Kinetic modeling of the monoamine oxidase-B radioligand [18F]SMBT-1 in human brain with positron emission tomography.

This paper describes pharmacokinetic analyses of the monoamine-oxidase-B (MAO-B) radiotracer [18F](S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([18F]SMBT-1) for positron emission tomography (PET) brain imaging. Brain MAO-B expression is widespread, predominantly within astrocytes. Reactive astrogliosis in response to neurodegenerative disease pathology is associated with MAO-B overexpression. Fourteen elderly subjects (8 control, 5 mild cognitive impairment, 1 Alzheimer's disease) with amyloid ([11C]PiB) and tau ([18F]flortaucipir) imaging assessments underwent dynamic [18F]SMBT-1 PET imaging with arterial input function determination. [18F]SMBT-1 showed high brain uptake and a retention pattern consistent with the known MAO-B distribution. A two-tissue compartment (2TC) model where the K1/k2 ratio was fixed to a whole brain value best described [18F]SMBT-1 kinetics. The 2TC total volume of distribution (VT) was well identified and highly correlated (r2∼0.8) with post-mortem MAO-B indices. Cerebellar grey matter (CGM) showed the lowest mean VT of any region and is considered the optimal pseudo-reference region. Simplified analysis methods including reference tissue models, non-compartmental models, and standard uptake value ratios (SUVR) agreed with 2TC outcomes (r2 > 0.9) but with varying bias. We found the CGM-normalized 70-90 min SUVR to be highly correlated (r2 = 0.93) with the 2TC distribution volume ratio (DVR) with acceptable bias (∼10%), representing a practical alternative for [18F]SMBT-1 analyses.

Acute Stress Increases Striatal Connectivity With Cortical Regions Enriched for µ and κ Opioid Receptors.

BACKGROUND: Understanding the neurobiological effects of stress is critical for addressing the etiology of major depressive disorder (MDD). Using a dimensional approach involving individuals with differing degree of MDD risk, we investigated 1) the effects of acute stress on cortico-cortical and subcortical-cortical functional connectivity (FC) and 2) how such effects are related to gene expression and receptor maps. METHODS: Across 115 participants (37 control, 39 remitted MDD, 39 current MDD), we evaluated the effects of stress on FC during the Montreal Imaging Stress Task. Using partial least squares regression, we investigated genes whose expression in the Allen Human Brain Atlas was associated with anatomical patterns of stress-related FC change. Finally, we correlated stress-related FC change maps with opioid and GABAA (gamma-aminobutyric acid A) receptor distribution maps derived from positron emission tomography. RESULTS: Results revealed robust effects of stress on global cortical connectivity, with increased global FC in frontoparietal and attentional networks and decreased global FC in the medial default mode network. Moreover, robust increases emerged in FC of the caudate, putamen, and amygdala with regions from the ventral attention/salience network, frontoparietal network, and motor networks. Such regions showed preferential expression of genes involved in cell-to-cell signaling (OPRM1, OPRK1, SST, GABRA3, GABRA5), similar to previous genetic MDD studies. CONCLUSIONS: Acute stress altered global cortical connectivity and increased striatal connectivity with cortical regions that express genes that have previously been associated with imaging abnormalities in MDD and are rich in µ and κ opioid receptors. These findings point to overlapping circuitry underlying stress response, reward, and MDD.

Cebranopadol, a novel long-acting opioid agonist with low abuse liability, to treat opioid use disorder: Preclinical evidence of efficacy.

The gold standard pharmacological treatment for opioid use disorder (OUD) consists of maintenance therapy with long-acting opioid agonists such as buprenorphine and methadone. Despite these compounds having demonstrated substantial efficacy, a significant number of patients do not show optimal therapeutic responses. Moreover, the abuse liability of these medications remains a major concern. Cebranopadol, is a new, long-acting pan-opioid agonist that also activates the nociception/orphanin FQ NOP receptor. Here we used rats to explore the therapeutic potential of this agent in OUD. First, in operant intravenous self-administration experiments we compared the potential abuse liability of cebranopadol with the prototypical opioid heroin. Under a fixed ratio 1 (FR1) contingency, rats maintained responding for heroin (1, 7, 20, 60 µg/inf) to a larger extent than cebranopadol (0.03, 0.1, 0.3, 1.0, 6.0 µg/inf). When the contingency was switched to a progressive ratio (PR) reinforcement schedule, heroin maintained responding at high levels at all except the lowest dose. Conversely, in the cebranopadol groups responding decreased drastically and the break point (BP) did not differ from saline controls. Next, we demonstrated that oral administration of cebranopadol (0, 25, 50 µg/kg) significantly attenuated drug self-administration independent of heroin dose (1, 7, 20, 60 µg/inf). Cebranopadol also reduced the break point for heroin (20 µg/inf). Furthermore, in a heroin self-administration training extinction/reinstatement paradigm, pretreatment with cebranopadol significantly attenuated yohimbine stress-induced reinstatement of drug seeking. Together, these data indicate that cebranopadol has limited abuse liability compared to heroin and is highly efficacious in attenuating opioid self-administration and stress-induced reinstatement, suggesting clinical potential of this compound for OUD treatment.

Imaging Nociceptin Opioid Peptide Receptors in Alcohol Use Disorder With [11C]NOP-1A and Positron Emission Tomography: Findings From a Second Cohort.

BACKGROUND: Nociceptin, which binds to the nociceptin opioid peptide receptor (NOP), regulates stress and reward in addiction. In a previous [11C]NOP-1A positron emission tomography (PET) study, we found no differences in NOP in non-treatment-seeking individuals with alcohol use disorder (AUD) relative to healthy control subjects Here, we evaluated NOP in treatment-seeking individuals with AUD to document its relationship with relapse to alcohol. METHODS: [11C]NOP-1A distribution volume (VT) was measured in recently abstinent individuals with AUD and healthy control subjects (n = 27/group) using an arterial input function-based kinetic analysis in brain regions that regulate reward and stress behaviors. Recent heavy drinking before PET was quantified using hair ethyl glucuronide (≥30 pg/mg was defined as heavy drinking). To document relapse, 22 subjects with AUD were followed with urine ethyl glucoronide tests (3/week) for 12 weeks after PET, where they were incentivized with money to abstain. RESULTS: There were no differences in [11C]NOP-1A VT between individuals with AUD and healthy control subjects. Individuals with AUD who drank heavily before the study had significantly lower VT than those with no recent heavy drinking history. Significant negative correlations between VT and the number of drinking days and the number of drinks consumed per drinking day in the 30 days before enrollment were also present. Individuals with AUD who relapsed (and dropped out) had significantly lower VT than those who abstained for 12 weeks. CONCLUSIONS: Lower NOP VT in heavy drinking AUD predicted relapse to alcohol during a 12-week follow-up period. The results of this PET study support the need to investigate medications that act at NOP to prevent relapse in individuals with AUD.

Beyond monoamines: I. Novel targets and radiotracers for Positron emission tomography imaging in psychiatric disorders.

With the emergence of positron emission tomography (PET) in the late 1970s, psychiatry had access to a tool capable of non-invasive assessment of human brain function. Early applications in psychiatry focused on identifying characteristic brain blood flow and metabolic derangements using radiotracers such as [15 O]H2 O and [18 F]FDG. Despite the success of these techniques, it became apparent that more specific probes were needed to understand the neurochemical bases of psychiatric disorders. The first neurochemical PET imaging probes targeted sites of action of neuroleptic (dopamine D2 receptors) and psychoactive (serotonin receptors) drugs. Based on the centrality of monoamine dysfunction in psychiatric disorders and the measured success of monoamine-enhancing drugs in treating them, the next 30 years witnessed the development of an armamentarium of PET radiopharmaceuticals and imaging methodologies for studying monoamines. Continued development of monoamine-enhancing drugs over this time however was less successful, realizing only modest gains in efficacy and tolerability. As patent protection for many widely prescribed and profitable psychiatric drugs lapsed, drug development pipelines shifted away from monoamines in search of novel targets with the promises of improved efficacy, or abandoned altogether. Over this period, PET radiopharmaceutical development activities closely paralleled drug development priorities resulting in the development of new PET imaging agents for non-monoamine targets. Part one of this review will briefly survey novel PET imaging targets with relevance to the field of psychiatry, which include the metabotropic glutamate receptor type 5 (mGluR5), purinergic P2 X7 receptor, type 1 cannabinoid receptor (CB1 ), phosphodiesterase 10A (PDE10A), and describe radiotracers developed for these and other targets that have matured to human subject investigations. Current limitations of the targets and techniques will also be discussed.

Beyond monoamines: II. Novel applications for PET imaging in psychiatric disorders.

Early applications of positron emission tomography (PET) in psychiatry sought to identify derangements of cerebral blood flow and metabolism. The need for more specific neurochemical imaging probes was soon evident, and these probes initially targeted the sites of action of neuroleptic (dopamine D2 receptors) and psychoactive (serotonin receptors) drugs. For nearly 30 years, the centrality of monoamine dysfunction in psychiatric disorders drove the development of an armamentarium of monoaminergic PET radiopharmaceuticals and imaging methodologies. However, continued investments in monoamine-enhancing drug development realized only modest gains in efficacy and tolerability. As patent protection for many widely prescribed and profitable psychiatric drugs lapsed, drug development pipelines shifted away from monoamines in search of novel targets with the promises of improved efficacy, or abandoned altogether. Over this period, PET radiopharmaceutical development activities closely parallelled drug development priorities, resulting in the development of new PET imaging agents for non-monoamine targets. In part two of this review, we survey clinical research studies using the novel targets and radiotracers described in part one across major psychiatric application areas such as substance use disorders, anxiety disorders, eating disorders, personality disorders, mood disorders, and schizophrenia. Important limitations of the studies described are discussed, as well as key methodologic issues, challenges to the field, and the status of clinical trials seeking to exploit these targets for novel therapeutics.

Prefrontal and Striatal Dopamine Release Are Inversely Correlated in Schizophrenia.

BACKGROUND: The dopamine (DA) hypothesis postulates hyperactivity of subcortical DA transmission and hypoactivity of cortical DA in schizophrenia (SCH). Positron emission tomography provides the ability to assess this hypothesis in humans. However, no studies have examined the relationship between cortical DA and striatal DA in this illness. METHODS: D2/3 receptor radiotracer [11C]FLB457 BPND (binding potential relative to nondisplaceable uptake) was measured in 14 off-medication subjects with SCH and 14 healthy control (HC) subjects at baseline and after the administration of 0.5 mg/kg oral d-amphetamine. The amphetamine-induced change in BPND (ΔBPND) was calculated as the difference between BPND in the postamphetamine condition and BPND in the baseline condition and expressed as a percentage of BPND at baseline. DA release in the striatum using the radiotracer [11C]NPA was also measured in these subjects. RESULTS: [11C]FLB457 ΔBPND was greater in the HC group compared with the SCH group (F1,26 = 5.7; p = .02) with significant differences in [11C]FLB457 ΔBPND seen across cortical brain regions. Only in the SCH group was a significant negative correlation observed between [11C]FLB457 ΔBPND in the dorsolateral prefrontal cortex and [11C]NPA ΔBPND in the dorsal caudate (r = -0.71, p = .005). CONCLUSIONS: Subjects with SCH demonstrated deficits of DA release in cortical brain regions relative to HC subjects. Examining both cortical and striatal DA release in the same subjects demonstrated an inverse relationship between cortical DA release and striatal DA release in SCH not present in HC subjects, providing support for the current DA hypothesis of SCH.

Imaging the Influence of Red Blood Cell Docosahexaenoic Acid Status on the Expression of the 18 kDa Translocator Protein in the Brain: A [11C]PBR28 Positron Emission Tomography Study in Young Healthy Men.

BACKGROUND: Docosahexaenoic acid (DHA) shows anti-inflammatory/proresolution effects in the brain. Higher red blood cell (RBC) DHA in humans is associated with improved cognitive performance and a lower risk for suicide. Here, we hypothesized that binding to the 18 kDa translocator protein (TSPO), a proxy for microglia levels, will be higher in individuals with low DHA relative to high DHA levels. We also postulated that higher TSPO would predict poor cognitive performance and impaired stress resilience. METHODS: RBC DHA screening was performed in 320 healthy males. [11C]PBR28 positron emission tomography was used to measure binding to TSPO in 38 and 32 males in the lowest and highest RBC DHA quartiles. Volumes of distribution expressed relative to total plasma ligand concentration (VT) was derived using an arterial input function-based kinetic analysis in 14 brain regions. RESULTS: [11C]PBR28 VT was significantly lower (by 12% and 20% in C/T and C/C rs6971 genotypes) in males with low RBC DHA than in males with high RBC DHA. Regional VT was correlated positively and negatively with RBC DHA and serum triglycerides, respectively. No relationships between VT and cognitive performance or stress resilience measures were present. CONCLUSIONS: Contrary to our hypothesis, we found lower TSPO binding in low-DHA than in high-DHA subjects. It is unclear as to whether low TSPO binding reflects differences in microglia levels and/or triglyceride metabolism in this study. Future studies with specific targets are necessary to confirm the effect of DHA on microglia. These results underscore the need to consider lipid parameters as a factor when interpreting TSPO positron emission tomography clinical findings.

Imaging beta-amyloid (Aß) burden in the brains of middle-aged individuals with alcohol-use disorders: a [11C]PIB PET study.

No in vivo human studies have examined the prevalence of Alzheimer's disease (AD) neuropathology in individuals with alcohol-use disorder (AUD), although recent research suggests that a relationship between the two exists. Therefore, this study used Pittsburgh Compound-B ([11C]PiB) PET imaging to test the hypothesis that AUD is associated with greater brain amyloid (Aß) burden in middle-aged adults compared to healthy controls. Twenty healthy participants (14M and 6F) and 19 individuals with AUD (15M and 4F), all aged 40-65 years, underwent clinical assessment, MRI, neurocognitive testing, and positron emission tomography (PET) imaging. Global [11C]PiB standard uptake value ratios (SUVRs), cortical thickness, gray matter volumes (GMVs), and neurocognitive function in subjects with AUD were compared to healthy controls. These measures were selected because they are considered markers of risk for future AD and other types of neurocognitive dysfunction. The results of this study showed no significant differences in % global Aß positivity or subthreshold Aß loads between AUD and controls. However, relative to controls, we observed a significant 6.1% lower cortical thickness in both AD-signature regions and in regions not typically associated with AD, lower GMV in the hippocampus, and lower performance on tests of attention as well as immediate and delayed memory in individuals with AUD. This suggest that Aß accumulation is not greater in middle-aged individuals with AUD. However, other markers of neurodegeneration, such as impaired memory, cortical thinning, and reduced hippocampal GMV, are present. Further studies are needed to elucidate the patterns and temporal staging of AUD-related pathophysiology and cognitive impairment. Imaging ß-amyloid in middle age alcoholics as a mechanism that increases their risk for Alzheimer's disease; Registration Number: NCT03746366 .

Imaging Cortical Dopamine Transmission in Cocaine Dependence: A [11C]FLB 457-Amphetamine Positron Emission Tomography Study.

BACKGROUND: Positron emission tomography studies have demonstrated less dopamine D2/3 receptor availability and blunted psychostimulant-induced dopamine release in cocaine-dependent subjects (CDSs). No studies in CDSs have reported the in vivo status of D2/3 and dopamine release in the cortex. Basic and functional imaging studies suggest a role for prefrontal cortical dopaminergic abnormalities in impaired executive function and relapse in cocaine dependence. We used [11C]FLB 457 positron emission tomography and amphetamine to measure cortical D2/3 receptors and dopamine release in CDSs. METHODS: [11C]FLB 457 and positron emission tomography were used to measure D2/3 receptor binding potential in cortical regions of interest in recently abstinent CDSs (n = 24) and healthy control subjects (n = 36) both before and after 0.5 mg kg-1 of oral d-amphetamine. Binding potential relative to nondisplaceable uptake (BPND) and binding potential relative to total plasma concentration (BPP) were derived using an arterial input function-based kinetic analysis. Cortical dopamine release in regions of interest was measured as the change in BPND and BPP after amphetamine. RESULTS: Baseline D2/3 receptor availability (BPP and BPND) and amphetamine-induced dopamine release (ΔBPND and ΔBPP) were significantly lower in the cortical regions in CDSs compared with healthy control subjects. Fewer D2/3 receptors and less dopamine release in CDSs were not associated with performance on working memory and attention tasks. CONCLUSIONS: The results of this study suggest that deficits in dopamine D2/3 transmission involve the cortex in cocaine dependence. Further studies to understand the clinical relevance of these findings are warranted.

Acute Elevations in Cortisol Increase the In Vivo Binding of [11C]NOP-1A to Nociceptin Receptors: A Novel Imaging Paradigm to Study the Interaction Between Stress- and Antistress-Regulating Neuropeptides.

BACKGROUND: An imbalance between neuropeptides that promote stress and resilience, such as corticotropin-releasing factor and nociceptin, has been postulated to underlie relapse in addiction. The objective of this study was to develop a paradigm to image the in vivo interaction between stress-promoting neuropeptides and nociceptin (NOP) receptors in humans. METHODS: [11C]NOP-1A positron emission tomography was used to measure the binding to NOP receptors at baseline (BASE) and following an intravenous hydrocortisone challenge (CORT) in 19 healthy control subjects. Hydrocortisone was used as a challenge because in microdialysis studies it has been shown to increase corticotropin-releasing factor release in extrahypothalamic brain regions such as the amygdala. [11C]NOP-1A total distribution volume (VT) in 11 regions of interest were measured using a 2-tissue compartment kinetic analysis. The primary outcome measure was hydrocortisone-induced ΔVT calculated as (VT CORT - VT BASE)/VT BASE. RESULTS: Hydrocortisone led to an acute increase in plasma cortisol levels. Regional [11C]NOP-1A VT was on average 11% to 16% higher in the post-hydrocortisone condition compared with the baseline condition (linear mixed model, condition, p = .005; region, p < .001; condition × region, p < .001). Independent Student's t tests in all regions of interest were statistically significant and survived multiple comparison correction. Hydrocortisone-induced ΔVT was significantly negatively correlated with baseline VT in several regions of interest. CONCLUSIONS: Hydrocortisone administration increases NOP receptor availability. Increased NOP in response to elevated cortisol might suggest a compensatory mechanism in the brain to counteract corticotropin-releasing factor and/or stress. The [11C]NOP-1A and hydrocortisone imaging paradigm should allow for the examination of interactions between stress-promoting neuropeptides and NOP in addictive disorders.

NOP receptor antagonism reduces alcohol drinking in male and female rats through mechanisms involving the central amygdala and ventral tegmental area.

BACKGROUND AND PURPOSE: Nociceptin/orphanin FQ (N/OFQ) peptide and its cognate receptor (NOP) are widely expressed in mesolimbic brain regions where they play an important role in modulating reward and motivation. Early evidence suggested that NOP receptor activation attenuates the rewarding effects of drugs of abuse, including alcohol. However, emerging data indicate that NOP receptor blockade also effectively attenuates alcohol drinking and relapse. To advance our understanding of the role of the N/OFQ-NOP receptor system in alcohol abuse, we examined the effect of NOP receptor blockade on voluntary alcohol drinking at the neurocircuitry level. EXPERIMENTAL APPROACH: Using male and female genetically selected alcohol-preferring Marchigian Sardinian (msP) rats, we initially evaluated the effects of the selective NOP receptor antagonist LY2817412 (3, 10, and 30 mg·kg-1 , p.o.) on alcohol consumption in a two-bottle free-choice paradigm. We then microinjected LY2817412 (3 and 6 µg·µl-1 per rat) in the central nucleus of the amygdala (CeA), ventral tegmental area (VTA), and nucleus accumbens (NAc). KEY RESULTS: Peripheral LY2817412 administration dose-dependently and selectively reduced voluntary alcohol intake in male and female msP rats. Central injections of LY2817412 markedly attenuated voluntary alcohol intake in both sexes following administration in the CeA and VTA but not in the NAc. CONCLUSION AND IMPLICATIONS: The present results revealed that the CeA and VTA are neuroanatomical substrates that mediate the effects of NOP receptor antagonism on alcohol consumption. Overall, our findings support the potential of NOP receptor antagonism as a treatment strategy to attenuate alcohol use and addiction.

Nociceptin Receptors Upregulated in Cocaine Use Disorder: A Positron Emission Tomography Imaging Study Using [11C]NOP-1A.

OBJECTIVE: Nociceptin/orphanin FQ (N/OFQ) is an antistress neuropeptide transmitter in the brain that counteracts corticotropin-releasing factor (CRF)-mediated stress and anxiety symptoms during drug and alcohol withdrawal. It also inhibits the release of a wide array of neurotransmitters, including dopamine and glutamate, which allows for it to block the rewarding properties of cocaine. Chronic cocaine administration in rodents has been shown to decrease N/OFQ and increase nociceptive opioid peptide (NOP) receptors in the nucleus accumbens. No previous studies have reported on the in vivo status of NOP in chronic cocaine-abusing humans. METHODS: [11C]NOP-1A and positron emission tomography (PET) were used to measure in vivo NOP binding in 24 individuals with cocaine use disorder and 26 healthy control subjects matched for age, sex, and smoking status. Participants with cocaine use disorder with no comorbid psychiatric or medical disorders were scanned after 2 weeks of outpatient-monitored abstinence. [11C]NOP-1A distribution volume (VT) was measured with kinetic analysis using the arterial input function in brain regions that mediate reward and stress behaviors. Participants with cocaine use disorder were followed up for 12 weeks after PET scanning to document relapse and relate it to VT. RESULTS: A significant increase in [11C]NOP-1A VT was observed in the cocaine use disorder group compared with the healthy control group. This increase, which was generalized across all regions of interest (approximately 10%), was most prominent in the midbrain, ventral striatum, and cerebellum. However, increased VT in these regions did not predict relapse. CONCLUSIONS: Increased NOP in cocaine use disorder suggests an adaptive response to decreased N/OFQ, or increased CRF transmission, or both. Future studies should examine the interactions between CRF and NOP to elucidate their role in negative reinforcement and relapse. NOP agonist medications to enhance N/OFQ should be explored as a therapeutic to treat cocaine use disorder.

Decreased Nociceptin Receptors Are Related to Resilience and Recovery in College Women Who Have Experienced Sexual Violence: Therapeutic Implications for Posttraumatic Stress Disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a stress disorder that develops in only some individuals following a traumatic event. Data suggest that a substantial fraction of women recover after sexual violence. Thus, the investigation of stress and antistress neuropeptides in this sample has the potential to inform the neurochemistry of resilience following trauma. Nociceptin is an antistress neuropeptide in the brain that promotes resilience in animal models of PTSD. METHODS: [11C]NOP-1A positron emission tomography was used to measure the in vivo binding to nociceptin receptors in 18 college women who had experienced sexual violence irrespective of whether they met DSM-5 diagnostic criteria for PTSD. [11C]NOP-1A data from 18 healthy control subjects were also included to provide a contrast with the sexual violence group. [11C]NOP-1A total distribution volume (VT) in the regions of interest were measured with kinetic analysis using the arterial input function. The relationships between regional VT and Clinician-Administered PTSD Scale for DSM-5 total symptom and subscale severity were examined using correlational analyses. RESULTS: No differences in [11C]NOP-1A VT were noted between the sexual violence and control groups. VT in the midbrain and cerebellum were positively correlated with PTSD total symptom severity in the past month before positron emission tomography. Intrusion/re-experiencing and avoidance subscale symptoms drove this relationship. Stratification of subjects by a DSM-5 PTSD diagnosis and contrasting their VT with that in control subjects showed no group differences. CONCLUSIONS: Decreased midbrain and cerebellum nociceptin receptors are associated with less severe PTSD symptoms. Medications that target nociceptin should be explored to prevent and treat PTSD.

Prevalence of optic disc haemorrhages in an elderly UK Caucasian population and possible association with reticular pseudodrusen-the Bridlington Eye Assessment Project (BEAP): a cross-sectional study (2002-2006).

AIMS: To determine disc haemorrhage (DH) prevalence in an elderly UK population-the Bridlington Eye Assessment Project (BEAP). METHODS: Thirty-degree fundus photographs (3549 participants ≥65 years) were graded for DH/macula changes. Glaucoma evaluation included Goldmann tonometry, 26-point suprathreshold visual-fields and mydriatic slit-lamp assessment for glaucomatous optic neuropathy. RESULTS: In all, 3548 participants with photographs in at least one eye. DHs were present in 53 subjects (1.49%), increasing from 1.17% (65- to 69-year age group) to 2.19% (80- to 84-year age group), p = 0.06. DH was found in 9/96 (9.38%) right eyes (RE) with open-angle glaucoma (OAG). Two of twelve RE (16.67%) with normal-tension glaucoma (NTG) had DH. Prevalence in eyes without glaucoma was lower (32/3452, [0.93%]). Reticular pseudodrusen (RPD) occurred in 170/3212 (5.29%) subjects without DH, and 8/131 subjects (6.11%) with OAG. Twenty eyes had NTG, two of whom had RPD (10%) (p = 0.264). Within a logistic regression model, DH was associated with glaucoma (OR 10.2, 95% CI 5.32-19.72) and increasing age (OR 1.05, 95% CI 1.00-1.10, p = 0.03). DH was associated with RPD (p = 0.05) with univariate analysis but this was not statistically significant in the final adjusted model. There was no significant association with gender, diabetes mellitus (DM), hypertension treatment or Age-related Macular Degeneration (AMD) grade. CONCLUSION: DH prevalence is 1.5% in those over 65 years old and significantly associated with glaucoma and increasing age. There appears to be increased RPD prevalence in eyes with DH and NTG with age acting as a confounding factor. Larger studies are required to fully assess the relationship and investigate a possible shared aetiology of choroidal ischaemia.

Imaging phosphodiesterase-10a availability in cocaine use disorder with [11 C]IMA107 and PET.

Phosphodiesterase-10a (PDE10a) is located exclusively in medium spiny neurons (MSN). Rodent studies show an increase in striatal MSN spine density following exposure to cocaine. These increases in MSN spine density are suggested to underlie neurobiological changes which contribute to cocaine self-administration. No postmortem or imaging studies have confirmed this finding in humans. Here, we hypothesized an increase in the MSN marker PDE10a in subjects with cocaine use disorder ("cocaine users") compared to controls. PDE10a availability was measured with [11 C]IMA107 and positron emission tomography in 15 cocaine users and 15 controls matched for age, gender, and nicotine status. Cocaine users with no comorbid psychiatric, medical, or drug abuse disorders were scanned following two weeks of outpatient-monitored abstinence. [11 C]IMA107 binding potential relative to nondisplaceable uptake (BPND ) in the regions of interest was derived with the simplified reference tissue method. No significant effect of diagnosis on BPND was demonstrated using linear mixed modeling with [11 C]IMA107 BPND as the dependent variable and regions of interest as a repeated measure. There were no significant relationships between BPND and clinical rating scales. To the extent that PDE10a is a valid proxy for MSN spine density, these results do not support its increase in recently abstinent cocaine users.

Failure to detect amphetamine-induced dopamine release in the cortex with [11 C]FLB 457 positron emission tomography (PET): Methodological considerations.

Studies in nonhuman primates and humans have demonstrated that amphetamine-induced dopamine release in the cortex can be measured with [11 C]FLB 457 and PET imaging. This technique has been successfully used in recent clinical studies to show decreased dopamine transmission in the prefrontal cortex in schizophrenia and alcohol dependence. Here, we present data from a cohort of twelve healthy controls in whom an oral amphetamine challenge (0.5 mg kg-1 ) did not lead to a significant reduction in [11 C]FLB 457 BPND (i.e., binding potential relative to non-displaceable uptake). Two factors that likely contributed to the inability to displace [11 C]FLB 457 BPND in this cohort relative to successful cohorts are: (a) the acquisition of the baseline and post-amphetamine scans on different days as opposed to the same day and (b) the initiation of the post-amphetamine [11 C]FLB 457 scan at ∼5 hours as opposed to ∼3 hours following oral amphetamine. Furthermore, we show [11 C]FLB 457 reproducibility data from a legacy dataset to support greater variability in cortical BPND when the test and retest scans are acquired on different days as compared to the same day. These results highlight the methodological challenges that continue to plague the field with respect to imaging dopamine release in the cortex.

Amphetamine-Induced Striatal Dopamine Release Measured With an Agonist Radiotracer in Schizophrenia.

BACKGROUND: Receptor imaging studies have reported increased amphetamine-induced dopamine release in subjects with schizophrenia (SCH) relative to healthy control subjects (HCs). A limitation of these studies, performed with D2/3 antagonist radiotracers, is the failure to provide information about D2/3 receptors configured in a state of high affinity for the agonists (i.e., D2/3 receptors coupled to G proteins [D2/3 HIGH]). The endogenous agonist dopamine binds with preference to D2/3 HIGH receptors relative to D2/3 LOW receptors, making it critical to understand the status of D2/3 HIGH receptors in SCH. METHODS: D2/3 agonist positron emission tomography radiotracer [11C]N-propyl-norapomorphine ([11C]NPA) binding potential (BPND) was measured in 14 off-medication subjects with SCH and 14 matched HCs at baseline and after the administration of 0.5 mg kg-1 oral D-amphetamine. The amphetamine-induced change in BPND (ΔBPND) was calculated as the difference between BPND in the postamphetamine condition and BPND in the baseline condition and was expressed as a percentage of BPND at baseline. RESULTS: A trend-level increase was observed in comparing baseline [11C]NPA BPND (repeated-measures analysis of variance, F1,26 = 3.34, p = .08) between the SCH and HC groups. Amphetamine administration significantly decreased BPND in all striatal regions across all subjects in both groups. No differences were observed in [11C]NPA ΔBPND (repeated-measures analysis of variance, F1,26 = 1.9, p = .18) between HCs and subjects with SCH. Amphetamine significantly increased positive symptoms in subjects with SCH (19.5 ± 5.3 vs. 23.7 ± 4.1, paired t test, p < .0001); however, no correlations were noted with [11C]NPA BPND or ΔBPND. CONCLUSIONS: This study provides in vivo indication of a role for postsynaptic factors in amphetamine-induced psychosis in SCH.

Nociceptin Receptors in Alcohol Use Disorders: A Positron Emission Tomography Study Using [11C]NOP-1A.

BACKGROUND: The neuropeptide transmitter nociceptin, which binds to the nociceptin/orphanin FQ peptide (NOP) receptor, is a core component of the brain's antistress system. Nociceptin exerts its antistress effect by counteracting the functions of corticotropin-releasing factor, the primary stress-mediating neuropeptide in the brain. Basic investigations support a role for medications that target nociceptin receptors in the treatment of alcohol use disorders. Thus, it is of high interest to measure the in vivo status of NOP receptors in individuals with alcohol use disorders. METHODS: Here, we used [11C]NOP-1A and positron emission tomography to measure the in vivo binding to NOP receptors in 15 alcohol-dependent humans as identified by DSM-IV and 15 healthy control subjects matched for age, sex, and smoking status. Alcohol-dependent individuals with no comorbid psychiatric, medical, or drug abuse disorders were scanned following 2 weeks of outpatient monitored abstinence (confirmed with three times per week urine alcohol metabolite testing). [11C]NOP-1A distribution volume in regions of interest (including the amygdala, hippocampus, and midbrain, striatal, and prefrontal cortical subdivisions) was measured with kinetic analysis using the arterial input function. RESULTS: Regional [11C]NOP-1A distribution volume in alcohol dependence was not significantly different compared with healthy control subjects. No relationship between [11C]NOP-1A distribution volume and other clinical measures (including duration and severity of alcohol abuse, craving, and anxiety or depressive symptoms) were significant after correction for the multiple hypotheses tested. CONCLUSIONS: The results of this study do not support alterations in the binding to NOP receptors in alcohol dependence. However, this finding does not necessarily rule out alterations in nociceptin transmission in alcohol dependence.