Faculty Bibliography

Utilizing postmortem data (Breese et al. [2000] Neuropsychopharmacology 23:351-364), we hypothesized that the densities of high-affinity neuronal alpha4beta2 nicotinic acetylcholine receptors (nAChRs) in the brain exist in a continuum from highest to lowest as follows: smokers without schizophrenia > smokers with schizophrenia > nonsmokers without schizophrenia > nonsmokers with schizophrenia. Application of the Kruskal-Wallis Test (Statacorp, 2003) to the postmortem data (Breese et al. [2000] Neuropsychopharmacology 23:351-364) confirmed the hypothesized order in the cortex and the hippocampus and attained significance in the caudate and the thalamus. Positron emission tomography (PET) was performed for 60 min at 6 h after the intravenous administration of 444 megabequerels [MBq] (12 mCi) 2-[(1)(8)F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[(1)(8)F]FA), a radiotracer for high-affinity neuronal alpha4beta2 nAChRs, as a bolus plus continuous infusion to 10 adults (seven men and three women) (six smokers including five with paranoid schizophrenia and four nonsmokers) ranging in age from 22 to 56 years (mean 40.1, standard deviation 13.6). The thalamic nondisplaceable binding potential (BP(ND) ) was 1.32 +/- 0.19 (mean +/- standard deviation) for healthy control nonsmokers; 0.50 +/- 0.19 for smokers with paranoid schizophrenia; and 0.51 for the single smoker without paranoid schizophrenia. The thalamic BP(ND) s of nonsmokers were significantly higher than those of smokers who smoked cigarettes a few hours before the scans (P = 0.0105) (StataCorp, 2003), which was likely due to occupancy of nAChRs by inhaled nicotine in smokers. Further research is needed to rule out the effects of confounding variables.

OBJECTIVES: Lutetium-177-labeled ethylenediamine-N,N,N',N'-tetrakis (methylene phosphonic acid) ((1)(7)(7)Lu-EDTMP), a beta-emitting bone-seeking therapeutic radiopharmaceutical being assessed as an agent for palliation of bone pain, can emit suitable gamma-photons for scintigraphy. This investigation sought to characterize its optimal conditions for whole-body gamma camera imaging in patients. MATERIALS AND METHODS: Eleven patients with bone metastases underwent whole-body bone scanning using both (9)(9)mTc-methyl-diphosphonate ((9)(9)mTc-MDP) and (1)(7)(7)Lu-EDTMP (29.4 +/- 12.5 MBq/kg BW) utilizing a dual-head camera. For lutetium-177 imaging, two types of collimators, low-energy high-resolution (LEHR) and medium-energy general-purpose (MEGP), and two different peak energies of 113 and 208 keV were used. RESULTS: The femur-to-muscle uptake ratio (F/M) of (9)(9)mTc-MDP was 2.69 +/- 1.06. For (1)(7)(7)Lu-EDTMP, the significantly highest F/Ms were found at 24 h (12.59 +/- 5.73) and 48 h (12.54 +/- 5.23) by applying MEGP collimators and collecting the 208 keV photons. In all the combinations of collimator and peak energy, the F/Ms at 24 and 48 h are significantly higher than those at 1 h, except the combination of LEHR collimator and 208 keV peak energy. Lesion-to-normal bone uptake ratios of the (9)(9)mTc-MDP bone scan and images at the 24 and the 48-h phases of Lu-EDTMP were analyzed. MEGP and 208 keV had significantly higher values in lesion-to-normal bone uptake ratios. The combination of LEHR and 208 keV provided the poorest images. CONCLUSION: (1)(7)(7)Lu-EDTMP can provide fine whole-body images with the best results when applying medium-energy collimation and collecting the 208 keV energy photons and alternatively by collecting both 208 and 113 keV photons for higher count statistics. The most appropriate time point for imaging is around 24 h after injection.

Rett syndrome (RTT) is a neurodevelopmental disability characterized by mutations in the X-linked methyl-CpG-binding protein 2 located at the Xq28 region. The severity is modified in part by X chromosomal inactivation resulting in wide clinical variability. We hypothesized that the ability to perform the activities of daily living (ADL) is correlated with the density of vesicular acetylcholine transporters in the striata of women with RTT. The density of the vesicular acetylcholine transporters in the living human brain can be estimated by single-photon emission-computed tomography (SPECT) after the administration of (-)-5-[(1)(2)(3)I]iodobenzovesamicol ([(1)(2)(3)I]IBVM). Twenty-four hours following the intravenous injection of approximately 333 MBq (9 mCi) [(1)(2)(3) I]IBVM, four women with RTT and nine healthy adult volunteer control participants underwent SPECT brain scans for 60 min. The Vesicular Acetylcholine Transporter Binding Site Index (Kuhl et al., 1994), a measurement of the density of vesicular acetylcholine transporters, was estimated in the striatum and the reference structure, the cerebellum. The women with RTT were assessed for certain ADL. Although the striatal Vesicular Acetylcholine Transporter Binding Site Index was not significantly lower in RTT (5.2 +/- 0.9) than in healthy adults (5.7 +/- 1.6), RTT striatal Vesicular Acetylcholine Transporter Binding Site Indices and ADL scores were linearly associated (ADL = 0.89*(Vesicular Acetylcholine Transporter Binding Site Index) + 4.5; R(2) = 0.93; P < 0.01), suggesting a correlation between the ability to perform ADL and the density of vesicular acetylcholine transporters in the striata of women with RTT. [(1)(2)(3)I]IBVM is a promising tool to characterize the pathophysiological mechanisms of RTT and other neurodevelopmental disabilities.

STUDY OBJECTIVES: Prior studies, all using SPECT techniques, failed to find any differences for dopamine transporter (DAT) in restless legs syndrome (RLS) subjects. The distinct pharmacokinetic properties associated with SPECT-determined DAT along with rapid biodynamic changes in DAT may, however, have missed membrane-bound DAT differences. The current studies assessed real-time DAT binding potentials (BP) in striatum of RLS patients using (11)C-methylphenidate and PET techniques. DESIGN: RLS medications were stopped at least 11 days prior to the PET study. Clinical severity of RLS was also assessed. PET scans were performed at 2 different times of day (starting at 08:30 and 19:30) in separate groups of subjects. The primary outcome measure was total striatal DAT BP. PARTICIPANTS: Thirty-six patients with primary RLS and 34 age- and gender-matched controls. RESULTS: RLS subjects had significantly lower DAT binding in the striatum compared to controls on both the Day and the Night scans. DAT was decreased in putamen and caudate but not the ventral striatum of RLS subjects. There were no diurnal differences in DAT for the total group or for control and RLS separately. DAT BP did not correlate with any clinical measures of RLS. CONCLUSION: The current study found a significant decrease in DAT BP in two independent studies. These results when viewed along with prior RLS SPECT and autopsy studies of DAT, and cell culture studies with iron deficiency and DAT, suggest that membrane-bound striatal DAT, but not total cellular DAT, may be decreased in RLS.

This review depicts characteristics of nuclear neuroimaging investigations of dopamine release in response to non-pharmacological stimuli. Investigations of dopamine release in response to pharmacological challenges have focused mainly on the striatum, a region with a relatively high density of dopamine D(2)/D(3) receptors. Non-pharmacological stimuli likely elicit dopamine release in extrastriatal regions with a relatively low density of dopamine D(2)/D(3) receptors. Several strategies will facilitate the optimal design of investigations of dopamine release in response to non-pharmacological stimuli. (1) Employ radioligands with relatively high affinities for dopamine D(2)/D(3) receptors in extrastriatal regions, including [(11)C] FLB457 and [(11)C] fallypride. (2) Correct images for head movement during the scanning procedure. (3) Develop protocols to incorporate the influences of regional blood flow on scans of dopamine D(2)/D(3) receptors in the striatum and in extrastriatal regions. (4) Recruit healthy adults aged 18 to 35 years to avoid the effects of ageing. (5) Identify the phase of the menstrual cycle for women to account for the normal alterations in dopamine release in the various hormonal stages. Utilization of novel techniques to quantitate the dopamine release in the appropriate extrastriatal regions will likely result in fruitful advances in knowledge about non-pharmacological alternative interventions including acupuncture, the external Qi of Yan Xin Qigong, and other therapies of traditional Chinese medicine. Neuroimaging investigations of dopamine release following these alternative treatments will likely facilitate the appropriate application of alternative treatments to a vast spectrum of nervous and mental diseases. Since the effects of dopamine release on drug and non-drug interventions are powerful tools to assess the pathophysiology and the treatment of neuropsychiatric disorders, we provide this review of the literature to guide future research.