Stephen J. Kish

Centre for Addiction and Mental Health, Toronto, Ontario, Canada

Are you Stephen J. Kish?

Claim your profile

Publications (274)1775.69 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cardiovascular and hypothalamic pituitary axis (HPA) disturbances have been observed in individuals who are pathological gamblers (PGs). These may partly derive from chronic exposure to gambling. Response to amphetamine (AMPH) may reveal such disturbances while controlling for differential conditioned responses to gambling in PGs vs healthy controls (HCs). This study assessed heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) and plasma cortisol following oral AMPH (0.4 mg/kg) in male PGs (n=12) and HCs (n=11) who underwent a positron emission tomography (PET) scan. The Stop Signal Task enabled assessment of the link between physiological and behavioral dysregulation. Trait moderating effects were explored. The responses of PGs to AMPH differed from those of HCs on every index. PGs displayed persistent elevation in DBP and concomitant reduction in HR (i.e. baroreflex) compared to HCs beyond 90 min post-dose. PGs displayed deficits in cortisol compared to HCs that were partially reversed by AMPH. Impairment on the Stop Signal Task correlated positively with HR in controls, but negatively with HR in PGs, suggesting that strong initial and compensatory cardiac responses to a stimulant may each predict disinhibition. Extraversion predicted greater disinhibition in PGs. Noradrenergic disturbances may contribute to sensitized responses to stimulant challenge and disinhibition in PGs. © The Author(s) 2015.
    Journal of Psychopharmacology 07/2015; DOI:10.1177/0269881115592338 · 2.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although gliosis is a normal response to brain injury, reports on the extent of astrogliosis in the degenerating substantia nigra in Parkinson's disease (PD) are conflicting. It has also been recently suggested that accumulation of nigral α-synuclein in this disorder might suppress astrocyte activation which in turn could exacerbate the degenerative process. This study examined brain protein levels (intact protein, fragments, and aggregates, if any) of astroglial markers and their relationship to α-synuclein in PD and in the positive control parkinson-plus conditions multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Autopsied brain homogenates of patients with PD (n=10), MSA (n=11), PSP (n=11) and matched controls (n=10) were examined for the astroglial markers glial fibrillary acidic protein (GFAP), vimentin, and heat shock protein-27 (Hsp27) by quantitative immunoblotting. As expected, both MSA (putamen > substantia nigra > caudate > frontal cortex) and PSP (substantia nigra > caudate > putamen, frontal cortex) showed widespread but regionally specific pattern of increased immunoreactivity of the markers, in particular for the partially proteolyzed fragments (all three) and aggregates (GFAP). In contrast, immunoreactivity of the three markers was largely normal in PD in brain regions examined with the exception of trends for variably increased levels of cleaved vimentin in substantia nigra and frontal cortex. In patients with PD, GFAP levels in the substantia nigra correlated inversely with α-synuclein accumulation whereas the opposite was true for MSA. Our biochemical findings of generally normal protein levels of astroglial markers in substantia nigra of PD, and negative correlation with α-synuclein concentration, are consistent with some recent neuropathology reports of mild astroglial response and with the speculation that astrogliosis might be suppressed in this disorder by excessive α-synuclein accumulation. Should astrogliosis protect, to some extent, the degenerating substantia nigra from damage, therapeutics aimed at normalization of astrocyte reaction in PD could be helpful. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 06/2015; 82. DOI:10.1016/j.nbd.2015.06.010 · 5.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Positron emission tomography with [(11)C]CURB was recently developed to quantify fatty acid amide hydrolase (FAAH), the enzyme responsible for hydrolyzing the endocannabinoid anandamide. This study investigated the test-retest reliability of [(11)C]CURB as well as its in vivo specificity and the validity of the kinetic model by using the highly specific FAAH inhibitor, PF-04457845. Five healthy volunteers completed test-retest [(11)C]CURB scans 1 to 2 months apart and six subjects completed baseline and blocking scans on the same day after PF-04457845 (p.o.) administration (1, 4, or 20 mg; n=2 each). The composite parameter λk3 (an index of FAAH activity, λ=K1/k2) was estimated using an irreversible two-tissue compartment model with plasma input function. There were no clinically observable responses to oral PF-04457845 or [(11)C]CURB injection. Oral administration of PF-04457845 reduced [(11)C]CURB binding to a homogeneous level at all three doses, with λk3 values decreased by ⩾91%. Excellent reproducibility and good reliability (test-retest variability=9%; intraclass correlation coefficient=0.79) were observed across all regions of interest investigated. Our findings suggest that λk3/[(11)C]CURB is a reliable, highly sensitive, and selective tool to measure FAAH activity in human brain in vivo. Moreover, PF-04457845 is a highly potent FAAH inhibitor (>95% inhibition at 1 mg) in living human brain.Journal of Cerebral Blood Flow & Metabolism advance online publication, 17 June 2015; doi:10.1038/jcbfm.2015.133.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 06/2015; DOI:10.1038/jcbfm.2015.133 · 5.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The common functional single-nucleotide polymorphism (rs324420, C385A) of the endocannabinoid inactivating enzyme fatty acid amide hydrolase (FAAH) has been associated with anxiety disorder relevant phenotype and risk for addictions. Here, we tested whether the FAAH polymorphism affects in vivo binding of the FAAH positron emission tomography (PET) probe [(11)C]CURB ([(11)C-carbonyl]-6-hydroxy-[1,10-biphenyl]-3-yl cyclohexylcarbamate (URB694)). Participants (n=24) completed one [(11)C]CURB/PET scan and were genotyped for rs324420. Relative to C/C (58%), A-allele carriers (42%) had 23% lower [(11)C]CURB binding (λk3) in brain. We report evidence that the genetic variant rs324420 in FAAH is associated with measurable differences in brain FAAH binding as per PET [(11)C]CURB measurement.Journal of Cerebral Blood Flow & Metabolism advance online publication, 3 June 2015; doi:10.1038/jcbfm.2015.119.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 06/2015; DOI:10.1038/jcbfm.2015.119 · 5.34 Impact Factor
  • [Show abstract] [Hide abstract]
    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
  • Drug and Alcohol Dependence 01/2015; 146:e65. DOI:10.1016/j.drugalcdep.2014.09.546 · 3.28 Impact Factor
  • [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    ABSTRACT: Animal data show that high doses of the stimulant drug methamphetamine can damage brain dopamine neurones; however, it is still uncertain whether methamphetamine, at any dose, is neurotoxic to human brain. Since gliosis is typically associated with brain damage and is observed in animal models of methamphetamine exposure, we measured protein levels (intact protein and fragments, if any) of markers of microgliosis (glucose transporter-5, human leukocyte antigens HLA-DRα [TAL.1B5] and HLA-DR/DQ/DPβ [CR3/43]) and astrogliosis (glial fibrillary acidic protein, vimentin, and heat shock protein-27) in homogenates of autopsied brain of chronic methamphetamine users (n=20) and matched controls (n=23). Intact protein levels of all markers were, as expected, elevated (+ 28%-1270%, P< 0.05) in putamen of patients with the neurodegenerative disorder multiple system atrophy (as a positive control) as were concentrations of fragments of glial fibrillary acidic protein, vimentin and heat shock protein-27 (+ 170%-4700%, P< 0.005). In contrast, intact protein concentrations of the markers were normal in dopamine-rich striatum (caudate, putamen) and in the frontal cortex of the drug users. However, striatal levels of cleaved vimentin and heat shock protein-27 were increased (by 98%-211%, P< 0.05), with positive correlations (r=0.41-0.60) observed between concentrations of truncated heat shock protein-27 and extent of dopamine loss (P= 0.006) and levels of lipid peroxidation products 4-hydroxynonenal (P= 0.046) and malondialdehyde (P= 0.11). Our failure to detect increased intact protein levels of commonly used markers of microgliosis and astrogliosis could be explained by exposure to methamphetamine insufficient to cause a toxic process associated with overt gliosis; however, about half of the subjects had died of drug intoxication suggesting that “high” drug doses might have been used. Alternatively, drug tolerance to toxic effects might have occurred in the subjects, who were all chronic methamphetamine users. Nevertheless, the finding of above-normal levels of striatal vimentin and heat shock protein-27 fragments (which constituted 10-28% of the intact protein), for which changes in the latter correlated with those of several markers possibly suggestive of damage, does suggest that some astrocytic “disturbance” had occurred, which might in principle be related to methamphetamine neurotoxicity or to a neuroplastic remodeling process. Taken together, our neurochemical findings do not provide strong evidence for either marked microgliosis or astrogliosis in at least a subgroup of human recreational methamphetamine users who used the drug chronically and shortly before death. However, a logistically more difficult quantitative histopathological study is needed to confirm whether glial changes occur or do not occur in brain of human methamphetamine (and amphetamine) users.
    Neurobiology of Disease 07/2014; 67. DOI:10.1016/j.nbd.2014.03.015 · 5.20 Impact Factor
  • [Show abstract] [Hide abstract]
    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
  • Journal of clinical psychopharmacology 04/2014; 34(3). DOI:10.1097/JCP.0b013e3182a95a27 · 3.76 Impact Factor
  • JAMA Psychiatry 01/2014; · 12.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Drug addiction has been associated with deficits in mesostriatal dopamine (DA) function, but whether this state extends to behavioral addictions such as pathological gambling (PG) is unclear. Here we used positron emission tomography and the D3 receptor-preferring radioligand [(11)C]-(+)-PHNO during a dual-scan protocol to investigate DA release in response to oral amphetamine in pathological gamblers (n=12) and healthy controls (n=11). In contrast with human neuroimaging findings in drug addiction, we report the first evidence that PG is associated with greater DA release in dorsal striatum (54-63% greater [(11)C]-(+)-PHNO displacement) than controls. Importantly, dopaminergic response to amphetamine in gamblers was positively predicted by D3 receptor levels (measured in substantia nigra), and related to gambling severity, allowing for construction of a mechanistic model that could help explain DA contributions to PG. Our results are consistent with a hyperdopaminergic state in PG, and support the hypothesis that dopaminergic sensitization involving D3-related mechanisms might contribute to the pathophysiology of behavioral addictions.Molecular Psychiatry advance online publication, 10 December 2013; doi:10.1038/mp.2013.163.
    Molecular Psychiatry 12/2013; 19(12). DOI:10.1038/mp.2013.163 · 15.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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; 39(4). DOI:10.1038/npp.2013.297 · 7.83 Impact Factor
  • [Show abstract] [Hide abstract]
    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
  • [Show abstract] [Hide abstract]
    ABSTRACT: The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D3 receptor system has recently attracted considerable clinical interest, and D3 antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioural relevance of the D3 receptor system in CD, using the positron emission tomography (PET) radiotracer [(11)C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7-240 days on scan day) and 15 matched healthy control (HC) subjects completed two PET scans: One with [(11)C]-(+)-PHNO to assess D3 receptor binding (BPND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [(11)C]raclopride to assess D2/3 binding. CD subjects also completed a behavioural battery to characterize the addiction behavioural phenotype. CD subjects showed higher [(11)C]-(+)-PHNO BPND than HC in the substantia nigra, which correlated with behavioural impulsiveness and risky decision-making. In contrast, [(11)C]raclopride BPND was lower across the striatum in CD, consistent with previous literature in 2 week abstinence. The data suggest that in contrast to a D2 deficiency, CD individuals may have heightened D3 receptor levels, which could contribute to addiction-relevant traits. D3 upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment.Neuropsychopharmacology accepted article preview online, 7 August 2013. doi:10.1038/npp.2013.192.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2013; DOI:10.1038/npp.2013.192 · 7.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: AimsPathological gambling (PG) shares diagnostic features with substance use disorder (SUD), but the neurochemical mechanisms underlying PG are poorly understood. Because dopamine (DA), a neurotransmitter implicated in reward and reinforcement, is probably involved, we used positron emission tomography (PET) to test whether PG is associated with abnormalities in D2 and D3 receptor levels, as observed in SUD. DesignCase–control study comparing PG to healthy control (HC) subjects. SettingAcademic research imaging centre. ParticipantsThirteen non-treatment-seeking males meeting DSM-IV criteria for PG, and 12 matched HC (11 of whom completed PET). MeasurementsTwo PET scans (one with the D3 receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) and the other with [11C]raclopride) to assess D2/3 DA receptor availability, and behavioural measures (self-report questionnaires and slot-machine game) to assess subjective effects and relationships to PET measures. FindingsBinding of both radiotracers did not differ between groups in striatum or substantia nigra (SN) (all P > 0.1). Across PG, [11C]-(+)-PHNO binding in SN, where the signal is attributable primarily to D3 receptors, correlated with gambling severity (r = 0.57, P = 0.04) and impulsiveness (r = 0.65, P = 0.03). In HC, [11C]raclopride binding in dorsal striatum correlated inversely with subjective effects of gambling (r = −0.70, P = 0.03) and impulsiveness (r = −0.70, P = 0.03). Conclusions Unlike with substance use disorder, there appear to be no marked differences in D2/D3 levels between healthy subjects and pathological gamblers, suggesting that low receptor availability may not be a necessary feature of addiction. However, relationships between [11C]-(+)-PHNO binding and gambling severity/impulsiveness suggests involvement of the D3 receptor in impulsive/compulsive behaviours.
    Addiction 05/2013; 108(5). DOI:10.1111/add.12066 · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Positron emission tomography (PET) imaging of monoamine oxidases (MAO-A: [(11)C]harmine, [(11)C]clorgyline, and [(11)C]befloxatone; MAO-B: [(11)C]deprenyl-D2) has been actively pursued given clinical importance of MAOs in human neuropsychiatric disorders. However, it is unknown how well PET outcome measures for the different radiotracers are quantitatively related to actual MAO protein levels. We measured regional distribution (n=38) and developmental/aging changes (21 hours to 99 years) of both MAOs by quantitative immunoblotting in autopsied normal human brain. MAO-A was more abundant than MAO-B in infants, which was reversed as MAO-B levels increased faster before 1 year and, unlike MAO-A, kept increasing steadily to senescence. In adults, regional protein levels of both MAOs were positively and proportionally correlated with literature postmortem data of MAO activities and binding densities. With the exception of [(11)C]befloxatone (binding potential (BP), r=0.61, P=0.15), correlations between regional PET outcome measures of binding in the literature and MAO protein levels were good (P<0.01) for [(11)C]harmine (distribution volume, r=0.86), [(11)C]clorgyline (λk(3), r=0.82), and [(11)C]deprenyl-D2 (λk(3) or modified Patlak slope, r=0.78 to 0.87), supporting validity of the latter imaging measures. However, compared with in vitro data, the latter PET measures underestimated regional contrast by ∼2-fold. Further studies are needed to address cause of the in vivo vs. in vitro nonproportionality.Journal of Cerebral Blood Flow & Metabolism advance online publication, 13 February 2013; doi:10.1038/jcbfm.2013.19.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2013; 33(6). DOI:10.1038/jcbfm.2013.19 · 5.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dopa-responsive dystonia (DRD) is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of levodopa. There are two known causative genes for DRD: (1) the GCH1 gene, coding for the enzyme GTP cyclohydrolase I (GTPCH) that catalyzes the rate-limiting step in the biosynthetic pathway for tetrahydrobiopterin (BH4, the essential cofactor for tyrosine hydroxylase [TH]), and (2) the TH gene, coding for the enzyme TH in the catecholamine biosynthesis. Many patients with DRD have shown dominantly inherited GCH1 mutations (GTPCH-deficient DRD, the major form of DRD), whereas a relatively small number of DRD patients have demonstrated recessively inherited TH mutations (TH-deficient DRD, the mild form of TH deficiency). Notwithstanding the discovery of these causative genes for DRD, a therapeutic trial with low-dose levodopa is still the most practical approach to the diagnosis of this treatable disorder, and the trial should be considered in all children with dystonic and/or parkinsonian symptoms or with unexplained gait disorders. This chapter summarizes clinical features as well as recent advances in the genetics and ­biochemistry of DRD.
    Movement Disorder Emergencies, 01/2013: pages 319-340; , ISBN: 978-1-60761-834-8
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endocannabinoid tone has recently been implicated in a number of prevalent neuropsychiatric conditions. [(11)C]CURB is the first available positron emission tomography (PET) radiotracer for imaging fatty acid amide hydrolase (FAAH), the enzyme which metabolizes the prominent endocannabinoid anandamide. Here, we sought to determine the most suitable kinetic modeling approach for quantifying [(11)C]CURB that binds selectively to FAAH. Six healthy volunteers were scanned with arterial blood sampling for 90 minutes. Kinetic parameters were estimated regionally using a one-tissue compartment model (TCM), a 2-TCM with and without irreversible trapping, and an irreversible 3-TCM. The 2-TCM with irreversible trapping provided the best identifiability of PET outcome measures among the approaches studied (coefficient of variation (COV) of the net influx constant K(i) and the composite parameter λk(3) (λ=K(1)/k(2)) <5%, and COV(k(3))<10%). Reducing scan time to 60 minutes did not compromise the identifiability of rate constants. Arterial spin labeling measures of regional cerebral blood flow were only slightly correlated with K(i), but not with k(3) or λk(3). Our data suggest that λk(3) is sensitive to changes in FAAH activity, therefore, optimal for PET quantification of FAAH activities with [(11)C]CURB. Simulations showed that [(11)C]CURB binding in healthy subjects is far from a flow-limited uptake.Journal of Cerebral Blood Flow & Metabolism advance online publication, 5 December 2012; doi:10.1038/jcbfm.2012.180.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 12/2012; 33(3). DOI:10.1038/jcbfm.2012.180 · 5.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The thalamus occupies a pivotal position within the corticobasal ganglia-cortical circuits. In Parkinson's disease (PD), the thalamus exhibits pathological neuronal discharge patterns, foremost increased bursting and oscillatory activity, which are thought to perturb the faithful transfer of basal ganglia impulse flow to the cortex. Analogous abnormal thalamic discharge patterns develop in animals with experimentally reduced thalamic noradrenaline; conversely, added to thalamic neuronal preparations, noradrenaline exhibits marked antioscillatory and antibursting activity. Our study is based on this experimentally established link between noradrenaline and the quality of thalamic neuronal discharges. We analyzed 14 thalamic nuclei from all functionally relevant territories of 9 patients with PD and 8 controls, and measured noradrenaline with high-performance liquid chromatography with electrochemical detection. In PD, noradrenaline was profoundly reduced in all nuclei of the motor (pallidonigral and cerebellar) thalamus (ventroanterior: -86%, P = .0011; ventrolateral oral: -87%, P = .0010; ventrolateral caudal: -89%, P = .0014): Also, marked noradrenaline losses, ranging from 68% to 91% of controls, were found in other thalamic territories, including associative, limbic and intralaminar regions; the primary sensory regions were only mildly affected. The marked noradrenergic deafferentiation of the thalamus discloses a strategically located noradrenergic component in the overall pathophysiology of PD, suggesting a role in the complex mechanisms involved with the genesis of the motor and non-motor symptoms. Our study thus significantly contributes to the knowledge of the extrastriatal nondopaminergic mechanisms of PD with direct relevance to treatment of this disorder. © 2012 Movement Disorder Society.
    Movement Disorders 11/2012; 27(13). DOI:10.1002/mds.25109 · 5.63 Impact Factor

Publication Stats

13k Citations
1,775.69 Total Impact Points

Institutions

  • 1998–2015
    • Centre for Addiction and Mental Health
      • • Research Imaging Centre
      • • Addictions Research Group
      Toronto, Ontario, Canada
  • 1985–2015
    • University of Toronto
      • • Department of Psychiatry
      • • Institute of Medical Sciences
      • • Division of Neurology
      • • Faculty of Medicine
      • • Department of Pharmacology and Toxicology
      Toronto, Ontario, Canada
  • 2014
    • Creatis Medical Imaging Research Center
      Lyons, Rhône-Alpes, France
  • 2012
    • University Health Network
      Toronto, Ontario, Canada
  • 2007–2008
    • University of Utah
      • Department of Pharmacology and Toxicology
      Salt Lake City, Utah, United States
  • 2003
    • Arkansas State Crime Laboratory
      Little Rock, Arkansas, United States
  • 2000
    • Armed Forces Institute of Pathology
      Ralalpindi, Punjab, Pakistan
  • 1999
    • University of Maryland, Baltimore
      • Department of Pathology
      Baltimore, Maryland, United States
  • 1996
    • University of Alabama at Birmingham
      • Department of Psychiatry and Behavioral Neurobiology
      Birmingham, AL, United States
  • 1987–1996
    • McGill University
      Montréal, Quebec, Canada
  • 1993
    • Montreal Heart Institute
      Montréal, Quebec, Canada
  • 1991
    • Oregon Health and Science University
      Portland, Oregon, United States
  • 1990
    • UHN: Toronto General Hospital
      Toronto, Ontario, Canada
    • The University of Western Ontario
      London, Ontario, Canada
    • Toronto Western Hospital
      Toronto, Ontario, Canada
  • 1989
    • University of Mississippi
      Mississippi, United States
  • 1979–1985
    • University of British Columbia - Vancouver
      • • Department of Anesthesiology, Pharmacology and Therapeutics
      • • Faculty of Pharmaceutical Sciences
      Vancouver, British Columbia, Canada