Elevated [18F]Fluorodopamine Turnover in Brain of Patients with Schizophrenia: An [18F]Fluorodopa/Positron Emission Tomography Study

Previous positron emission tomography (PET) studies with levodopa analogs have revealed a modestly increased capacity for dopamine synthesis in the striatum of patients with schizophrenia compared with healthy age-matched control subjects. We hypothesized that not just the synthesis but also the turnover of radiolabeled dopamine is elevated in patients. To test the hypothesis, we reanalyzed 2-h-long [18F]fluorodopa (FDOPA)/PET recordings from eight unmedicated patients with schizophrenia and 15 healthy age-matched control subjects, using new methods for the quantification of [18F]fluorodopamine steady-state kinetics. The fractional rate constant for the catabolism and elimination of [18F]fluorodopamine was elevated nearly twofold in striatum, the largest biochemical difference in brain of schizophrenics yet reported. The magnitude of the intrinsic blood–brain FDOPA clearance with correction for this loss of [18F]fluorodopamine metabolites was increased by 20% in caudate and putamen and by 50% in amygdala and midbrain of the patients. However, the magnitude of the steady-state storage of FDOPA and its decarboxylated metabolites (Vd) was reduced by one-third in the caudate nucleus and amygdala of the schizophrenic group. Thus, reduced steady-state storage of [18F]fluorodopamine occurs in the midst of accelerated synthesis in brain of untreated patients. Positive scores of the positive and negative syndrome scale correlated inversely with the magnitude of Vd in amygdala, suggesting an association between positive symptoms and impaired steady-state storage of FDOPA metabolites in that structure.

[1]  Albert Gjedde,et al.  The kinetic behaviour of [3H]DOPA in living rat brain investigated by compartmental modelling of static autoradiograms , 1997, Journal of Neuroscience Methods.

[2]  Doris J. Doudet,et al.  In Vivo Receptor Assay with Multiple Ligand Concentrations: An Equilibrium Approach , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[3]  P. Cumming,et al.  Kinetics of the metabolism of four PET radioligands in living minipigs. , 2001, Nuclear medicine and biology.

[4]  Albert Gjedde,et al.  PET Studies of Net Blood—Brain Clearance of FDOPA to Human Brain: Age-Dependent Decline of [18F]Fluorodopamine Storage Capacity , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[5]  Alan C. Evans,et al.  Dopa decarboxylase activity of the living human brain. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[6]  C S Patlak,et al.  Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data , 1983, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  D. Doudet,et al.  Loss of metabolites from monkey striatum during PET with FDOPA , 2001, Synapse.

[8]  Alan C. Evans,et al.  Elevated dopa decarboxylase activity in living brain of patients with psychosis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[9]  K. Davis,et al.  Dopamine in schizophrenia: a review and reconceptualization. , 1991, The American journal of psychiatry.

[10]  Alan C. Evans,et al.  Human Striatal l-DOPA Decarboxylase Activity Estimated in vivo Using 6-[18F]fluoro-DOPA and Positron Emission Tomography: Error Analysis and Application to Normal Subjects , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  O. Wolkowitz,et al.  Structural brain pathology in schizophrenia revisited. Prefrontal cortex pathology is inversely correlated with cerebrospinal fluid levels of homovanillic acid. , 1987, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology.

[12]  Scott T. Grafton,et al.  Kinetics and Modeling of l-6-[18F]Fluoro-DOPA in Human Positron Emission Tomographic Studies , 1991, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[13]  A. Gjedde,et al.  Effect of catechol‐O‐methyltransferase inhibition on brain uptake of [18F]fluorodopa: Implications for compartmental modelling and clinical usefulness , 1998, Synapse.

[14]  G. Heninger,et al.  Cerebrospinal fluid 5-hydroxyindoleactiic acid and homovanillic acid in psychiatric patients. , 1969, International journal of neuropharmacology.

[15]  J. Hietala,et al.  Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients , 1995, The Lancet.

[16]  A. Gjedde,et al.  Compartmental analysis of dopa decarboxylation in living brain from dynamic positron emission tomograms , 1998, Synapse.

[17]  Albert Gjedde,et al.  Dopamine Storage Capacity in Caudate and Putamen of Patients with Early Parkinson's Disease: Correlation with Asymmetry of Motor Symptoms , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[18]  J. Mazziotta,et al.  Rapid Automated Algorithm for Aligning and Reslicing PET Images , 1992, Journal of computer assisted tomography.

[19]  Anthony A. Grace,et al.  Regulation of conditioned responses of basolateral amygdala neurons , 2002, Physiology & Behavior.

[20]  C. Patlak,et al.  Nigrostriatal function in humans studied with positron emission tomography , 1989, Annals of neurology.

[21]  O. Blin,et al.  Dopaminergic Contribution to the Regulation of Emotional Perception , 2005, Clinical neuropharmacology.

[22]  A. Gjedde,et al.  Enhanced [3H]DOPA and [3H]Dopamine Turnover in Striatum and Frontal Cortex In Vivo Linked to Glutamate Receptor Antagonism , 1998, Journal of neurochemistry.

[23]  Paul Cumming,et al.  Correlation of alcohol craving with striatal dopamine synthesis capacity and D2/3 receptor availability: a combined [18F]DOPA and [18F]DMFP PET study in detoxified alcoholic patients. , 2005, The American journal of psychiatry.

[24]  H. Baker,et al.  Monoamine Mechanisms in Chronic Schizophrenia: Post-Mortem Neurochemical Findings , 1979, British Journal of Psychiatry.

[25]  A Reilhac,et al.  Levodopa effect on [18F]fluorodopa influx to brain: normal volunteers and patients with Parkinson's disease , 2004, Acta neurologica Scandinavica.

[26]  R. Rimón,et al.  The content of 5-hydroxyindoleacetic acid and homovanillic acid in the cerebrospinal fluid of patients with acute schizophrenia. , 1971, Journal of psychosomatic research.

[27]  A. Malhotra,et al.  Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  V Sossi,et al.  Graphical analysis of 6-fluoro-L-dopa trapping: effect of inhibition of catechol-O-methyltransferase. , 1997, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[29]  J. Hietala,et al.  Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia , 1999, Schizophrenia Research.

[30]  Albert Gjedde,et al.  Subchronic Haloperidol Downregulates Dopamine Synthesis Capacity in the Brain of Schizophrenic Patients In Vivo , 2003, Neuropsychopharmacology.

[31]  Albert Gjedde,et al.  High‐ and Low‐Affinity Transport of D‐Glucose from Blood to Brain , 1981, Journal of neurochemistry.

[32]  Albert Gjedde,et al.  Calculation of cerebral glucose phosphorylation from brain uptake of glucose analogs in vivo: A re-examination , 1982, Brain Research Reviews.

[33]  Andrew D. Roberts,et al.  FluoroDOPA PET shows the nondopaminergic as well as dopaminergic destinations of levodopa , 1999, Neurology.

[34]  V Sossi,et al.  A Reversible Tracer Analysis Approach to the Study of Effective Dopamine Turnover , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[35]  Bradley T. Christian,et al.  D2/D3 dopamine receptor binding with [F-18]fallypride in thalamus and cortex of patients with schizophrenia , 2006, Schizophrenia Research.

[36]  A. Meyer-Lindenberg,et al.  Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia , 2002, Nature Neuroscience.

[37]  M. Laruelle,et al.  Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies , 1999, Journal of psychopharmacology.

[38]  N. Andreasen,et al.  Exclusion of close linkage between the synaptic vesicular monoamine transporter locus and schizophrenia spectrum disorders. , 1995, American journal of medical genetics.

[39]  A. Gjedde,et al.  Pharmacokinetics of Plasma 6-[18F]Fluoro-l-3,4-Dihydroxyphenylalanine ([18F]FDOPA) in Humans , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[40]  A. Gjedde,et al.  On the accuracy of an [18F]FDOPA compartmental model: evidence for vesicular storage of [18F]fluorodopamine in vivo , 1997, Journal of Neuroscience Methods.

[41]  Hans-Georg Buchholz,et al.  Modulation of [18F]fluorodopa (FDOPA) kinetics in the brain of healthy volunteers after acute haloperidol challenge , 2006, NeuroImage.

[42]  K. Davis,et al.  A comparison of plasma homovanillic acid concentrations in schizophrenic patients and normal controls. , 1988, Archives of general psychiatry.

[43]  A. Lawrence,et al.  Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study. , 2004, Archives of general psychiatry.

[44]  J. Krystal,et al.  Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. , 1998, The American journal of psychiatry.

[45]  C. Patlak,et al.  Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data. Generalizations , 1985, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[46]  G. Sedvall,et al.  Aberrant monoamine metabolite levels in CSF and family history of schizophrenia. Their relationships in schizophrenic patients. , 1980, Archives of general psychiatry.

[47]  M. Bergström,et al.  Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(β-11C) DOPA and PET , 1999, Biological Psychiatry.

[48]  Paul Cumming,et al.  The effect of unilateral neurotoxic lesions to serotonin fibres in the medial forebrain bundle on the metabolism of [3H]DOPA in the telencephalon of the living rat , 1997, Brain Research.

[49]  J. Fudge,et al.  The extended amygdala and the dopamine system: another piece of the dopamine puzzle. , 2003, The Journal of neuropsychiatry and clinical neurosciences.

[50]  R. Koeppe,et al.  In Vivo Measurement of the Vesicular Monoamine Transporter in Schizophrenia , 2000, Neuropsychopharmacology.

[51]  J. Krystal,et al.  Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[52]  H. Tuckwell,et al.  A meta-analysis of homovanillic acid concentrations in schizophrenia. , 1993, The International journal of neuroscience.

[53]  A. Gjedde,et al.  Cerebral 6‐[18F]fluoro‐L‐DOPA (FDOPA) metabolism in pig studied by positron emission tomography , 1999 .

[54]  A. Carlsson,et al.  Different corticostriatal patterns of L-DOPA utilization in patients with untreated schizophrenia and patients treated with classical antipsychotics or clozapine. , 2003, Scandinavian journal of psychology.

[55]  A. Gjedde,et al.  Cerebral 6-[(18)F]fluoro-L-DOPA (FDOPA) metabolism in pig studied by positron emission tomography. , 1999, Synapse.