Andrew D. Roberts

The impact of prenatal stress, fetal alcohol exposure, or both on development: perspectives from a primate model

The question of whether psychosocial stress during pregnancy (alone or in combination with fetal alcohol exposure) has negative consequences for offspring has not been clearly established in human studies. In this article, we present an overview of three prospective longitudinal studies. Using rhesus monkeys as subjects, a noise or hormone stressor, alone or in combination with moderate level alcohol solution, was presented daily during different stages of pregnancy. Prenatal stress resulted in lighter birth weights in two of three studies, and males from the alcohol plus noise stress condition had reduced birth weights. There were no significant effects of any of the prenatal treatments on gestation duration. Both prenatal stress and moderate fetal alcohol exposure reduced attention span and neuromotor capabilities of offspring during the first month of life, while early gestation prenatal stress, during the period of neuronal migration, emerged as a period of enhanced vulnerability for these effects. Under conditions of challenge, prenatally stressed monkeys showed more disturbance behaviors and reduced locomotion and exploration as well as altered hypothalamic-pituitary-adrenal (HPA) axis reactivity to stress. Fetal alcohol exposed monkeys also showed increased HPA axis activity in response to stressful conditions. Finally, altered patterns of alcohol consumption during adolescence were associated with prenatal stress.

Subthalamic Glutamic Acid Decarboxylase Gene Therapy: Changes in Motor Function and Cortical Metabolism

Parkinsons disease (PD) is associated with increased excitatory activity within the subthalamic nucleus (STN). We sought to inhibit STN output in hemiparkinsonian macaques by transfection with adeno-associated virus (AAV) containing the gene for glutamic acid decarboxylase (GAD). In total, 13 macaques were rendered hemiparkinsonian by right intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. Seven animals were injected with AAV-GAD into the right STN, and six received an AAV gene for green fluorescent protein (GFP). Videotaped motor ratings were performed in a masked fashion on a weekly basis over a 55-week period. At 56 weeks, the animals were scanned with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Histological examination was performed at the end of the study. No adverse events were observed after STN gene therapy. We found that the clinical rating scores for the two treatment groups had different patterns of change over time (group × time interaction, P<0.001). On FDG PET, the GAD animals exhibited an increase in glucose utilization in the right motor cortex relative to GFP controls (P<0.001). Metabolism in this region correlated with clinical ratings at end point (P<0.01). Histology confirmed GAD expression in treated animals. These findings suggest that STN AAV-GAD is well tolerated and potentially effective in a primate model of PD. The changes in motor cortical glucose utilization observed after gene therapy are consistent with the modulation of metabolic brain networks associated with this disorder.

FluoroDOPA PET shows the nondopaminergic as well as dopaminergic destinations of levodopa

Objective: To evaluate the visible and quantitative anatomic distribution of fluorine-18–labeled l-DOPA in the healthy human brain, to thereby expand the understanding of extrastriatal sites of levodopa function, and to provide a broader foundation for clinical and research studies of fluoroDOPA accumulation in patients. Methods: The authors performed dynamic three-dimensional fluoroDOPA PET imaging in 10 healthy volunteers and analyzed the images visually and quantitatively. Twenty-eight regions of interest were applied to parametric images of the uptake rate constant (using the multiple-time graphic plot method with cortical input function) and also were used to quantitate regional radioactivity at 80 to 90 minutes. The authors correlated the uptake constants with published human regional neurotransmitter and decarboxylation data. Results: PET imaging with fluoroDOPA demonstrates trapping of labeled dopamine or its metabolites in substantial quantities in many areas of the brain other than the mesostriatal pathways, including considerable uptake in the serotonergic and noradrenergic areas of the hypothalamus and brainstem as well as in extrastriatal cerebral sites. Total fluoroDOPA uptake correlates best with the sum of catecholamine and indolamine concentrations in the brain and moderately well with regional activity of aromatic l-amino acid decarboxylase, but correlates poorly with extrastriatal dopamine concentration. Conclusion: Neither l-DOPA nor its radiolabeled analog fluoroDOPA is metabolized or accumulates specifically in dopaminergic or even catecholaminergic neurons. Substantial dopamine production within serotonin and norepinephrine neurons may play a role in either therapeutic effects or adverse effects of therapy with l-DOPA.

A High-Brightness Source for Polarized Atomic Hydrogen and Deuterium

Abstract An atomic beam source for polarized hydrogen and deuterium is described. The source, which will be used to supply atoms to a polarized gas target cell for internal-target experiments in storage rings, was designed to optimize the flux of polarized atoms into a 1 cm diameter 13 cm long tube placed 26 cm from the end of the last magnet. High-field permanent magnet sixpoles with a tapered bore are employed. Studies of gas scattering and dissociator output were combined with ray tracing calculations of atomic trajectories to find an optimum source design. The beam is cooled by thermal accomodation to an aluminum dissociator nozzle at 84 K. The beam intensity which passes through the 1 cm diameter, 13 cm long tube is (6.7 ± 0.1) × 10 16 atoms/s. The total hydrogen beam intensity is 8.6 × 10 16 atoms/s in two hyperfine spin states. The measured beam profile and intensity agree with calculations to within 10%.

Prenatal Stress Alters Early Neurobehavior, Stress Reactivity and Learning in Non-human Primates: A Brief Review

In this paper we review three prospective longitudinal studies from our laboratory examining the effects of prenatal stress on early neurobehavior, stress reactivity and learning performance in rhesus monkeys. Either a noise stressor or ACTH treatment was administered to pregnant monkeys during specific periods of pregnancy and offspring were examined repeatedly across development. In all three studies, the prenatally stressed monkeys showed reduced attention and impaired neuromotor functioning during the first month of life compared to controls from undisturbed pregnancies. When the monkeys were separated from their mothers or peers at 6–8 months of age, prenatally stressed monkeys exhibited more disturbance behavior and showed hypothalamic-pituitary-adrenal axis dysregulation. During adolescence, they exhibited impairments in learning, compared to controls.

Development of an improved target for [18F]F2 production

An A1 body target with improved yields of electrophilic [18F]F2 on the Siemens/CTI 11 MeV proton cyclotron at Wisconsin has been developed. The saturation yield is 3.10 +/- 0.40 GBq/microA for beam currents up to 45 microA. The target has routinely produced 20-40 GBq of [18F]F2 for clinical and experimental use over 1600 microA-h operation, with a maximum yield to date of 45.5 GBq (1.2 Ci). Target design, performance and reliability are discussed.

Water-cooled grid support for high-power irradiation with thin target windows.

A new thin window support system for the accelerator production of positron emitters (e.g. 17F, 18F 11C, 15O) has been developed. The integrated support grid and cooling design has been optimized for 6-13 MeV protons or deuterons. The water-cooled support grid regularly operated at > 100 microA of 6 MeV deuterons and protons. The grid performed without failure at > or = 50 microA of 13 MeV protons on a 3.1 MPa gas target using 25.4 microm aluminum target foil. Transmission for the smallest hole grid of 72% based on uniform parallel beam agreed with the measured yield of 71 +/- 1% compared to the theoretical maximum yield.

A High Power Target for the Production of 18F Fluoride

Abstract A target for high yield production of aqueous [ 18 F] fluoride at high beam currents has been developed for the 11 MeV Siemens/CTI RDS proton cyclotron at the University of Wisconsin. The silver body, gold backed target is characterized a small volume (400 μl) and is operated at high pressure (40 bar). The target yield is 79% of the theoretical maximum for beam currents up to 40 μA. The highest yield to date is 70 GBq. Target construction and performance are presented, and recent applications to PET radioisotope syntheses and radioactive beam production are discussed.

PET Measurement of rCBF in the presence of a neurochemical tracer

Functional neurochemical imaging can indicate neurotransmitter release by detecting changes in receptor occupancy. A dual tracer positron emission tomography (PET) technique is presented here to extend such studies by simultaneously measuring changes in regional cerebral blood flow (rCBF). This would permit correlations of task or drug induced changes in rCBF and neurochemical function. In this proposed method, the rapidly varying signal from a blood flow tracer is distinguished from the slowly changing signal due to a long-lived neurochemical tracer. As a proof of principle, baseline studies were carried out in rhesus monkeys. Two monkeys were anesthetized with isoflurane, and [18F]fallypride (t1/2=110 min), a dopamine D2 receptor antagonist, was injected. Starting 99-137 min after injection, PET images were acquired every 10 s while the blood flow tracer [17F]fluoromethane (t1/2=65 s) was administered by inhalation in a repeating pattern of 45 s on/45 s off. The observed time-activity curves for 2 ml brain regions were fit with a three compartment lung-body-brain model of fluoromethane kinetics with whole brain perfusion fixed. Comparing consecutive 6 min scans, reproducibility of relative rCBF and striatal [18F]fallypride concentration were 9 and 8%, respectively.

Localization of Trapping of 6-[18F] Fluoro-L-m-tyrosine, an Aromatic L-Amino Acid Decarboxylase Tracer for PET

The purpose of this study was to address four major questions regarding 6‐FMT, a noncatecholic PET tracer for AAAD: 1) Where is the specific uptake of 6‐FMT? 2) Why does it accumulate where and to the degree that it does? 3) How does its uptake differ from that of fluoroDOPA globally? and 4) Does its regional uptake differ significantly from that of fluoroDOPA? High‐resolution PET scans were obtained in three rhesus monkeys using 6‐FMT and in two of them using fluoroDOPA. Anatomic distribution was analyzed visually and quantitative uptake of 6‐FMT was compared with published regional decarboxylase activity and monoamine neurotransmitter concentrations. In addition to high uptake in the dopamine‐rich striatal nuclei, there was specific uptake of 6‐FMT in brain regions which have little dopaminergic innervation but which have other amines in significant concentration. 6‐FMT uptake correlated best with regional AAAD activity (r = 0.97). It correlated slightly less well with the sum of catecholamine and indolamine neurotransmitter concentrations, but does not correlate with dopamine concentration. The uptake of 6‐FMT is greater than that of fluoroDOPA, with only slight differences in their regional distributions. Radiolabeled analogs of DOPA are often implicitly or explicitly regarded as tracers for presynaptic dopaminergic function. However, localization of these tracers more broadly includes many regions with relatively high concentrations of norepinephrine and serotonin. This may be especially important in diseases or experimental states in which dopaminergic neurons are selectively reduced, and may allow for the study of nondopaminergic neuronal systems in vivo with this tracer. Synapse 34:111–123, 1999.