11 C-SCH442416 was reported in preclinical studies with rodents and primates to be the first nonxanthine radioligand suitable for the in vivo imaging of adenosine A2A receptors with positron emission tomography (PET). The aim of the present work was to investigate the suitability of 11 CSCH442416 for the in vivo quantification of A2A receptors in human brain. Methods: Five male healthy subjects were scanned with 364 MBq bolus injections of 11 CSCH442416. 90 minutes of dynamic PET emission data were acquired, and arterial blood samples Journal of Diagnostic Imaging in Therapy. 2014; 1(1): 1-19 Grachev et al. ISSN: 2057-3782 (Online) http://dx.doi.org/10.17229/jdit.2014-0620-001 2 were taken throughout the scan to generate an arterial plasma input function. Using the individual MR images, regions-of-interest (ROIs) were defined for cerebellum, caudate, putamen and thalamus. Spectral analysis was used to determine the frequency components of the 11 C-SCH442416 tissue response for regional and voxel time-activity curves (TACs). Results: 11 C-SCH442416 was rapidly metabolised in blood, the fraction of unmetabolised parent tracer in plasma being 41% at 15 minutes and 15% at 95 minutes, lower than that reported in rats and macaca nemestrina. No lipophilic radiolabelled metabolites were found in human plasma. Rapid uptake of 11 C-SCH442416 was observed in all brain regions, reaching a maximum at about 3 minutes. When spectral analysis was applied to regional brain time activity curves (TACs), relatively rapid reversible region dependent and slower irreversible, region independent but subject specific components were identified. These components were further separated into irreversible nonspecific binding, reversible nonspecific binding, reversible specific binding and a blood component. Binding potentials of the nondisplaceable binding BPND were calculated using cerebellar volume of distribution as an estimate of the reversible nondisplaceable binding across the entire brain. Mean binding potentials BPND were: 2.5 (putamen), 1.6 (caudate) and 0.5 (thalamus). Conclusion: Our study demonstrates that A2A receptor binding can be quantified in striatal regions of the human brain with 11 C-SCH442416 PET. Despite the complex tracer kinetics and its low specific binding, reliable binding potentials could be estimated with spectral analysis.

Adenosine A 2A receptors are found on striatal neurones projecting to the external pallidum. KW‐6002 (istradefylline) is a potent and selective antagonist for the adenosine A 2A receptors in the CNS and acts to inhibit the excessive activity of this pathway in the MPTP marmoset model of PD, thus relieving parkinsonism. The objectives of this study were to investigate the regional binding of the novel positron emission tomography tracer [ 11 C]KW‐6002 in the healthy human brain and the rat brain, along with receptor occupancy by cold KW‐6002 at varying doses in human. The highest [ 11 C]KW‐6002 uptake in the rat brain was seen in striatum and lower levels in cortex and cerebellum. Brain [ 11 C]KW‐6002 uptake was well characterized in humans by a two‐tissue compartmental model with a blood volume term, and the ED 50 of cold KW‐6002 was 0.5 mg in the striatum. Over 90% receptor occupancy was achieved with daily oral doses of greater than 5 mg. In humans, blockable binding was present in all gray matter structures including the cerebellum, which has not been reported to express A 2A receptors. MRS 1745, an A 2B receptor selective antagonist, had no effect on the cerebellar binding of [ 11 C]KW‐6002 in rats, suggesting that this blockable signal is unlikely to result from an affinity for adenosine A 2B receptors. Synapse 62:671–681, 2008. © 2008 Wiley‐Liss, Inc.

A small group of Parkinson's disease (PD) patients compulsively use dopaminergic drugs despite causing harmful social, psychological, and physical effects and fulfil core Diagnostic and Statistical Manual (of Mental Disorders) Fourth Edition criteria for substance dependence (dopamine dysregulation syndrome [DDS]). We aimed to evaluate levodopa‐induced dopamine neurotransmission in the striatum of patients with DDS compared with PD control patients.

The reason for the high frequency of depression and anxiety in Parkinson's disease is poorly understood. Degeneration of neurotransmitter systems other than dopamine might play a specific role in the occurrence of these affective disorders. We used [11C]RTI-32 PET, an in vivo marker of both dopamine and noradrenaline transporter binding, to localize differences between depressed and non-depressed patients. We studied eight and 12 Parkinson's disease patients with and without a history of depression matched for age, disease duration and doses of antiparkinsonian medication. The depressed Parkinson's disease cohort had lower [11C]RTI-32 binding than non-depressed Parkinson's disease cases in the locus coeruleus and in several regions of the limbic system including the anterior cingulate cortex, the thalamus, the amygdala and the ventral striatum. Exploratory analyses revealed that the severity of anxiety in the Parkinson's disease patients was inversely correlated with the [11C]RTI-32 binding in most of these regions and apathy was inversely correlated with [11C]RTI-32 binding in the ventral striatum. These results suggest that depression and anxiety in Parkinson's disease might be associated with a specific loss of dopamine and noradrenaline innervation in the limbic system.

Conference Abstract| April 01 2003 Serotonin Studies Provide a Novel Clue to Pathogenesis in Motor Neuron Disease MR Turner; MR Turner 1King's MND Care & Research Clinic, King's College London Search for other works by this author on: This Site PubMed Google Scholar EA Rabiner, MRC; EA Rabiner, MRC 2Cyclotron Unit, Hammersmith Hospital, London Search for other works by this author on: This Site PubMed Google Scholar M Doder, MRC; M Doder, MRC 3Cyclotron Unit, Hammersmith Hospital, London Search for other works by this author on: This Site PubMed Google Scholar PM Grasby, MRC; PM Grasby, MRC 4Cyclotron Unit, Hammersmith Hospital, London Search for other works by this author on: This Site PubMed Google Scholar CE Shaw, King's MND; CE Shaw, King's MND 5Care & Research Clinic, GKT Medical Schools, London Search for other works by this author on: This Site PubMed Google Scholar DJ Brooks, MRC; DJ Brooks, MRC 6Cyclotron Unit, Hammersmith Hospital & Institute of Neurology, Queen Square, London Search for other works by this author on: This Site PubMed Google Scholar PN Leigh, King's MND PN Leigh, King's MND 7Care & Research Clinic, King's College London. Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (2003) 104 (s49): 40P. https://doi.org/10.1042/cs104040P Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation MR Turner, EA Rabiner, M Doder, PM Grasby, CE Shaw, DJ Brooks, PN Leigh; Serotonin Studies Provide a Novel Clue to Pathogenesis in Motor Neuron Disease. Clin Sci (Lond) 1 April 2003; 104 (s49): 40P. doi: https://doi.org/10.1042/cs104040P Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 2003 The Biochemical Society and the Medical Research Society2003 Article PDF first page preview Close Modal You do not currently have access to this content.

BACKGROUND:The pathophysiologic mechanisms underlying parkinsonian tremor remain unclear. The response to dopaminergic treatment is variable and nondopaminergic mechanisms may play a role in tremor generation. Midbrain raphe 5-HT(1A) binding provides a functional measure of serotonergic system integrity. With PET, the aim of this study was to examine regional cerebral (11)C-WAY 100635 binding to 5-HT(1A) receptors in patients with PD and to correlate it with severity of tremor.METHODS:(11)C-WAY 100635 PET was performed on 23 patients with PD and eight age-matched healthy volunteers. Brain 5-HT(1A) receptor binding was computed using compartmental modeling with a cerebellar reference tissue input function.RESULTS:The authors found mean 27% reduction in the midbrain raphe 5-HT(1A) binding potential in patients with PD compared to healthy volunteers (p < 0.001). They also showed that Unified Parkinson's Disease Rating Scale composite tremor scores, but not rigidity or bradykinesia, correlate with 5-HT(1A) binding in the raphe (p < 0.01).CONCLUSIONS:These findings support previous indirect evidence that serotonergic neurotransmission is decreased in PD in vivo. The authors hypothesize that the reduction in raphe 5-HT(1A) binding represents receptor dysfunction or loss of cell bodies due to Lewy body degeneration in PD, or both. An association between 5-HT(1A) receptor availability in the raphe and severity of parkinsonian tremor was also found.

In this review we consider the prevalence and aetiology of depression in Parkinson's disease and suggest approaches towards its management.

In this 12-week, randomized, open-label, blinded-rater, parallel-group trial, the efficacy, safety, and tolerability of tolcapone and pergolide were compared in parkinsonian patients with a fluctuating response to levodopa. Patients received tolcapone 100 mg three times daily (t.i.d.), with a possible increase to 200 mg t.i.d., or pergolide titrated to a maximum dose of 5 mg/day by week 9 (mean final dose 2.2 mg/day). The trial involved 203 patients. Efficacy variables that decreased from baseline to week 12 with tolcapone and pergolide included "off" time (reduced by 2-3 hours/day), daily levodopa intake, sickness impact profile scores, Parkinson's disease questionnaire (PDQ)-39 scores, and Unified Parkinson's Disease Rating Scale (UPDRS) scores. Improvements in efficacy variables were similar with tolcapone and pergolide, with the exception of improvements in quality of life, which were significantly greater with tolcapone; the relative changes in PDQ-39 score at week 12 were -8.7 and -14.2 (P < 0.05) with pergolide and tolcapone, respectively. Improvements in the investigator's global assessment (IGA) of overall efficacy were recorded in 86% of tolcapone-treated patients and in 78% of pergolide-treated patients. The proportion of patients who withdrew because of adverse events was higher in the pergolide group (15%) than in the tolcapone group (5%). Confusion, hypotension, nausea, constipation, abdominal pain, and dyspepsia occurred more frequently with pergolide, whereas diarrhea and urine discoloration occurred more frequently with tolcapone. Tolcapone was better tolerated than pergolide (P < 0.01) according to the IGA of overall tolerability. We conclude that, in this 3-month study, both tolcapone and pergolide provided improvements in motor fluctuations and allowed reductions in levodopa intake when added to levodopa therapy; intent to treat analysis and a less than maximal dose of pergolide may have biased the results in favor of tolcapone. Tolcapone provided greater improvements in quality of fife, was better tolerated, and had a more favorable adverse-event profile than pergolide.

Depression is a common accompaniment of Parkinson's disease. Reported prevalences vary from 2.7% to 90% [1,2] but most surveys have suggested 40-50% levels [3-7]. Depression affects all aspects of the patient's activities of daily living. Four surveys, one worldwide, have concluded that depression, disability, postural instability, medication, age and cognitive impairment are the major factors having the greatest influence on quality of life in Parkinson's disease [8(. .)9,10(.),11]. A prospective longitudinal study found significantly greater decline in activities of daily living over a 1-year period in Parkinson's disease patients with major depression compared to those who had only minor mood changes or those without depression [12]. It has been suggested that depression in Parkinson's disease may be qualitatively different from primary major depression with less associated suicide, guilt, feeling of failure, and self-blame [4,7,13]. Its neurochemical basis, however, remains unknown; is depression associated with Parkinson's disease an endogenous phenomenon, reflecting the pathophysiological substrate of the disease, or is it simply an adaptive response to motor disability?

OBJECTIVE To evaluate whether visual assessment of [123I]-FP-CIT (DaTSCAN , Nycomed Amersham, plc) single photon emission computerized tomography (SPECT) images can differentiate between parkinsonism and essential tremor (ET). METHODS [123I]-FP-CIT SPECT imaging was conducted in a six-center study of 158 patients with a clinical diagnosis of parkinsonism compared with 27 ET cases and 35 healthy volunteers. Striatal uptake of the radioligand was graded normal or abnormal, and abnormal images were further graded to three levels of severity. An institutional read whereby each center visually assessed the images blinded to the clinical data and a consensus blinded read by a panel of five was undertaken. RESULTS The institutional reading scored 154 of 158 cases of parkinsonism abnormal, all 27 cases of ET as normal, and 34 of 35 healthy volunteers as normal compared with the consensus blinded read scoring 150 cases of parkinsonism as abnormal, 25 ET cases as normal, and 33 healthy volunteers as normal. Sensitivity for the clinical diagnosis of parkinsonism was 97% and specificity for ET was 100% for the institutional read, whereas sensitivity was 95% and specificity 93% for the consensus blinded read. Semiquantitative analysis of specific: nonspecific caudate and putamen uptake were consistent with the results of visual inspection. CONCLUSION Visual assessment of [123I]-FP-CIT SPECT images is an easily applied diagnostic test which is helpful in the differential diagnosis of tremor disorders and in confirming a clinical diagnosis of a hypokinetic-rigid syndrome.

A 36 year old man, who sustained a skull fracture in 1984, was unconscious for 24 hours, and developed signs of Parkinson's syndrome 6 weeks after the injury. When assessed in 1995, neuroimaging disclosed a cerebral infarction due to trauma involving the left caudate and lenticular nucleus. Parkinson's syndrome was predominantly right sided, slowly progressive, and unresponsive to levodopa therapy. Reaction time tests showed slowness of movement initiation and execution with both hands, particularly the right. Recording of movement related cortical potentials suggested bilateral deficits in movement preparation. Neuropsychological assessment disclosed no evidence of major deficits on tests assessing executive function or working memory, with the exception of selective impairments on the Stroop and on a test of self ordered random number sequences. There was evidence of abulia. The results are discussed in relation to previous literature on basal ganglia lesions and the effects of damage to different points of the frontostriatal circuits.