title: Dopaminergic denervation severity depends on COMT Val158Met polymorphism in Parkinson's disease.
abstract: BACKGROUND
  Catecholamine-O-methyl-tranferase (COMT) initiates dopamine degradation. Its activity is mainly determined by a single nucleotide polymorphism in the COMT gene (Val158Met, rs4680) separating high (Val/Val, COMT(HH)), intermediate (Val/Met, COMT(HL)) and low metabolizers (Met/Met, COMT(LL)). We investigated dopaminergic denervation in the striatum in PD patients according to COMT rs4680 genotype.
  
  
  METHODS
  Patients with idiopathic PD were assessed for motor severity (UPDRS-III rating scale in OFF-state), dopaminergic denervation using [123I]-FP-CIT SPECT imaging, and genotyped for the COMT rs4680 enzyme. [123I]-FP-CIT binding potential (BP) for each voxel was defined by the ratio of tracer-binding in the region of interest (striatum, caudate nucleus and putamen) to that in a region of non-specific activity. Genotyping was performed using TaqMan(®) SNP genotyping assay. We used a regression model to evaluate the effect of COMT genotype on the BP in the striatum and its sub-regions.
  
  
  RESULTS
  Genotype distribution was: 11 (27.5%) COMT(HH), 26 (65%) COMT(HL) and 3 (7.5%) COMT(LL). There were no significant differences in disease severity, treatments, or motor scores between genotypes. When adjusted to clinical severity, gender and age, low and intermediate metabolizers showed significantly higher rates of striatal denervation (COMT(HL+LL) BP = 1.32 ± 0.04) than high metabolizers (COMT(HH), BP = 1.6 ± 0.08; F(1.34) = 9.0, p = 0.005). Striatal sub-regions showed similar results. BP and UPDRS-III motor scores (r = 0.44, p = 0.04) (p < 0.001) were highly correlated. There was a gender effect, but no gender-genotype interaction.
  
  
  CONCLUSIONS
  Striatal denervation differs according to COMT-Val158Met polymorphism. COMT activity may play a role as a compensatory mechanism in PD motor symptoms.
authors.affiliation: Department of Neurology, Inselspital, Freiburgstrasse 100, 3010 Bern, Switzerland; Sorbonne University, UPMC Paris 06 UMR S 1127, and Inserm U 1127 and CIC 1422, and CNRS UR 7225, and ICM, 75013 Paris, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Muellner
authors.affiliation: Sorbonne University, UPMC Paris 06 UMR S 1127, and Inserm U 1127 and CIC 1422, and CNRS UR 7225, and ICM, 75013 Paris, France.
authors.forename: Iman
authors.initials: I
authors.lastname: Gharrad
authors.affiliation: AP-HP, Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, UPMC Paris 06, CNRS UMR 7371, INSERM U1146, 75013 Paris, France.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Habert
authors.affiliation: AP-HP, Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, UPMC Paris 06, CNRS UMR 7371, INSERM U1146, 75013 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Kas
authors.affiliation: AP-HP, Department of Nuclear Medicine, Pitié-Salpêtrière Hospital, Sorbonne University, UPMC Paris 06, CNRS UMR 7371, INSERM U1146, 75013 Paris, France; Centre d'Analyse et de Traitement des Images (CATI), 75013 Paris, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Martini
authors.affiliation: Sorbonne University, UPMC Paris 06 UMR S 1127, and Inserm U 1127 and CIC 1422, and CNRS UR 7225, and ICM, 75013 Paris, France; AP-HP, Department of Neurology, Pitié-Salpêtrière Hospital, 75013 Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Cormier-Dequaire
authors.affiliation: Sorbonne University, UPMC Paris 06 UMR S 1127, and Inserm U 1127 and CIC 1422, and CNRS UR 7225, and ICM, 75013 Paris, France.
authors.forename: Khadija
authors.initials: K
authors.lastname: Tahiri
authors.affiliation: Sorbonne University, UPMC Paris 06 UMR S 1127, and Inserm U 1127 and CIC 1422, and CNRS UR 7225, and ICM, 75013 Paris, France; AP-HP, Department of Neurology, Pitié-Salpêtrière Hospital, 75013 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vidailhet
authors.affiliation: Department of Neurology, Inselspital, Freiburgstrasse 100, 3010 Bern, Switzerland; Sorbonne University, UPMC Paris 06 UMR S 1127, and Inserm U 1127 and CIC 1422, and CNRS UR 7225, and ICM, 75013 Paris, France.
authors.forename: Niklaus
authors.initials: N
authors.lastname: Meier
authors.affiliation: Sorbonne University, UPMC Paris 06 UMR S 1127, and Inserm U 1127 and CIC 1422, and CNRS UR 7225, and ICM, 75013 Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Department of Neurology, Inselspital, Freiburgstrasse 100, 3010 Bern, Switzerland; Sorbonne University, UPMC Paris 06 UMR S 1127, and Inserm U 1127 and CIC 1422, and CNRS UR 7225, and ICM, 75013 Paris, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Schuepbach
authors.affiliation: Inserm U436, Laboratory of Mathematical and Statistical Modelisation in Biology and Medicine, Pitié-Salpêtrière Hospital, 91 bd de l'hôpital, 75634 Paris Cedex 13, France; APHP, Clinical Research Unit, Department of Biostatistics, Pitié-Salpêtrière Hospital, 75013 Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Mallet
authors.affiliation: Sorbonne University, UPMC Paris 06 UMR S 1127, and Inserm U 1127 and CIC 1422, and CNRS UR 7225, and ICM, 75013 Paris, France; AP-HP, Department of Neurology, Pitié-Salpêtrière Hospital, 75013 Paris, France.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Sorbonne University, UPMC Paris 06 UMR S 1127, and Inserm U 1127 and CIC 1422, and CNRS UR 7225, and ICM, 75013 Paris, France; AP-HP, Department of Neurology, Pitié-Salpêtrière Hospital, 75013 Paris, France. Electronic address: jean-christophe.corvol@psl.aphp.fr.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003342:Corpus Striatum / Q000000981:diagnostic imaging; D003714:Denervation; D059290:Dopaminergic Neurons / Q000000981:diagnostic imaging; D005260:Female; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics*; D008875:Middle Aged; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D014633:Valine / Q000235:genetics*
chemical_list: D008715:Methionine; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D014633:Valine
keywords: COMT; Compensatory mechanism; Dopaminergic denervation; Motor symptoms; Parkinson's disease