Karmen K. Yoder

Striatal dopamine transporter availability in unmedicated bipolar disorder

OBJECTIVES Dopamine transmission abnormalities have been implicated in the etiology of bipolar disorder (BPD). However, there is a paucity of receptor imaging studies in BPD, and little information is available about the dopamine system in BPD. Reuptake of synaptic dopamine by the dopamine transporter (DAT) is the principal mechanism regulating dopamine neurotransmission, and is often used as a marker for presynaptic dopamine function. This positron emission tomography (PET) study investigated whether DAT availability differed between BPD and healthy control subjects. METHODS A total of 11 unmedicated BPD patients in either the euthymic or depressed phase and 13 closely matched healthy subjects underwent PET imaging with the DAT-selective radiotracer [(11) C]CFT and a structural magnetic resonance imaging (MRI) scan. Striatal binding potential (BP(ND) ) was estimated using the multilinear reference tissue model. Region of interest and analyses were conducted to test for differences in [(11) C]CFT BP(ND) between groups. RESULTS Unmedicated BPD subjects had significantly lower DAT availability relative to healthy controls in bilateral dorsal caudate. CONCLUSIONS The results of this study support the hypothesis that there are abnormalities in the dopaminergic system in BPD, and suggest that DAT availability may be related to the neuropathology of BPD. Future studies are needed to determine if DAT availability cycles with disease phase.

Influence of TSPO Genotype on 11C-PBR28 Standardized Uptake Values

11C-PBR28 binds to the high-affinity state of the translocator protein 18 kDa (TSPO). A single-nucleotide polymorphism (rs6971) within the human TSPO gene determines the affinity state of the TSPO. The rs6971 genotype determines whether individuals express the high-, low-, or mixed-affinity phenotype of TSPO. The rs6971 genotype corresponds to in vivo 11C-PBR28 binding, as measured quantitatively by total volume of distribution. However, it is not known whether standardized uptake value (SUV) can detect differences in brain 11C-PBR28 uptake by TSPO genotype. Methods: Thirty-two older adults (71.8 ± 7.94 y old) underwent 11C-PBR28 PET scanning; rs6971 genotype was imputed after genomewide genotyping. SUV was extracted for several brain regions. The sample included 19 C/C carriers (high-affinity phenotype), 12 T/C carriers (mixed-affinity), and 1 T/T carrier (low-affinity) for rs6971. Results: SUV was 30% lower in T/C subjects than in C/C subjects. Conclusion: The results indicate that brain 11C-PBR28 SUV is sensitive to TSPO genotype.

An improved synthesis of dopamine D2/D3 receptor radioligands [11C]fallypride and [18F]fallypride

Improved syntheses of dopamine D(2)/D(3) receptor radioligands [(11)C]Fallypride and [(18)F]Fallypride are reported. The phenolic precursor (9) for C-11 labeling and the Fallypride (10) reference standard were synthesized from the starting material 2-hydroxy-3-methoxy-5-(2-propenyl)benzoic acid methyl ester (1) in 7 and 8 steps with 16% and 5% overall chemical yields, respectively. The tosylated precursor (15) for F-18 labeling was synthesized from compound 1 in 5 steps with 32% overall chemical yield. An alternate synthetic approach for Fallypride has been developed using the same starting material 1 in 5 steps with 26% overall chemical yield. [(11)C]Fallypride ([(11)C]10) was prepared by O-[(11)C]methylation of the phenolic precursor with [(11)C]methyl triflate and purified with a semi-preparative HPLC method in 50-60% radiochemical yield, decay corrected to end of bombardment (EOB), based on [(11)C]CO(2), and 370+/-185 GBq/micromol specific radioactivity at EOB. [(18)F]Fallypride ([(18)F]10) was prepared by nucleophilic substitution of the tosylated precursor with K[(18)F]F/Kryptofix 2.2.2 and HPLC combined with solid-phase extraction (SPE) purification in variable (up to 50%) decay corrected radiochemical yield from K[(18)F]F and 111-222 GBq/micromol specific activity at EOB.

Positron emission tomography displacement sensitivity: predicting binding potential change for positron emission tomography tracers based on their kinetic characteristics

There is great interest in positron emission tomography (PET) as a noninvasive assay of fluctuations in synaptic neurotransmitter levels, but questions remain regarding the optimal choice of tracer for such a task. A mathematical method is proposed for predicting the utility of any PET tracer as a detector of changes in the concentration of an endogenous competitor via displacement of the tracer (a.k.a., its ‘vulnerability’ to competition). The method is based on earlier theoretical work by Endres and Carson and by the authors. A tracer-specific predictor, the PET Displacement Sensitivity (PDS), is calculated from compartmental model simulations of the uptake and retention of dopaminergic radiotracers in the presence of transient elevations of dopamine (DA). The PDS predicts the change in binding potential (ΔBP) for a given change in receptor occupancy because of binding by the endogenous competitor. Simulations were performed using estimates of tracer kinetic parameters derived from the literature. For D2/D3 tracers, the calculated PDS indices suggest a rank order for sensitivity to displacement by DA as follows: raclopride (highest sensitivity), followed by fallypride, FESP, FLB, NMSP, and epidepride (lowest). Although the PDS takes into account the affinity constant for the tracer at the binding site, its predictive value cannot be matched by either a single equilibrium constant, or by any one rate constant of the model. Values for ΔBP have been derived from published studies that employed comparable displacement paradigms with amphetamine and a D2/D3 tracer. The values are in good agreement with the PDS-predicted rank order of sensitivity to displacement.

Beer Flavor Provokes Striatal Dopamine Release in Male Drinkers: Mediation by Family History of Alcoholism

Striatal dopamine (DA) is increased by virtually all drugs of abuse, including alcohol. However, drug-associated cues are also known to provoke striatal DA transmission- a phenomenon linked to the motivated behaviors associated with addiction. To our knowledge, no one has tested if alcohol’s classically conditioned flavor cues, in the absence of a significant pharmacologic effect, are capable of eliciting striatal DA release in humans. Employing positron emission tomography (PET), we hypothesized that beer’s flavor alone can reduce the binding potential (BP) of [11C]raclopride (RAC; a reflection of striatal DA release) in the ventral striatum, relative to an appetitive flavor control. Forty-nine men, ranging from social to heavy drinking, mean age 25, with a varied family history of alcoholism underwent two [11C]RAC PET scans: one while tasting beer, and one while tasting Gatorade. Relative to the control flavor of Gatorade, beer flavor significantly increased self-reported desire to drink, and reduced [11C]RAC BP, indicating that the alcohol-associated flavor cues induced DA release. BP reductions were strongest in subjects with first-degree alcoholic relatives. These results demonstrate that alcohol-conditioned flavor cues can provoke ventral striatal DA release, absent significant pharmacologic effects, and that the response is strongest in subjects with a greater genetic risk for alcoholism. Striatal DA responses to salient alcohol cues may thus be an inherited risk factor for alcoholism.

Striatal D2/D3 receptor availability is inversely correlated with cannabis consumption in chronic marijuana users

BACKGROUND Although the incidence of cannabis abuse/dependence in Americans is rising, the neurobiology of cannabis addiction is not well understood. Imaging studies have demonstrated deficits in striatal D(2)/D(3) receptor availability in several substance-dependent populations. However, this has not been studied in currently using chronic cannabis users. OBJECTIVE The purpose of this study was to compare striatal D(2)/D(3) receptor availability between currently using chronic cannabis users and healthy controls. METHODS Eighteen right-handed males age 18-34 were studied. Ten subjects were chronic cannabis users; eight were demographically matched controls. Subjects underwent a [(11)C]raclopride (RAC) PET scan. Striatal RAC binding potential (BP(ND)) was calculated on a voxel-wise basis. Prior to scanning, urine samples were obtained from cannabis users for quantification of urine Δ-9-tetrahydrocannabinol (THC) and THC metabolites (11-nor-Δ-9-THC-9-carboxylic acid; THC-COOH and 11-hydroxy-THC;OH-THC). RESULTS There were no differences in D(2)/D(3) receptor availability between cannabis users and controls. Voxel-wise analyses revealed that RAC BP(ND) values were negatively associated with both urine levels of cannabis metabolites and self-report of recent cannabis consumption. CONCLUSIONS In this sample, current cannabis use was not associated with deficits in striatal D(2)/D(3) receptor availability. There was an inverse relationship between chronic cannabis use and striatal RAC BP(ND). Additional studies are needed to identify the neurochemical consequences of chronic cannabis use on the dopamine system.

Role of the Basolateral Amygdala in Panic Disorder

Anxiety disorders are the most prevalent of all psychiatric problems. The neurobiological mechanisms of severe anxiety states, such as panic disorder, are still poorly understood. A number of CNS areas have been implicated in the generation of panic responses, and it is likely that a “network” of interconnected nuclei may regulate this important survival reflex under normal circumstances. In pathological conditions, such as panic disorder, one or more critical regulatory sites may be dysfunctional, such that a panic response is elicited with minimal or inappropriate stimuli. One such regulatory area is the dorsomedial hypothalamus (DMH), where chronic GABA dysfunction results in a panic-like response.1 Another area is the anterior basolateral amygdala (aBLA), where blocking a tonic GABAergic inhibition results in physiological and behavioral responses associated with panic attacks. The aBLA has pyramidal cells that are probably glutamatergic and nonpyramidal cells that contain GABA and presumably function as inhibitory neurons on the pyramidal cells.2 Blockade of GABAA receptors in the aBLA with bicuculline methiodide (BMI) elicits increases in heart rate (HR), blood pressure (BP), respiratory rate, and anxiety, as measured by the social interaction (SI) test,3 suggesting a panic-like response. In addition, injecting repeated subthreshold doses of BMI into the aBLA induces long-term synaptic plasticity (termed “priming”) in the aBLA, such that the animals become chronically anxious and reactive to previously subthreshold stimuli.4 Further, there appears to be a tonic GABAergic inhibition and EAA-mediated excitation within the aBLA,5 and the panic-like responses following GABAA receptor blockade or the priming phenomenon seen with subthreshold GABA blockade is an N-methyl-D-aspartate (NMDA) receptor-dependent phenomenon.6 Also, if priming of aBLA is similar to the development of pathological anxiety states, such as panic disorder, then the primed animals would be predicted to become responsive to sodium lactate (and yohimbine) infusions that provoke panic attacks clinically. This study reports some preliminary findings about the panic responses in rats primed with repeated subthreshold GABAA receptor blockade in the aBLA.

Amyloid pathway-based candidate gene analysis of [ 11 C]PiB-PET in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort

Amyloid imaging with [11 C]Pittsburgh Compound-B (PiB) provides in vivo data on plaque deposition in those with, or at risk for, Alzheimer’s disease (AD). We performed a gene-based association analysis of 15 quality-controlled amyloid-pathway associated candidate genes in 103 Alzheimer’s Disease Neuroimaging Initiative participants. The mean normalized PiB uptake value across four brain regions known to have amyloid deposition in AD was used as a quantitative phenotype. The minor allele of an intronic SNP within DHCR24 was identified and associated with a lower average PiB uptake. Further investigation at whole-brain voxel-wise level indicated that non-carriers of the minor allele had higher PiB uptake in frontal regions compared to carriers. DHCR24 has been previously shown to confer resistance against beta-amyloid and oxidative stress-induced apoptosis, thus our findings support a neuroprotective role. Pathway-based genetic analysis of targeted molecular imaging phenotypes appears promising to help elucidate disease pathophysiology and identify potential therapeutic targets.

GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer’s disease implicates microglial activation gene IL1RAP

Brain amyloid deposition is thought to be a seminal event in Alzheimers disease. To identify genes influencing Alzheimers disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by (18)F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10(-9)) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimers disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical (11)C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.

Fully automated synthesis and initial PET evaluation of [11C]PBR28

Fully automated synthesis and initial PET evaluation of a TSPO radioligand, [11C]PBR28 (N-(2-[11C]methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide), are reported. These results facilitate the potential preclinical and clinical PET studies of [11C]PBR28 in animals and humans.