, we compared striatal positron emission tomographic (PET) measurements by using [11C]dihydrotetrabenazine ([11C]DTBZ; labeling the vesicular monoamine transporter type 2), [11C]methylphenidate (labeling the plasma membrane DA transporter), and [18F]dopa (reflecting synthesis and storage of DA). Three consecutive PET scans were performed in three-dimensional mode by using each tracer on 35 patients and 16 age-matched, normal controls. PET measurements by the three tracers were compared between subgroups of earlier and later stages of PD, between drug-naive and drug-treated subgroups of PD, and between subregions of the parkinsonian striatum. The quantitative relationships of [18F]dopa and [11]DTBZ, and of [11C]methylphenidate and [11C]DTBZ, were compared between the PD and the normal control subjects. We found that [18F]dopa Ki was reduced less than the binding potential (Bmax/Kd) for [11C]DTBZ in the parkinsonian striatum, whereas the [11C]methylphenidate binding potential was reduced more than [11C]DTBZ binding potential. These observations suggest that the activity of aromatic L-amino acid decarboxylase is up-regulated, whereas the plasma membrane DA transporter is down-regulated in the striatum of patients with PD.
Abstract: Knobloch syndrome (KS) is an autosomal recessive disorder defined by the occurrence of high myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities and occipital encephalocele. The KS causative gene had been assigned to a 4.3 cM interval at 21q22.3 by linkage analysis of a large consanguineous Brazilian family. We reconstructed the haplotypes of this family with ten additional markers (five were novel) and narrowed the candidate interval to a region of <245 kb, which contains 24 expressed sequence tags, the KIAA0958 gene and the 5' end of the COL18A1 gene. We identified a homozygous mutation at the AG consensus acceptor splice site of COL18A1 intron 1 exclusively among the 12 KS patients, which was not found among 140 control chromosomes. This mutation predicts the creation of a stop codon in exon 4 and therefore the truncation of the alpha1(XVIII) collagen short form, which was expressed in human adult retina. These findings provide evidence that KS is caused by mutations in COL18A1 which, therefore, has a major role in determining the retinal structure as well as in the closure of the neural tube. Therefore, we show for the first time that the absence of a collagen isoform impairs embryonic cell proliferation and/or migration as a primary or secondary effect.
Abstract: Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder which presents with various clinical phenotypes ranging from severe to very mild. All forms are caused by the homozygous absence of the survival motor neuron ( SMN1 ) gene. SMN1 and a nearly identical copy ( SMN2 ) are located in a duplicated region at 5q13 and encode identical proteins. The genetic basis for the clinical variability of SMA remains unclear, but it has been suggested that the copy number of SMN2 could influence the disease severity. We have assessed the number of SMN2 genes in patients with different clinical phenotypes by fluorescence in situ hybridization (FISH) using as SMN probe a mixture of small specific DNA fragments. Gene copy number was established by FISH on interphase nuclei, but the presence of two SMN2 genes on the same chromosome could also be revealed by FISH on metaphase spreads. All patients had at least two SMN2 genes. We found two or three copies of SMN2 in severely affected type I patients, three copies in intermediately affected type II patients, generally four copies in mildly affected type III patients and four or eight copies in patients with very mild adult-onset SMA. No alterations of the genes were detected by Southern blot and sequence analysis, suggesting that all gene copies of SMN2 were intact. These data provide additional evidence that the SMN2 genes modulate the disease severity and suggest that knowledge of the gene copy number could be of some prognostic value.
Abstract: OBJECTIVE: To assess the pattern of dopaminergic abnormalities in a Greek-American kindred (family H) with autosomal dominantly inherited, levodopa-responsive parkinsonism caused by a mutation of the gene encoding alpha-synuclein. BACKGROUND: Mutations of alpha-synuclein have been associated recently with dominantly inherited, levodopa-responsive parkinsonism. The pattern of dopamine deficiency and status of postsynaptic dopamine receptors in this condition have not been reported previously. The authors followed a large, six-generation family in whom the affected members carry the recently reported G209A mutation in the gene encoding alpha-synuclein. METHODS: The authors studied four affected and two clinically unaffected gene-negative members of family H using [18F]-6-fluoro-L-dopa (FD) and [11C]-raclopride (RAC) PET to assess presynaptic dopaminergic function and dopamine D2 receptors. The results were compared with normal subjects and patients with sporadic, idiopathic PD (IP). RESULTS: In affected individuals, FD uptake was reduced in both the caudate and the putamen, but the putamen was affected more severely than the caudate, as seen in IP. RAC binding was within the normal range, but the ratio of RAC binding in the putamen to that in the caudate was increased in affected members of family H. This pattern is similar to that seen in IP. CONCLUSIONS: PET of the nigrostriatal system in parkinsonism associated with a mutation in the ac-synuclein gene indicates that it results in a pattern of dopamine deficiency, with preserved D2 binding, indistinguishable from IP.
Abstract: The gene-rich telomeric region of 21q harbors several loci relevant to human diseases including autoimmune polyglandular disease type I, nonsyndromic deafness, Knobloch syndrome, holoprosencephaly, and bipolar affective disorder. A contig of genomic clones in this region would facilitate the isolation of these genes. However, distal 21q22.3 has yet been poorly mapped, presumably due to the presence of sequences that are underrepresented in yeast artificial chromosome (YAC) libraries. We generated a framework of YACs and used these clones as starting points for the isolation of a combination of bacterial artificial chromosome clones, P1-derived artificial chromosome clones, and cosmid clones by chromosome walking procedures. These studies resulted in the construction of a high-resolution contig map spanning the 2.5-Mb region from PFKL to the telomere, approximately 2 Mb of which are covered by ready-to-sequence contigs. Within this map we determined the location and relative distance of 21 markers. These include 9 established genetic markers, the order of which is cen-PFKL-D21S154-D21S170-D21S171-D21S1903- D21S1897- D21S112-D21S1446-D21S1575-tel. Moreover, we established the precise map position of 13 genes and 4 ESTs including the recently isolated genes C21ORF2, SMT3H1, RNA editing deaminase 1 (ADARB1), folate transporter (SLC19A1), COL18A1, lanosterol synthase (LSS-PEN), pericentrin (PCNT), and arginine methyltransferase (HRMT1L1). This integrated map provides a useful resource for the mapping and isolation of disease genes and for the construction of a complete transcription map of distal 21q as well as for large-scale sequencing efforts.
Abstract: For 3D PET normalization methods, a balance must be struck between statistical accuracy and individual detector or line-of-response (LOR) fidelity. Methods with potentially the best LOR accuracy tend to be statistically poor, while techniques to improve the statistical quality tend to reduce the individual detector fidelity. We have developed and implemented a 3D PET normalization method for our ECAT 953B scanner (Siemens/CTI) that determines the detector normalization factors (NFs) as a product of a four-dimensional matrix of measured geometric factors (GFs) and single detector efficiency factors (epsilon). The effects of various alterations to the algorithm on the accuracy of the normalization have been examined through the impact on reconstructed images. An accurate set of GFs is crucial, as inaccurate NFs can result if LORs with similar but not identical geometric symmetries are grouped together. The general method can be extended to other tomographs, although the dimensionality of a GF matrix may be scanner-specific; the key is to determine the optimal number of dimensions in the GF matrix. The GFs for our scanner are specified by: (i) the two detector rings for each LOR; (ii) the radial distance of the LOR from the tomograph centre; and (iii) the positions within the detector block of the two crystals defining the LOR. Some residual radial non-uniformities are present in all the NF variations we examined. For the NF method presented here, the radial non-uniformities are attributed to the interaction between object-dependent scatter and normalization. Results indicate that this non-uniformity is detectable for scans with as few as 13 million total counts.
Abstract: The aim of this study was to test the quantitation accuracy of three-dimensional PET in brain scanning. METHODS: Three-dimensional data from 11 human subjects were tested using 11C-dihydrotetrabenazine, 11C-Schering 23390 and 18F-FDG as tracers. Two-dimensional scans were performed on the same subjects and the distribution volume, distribution volume ratio and local metabolic rate of glucose (LMRGlu) values obtained from these were used as reference. Three-dimensional data were processed as follows: iterative convolution subtraction scatter correction, detector normalization including radial and axial geometric factors, attenuation correction extracted from a two-dimensional transmission scan, Kinahan-Rogers reconstruction and region-of-interest-based sensitivity calibration. RESULTS: No major systematic differences between the two methods were found. The agreement between the two-dimensional and three-dimensional data was within 5%. Although statistical analysis generally did not show this difference to be significant, reliability analysis indicated that comparing two-dimensional and three-dimensional data might introduce some inaccuracies. CONCLUSION: Three-dimensional PET yields quantitatively valid results for brain scanning.
Abstract: Phantom studies are used to develop a reliable quantitative data processing protocol for 3D PET brain scanning for conditions typically encountered in FDG and neuroreceptor brain imaging. These protocols often span several half-lives of the injected radiotracer thus resulting in a greatly varying statistical content of the acquired data over the study duration. Detector normalization, scatter correction and their interplay over a wide range of statistical content of acquired data were evaluated. Overall sensitivity calibration factors were determined after all other quantification corrections were applied to the data. The result is an optimum data processing protocol that includes an iterative convolution subtraction scatter correction method, a normalization procedure that takes into account the geometric properties of the scanner and a region of interest based calibration procedure, applied in this order. This protocol yields a 3D PET quantification accuracy within approximately 3% of independently measured concentration values for scanning conditions that include variation in the number of acquired counts from one million to several hundred millions and variation in size and shape from a 20 cm diameter phantom to a tapered phantom with minimum cross section of 3.7 x 14.5 cm2. This performance is comparable with that of the 2D acquisition mode.
Abstract: 1. Until recently studies of intestinal aluminium absorption used pharmacological amounts of stable 27Al. 2. To examine the intestinal absorption of trace amounts of different chemical compounds of aluminium, in the present study we have employed the long half-life isotope of aluminium, 26Al, and accelerator mass spectrometry. Trace amounts of 26Al (2.7-12.1 ng) as the hydroxide, citrate, citrate plus 1 mmol/kg sodium citrate, or maltolate respectively, were administered to four groups of rats (n = 9 per group) by gavage. Blood and urine samples were collected for 5 h and the 26Al content (as a percentage of the administered dose) determined by accelerator mass spectrometry. 3. The 5 h urinary 26Al excretion amounted to 0.1 +/- 0.02, 0.7 +/- 0.2, 5.1 +/- 1.5 and 0.1 +/- 0.1% of administered dose in the four groups respectively. There was a strong positive correlation between peak plasma 26Al (r = 0.98) and urinary 26Al excretion in individual animals (P < 0.001). 4. We conclude that the fractional intestinal absorption of trace oral doses of aluminium hydroxide is at least 0.1% (compared with the previous estimate of 0.01% using large 27Al oral loads). Absorption of aluminium citrate given alone is significantly greater (0.7%) and is further increased to 5% by the accompanying sodium citrate, consistent with an enhancing effect of added citrate upon mucosal aluminium permeability. Aluminium maltolate absorption approximates that of aluminium hydroxide (0.1%).
Abstract: Graphical methods to analyze tracer time-course data allow reliable quantitation of the rate of incorporation of tracer from plasma into a "trapped" kinetic component, even when the details of the kinetic model are unknown. Applications of the method over long time periods often expose the slow reversibility of the trapping process. In the extended graphical method, both trapping rate and a presumed first-order loss rate constant are estimated simultaneously from the time-course data. METHODS: We applied the extended graphical method to 6-fluoro-L-dopa (6-FD), simultaneously estimating the rate of uptake (Ki) and the rate constant for loss from the trapped component (K(loss)) in a single fitting procedure. We applied this approach to study the effects of two catechol-O-methyl-transferase inhibitors on the kinetics of 6-FD in cynomolgus monkeys. RESULTS: Inhibition of peripheral O-methylation with either inhibitor, confirmed by high-performance liquid chromatography analysis of labeled compounds in arterial plasma, had no significant effect on Ki, in agreement with previously reported studies. In contrast, tolcapone, a catechol-O-methyl-transferase inhibitor, having central effects in addition to peripheral effects at the dosage used, decreased K(loss) by 40% from control values (p < 0.002), whereas nitecapone, which has no known central activity, had no significant effect. CONCLUSION: This method provides insight into the neurochemical basis for the kinetic behavior of 6-FD in both health and disease and may be used to define the action of centrally active drugs that influence the metabolism of dopamine.
Abstract: 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.
Abstract: OBJECTIVE: We have tested the feasibility of applying an approximate three-dimensional (3D) reconstruction algorithm, the single slice rebinning method followed by standard 2D filtered back-projection (SSRB), to human basal ganglia studies. Such an approximate algorithm solves the problem of long reconstruction times and large dataset size associated with mathematically correct 3D reconstruction algorithms. MATERIALS AND METHODS: First, recovery achieved when images were reconstructed with the SSRB method was compared with that achieved when a mathematically correct 3D reconstruction algorithm (3D method) was used with a series of spherical phantom studies. The SSRB method was then applied to 14 human receptor studies and the images compared with those obtained with the 3D method. The striatum/background contrast dependence of the SSRB method performance was tested by extending the comparison of the two reconstruction methods to single frames of two dynamic scanning sequences. RESULTS: There was no significant visual difference in the human images obtained with the two methods and a quantitative striatal/cortical activity ratio analysis showed a contrast decrease of approximately 3% for the SSRB method. The analysis of the dynamic sequence did not show any contrast dependence of the SSRB method performance. CONCLUSION: The SSRB method was found adequate for processing data related to human striatal imaging for this particular tomograph geometry.
Abstract: A trace quantity of 26aluminum (26Al) was administered intravenously to 1 normal and 1 uremic rat. After a 3-week period, the animals were sacrificed and samples of bone, muscle, kidney, liver, heart, and brain were analyzed for their 26Al content. In the normal and uremic rats, most of the tissue 26Al was found in bone amounting to 0.9% and 2.0%, respectively, of administered dose/g dry weight of tissue. Much smaller amounts of isotope were found in the other tissues in both animals. In the normal rat, the descending order of 26Al content in other tissues was: kidney, 0.2% > liver, 0.06% > heart, 0.03%, > brain and muscle, 0.02%. In the uremic rat, the same order of tissue 26Al content was found with kidney, 0.37% > liver, 0.06% > heart, 0.02% > brain and muscle, 0.01% per g dry weight of tissue. When expressed per g wet weight of tissue in the 2 animals, a similar order of tissue 26Al content was found. In comparing the amount of 26Al in the bone of the 2 rats, the uremic animal was found to have more than twice that found in the bone of the normal rat when expressed either per g dry or wet weight of bone. However, 26Al content of other tissues was similar in the 2 animals. This suggests that uremic bone may have a greater affinity for aluminum than normal bone, but kidney, liver, brain, heart, and muscle appear to behave similarly in uremic and normal rats in regard to incorporation of a single trace dose of isotope in the 3-week time frame of the present study.
Abstract: 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.
Abstract: 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%.
Abstract: PET examinations using L-18F-DOPA were performed on 14 patients with Parkinsonism-plus syndromes (PPLUS). A rate constant Ki was calculated by a graphical method using an arterial input function. Sequential PET images were obtained and no specific activity was measured both in cortical and cerebellar background regions. These results were compared with those in 20 normal controls and tested for intra- and interobserver variability. All patients with PPLUS showed reduced Ki values with a mean of 0.154 (ml/striatum/min), whereas controls exhibited Ki values with a mean of 0.690 (ml/striatum/min) using cortical background regions. The correlation coefficient was calculated to be r = 0.973 for the intraobserver variability and r = 0.879 for the interobserver variability in controls, and r = 0.989 or = 0.973 in PPLUS, resp. There was no significant difference in the Ki values for cortical and cerebellar background regions (p = 0.1). PET examinations using L-18F-DOPA can reliably assess the extent of nigrostriatal degeneration in vivo. Since this radiotracer binds irreversibly within the striatum PET examinations allow the quantification of a disturbed dopaminergic function which is observer-independent.
