Anne M. Landau

In vivo imaging of neuromelanin in Parkinson's disease using 18F-AV-1451 PET.

The tau tangle ligand (18)F-AV-1451 ((18)F-T807) binds to neuromelanin in the midbrain, and may therefore be a measure of the pigmented dopaminergic neuronal count in the substantia nigra. Parkinsons disease is characterized by progressive loss of dopaminergic neurons. Extrapolation of post-mortem data predicts that a ∼30% decline of nigral dopamine neurons is necessary to cause motor symptoms in Parkinsons disease. Putamen dopamine terminal loss at disease onset most likely exceeds that of the nigral cell bodies and has been estimated to be of the order of 50-70%. We investigated the utility of (18)F-AV-1451 positron emission tomography to visualize the concentration of nigral neuromelanin in Parkinsons disease and correlated the findings to dopamine transporter density, measured by (123)I-FP-CIT single photon emission computed tomography. A total of 17 patients with idiopathic Parkinsons disease and 16 age- and sex-matched control subjects had (18)F-AV-1451 positron emission tomography using a Siemens high-resolution research tomograph. Twelve patients with Parkinsons disease also received a standardized (123)I-FP-CIT single photon emission computed tomography scan at our imaging facility. Many of the patients with Parkinsons disease displayed visually apparent decreased (18)F-AV-1451 signal in the midbrain. On quantitation, patients showed a 30% mean decrease in total nigral (18)F-AV-1451 volume of distribution compared with controls (P = 0.004), but there was an overlap of the individual ranges. We saw no significant correlation between symptom dominant side and contralateral nigral volume of distribution. There was no correlation between nigral (18)F-AV-1451 volume of distribution and age or time since diagnosis. In the subset of 12 patients, who also had a (123)I-FP-CIT scan, the mean total striatal dopamine transporter signal was decreased by 45% and the mean total (18)F-AV-1451 substantia nigra volume of distribution was decreased by 33% after median disease duration of 4.7 years (0.5-12.4 years). (18)F-AV-1451 positron emission tomography may be the first radiotracer to reflect the loss of pigmented neurons in the substantia nigra of parkinsonian patients. The magnitude of the nigral signal loss was smaller than the decrease in striatal dopamine transporter signal measured by dopamine transporter single photon emission computed tomography. These findings suggest a more severe loss of striatal nerve terminal function compared with neuronal cell bodies, in accordance with the post-mortem literature.

Serotonergic modulation of receptor occupancy in rats treated with L-DOPA after unilateral 6-OHDA lesioning.

J. Neurochem (2012) 120, 806–817.

Electroconvulsive therapy alters dopamine signaling in the striatum of non-human primates.

Electroconvulsive therapy (ECT) is one of the most effective therapies for depression and has beneficial motor effects in parkinsonian patients. However, little is known about the mechanisms of therapeutic action of ECT for either condition. The aim of this work was to explore the impact of ECT on dopaminergic function in the striatum of non-human primates. Rhesus monkeys underwent a course of six ECT treatments under a human clinical protocol. Longitudinal effects on the dopaminergic nigrostriatal system were studied over 6 weeks using the in vivo capabilities of positron emission tomography (PET). PET scans were performed prior to the onset of ECT treatments and at 24–48 h, 8–10 days, and 6 weeks after the final ECT treatment. Early increases in dopamine transporter and vesicular monoamine transporter 2 binding returned to baseline levels by 6 weeks post-ECT. Transient increases in D1 receptor binding were also observed, whereas the binding potential to D2 receptors was unaltered. The increase in dopaminergic neurotransmission suggested by our results may account in part for the therapeutic effect of ECT in mood disorders and Parkinsons disease.

Acute Vagal Nerve Stimulation Lowers α2 Adrenoceptor Availability: Possible Mechanism of Therapeutic Action.

BACKGROUND Vagal nerve stimulation (VNS) emerged as an anti-epileptic therapy, and more recently as a potential antidepressant intervention. OBJECTIVE/HYPOTHESIS We hypothesized that salutary effects of VNS are mediated, at least in part, by augmentation of the inhibitory effects of cortical monoaminergic neurotransmission at appropriate receptors, specifically adrenoceptors. Our objective was to measure the effect of acute VNS on α2 adrenoceptor binding. METHODS Using positron emission tomography (PET), we measured changes in noradrenaline receptor binding associated with acute VNS stimulation in six anesthetized Göttingen minipigs. We used the selective α2 adrenoceptor antagonist [11C]yohimbine, previously shown to be sensitive to competition from the receptors endogenous ligands, as a surrogate marker of monoamine release. PET records were acquired 4-6 weeks after the implant of a VNS electrode in minipigs before and within 30 min of the initiation of 1 mA stimulation. Kinetic analysis with the Logan graphical linearization generated tracer volumes of distribution for each condition. We used an averaged value of the distribution volume of non-displaceable ligand (VND), to calculate binding potentials for selected brain regions of each animal. RESULTS VNS treatment markedly reduced the binding potential of yohimbine in limbic, thalamic and cortical brain regions, in inverse correlation with the baseline binding potential. CONCLUSION The result is consistent with release of noradrenaline by antidepressant therapy, implying a possible explanation for the antidepressant effect of VNS.

Effects of Anesthesia and Species on the Uptake or Binding of Radioligands In Vivo in the Göttingen Minipig

Progress in neuroscience research often involves animals, as no adequate alternatives exist to animal models of living systems. However, both the physiological characteristics of the species used and the effects of anesthesia raise questions of common concern. Here, we demonstrate the confounding influences of these effects on tracer binding in positron emission tomography (PET). We determined the effects of two routinely used anesthetics (isoflurane and propofol) on the binding of two tracers of monoamine function, [11C]SCH23390, a tracer of the dopamine D1 and D5 receptors, and the alpha2-adrenoceptor antagonist, [11C]yohimbine, in Göttingen minipigs. The kinetics of SCH23390 in the pigs differed from those of our earlier studies in primates. With two different graphical analyses of uptake of SCH23390, the initial clearance values of this tracer were higher with isoflurane than with propofol anesthesia, indicative of differences in blood flow, whereas no significant differences were observed for the volumes of distribution of yohimbine. The study underscores the importance of differences of anesthesia and species when the properties of radioligands are evaluated under different circumstances that may affect blood flow and tracer uptake. These differences must be considered in the choice of a particular animal species and mode of anesthesia for a particular application.

Electroconvulsive shocks decrease α2-adrenoceptor binding in the Flinders rat model of depression

Despite years of drug development, electroconvulsive therapy (ECT) remains the most effective treatment for severe depression. The exact therapeutic mechanism of action of ECT is still unresolved and therefore we tested the hypothesis that the beneficial effect of ECT could in part be the result of increased noradrenergic neurotransmission leading to a decrease in α2-adrenoceptor binding. We have previously shown that both the Flinders sensitive line (FSL) and Flinders resistant line (FRL) rats had altered α2-adrenoceptor binding compared to control Sprague-Dawley (SD) rats. In this study, we treated female FSL, FRL and SD rats with electroconvulsive shock (ECS), an animal model of ECT, or sham stimulation for 10 days before brains were removed and cut into 20µm thick sections. Densities of α2-adrenoceptors were measured by quantitative autoradiography in the hippocampus, thalamic nucleus, hypothalamus, amygdala, frontal cortex, insular cortex, and perirhinal cortex using the α2-adrenoceptor antagonist, [(3)H]RX 821002. ECS decreased the binding of α2-adrenoceptors in cortical regions in the FSL and cortical and amygdaloid regions in the control FRL rats compared to their respective sham treated group. The normal SD controls showed no significant response to ECS treatment. Our data suggest that the therapeutic effect of ECS may be mediated through a decrease of α2-adrenoceptors, probably due to a sustained increase in noradrenaline release. These data confirm the importance of the noradrenergic system and the α2-adrenoceptor in depression and in the mechanism of antidepressant treatments.

Early synaptic dysfunction induced by α-synuclein in a rat model of Parkinson’s disease

Evidence suggests that synapses are affected first in Parkinson’s disease (PD). Here, we tested the claim that pathological accumulation of α-synuclein, and subsequent synaptic disruption, occur in absence of dopaminergic neuron loss in PD. We determined early synaptic changes in rats that overexpress human α-synuclein by local injection of viral-vectors in midbrain. We aimed to achieve α-synuclein levels sufficient to induce terminal pathology without significant loss of nigral neurons. We tested synaptic disruption in vivo by analyzing motor defects and binding of a positron emission tomography (PET) radioligand to the vesicular monoamine transporter 2, (VMAT2), [11C]dihydrotetrabenazine (DTBZ). Animals overexpressing α-synuclein had progressive motor impairment and, 12 weeks post-surgery, showed asymmetric in vivo striatal DTBZ binding. The PET images matched ligand binding in post-mortem tissue, and histological markers of dopaminergic integrity. Histology confirmed the absence of nigral cell death with concomitant significant loss of striatal terminals. Progressive aggregation of proteinase-K resistant and Ser129-phosphorylated α-synuclein was observed in dopaminergic terminals, in dystrophic swellings that resembled axonal spheroids and contained mitochondria and vesicular proteins. In conclusion, pathological α-synuclein in nigro-striatal axonal terminals leads to early axonal pathology, synaptic disruption, dysfunction of dopaminergic neurotransmission, motor impairment, and measurable change of VMAT2 in the absence of cell loss.

Increased GABAA receptor binding in amygdala after prenatal administration of valproic acid to rats

Objective Prenatal exposure to valproic acid (VPA) enhances the risk for later development of autism spectrum disorders (ASD). An altered gamma-aminobutyric acid (GABA) system may be a key factor in ASD. Here we investigated possible changes in the GABA system in rats exposed to a low dose of prenatal VPA. Method We performed autoradiography with [3H]muscimol, (a GABAA receptor agonist), and [11C]Ro15-4513 (a partial agonist of the GABAA α1+5 receptor subtypes), in brain sections containing amygdala, thalamus and hippocampus of rats treated prenatally with 20 mg/kg VPA or saline from the 12th day of gestation. Result Prenatal VPA significantly increased [11C]Ro15-4513 binding in the left amygdala compared with controls (p<0.05). This difference was not observed in the hippocampus, thalamus or right amygdala. No differences were observed in [3H]muscimol binding. Conclusion We observed an asymmetric increase in GABAA receptor binding. Disturbances in the GABAA receptor system have also been detected in human autism with [11C]Ro15-4513.

Decreased in vivo α2 adrenoceptor binding in the Flinders Sensitive Line rat model of depression.

Depression is a debilitating heterogeneous disorder and the underlying mechanisms remain elusive. Alterations in monoaminergic neurotransmission, including noradrenergic, have been implicated in the etiology of depression. Although depression is difficult to model in animals, the availability of animal models with face, predictive and construct validity permits more in-depth investigations resulting in a greater understanding of the disease. We investigated the role of noradrenaline (NA) and α2 adrenoceptors in vivo in a genetic model of depression, the Flinders Sensitive Line (FSL) rat. We determined baseline differences in NA receptor volume of distribution to α2 adrenoceptors in FSL, in comparison with two routinely used controls, Flinders Resistant Line (FRL) and Sprague-Dawley (SD) rats using positron emission tomography (PET) imaging and the carbon-11 labeled radioligand yohimbine. We demonstrate a 42-47% reduction in the binding of the tracer in the cortex, striatum, cerebellum, thalamus and pons of FSL rats compared to the two control groups. Our results suggest that the behavioral deficits expressed in the FSL depression model are associated with functional over-activity of the NA system.

Quantification of [11C]yohimbine Binding to α2 Adrenoceptors in Rat Brain in vivo

We quantified the binding potentials (BPND) of [11C]yohimbine binding in rat brain to alpha-2 adrenoceptors to evaluate [11C]yohimbine as an in vivo marker of noradrenergic neurotransmission and to examine its sensitivity to the level of noradrenaline. Dual [11C]yohimbine dynamic positron emission tomography (PET) recordings were applied to five Sprague Dawley rats at baseline, followed by acute amphetamine administration (2 mg/kg) to induce elevation of the endogenous level of noradrenaline. The volume of distribution (VT) of [11C]yohimbine was obtained using Logan plot with arterial plasma input. Because alpha-2 adrenoceptors are distributed throughout the brain, the estimation of the BPND is complicated by the absence of an anatomic region of no displaceable binding. We used the Inhibition plot to acquire the reference volume, VND, from which we calculated the BPND. Acute pharmacological challenge with amphetamine induced a significant decline of [11C]yohimbine BPND of ∼38% in all volumes of interest. The BPND was greatest in the thalamus and striatum, followed in descending order by, frontal cortex, pons, and cerebellum. The experimental data demonstrate that [11C]yohimbine binding is sensitive to a challenge known to increase the extracellular level of noradrenaline, which can benefit future PET investigations of pathologic conditions related to disrupted noradrenergic neurotransmission.