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Template region object map (white outlines) overlying putamen and caudate nucleus bilaterally in normalized ADD (summed) image, 18 F-DOPA template, and single subject T1 MRI found in SPM99.
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We have recently completed a large 6-(18)F-fluoro-L-DOPA ((18)F-DOPA) PET study comparing rates of loss of dopamine terminal function in Parkinson's disease (PD) patients taking either the dopamine agonist ropinirole or L-DOPA. This trial involved a "distributed acquisition/centralized analysis" method, in which (18)F-DOPA images were acquired at 6...
Context in source publication
Context 1
... transformed the ADD, and, subsequently, the K i images to standard space, the volumes-of-interest template (object map) was applied (Fig. 3). The object map defined both putamen, heads of caudate nuclei, and ventral striatum. ROI objects were drawn freehand on the MNI single-subject MRI (26,30) found in SPM99 by an expert neuroanatomist. Visual inspection of each normalized plane of both K i and ADD images was then made to ensure correct placement of the template region ...
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Methods:
Subjects were clinically diagnosed as: 4 young cognitively normal (YCN), 5 old cognitively normal (OCN), 5 mild cognitive impairment (MCI) and 5 Alzheimer's Disease (AD). Kinetic modeling was performed using Logan graphical analysis with the cerebellum crus as a reference region. Voxel-wise binding potential ( ) and standardized uptake va...
Purpose:
Imaging of the 18-kDa translocator protein (TSPO) is a potential tool for examining microglial activation and neuroinflammation in early Alzheimer's disease (AD). [(18)F]FEMPA is a novel high-affinity second-generation TSPO radioligand that has displayed suitable pharmacokinetic properties in preclinical studies. The aims of this study we...
Citations
... Maps of the influx rate constant (K i in minutes −1 ) and distribution volume (V) were generated using the dynamic PET frames, and a TAC obtained over the reference region corresponding to the cerebellum. 49 This technique is appropriate when the tracer is irreversibly trapped in tissue. We hypothesized that the bias would be higher at later time frames compared to early time frames. ...
Purpose
We assess the performance of a recurrent frame generation algorithm for prediction of late frames from initial frames in dynamic brain PET imaging.
Methods
Clinical dynamic ¹⁸F‐DOPA brain PET/CT studies of 46 subjects with ten folds cross‐validation were retrospectively employed. A novel stochastic adversarial video prediction model was implemented to predict the last 13 frames (25–90 minutes) from the initial 13 frames (0–25 minutes). The quantitative analysis of the predicted dynamic PET frames was performed for the test and validation dataset using established metrics.
Results
The predicted dynamic images demonstrated that the model is capable of predicting the trend of change in time‐varying tracer biodistribution. The Bland‐Altman plots reported the lowest tracer uptake bias (−0.04) for the putamen region and the smallest variance (95% CI: −0.38, +0.14) for the cerebellum. The region‐wise Patlak graphical analysis in the caudate and putamen regions for eight subjects from the test and validation dataset showed that the average bias for Ki and distribution volume was 4.3%, 5.1% and 4.4%, 4.2%, (P‐value <0.05), respectively.
Conclusion
We have developed a novel deep learning approach for fast dynamic brain PET imaging capable of generating the last 65 minutes time frames from the initial 25 minutes frames, thus enabling significant reduction in scanning time.
... Striatal DaT binding was reduced by approximately 2% in both groups after 1 year, without evidence of differential progression in the nicotine-treated patients versus the untreated patients. These data do not provide evidence in favor of a possible neuroprotective action of high doses of nicotine, but the number of patients and the time between scans were not sufficient to measure such an effect [28]. ...
Background:
Studies of the effects of nicotine on motor symptoms in Parkinson's disease (PD) brought out discordant results. The aim of the present study was to evaluate the efficacy and safety of high doses of transdermal nicotine on motor symptoms in PD.
Methods:
Forty PD patients were randomly assigned to a treated and untreated arm in an open-label study. Treated patients received increasing doses of nicotine to reach 90 mg/day by 11 weeks. This dosage was maintained for 28 weeks (W39), and then reduced over six weeks. Final evaluation was performed six weeks after washout. The main outcome measure was the off-dopa UPDRS motor score measured on video recordings by raters blinded to the medication status of the patients.
Results:
There was no significant difference in off-dopa UPDRS motor scores between the nicotine-treated and non-treated groups, neither at W39 (19.4±9.3 vs. 21.5±14.2), nor considering W39 differences from baseline (-1.5±12.1 vs. +0.9±12.1). PDQ-39 scores decreased in nicotine-treated patients and increased in non-treated patients, but the difference was not significant. Overall tolerability was acceptable, and 12/20 treated patients reached the maximal dosage.
Conclusions:
High doses of transdermal nicotine were tolerated, but our study failed to demonstrate significant improvement in UPDRS motor scores. Improvement in unblinded secondary outcomes (UPDRS-II, UPDRS-IV, doses of L-dopa-equivalents) suggest a possible benefit for patients treated with nicotine, which should be confirmed in larger double blind, placebo-controlled studies. This article is protected by copyright. All rights reserved.
... The influx rate constant, Ki (min -1 ), for 18F-DOPA uptake in caudate and putamen was calculated (Table 2) using the Patlak multiple-time graphical analysis and the occipital cortex, a region with poor dopaminergic innervation [31,32], as reference region to estimate free and non-specific binding of the radiotracer in the brain [33]. For each animal, voxel-wise parametric maps of Ki were also generated using the Patlak approach and the occipital cortex as reference region as implemented in PMOD V3.605. ...
Objective: Previous evidence was provided that parkinsonian monkeys exhibited significant though incomplete behavioral recovery following a cell therapy consisting of auto-transplantation of adult neural progenitor cells. The aim of the present study was to assess for the first time in this parkinsonian non-human primate model the striatal dopaminergic function, in parallel to further behavioral assessment. In other words, is the behavioral recovery associated to a reversal of dopaminergic function despite the auto-transplanted cells are not dopaminergic. Methods: Striatal dopaminergic function and motor behavior (spontaneous motion activities) were monitored in adult parkinsonian macaques in relation to autologous neural cell ecosystem (ANCE) transplantation. In four MPTP intoxicated macaques, adult progenitor cells derived from cortical biopsies were re-implanted in the same animal after a phase of spontaneous functional recovery. The function of the striatal dopaminergic system was assessed using 18F-DOPA positron tomography imaging and the motor function was quantified. Results: Two parkinsonian animals exhibited severe motor symptoms, which were moderate and transient in two other monkeys. 18F-DOPA striatal uptake decreased by 80% in three animals, consistent with losses of dopaminergic neurons in substantia nigra and reduced striatal density of dopaminergic projections. Six months after autologous transplantation, all animals improved their motor functions. This functional recovery was largely consistent with positron emission tomography results showing some recovery of 18F-DOPA striatal uptake toward baseline value following transplantation. Conclusion: The present data confirm that symptoms are variable across individual parkinsonian monkeys and that autologous neural cell ecosystem transplantation indeed attenuates parkinsonian motor symptoms. Yet the present study provides for the first time evidence in favor of an increase in the striatal dopaminergic activity that correlates with motor recovery in this novel therapeutic approach, although the implanted cells are not dopaminergic.
... The transformation matrices were then applied to the corresponding RAC parametric image. A standard region-of-interest (ROI) object map that outlined putamen, heads of caudate nucleus and ventral striatum was defined on the RAC template with magnetic resonance imaging guidance (Whone et al., 2004). The ROI object map was then applied to the individual RAC parametric images to sample RAC BP ND . ...
The basal ganglia (BG) mediate certain types of procedural learning, such as probabilistic classification learning on the ‘weather prediction task’ (WPT). Patients with Parkinson's disease (PD), who have BG dysfunction, are impaired at WPT-learning, but it remains unclear what component of the WPT is important for learning to occur. We tested the hypothesis that learning through processing of corrective feedback is the essential component and is associated with release of striatal dopamine. We employed two WPT paradigms, either involving learning via processing of corrective feedback (FB) or in a paired associate manner (PA). To test the prediction that learning on the FB but not PA paradigm would be associated with dopamine release in the striatum, we used serial 11C-raclopride (RAC) positron emission tomography (PET), to investigate striatal dopamine release during FB and PA WPT-learning in healthy individuals. Two groups, FB, (n = 7) and PA (n = 8), underwent RAC PET twice, once while performing the WPT and once during a control task. Based on a region-of-interest approach, striatal RAC-binding potentials reduced by 13–17% in the right ventral striatum when performing the FB compared to control task, indicating release of synaptic dopamine. In contrast, right ventral striatal RAC binding non-significantly increased by 9% during the PA task. While differences between the FB and PA versions of the WPT in effort and decision-making is also relevant, we conclude striatal dopamine is released during FB-based WPT-learning, implicating the striatum and its dopamine connections in mediating learning with FB. Hum Brain Mapp, 2014. © 2014
... It is possible that, rather than reflecting an underlying neurobiological risk factor for ICDs in PD, increased VS FDOPA uptake could be the result of disease-related and/or drug-induced neuroplastic changes leading to disease-and/or drug-induced disinhibition. In the current sample of early-stage PD patients, who had only recently begun DA replacement therapy, however, mean ventral striatal FDOPA K I values were very similar to those of healthy controls (Whone et al., 2004) and were unrelated to severity of PD. In animal models, there is some evidence that repeated treatments with DA agonist drugs can enhance basal DA synthesis in the VS (Rowlett et al., 1997) and frontal cortex (Chernoloz et al., 2012). ...
Impulse control disorders (ICDs), including disordered gambling, can occur in a significant number of patients with Parkinson's disease (PD) receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait "disinhibition" is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioral disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[F]Fluoro-l-DOPA (FDOPA) positron emission tomography scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.
... This makes 18 F-dopa PET a marker of the pattern of monoaminergic neuron innervation in areas in which such innervation predominates-the dopaminergic neurons in the striatum and the NE neurons of the locus coeruleus (25). Here, we used a centralized analysis technique to implement quality control as has been described elsewhere (50). 18 F-Dopa influx rate constant (K i ) values for each ROI were computed with the multiple-time linear graphical analysis method (51) with occipital cortex activity providing a reference input function representing nonspecific tissue tracer uptake (52). ...
Cell therapy studies in patients with Parkinson's disease (PD) have been confined to intrastriatal transplantation of dopamine-rich fetal mesencephalic tissue in efforts to improve motor performance. Although some PD patients receiving the dopamine-rich grafts showed improvements in motor symptoms due to replacement of dopaminergic neurons, they still suffered from nonmotor symptoms including depression, fatigue, visual hallucinations, and sleep problems. Using functional imaging and clinical evaluation of motor and nonmotor symptoms in three PD patients transplanted with intrastriatal fetal grafts 13 to 16 years previously, we assessed whether reestablishment of dopaminergic neuronal networks is sufficient to improve a broad range of symptoms. At 13 to 16 years after transplantation, dopaminergic innervation was restored to normal levels in basal ganglia and preserved in a number of extrabasal ganglia areas. These changes were associated with long-lasting relief of motor symptoms. Then, we assessed the integrity of their serotonergic and norepinephrine neuronal systems using [¹¹C]DASB {[¹¹C]3-amino-4-(2-dimethylaminomethylphenylthio) benzonitrile} positron emission tomography (PET) and ¹⁸F-dopa PET, respectively. ¹⁸F-dopa uptake in the locus coeruleus was within the normal range. In contrast, [¹¹C]DASB uptake in the raphe nuclei and regions receiving serotonergic projections was markedly reduced. These results indicate ongoing degeneration of serotonergic raphe nuclei and their projections to regions involved in the regulation of sleep, arousal, feeding, satiety, mood, and emotion. Our findings indicate that future cell-based therapies using fetal tissue or stem cells in PD patients may require additional grafts of serotonergic neurons to relieve nonmotor symptoms by restoring serotonergic neurotransmission in specific cerebral targets.
... Several double-blind parallel group clinical trials have considered course-of-illness slope divergence to ascertain neuroprotective properties in PD. These studies also employed positron emission tomography (PET) and include a 5-year multicenter study of 288 patients with early PD randomized to either ropinirole or L-DOPA [92], the REAL-PET 2-year multicenter trial in 186 patients with PD randomized to ropinirole or L-DOPA [93, 94], a study of 45 patients randomized to ropinirole or L-DOPA [95], and the CALM-PD 2-year multicenter trial in 301 patients with PD randomized to either pramipexole-plusplacebo " L-DOPA " or L-DOPA-plus-placebo " pramipexole " [96]. The ropinirole study involving 288 patients found less dyskinesia with ropinirole but no difference in clinical markers of PD progression [92], and it is not clear that dyskinesia can be considered as a marker of PD pathobiological progression. ...
... The CALM-PD study showed less dopaminergic motor complications with pramipexole but greater UPDRS Parkinson scale improvement with L- DOPA or L-DOPA-plus-placebo " pramipexole " [96], yet neuroprotective conclusions are not possible because of uncertain dose equivalence between the two study arms and other limitations. Imaging markers in the REAL- PD investigation revealed slower putamenal (18)F-DOPA (dopaminergic presynaptic terminal marker) signal decline with ropinirole [93, 94] while the CALM-PD study demonstrated reduced β-CIT (dopamine transporter marker) decrement with pramipexole [97] ; however alternative pharmacological explanations [98, 99] and other limitations preventing neuroprotective conclusions for the REAL-PET [98, 100] and CALM-PD [99, 101] studies have been detailed. Dextromethorphan combined with quinidine is a new FDA-approved treatment for pseudobulbar affect. ...
Neuroprotective treatments in Parkinson's disease (PD) have remained elusive. Psychotropics are commonly prescribed in PD without regard to their pathobiological effects. The authors investigated the effects of psychotropics on pathobiological proteins, proteasomal activity, mitochondrial functions, apoptosis, neuroinflammation, trophic factors, stem cells, and neurogenesis. Only findings replicated in at least 2 studies were considered for these actions. Additionally, PD-related gene transcription, animal model, and human neuroprotective clinical trial data were reviewed. Results indicate that, from a PD pathobiology perspective, the safest drugs (i.e., drugs least likely to promote cellular neurodegenerative mechanisms balanced against their likelihood of promoting neuroprotective mechanisms) include pramipexole, valproate, lithium, desipramine, escitalopram, and dextromethorphan. Fluoxetine favorably affects transcription of multiple genes (e.g., MAPT, GBA, CCDC62, HIP1R), although it and desipramine reduced MPTP mouse survival. Haloperidol is best avoided. The most promising neuroprotective investigative priorities will involve disease-modifying trials of the safest agents alone or in combination to capture salutary effects on H3 histone deacetylase, gene transcription, glycogen synthase kinase-3, α-synuclein, reactive oxygen species (ROS), reactive nitrogen species (RNS), apoptosis, inflammation, and trophic factors including GDNF and BDNF.
... Frames 4 to 26 of dynamic scans were co-registered to frame 3 (the first frame with high signal-to-noise ratio) and the transformation matrices were applied to the corresponding frames of the attenuation corrected dynamic images. 18 F-dopa images were analyzed as previously described (Whone et al, 2004). Individual parametric images of 18 F-dopa influx rate constant (Ki maps) were created using a standard multiple-time graphical approach (Patlak and Blasberg, 1985) with an occipital reference input function. ...
... The transformation matrices were then applied to the corresponding Ki maps. A standard region-of-interest object map that outlined putamen, heads of caudate nucleus and ventral striatum was defined on the 18 F-dopa template with magnetic resonance imaging guidance (Whone et al, 2004). This object map was then ...
Ecstasy (±3,4-methylenedioxymethamphetamine, MDMA) is a popular recreational drug with known serotonergic neurotoxicity. Its long-term effects on dopaminergic function are less certain. Studying the long-term effects of ecstasy is often confounded by concomitant polydrug use and the short duration of abstinence. We used (18)F-dopa positron emission tomography (PET) to investigate the long-term effects of ecstasy on nigrostriatal dopaminergic function in a group of male ex-recreational users of ecstasy who had been abstinent for a mean of 3.22 years. We studied 14 ex-ecstasy users (EEs), 14 polydrug-using controls (PCs) (matched to the ex-users for other recreational drug use), and 12 drug-naive controls (DCs). Each participant underwent one (18)F-dopa PET, cognitive assessments, and hair and urinary analyses to corroborate drug-use history. The putamen (18)F-dopa uptake of EEs was 9% higher than that of DCs (p=0.021). The putamen uptake rate of PCs fell between the other two groups, suggesting that the hyperdopaminergic state in EEs may be due to the combined effects of ecstasy and polydrug use. There was no relationship between the amount of ecstasy used and striatal (18)F-dopa uptake. Increased putaminal (18)F-dopa uptake in EEs after an abstinence of >3 years (mean) suggests that the effects are long lasting. Our findings suggest potential long-term effects of ecstasy use, in conjunction with other recreational drugs, on nigrostriatal dopaminergic functions. Further longitudinal studies are required to elucidate the significance of these findings as they may have important public health implications.
... After attenuation-correction, these 18 F-DOPA scans were registered to the last image and affine-normalized to an 18 F-DOPA PET template using Statistical Parametric Mapping software (SPM99; Wellcome Department of Cognitive Neurology, London, UK; http://www.fil.ion.ucl.ac.uk/spm/) (Friston et al., 1994 ). The kinetic rate constant K i for 18 F- DOPA uptake was calculated voxel-by-voxel using a linear fit based on the Patlak method (Patlak et al., 1983), with a time activity curve in an occipital reference region as the input function (Whone et al., 2004). All time-activity curves were visually inspected to rule out saturation artifacts. ...
Past studies in rodents have demonstrated circannual variation in central dopaminergic activity as well as a host of compelling interactions between melatonin--a scotoperiod-responsive neurohormone closely tied to seasonal adaptation--and dopamine in the striatum and in midbrain neuronal populations with striatal projections. In humans, seasonal effects have been described for dopaminergic markers in CSF and postmortem brain, and there exists a range of affective, psychotic, and substance abuse disorders that have been associated with both seasonal symptomatic fluctuations and dopamine neurotransmission abnormalities. Together, these data indirectly suggest a potentially crucial link between circannual biorhythms and central dopamine systems. However, seasonal effects on dopamine function in the living, healthy human brain have never been tested. For this study, 86 healthy adults underwent (18)F-DOPA positron emission tomography scanning, each at a different time throughout the year. Striatal regions of interest (ROIs) were evaluated for differences in presynaptic dopamine synthesis, measured by the kinetic rate constant, K(i), between fall-winter and spring-summer scans. Analyses comparing ROI average K(i) values showed significantly greater putamen (18)F-DOPA K(i) in the fall-winter relative to the spring-summer group (p = 0.038). Analyses comparing voxelwise K(i) values confirmed this finding and evidenced intrastriatal localization of seasonal effects to the caudal putamen (p < 0.05, false-discovery rate corrected), a region that receives dopaminergic input predominantly from the substantia nigra. These data are the first to directly demonstrate a seasonal effect on striatal presynaptic dopamine synthesis and merit future research aimed at elucidating underlying mechanisms and implications for neuropsychiatric disease and new treatment approaches.
... The parameters computed were the uptake rate (Ki, 10 -3 min −1 ) for 18 F-DOPA and the binding potential (BP) of VMAT2 transporter for 11 C-DTBZ. The 18 F-DOPA Ki was calculated using the Patlak graphical analysis, considering the occipital cortex as the reference area (Whone et al., 2004). The Ichise Multilinear Reference Tissue Model (Ichise et al., 1996) was used for 11 C-DTBZ quantification, using the striatum as transporter-rich region and occipital cortex as transporter-poor region. ...
Unlabelled:
Dopaminergic depletion in the nigrostriatal system is the neurochemical hallmark of Parkinson's disease (PD). Although numerous efforts have been made to determine the evolution of dopaminergic depletion in PD, "in vivo" data concerning the stages of this process are still scarce. We evaluated 6-[18F]-fluoro-l-DOPA ((18)F-DOPA) and 11C-(+)-alpha-dihydrotetrabenazine ((11)C-DTBZ) using PET in a model of chronically MPTP-induced parkinsonism in non-human primates.
Methods:
Sixty-seven cynomolgus monkeys (Macacafascicularis) were included in the study. Progressive parkinsonism was induced by repeated administration of small doses of MPTP (iv) over several months. Animals were classified as controls, asymptomatic, recovered (having exhibited parkinsonian features transiently) and stable parkinsonian, according to their motor status. Analysis of striatal dopaminergic activity was conducted by regions of interest (ROI) and statistical parametric mapping (SPM) over normalized parametric images.
Results:
A progressive loss of striatal uptake was evident among groups for both radiotracers, which correlated significantly with the clinical motor status. Changes occurred earlier, i.e. in the less affected stages, with (11)C-DTBZ. Similar results were achieved by ROI and SPM analysis. Uptake was similar with both radiotracers for the asymptomatic and recovered groups.
Conclusions:
Serial assessment with (18)F-DOPA and (11)C-DTBZ PETs provides an effective approach to evaluate evolution of dopaminergic depletion in monkeys with MPTP-induced parkinsonism. This approach could be useful to perform studies aiming to test the effect of early therapeutic intervention and putative neuroprotective treatments.
