Physical performance of a positron tomograph for brain imaging with retractable septa

Spinks, T.J.; Jones, Terry; Bailey, Dale L.; Townsend, David W.; Grootoonk, S.; Bloomfield, Peter; Gilardi, M.C.; Casey, M.; Sipe, B.; Reed, Julie

doi:10.1088/0031-9155/37/8/002

Cited by 286 publications

(128 citation statements)

References 16 publications

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“…Subject preparation and PET scans were collected, reconstructed to about 6 mm FWHM, and aligned as previously described (Racette et al 2001) using a Siemens/CTI 953B scanner in 3D-mode. (Spinks et al 1993) A reviewer blinded to the clinical status of the subject outlined an occipital region as well as the entire caudate, anterior and posterior putamen on each side of a magnetic resonance image (3D MPRAGE) for each subject. This MR image was co-registered to the [ 18 F]FDOPA PET image using a validated method.…”

Section: [ 18 F]fdopa Pet Studiesmentioning

confidence: 99%

[¹⁸F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

Racette

Good

Antenor

et al. 2006

American J of Med Genetics Pt B

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Parkinson Disease (PD) is a late onset disorder with age-dependent penetrance that may confound genetic studies since affected individuals may not demonstrate clinical manifestations at the time of evaluation. The use of endophenotypes, biologic surrogates for clinical disease diagnoses, may permit more accurate classification of at-risk subjects. Positron emission tomography (PET) measurements of 6-[ 18 F]fluorodopa ([ 18 F]FDOPA) uptake indicate nigrostriatal neuronal integrity and may provide a useful endophenotype for PD linkage studies. We performed [ 18 F]FDOPA PET in 11 members of a large, multi-incident Amish family with PD, 24 normals and 48 people with clinically definite idiopathic PD (PD controls). Clinical diagnoses in the Amish were clinically definite PD in four, clinically probable in one, clinically possible in five, and normal in one. Abnormal [ 18 F]FDOPA posterior putamen uptake was defined as less than three standard deviations below the normal mean. The criteria were applied to the Amish sample to determine a PET endophenotype for each. We performed genetic simulations using SLINK to model the effect phenoconversion with the PET endophenotype had on logarithm of odds (LOD) scores. PET endophenotype confirmed the status of two clinically definite subjects. Two clinically definite Amish PD subjects had normal PETs. Two possible PD were converted to "PET definite PD". The remainder had normal PETs. The average maximum LOD score with the pre-PET was 6.14±0.84. Simulating phenoconversion of subjects with unknown phenotypes increased the LOD score to 7.36±1.23. The [ 18 F]FDOPA PET endophenotype permits phenoconversion in multi-incident PD families and may increase LOD score accuracy and power of an informative pedigree.

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Section: [ 18 F]fdopa Pet Studiesmentioning

confidence: 99%

[¹⁸F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

Racette

Good

Antenor

et al. 2006

American J of Med Genetics Pt B

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“…The ECAT 953B scanner has an axial field of view of 10.65 cm (Spinks et al, 1992). The mean spatial resolution is 5.8 mm (x) Â 5.8 mm (y) Â 5.9 mm (z) at full-width at halfmaximum.…”

Section: Estimation Of Flesinoxan Occupancy In Man Using [ 11 C]way-1mentioning

confidence: 99%

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Bantick

Rabiner

Hirani

et al. 2003

Neuropsychopharmacol

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Drugs acting on the 5-HT 1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT 1A receptor occupancy by the 5-HT 1A agonist drugs flesinoxan (a highly selective probe for the 5-HT 1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT 1A antagonist radiotracer [ 11 C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [ 11 C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT 1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (71 SD) for flesinoxan was 8.7% (713%), and for ziprasidone 4.6% (717%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17-57%) at 0.25 mg/kg and above. We conclude that 5-HT 1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT 1A antagonists bind equally to low-and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.

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“…PET scans were performed on an ECAT 953B PET camera (CTI/Siemens, Knoxville, TN, USA) (Spinks et al 1992) in three-dimensional mode with dual window scatter correction (Grootoonk et al 1996). [ 11 C]WAY-100635 was prepared at the Cyclotron Unit by 11 C-carboxylation of a Grignard reagent .…”

Section: Pet Scan Acquisitionmentioning

confidence: 99%

β-blocker Binding to Human 5-HT1A Receptors in vivo and in vitro Implications for Antidepressant Therapy

Rabiner

2000

Neuropsychopharmacology

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A novel strategy for improving the treatment of depressive illness is augmentation of antidepressants with a 5-HT1SSRIs are increasingly used in the pharmacological treatment of depression. SSRIs specifically block 5-HT reuptake sites leading to an eventual increase of 5-HT in terminal synapses; an effect considered to be an important component of antidepressant action ). SSRIs are better tolerated than less selective agents such as tricyclic antidepressants (TCAs) (Anderson 1997), however, their efficacy is no greater (Rudorfer and Potter 1989) ( ≅ 70% of patients respond), and at least 2-3 weeks of treatment is required for the appearance of meaningful therapeutic response (Paykel and Priest 1992).Preclinical studies suggest the inhibition of 5-HT reuptake by SSRIs, does not lead to increased 5-HT levels in terminal synapses until an adaptive desensitization of inhibitory 5-HT 1A autoreceptors has occurred (Blier et al. NO . 3 1990;Chaput et al. 1986;Chaput et al. 1991;de Montigny et al. 1990;Hjorth and Auerbach 1994). These autoreceptors, located on 5-HT neuronal cell bodies in the raphe nuclei, inhibit 5-HT neurone firing, and hence 5-HT release in terminal synapses (VanderMaelen et al. 1986;Adell and Artigas 1991;Invernizzi et al. 1992;Sharp et al. 1989). Thus, indirect 5-HT 1A autoreceptor activation by SSRIs (via elevated 5-HT in the raphe nuclei) may impair the drug's therapeutic efficacy until desensitization has occurred. Theoretically, co-administration of 5-HT 1A autoreceptor antagonists (blocking the tonic inhibitory effect of 5-HT on the autoreceptor), together with SSRIs, may decrease the time needed to achieve clinical benefit and lead to a greater therapeutic effect (Hjorth 1993; Artigas 1993). In the absence of selective 5-HT 1A receptor antagonists for human use, therapeutic trials have been conducted with pindolol, a ␤ -blocker with nanomolar affinity for the human 5-HT 1A receptor in transfected cells in culture (Newman-Tancredi et al. 1998). Controlled clinical trials have produced mixed results. Four studies demonstrated a beneficial effect of pindolol augmentation of SSRI treatment (Zanardi et al. 1997;Perez et al. 1997;Bordet et al. 1998;Maes et al. 1996), one study showed a mixed response (Tome et al. 1997), while three studies failed to demonstrate any antidepressant benefit (Moreno et al. 1997;Berman et al. 1997;Perez et al. 1999).The equivocal results of clinical studies raise several questions about pindolol's proposed mechanism of action. Firstly it is not clear whether the dose of pindolol used clinically (typically 2.5 mg thrice daily (tds)), achieves a significant occupancy of 5-HT 1A receptors in the living human brain. Secondly, emergent evidence from preclinical studies indicates that pindolol, unlike certain other ␤ -blockers, may have 5-HT 1A partial agonist properties (Hjorth and Carlsson 1986;Newman-Tancredi et al. 1998;Clifford et al. 1998;Gartside et al. 1999). Partial agonism could lead to an activation of 5-HT 1A autoreceptors with subsequent decrease in 5-HT rele...

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Physical performance of a positron tomograph for brain imaging with retractable septa

Cited by 286 publications

References 16 publications

[¹⁸F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

[¹⁸F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

Occupancy of Agonist Drugs at the 5-HT1A Receptor

β-blocker Binding to Human 5-HT1A Receptors in vivo and in vitro Implications for Antidepressant Therapy

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Physical performance of a positron tomograph for brain imaging with retractable septa

Cited by 286 publications

References 16 publications

[18F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

[18F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

Occupancy of Agonist Drugs at the 5-HT1A Receptor

β-blocker Binding to Human 5-HT1A Receptors in vivo and in vitro Implications for Antidepressant Therapy

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Product

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[¹⁸F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies

[¹⁸F]FDOPA PET as an endophenotype for Parkinson's Disease linkage studies