Alan A Wilson

University of Toronto, Toronto, Ontario, Canada

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Publications (241)1038.23 Total impact

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    ABSTRACT: No study has examined dopamine D2/3 receptor (D2/3R) availability in antipsychotic-free older patients with schizophrenia. We included patients with schizophrenia 50years or older who were antipsychotic-free for at least 3months. We compared non-displaceable binding potential (BPND) of [(11)C]-raclopride in the caudate, putamen, ventral striatum, and globus pallidus between patients and age- and sex-matched healthy controls. Ten patients participated (antipsychotic-naive=4). No differences in BPND were found between patients and controls in any ROIs (F(1, 72)=.42, p=.52). The preliminary results suggest no differences in D2/3R availability between antipsychotic-free older patients with schizophrenia and controls. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 03/2015; DOI:10.1016/j.schres.2015.02.020 · 4.43 Impact Factor
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    ABSTRACT: The neuroinflammatory hypothesis of major depressive disorder is supported by several main findings. First, in humans and animals, activation of the immune system causes sickness behaviors that present during a major depressive episode (MDE), such as low mood, anhedonia, anorexia, and weight loss. Second, peripheral markers of inflammation are frequently reported in major depressive disorder. Third, neuroinflammatory illnesses are associated with high rates of MDEs. However, a fundamental limitation of the neuroinflammatory hypothesis is a paucity of evidence of brain inflammation during MDE. Translocator protein density measured by distribution volume (TSPO VT) is increased in activated microglia, an important aspect of neuroinflammation. To determine whether TSPO VT is elevated in the prefrontal cortex, anterior cingulate cortex (ACC), and insula in patients with MDE secondary to major depressive disorder. Case-control study in a tertiary care psychiatric hospital from May 1, 2010, through February 1, 2014. Twenty patients with MDE secondary to major depressive disorder and 20 healthy control participants underwent positron emission tomography with fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]FEPPA). Patients with MDE were medication free for at least 6 weeks. All participants were otherwise healthy and nonsmokers. Values of TSPO VT in the prefrontal cortex, ACC, and insula. In MDE, TSPO VT was significantly elevated in all brain regions examined (multivariate analysis of variance, F15,23 = 4.5 [P = .001]). The magnitude of TSPO VT elevation was 26% in the prefrontal cortex (mean [SD] TSPO VT, 12.5 [3.6] in patients with MDE and 10.0 [2.4] in controls), 32% in the ACC (mean [SD] TSPO VT, 12.3 [3.5] in patients with MDE and 9.3 [2.2] in controls), and 33% in the insula (mean [SD] TSPO VT, 12.9 [3.7] in patients with MDE and 9.7 [2.3] in controls). In MDE, greater TSPO VT in the ACC correlated with greater depression severity (r = 0.63 [P = .005]). This finding provides the most compelling evidence to date of brain inflammation, and more specifically microglial activation, in MDE. This finding is important for improving treatment because it implies that therapeutics that reduce microglial activation should be promising for MDE. The correlation between higher ACC TSPO VT and the severity of MDE is consistent with the concept that neuroinflammation in specific regions may contribute to sickness behaviors that overlap with the symptoms of MDE.
    JAMA Psychiatry 01/2015; DOI:10.1001/jamapsychiatry.2014.2427 · 12.01 Impact Factor
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    ABSTRACT: Dopamine agonist medications with high affinity for the D3 dopamine receptor are commonly used to treat Parkinson's disease, and have been associated with pathological behaviors categorized under the umbrella of impulse control disorders (ICD). The aim of this study was to investigate whether ICD in Parkinson's patients are associated with greater D3 dopamine receptor availability. We used positron emission tomography (PET) radioligand imaging with the D3 dopamine receptor preferring agonist [(11) C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) in Parkinson's patients with (n = 11) and without (n = 21) ICD, and age-, sex-, and education-matched healthy control subjects (n = 18). Contrary to hypotheses, [(11) C]-(+)-PHNO binding in D3 -rich brain areas was not elevated in Parkinson's patients with ICD compared with those without; instead, [(11) C]-(+)-PHNO binding in ventral striatum was 20% lower (P = 0.011), correlating with two measures of ICD severity (r = -0.8 and -0.9), which may reflect higher dopamine tone in ventral striatum. In dorsal striatum, where [(11) C]-(+)-PHNO binding is associated with D2 receptor levels, [(11) C]-(+)-PHNO binding was elevated across patients compared with controls. We conclude that although D3 dopamine receptors have been linked to the occurrence of ICD in Parkinson's patients. Our findings do not support the hypothesis that D3 receptor levels are elevated in Parkinson's patients with ICD. We also did not find ICD-related abnormalities in D2 receptor levels. Our findings argue against the possibility that differences in D2/3 receptor levels can account for the development of ICD in PD; however, we cannot rule out that differences in dopamine levels (particularly in ventral striatum) may be involved. © 2015 International Parkinson and Movement Disorder Society. © 2015 International Parkinson and Movement Disorder Society.
    Movement Disorders 01/2015; 30(2). DOI:10.1002/mds.26135 · 5.63 Impact Factor
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    ABSTRACT: Monoamine oxidase-A (MAO-A) is a treatment target in neurodegenerative illness and mood disorders that increases oxidative stress and predisposition toward apoptosis. Increased MAO-A levels in prefrontal cortex (PFC) and anterior cingulate cortex (ACC) occur in rodent models of depressive behavior and human studies of depressed moods. Extreme dysphoria is common in borderline personality disorder (BPD), especially when severe, and the molecular underpinnings of severe BPD are largely unknown. We hypothesized that MAO-A levels in PFC and ACC would be highest in severe BPD and would correlate with symptom magnitude. [(11)C] Harmine positron emission tomography measured MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in severe BPD subjects (n = 14), moderate BPD subjects (n = 14), subjects with a major depressive episode (MDE) only (n = 14), and healthy control subjects (n = 14). All subjects were female. Severe BPD was associated with greater PFC and ACC MAO-A VT compared with moderate BPD, MDE, and healthy control subjects (multivariate analysis of variance group effect: F6,102 = 5.6, p < .001). In BPD, PFC and ACC MAO-A VT were positively correlated with mood symptoms (PFC: r = .52, p = .005; ACC: r = .53, p = .004) and suicidality (PFC: r = .40, p = .037; ACC: r = .38, p = .046), while hippocampus MAO-A VT was negatively correlated with verbal memory (r = -.44, p = .023). These results suggest that elevated MAO-A VT is associated with multiple indicators of BPD severity, including BPD symptomatology, mood symptoms, suicidality, and neurocognitive impairment. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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    ABSTRACT: Carbon-11 labeled SL25.1188 ((S)-5-(methoxymethyl)-3-(6-(4,4,4-trifluorobutoxy)benzo[d]isoxazol-3-yl)oxazolidin-2-one) is a reversible radiotracer for monoamine oxidase B that was recently evaluated in healthy volunteers by positron emission tomography (PET). Herein we report the preparation and ex vivo evaluation of a fluorinated SL25.1188 derivative as a candidate 18F-labeled PET radiotracer. (S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxy methyl)oxazolidin-2-one (1) was labeled with fluorine-18 in 51% uncorrected radiochemical yield having high radiochemical purity (>98%) and specific activity (109 ± 26 GBq/μmol). Ex vivo biodistribution studies demonstrated low radioactivity retention specific binding and metabolic stability within rat brains. High uptake of radioactivity in bone is consistent with metabolic defluorination. In vitro binding assays of longer chain fluoroalkoxy derivatives revealed that the length of the carbon chain is an integral feature in MAO-B inhibitor potency and selectivity within this scaffold.
    Bioorganic & Medicinal Chemistry Letters 11/2014; 25(2). DOI:10.1016/j.bmcl.2014.11.048 · 2.33 Impact Factor
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    ABSTRACT: (11)C-carbonyl-URB694 ((11)C-CURB) is a novel (11)C-labeled suicide irreversible radiotracer for PET developed as a surrogate measure of activity of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase. The aim of the study was to investigate the whole-body biodistribution and estimate the radiation dosimetry from (11)C-CURB scans in humans. Six healthy volunteers (3 men and 3 women) completed a single whole-body scan (∼120 min, 9 time frames) on a PET/CT scanner after administration of (11)C-CURB (∼350 MBq and ∼2 μg). Time-radioactivity curves were extracted in 11 manually delineated organs and corrected for injected activity, specific organ density, and volume to obtain normalized cumulated activities. OLINDA/EXM 1.1 was used to estimate standard internal dose exposure in each organ. The mean effective dose was calculated using the male and female models for the full sample and female-only sample, respectively. (11)C-CURB was well tolerated in all subjects, with no radiotracer-related adverse event reported. The mean effective dose (±SD) was estimated to be 4.6 ± 0.3 μSv/MBq for all subjects and 5.2 ± 0.3 μSv/MBq for the female sample. Organs with the highest normalized cumulated activities (in h) were the liver (0.117), gallbladder wall (0.046), and small intestine (0.033), and organs with the highest dose exposure (in μGy/MBq) were the gallbladder wall (111 ± 60), liver (21 ± 7), kidney (14 ± 3), and small intestine (12 ± 2). Organ radiation exposure for the irreversible fatty acid amide hydrolase enzyme probe (11)C-CURB is within the same range as other radiotracers labeled with (11)C, thus allowing for safe, serial PET scans in the same individuals. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Journal of Nuclear Medicine 11/2014; DOI:10.2967/jnumed.114.146464 · 5.56 Impact Factor
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    ABSTRACT: Neuroinflammation and abnormal immune responses have been implicated in schizophrenia (SCZ). Past studies using positron emission tomography (PET) that examined neuroinflammation in patients with SCZ in vivo using the translocator protein 18kDa (TSPO) target were limited by the insensitivity of the first-generation imaging agent [(11)C]-PK11195, scanners used, and the small sample sizes studied. Present study uses a novel second-generation TSPO PET radioligand N-acetyl-N-(2-[(18)F]fluoroethoxybenzyl)-2-phenoxy-5-pyridinamine ([(18)F]-FEPPA) to evaluate whether there is increased neuroinflammation in patients with SCZ. A cross-sectional study was performed using [(18)F]-FEPPA and a high-resolution research tomograph (HRRT). Eighteen patients with SCZ with ongoing psychotic symptoms and 27 healthy volunteers (HV) were recruited from a tertiary psychiatric clinical setting and the community, respectively. All participants underwent [(18)F]-FEPPA PET and magnetic resonance imaging, and PET data were analyzed to obtain [(18)F]-FEPPA total volume of distribution (V T) using a 2-tissue compartment model with an arterial plasma input function, as previously validated. All subjects were classified as high-, medium- or low-affinity [(18)F]-FEPPA binders on the basis of rs6971 polymorphism, and genotype information was incorporated into the analyses of imaging outcomes. No significant differences in neuroinflammation indexed as [(18)F]-FEPPA V T were observed between groups in either gray (F (1,39) = 0.179, P = .674) or white matter regions (F (1,38) = 0.597, P = .445). The lack of significant difference in neuroinflammation in treated patients with SCZ in the midst of a psychotic episode and HV suggests that neuroinflammatory processes may take place early in disease progression or are affected by antipsychotic treatment.
    Schizophrenia Bulletin 11/2014; DOI:10.1093/schbul/sbu157 · 8.61 Impact Factor
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    ABSTRACT: The ability to quantify translocator protein 18kDa (TSPO) in white matter (WM) is important to understand the role of neuroinflammation in neurological disorders with WM involvement. This article aims to extend the utility of TSPO imaging in WM using a second-generation radioligand, [18F]-FEPPA, and High-Resolution Research Tomograph (HRRT) positron emission tomography (PET) camera system. Four WM regions of interests (WM-ROI), relevant to the study of aging and neuroinflammatory diseases, were examined. The corpus callosum, cingulum bundle, superior longitudinal fasciculus, and posterior limb of internal capsule were delineated automatically onto subject’s T1-weighted magnetic resonance image using a Diffusion Tensor Imaging (DTI)-based WM template. The TSPO polymorphism (rs6971) stratified individuals to three genetic groups: high-affinity binders (HAB), mixed-affinity binders (MAB), and low-affinity binders (LAB). [18F]- FEPPA PET scans were acquired on 32 healthy subjects and analyzed using a full kinetic compartment analysis. The two-tissue compartment model showed moderate identifiability (coefficient of variation: 15-19%) for [18F]-FEPPA total volume distribution (VT) in WM-ROIs. Noise affects VT variability, although its effect on bias was small (6%). In a worst-case scenario, ≤ 6% of simulated data did not fit reliably. A simulation of increased TSPO density exposed minimal effect on variability and identifiability of [18F]-FEPPA VT in WM-ROIs. We found no association between age and [18F]-FEPPA VT in WM-ROIs. The VT values were 15% higher in HAB than in MAB, although the difference was not statistically significant. This study provides evidence for the utility and limitations of [18F]-FEPPA PET to measure TSPO expression in WM. Synapse, 2014. © 2014 Wiley Periodicals, Inc.
    Synapse 11/2014; 68(11). DOI:10.1002/syn.21765 · 2.43 Impact Factor
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    ABSTRACT: Purpose Fatty acid amide hydrolase (FAAH), a catabolic enzyme which regulates lipid transmitters in the endocannabinoid system, is an avidly sought therapeutic and positron emission tomography (PET) imaging target for studies involving addiction and neurological disorders. We report the synthesis of a new fluorine-18-labeled FAAH inhibitor, trans-3-(4, 5-dihydrooxazol-2-yl)phenyl-4-[18F]fluorocyclohexylcarbamate ([18F]FCHC), and its evaluation in rat brain. Procedures The synthesis of [18F]FCHC was conducted via a 3-step, 1-pot reaction, resulting in uncorrected radiochemical yields between 10 and 20 % (n = 5) relative to [18F]fluoride, with specific activities of >5 Ci/μmol at the end of the synthesis. The radiosynthesis was seamlessly automated using a commercial radiofluorination apparatus. Ex vivo biodistribution and preliminary PET imaging studies were carried out in male Sprague-Dawley rats. Results Rat brain biodistribution at 2 min post-injection showed a standard uptake value of 4.6 ± 0.1 in the cortex, which increased to 7.8 ± 0.1 at 40 min. Pretreatment with the selective FAAH inhibitor URB597 reduced uptake of radioactivity in all brain regions by >90 %, with 98 % blockade in the FAAH-rich cortex. PET imaging was consistent with biodistribution studies. Conclusions [18F]FCHC appears to be a highly sensitive 18F-labeled radiotracer for imaging FAAH in the central nervous system, and these results warrant further imaging in nonhuman primates.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 10/2014; 17(2). DOI:10.1007/s11307-014-0789-1 · 2.87 Impact Factor
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    ABSTRACT: Introduction Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are the two primary enzymes that regulate the tone of endocannabinoid signaling. Although new PET radiotracers have been discovered for imaging FAAH in vivo, no such radiotracer exists for imaging MAGL. Here we report the radiosynthesis of five candidate MAGL radiotracers and their ex vivo evaluations in mice and rats. Methods Candidate carbamate and urea MAGL inhibitors were radiolabeled at the carbonyl position by [11C]CO2 fixation. Radiotracers were administered (tail-vein injection) to rodents and brain uptake of radioactivity measured at early and late time points ex vivo. Specificity of uptake was explored by pretreatment with unlabeled inhibitors (2 mg/kg, ip) 30 min prior to radiotracer administration. Results: All five candidate MAGL radiotracers were prepared in high specific activity (> 65 GBq/μmol) and radiochemical purity (> 98%). Moderate brain uptake (0.2 - 0.8 SUV) was observed for each candidate while pretreatment did not reduce uptake for four of the five tested. For two candidates ([11C]12 and [11C]14), high retention of radioactivity was observed in the blood (ca. 10 and 4 SUV at 40 min) which was blocked by pretreatment with unlabeled inhibitors. The most promising candidate, [11C]18, demonstrated moderate brain uptake (ca. 0.8 SUV) which showed 50% blockade by pretreatment with unlabeled 18. Conclusion One putative and four reported potent and selective MAGL inhibitors have been radiolabeled via [11C]CO2 fixation as radiotracers for this enzyme. Despite the promising in vitro pharmacological profile, none of the five candidate radiotracers exhibited in vivo behavior suitable for PET neuroimaging.
    Nuclear Medicine and Biology 09/2014; 41(8). DOI:10.1016/j.nucmedbio.2014.05.001 · 2.41 Impact Factor
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    ABSTRACT: Postpartum depression (PPD) has a prevalence rate of 13% and a similarly high proportion of women report a subclinical state of one or more MDE symptoms. The aim was to investigate whether monoamine oxidase-A (MAO-A) VT, an index of MAO-A density, is increased in the prefrontal and anterior cingulate cortex (PFC and ACC), during PPD or when a PPD spectrum symptom, greater predisposition to crying, is present. MAO-A is an enzyme that increases in density after estrogen decline, and has several functions including creating oxidative stress, influencing apoptosis and monoamine metabolism. Fifty seven women were recruited including 15 first onset, antidepressant naive, PPD subjects, 12 postpartum healthy who cry due to sad mood, 15 asymptomatic postpartum healthy women and 15 healthy women not recently pregnant. Each underwent [(11)C]-harmine positron emission tomography (PET) scanning to measure MAO-A VT. Both PPD, and greater predisposition to crying were associated with greater MAO-A VT in the PFC and ACC (multivariate analysis of variance (MANOVA), group effect, F21,135 =1.856; p=0.019; mean combined region elevation 21% and 14% in PPD and crying groups, respectively, relative to postpartum asymptomatic). Greater MAO-A VT in the PFC and ACC represents a new biomarker in PPD, and the PPD symptom of predisposition to crying. Novel strategies for preventing PPD (and some PPD symptoms) may be possible by avoiding environmental conditions that elevate MAO-A level and enhancing conditions that normalize MAO-A level. These findings also argue for clinical trials in PPD with the newer, well-tolerated MAO-A inhibitor antidepressants.Neuropsychopharmacology accepted article preview online, 30 July 2014; doi:10.1038/npp.2014.190.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2014; 40(2). DOI:10.1038/npp.2014.190 · 8.68 Impact Factor
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    ABSTRACT: There is considerable interest in developing highly selective dopamine (DA) D3 receptor ligands for a variety of mental health disorders. DA D3 receptors have been implicated in Parkinson's disease, schizophrenia, anxiety, depression, and substance use disorders. The most concrete evidence suggests a role for the D3 receptor in drug-seeking behaviors. D3 receptors are a subtype of D2 receptors, and traditionally the functional role of these two receptors has been difficult to differentiate. Over the past 10-15 years a number of compounds selective for D3 over D2 receptors have been developed. However, translating these findings into clinical research has been difficult as many of these compounds cannot be used in humans. Therefore, the functional data involving the D3 receptor in drug addiction mostly comes from pre-clinical studies. Recently, with the advent of [(11)C]-(+)-PHNO, it has become possible to image D3 receptors in the human brain with increased selectivity and sensitivity. This is a significant innovation over traditional methods such as [(11)C]-raclopride that cannot differentiate between D2 and D3 receptors. The use of [(11)C]-(+)-PHNO will allow for further delineation of the role of D3 receptors. Here, we review recent evidence that the role of the D3 receptor has functional importance and is distinct from the role of the D2 receptor. We then introduce the utility of analyzing [(11)C]-(+)-PHNO binding by region of interest. This novel methodology can be used in pre-clinical and clinical approaches for the measurement of occupancy of both D3 and D2 receptors. Evidence that [(11)C]-(+)-PHNO can provide insights into the function of D3 receptors in addiction is also presented.
    Frontiers in Pharmacology 07/2014; 5:161. DOI:10.3389/fphar.2014.00161
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    ABSTRACT: Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [11C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [18F]DOPP ([18F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising 18F-labeled analog based on rodent studies. The goal of this work is to evaluate [18F]DOPP in non-human primates to support its clinical translation. High specific activity [18F]DOPP (5 - 6 Ci•µmol-1) was administered intravenously (i.v.) to three baboons (2M/1F, 3 - 4 yr). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 µg/kg i.v., 10 min prior to [18F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ~95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [18F]DOPP is believed to covalently link to the active site of FAAH. Consistent with previous findings for [11C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter λk3 was therefore used to evaluate whole brain (WB) and regional binding of [18F]DOPP. Pretreatment studies showed inhibition of λk3 across all brain regions (WB baseline: 0.112 mL/cm3/min; 300 µg/kg URB597: 0.058 mL/cm3/min) suggesting that [18F]DOPP binding is specific for FAAH, consistent with previous rodent data.
    Molecular Pharmaceutics 07/2014; 11(11). DOI:10.1021/mp500316h · 4.79 Impact Factor
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    ABSTRACT: IMPORTANCE Perimenopause is a period of high risk for mood disorders, and it has been proposed that perimenopause is also a window of risk for processes linked to later dementia. However, in human perimenopause, the neurobiological changes implicated in the genesis of mood disorders or dementia have not been identified. Monoamine oxidase A (MAO-A) is an important brain enzyme that creates oxidative stress, influences apoptosis, and metabolizes monoamines. After declines in estrogen level, MAO-A density may be elevated for a month or longer, and repeated declines in estrogen level occur with greater magnitude during perimenopause. OBJECTIVE To investigate whether MAO-A total distribution volume (VT), an index of MAO-A density, is elevated in women of perimenopausal age (41-51 years). DESIGN, SETTING, AND PARTICIPANTS In a cross-sectional study at a tertiary care psychiatric hospital, 58 women underwent carbon 11-labeled harmine positron emission tomography. These included 19 young women of reproductive age (mean [SD], 28.26 [5.05] years), 27 women of perimenopausal age (mean [SD] age, 45.21 [3.41] years; including 14 women with change in menstrual cycle length with a mean [SD] age of 45.50 [4.00] years and 13 women with no change in menstrual cycle length with a mean [SD] age of 44.92 [2.81] years), and 12 women in menopause (mean [SD] age, 56.25 [3.19] years). MAIN OUTCOMES AND MEASURES Values of MAO-A VT in the prefrontal cortex, anterior cingulate cortex, dorsal striatum, ventral striatum, thalamus, hippocampus, and midbrain. RESULTS On average, MAO-A VT in perimenopausal age was elevated by 34% compared with reproductive age and by 16% compared with menopause (multivariate analysis of variance, group effect, F16,94 = 3.03; P < .001). Within the perimenopausal age group, meeting Stages of Reproductive Aging Workshop criteria for perimenopause, which is mainly based on menstrual cycle length, was not associated with MAO-A VT (F8,18 = 0.548; P = .81) but tendency to cry was positively correlated with MAO-A VT in the prefrontal cortex (r = 0.54; P = .008). CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report of a change in a central biomarker during perimenopausal age that is also present during major depressive episodes and high-risk states for major depressive episodes. The functions of MAO-A influence oxidative stress and apoptosis, 2 processes implicated as excessive in both mood disorders and dementia. Hence, greater MAO-A VT during perimenopause may represent a new target for assessing novel interventions to prevent mood disorders and reduce longer-term risk of neurodegenerative disease.
    JAMA Psychiatry 06/2014; 71(8). DOI:10.1001/jamapsychiatry.2014.250 · 12.01 Impact Factor
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    ABSTRACT: This article describes the kinetic modeling of [(11)C]SL25.1188 ([(S)-5-methoxymethyl-3-[6-(4,4,4-trifluorobutoxy)-benzo[d]isoxazol-3-yl]-oxazolidin-2-[(11)C]one]) binding to monoamine oxidase B (MAO-B) in the human brain using high-resolution positron emission tomography (PET). Seven healthy subjects underwent two separate 90- minute PET scans after an intravenous injection of [(11)C]SL25.1188. Complementary arterial blood sampling was acquired. Radioactivity was quickly eliminated from plasma with 80% of parent compound remaining at 90 minutes. Metabolites were more polar than the parent compound. Time-activity curves showed high brain uptake, early peak and washout rate consistent with known regional MAO-B concentration. A two-tissue compartment model (2-TCM) provided better fits to the data than a 1-TCM. Measurement of total distribution volume (VT) showed very good identifiability (based on coefficient of variation (COV)) for all regions of interest (ROIs) (COV(VT)<8%), low between-subject variability (∼20%), and quick temporal convergence (within 5% of final value at 45 minutes). Logan graphical method produces very good estimation of VT. Regional VT highly correlated with previous postmortem report of MAO-B level (r(2)=0.9). Specific binding would account from 70% to 90% of VT. Hence, VT measurement of [(11)C]SL25.1(1)88 PET is an excellent estimation of MAO-B concentration.Journal of Cerebral Blood Flow & Metabolism advance online publication, 12 February 2014; doi:10.1038/jcbfm.2014.34.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2014; DOI:10.1038/jcbfm.2014.34 · 5.34 Impact Factor
  • JAMA Psychiatry 01/2014; · 12.01 Impact Factor
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    ABSTRACT: Research on the environmental risk factors for schizophrenia has focused on either psychosocial stress or drug exposure, with limited investigation of their interaction. A heightened dopaminergic stress response in patients with schizophrenia and individuals at clinical high risk (CHR) supports the dopaminergic sensitization hypothesis. Cannabis is believed to contribute to the development of schizophrenia, possibly through a cross-sensitization with stress. Twelve CHR and 12 cannabis-using CHR (CHR-CU, 11 dependent) subjects underwent [(11)C]-(+)-PHNO positron emission tomography scans while performing a sensorimotor control task (SMCT) and a stress condition (Montreal Imaging Stress task; MIST). The simplified reference tissue model was used to obtain binding potential relative to non-displaceable binding (BPND) in the whole striatum, its functional subdivisions (limbic striatum (LST), associative striatum (AST) and sensorimotor striatum (SMST)), globus pallidus (GP) and substantia nigra (SN). Changes in BPND, reflecting alterations in synaptic dopamine levels, were tested with ANOVA. SMCT BPND was not significantly different between groups in any brain region (P>0.21). While stress elicited a significant reduction in BPND in the CHR group, CHR-CU group exhibited an increase in BPND. Stress-induced changes in regional BPND between CHR-CU and CHR were significantly different in AST (P<0.001), LST (P=0.007), SMST (P=0.002), SN (P=0.021) and whole striatum (P=0.001), with trend level in the GP (P=0.099). All subjects experienced an increase in positive (attenuated) psychotic symptoms (P=0.001) following the stress task. Our results suggest altered DA stress reactivity in CHR who concurrently use cannabis, as compared to CHR. Our finding does not support the cross-sensitization hypothesis, which posits greater dopaminergic reactivity to stress in CHR cannabis users, but adds to the growing body of literature showing reduced dopamine (stress) response in addiction.Neuropsychopharmacology accepted article preview online, 24 December 2013. doi:10.1038/npp.2013.347.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 12/2013; DOI:10.1038/npp.2013.347 · 7.83 Impact Factor
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    ABSTRACT: Inadequate treatment response occurs in approximately 40% of major depressive episodes (MDE), and one approach to solve this is careful matching of treatment to the specific pathologies of MDE. One such biological abnormality is elevated monoamine oxidase A (MAO-A) levels, which occurs primarily in the prefrontal and anterior cingulate cortex (PFC and ACC) during MDE however, the subtypes for which this abnormality is most prominent are unknown. We hypothesized that MAO-A levels in the PFC and ACC are most elevated in MDE with greater severity and reversed neurovegetative symptoms (hypersomnia and either hyperphagia or weight gain). MAO-A VT (an index of MAO-A density) was measured using [(11)C]harmine positron emission tomography (PET) in 42 subjects with MDE secondary to major depressive disorder (MDD) and 37 healthy controls. The effect of severity and reversed neurovegetative symptoms on MAO-A VT in the PFC and ACC were analyzed using a multivariate analysis of variance (MANOVA). Greater severity and reversed neurovegetative symptoms were associated with elevated MAO-A VT in the PFC and ACC (MANOVA, severity: F (2,38)=5.44, p=0.008; reversed neurovegetative symptoms: F (2,38) =5.13, p=0.01). Increased MAO-A level, when greater severity and reversed neurovegetative symptoms are present, may explain the association of these clinical features with a preferential response to MAO inhibitors, which is especially well-evidenced for reversed neurovegetative symptoms in MDE. Since MAO-A creates oxidative stress, facilitates apoptosis and metabolizes monoamines, therapeutics opposing these processes are predicted to best treat MDE with greater severity and reversed neurovegetative symptoms.Neuropsychopharmacology accepted article preview online, 24 October 2013; doi:10.1038/npp.2013.297.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2013; DOI:10.1038/npp.2013.297 · 7.83 Impact Factor
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    ABSTRACT: Alcohol dependence (AD) is a multiorgan disease in which excessive oxidative stress and apoptosis are implicated. Monoamine oxidase A (MAO-A) is an important enzyme on the outer mitochondrial membrane that participates in the cellular response to oxidative stress and mitochondrial toxicity. It is unknown whether MAO-A levels are abnormal in AD. We hypothesized that MAO-A VT, an index of MAO-A level, is elevated in the prefrontal cortex (PFC) during AD, because markers of greater oxidative stress and apoptosis are reported in the brain in AD and a microarray analysis reported greater MAO-A messenger RNA in the PFC of rodents exposed to alcohol vapor. Sixteen participants with alcohol dependence and 16 healthy control subjects underwent [(11)C]-harmine positron emission tomography. All were nonsmoking, medication- and drug-free, and had no other past or present psychiatric or medical illnesses. MAO-A VT was significantly greater in the PFC (37%, independent samples t test, t30 = 3.93, p < .001), and all brain regions analyzed (mean 32%, multivariate analysis of variance, F7,24 = 3.67, p = .008). Greater duration of heavy drinking correlated positively with greater MAO-A VT in the PFC (r = .67, p = .005) and all brain regions analyzed (r = .73 to .57, p = .001-.02). This finding represents a new pathological marker present in AD that is therapeutically targetable through direct inhibition or by novel treatments toward oxidative/pro-apoptotic processes implicated by MAO-A overexpression.
    Biological psychiatry 10/2013; DOI:10.1016/j.biopsych.2013.10.010 · 9.47 Impact Factor
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    ABSTRACT: Inhibitors of the metabolism of the endogenous cannabinoid ligand anandamide by fatty acid amide hydrolase (FAAH) reduce the gastric damage produced by non-steroidal anti-inflammatory agents and synergise with them in experimental pain models. This motivates the design of compounds with joint FAAH / cyclooxygenase (COX) inhibitory activity. Here we present data on the N-(3-methylpyridin-2-yl)amide derivatives of flurbiprofen and naproxen (Flu-AM1 and Nap-AM1, respectively) with respect to their properties towards these two enzymes. Flu-AM1 and Nap-AM1 inhibited FAAH-catalysed hydrolysis of [(3)H]anandamide by rat brain homogenates with IC50 values of 0.44 and 0.74µM, respectively. The corresponding values for flurbiprofen and naproxen were 29 and >100µM, respectively. The inhibition by Flu-AM1 was reversible, mixed-type, with K(i)slope and K(i)intercept values of 0.21 and 1.4µM, respectively. Flurbiprofen and Flu-AM1 both inhibited COX in the same manner with the order of potencies COX-2 vs. 2-arachidonoylglycerol>COX-1 vs. arachidonic acid>COX-2 vs. arachidonic acid with flurbiprofen being approximately 2-3 fold more potent than flu-AM1 in the assays. Nap-AM1 was a less potent inhibitor of COX. Flu-AM1 at low µM concentrations inhibited the FAAH-driven uptake of [(3)H]anandamide into RBL2H3 basophilic leukaemia cells in vitro, but did not penetrate the brain in vivo sufficiently to block the binding of [(18)F]DOPP to brain FAAH. It is concluded that Flu-AM1 is a dual-action inhibitor of FAAH and COX that may be useful in exploring the optimal balance of effects on these two enzyme systems in producing peripheral alleviation of pain and inflammation in experimental models.
    European journal of pharmacology 10/2013; 720(1-3). DOI:10.1016/j.ejphar.2013.09.065 · 2.68 Impact Factor

Publication Stats

7k Citations
1,038.23 Total Impact Points

Institutions

  • 1994–2015
    • University of Toronto
      • • Department of Psychiatry
      • • Institute of Medical Sciences
      • • Faculty of Medicine
      Toronto, Ontario, Canada
    • University of Southern California
      Los Ángeles, California, United States
  • 1999–2014
    • Centre for Addiction and Mental Health
      • • Research Imaging Centre
      • • Schizophrenia Program
      Toronto, Ontario, Canada
  • 2012
    • University Health Network
      Toronto, Ontario, Canada
  • 1985–2006
    • Johns Hopkins Medicine
      • Division of Nuclear Medicine
      Baltimore, Maryland, United States
  • 1987–1994
    • Johns Hopkins University
      • • Division of Nuclear Medicine
      • • Department of Radiology
      Baltimore, Maryland, United States
  • 1990
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Environmental Health Sciences
      Baltimore, Maryland, United States