title: COMT Val158Met genotype influences neurodegeneration within dopamine-innervated brain structures.
abstract: OBJECTIVE
  We sought to determine whether the Val(158)Met polymorphism in the catechol-O-methyltransferase (COMT) gene influences neurodegeneration within dopamine-innervated brain regions.
  
  
  METHODS
  A total of 252 subjects, including healthy controls and patients with Alzheimer disease, behavioral variant frontotemporal dementia, and semantic dementia, underwent COMT genotyping and structural MRI.
  
  
  RESULTS
  Whole-brain voxel-wise regression analyses revealed that COMT Val(158)Met Val allele dosage, known to produce a dose-dependent decrease in synaptic dopamine (DA) availability, correlated with decreased gray matter in the region of the ventral tegmental area (VTA), ventromedial prefrontal cortex, bilateral dorsal midinsula, left dorsolateral prefrontal cortex, and right ventral striatum. Unexpectedly, patients carrying a Met allele showed greater VTA volumes than age-matched controls. Gray matter intensities within COMT-related brain regions correlated with cognitive and behavioral deficits.
  
  
  CONCLUSIONS
  The results are consistent with the hypothesis that increased synaptic DA catabolism promotes neurodegeneration within DA-innervated brain regions.
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California-San Francisco, CA, USA.
authors.forename: E D
authors.initials: ED
authors.lastname: Gennatas
authors.forename: J A
authors.initials: JA
authors.lastname: Cholfin
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.forename: R K
authors.initials: RK
authors.lastname: Crawford
authors.forename: D A
authors.initials: DA
authors.lastname: Sasaki
authors.forename: A
authors.initials: A
authors.lastname: Karydas
authors.forename: A L
authors.initials: AL
authors.lastname: Boxer
authors.forename: S J
authors.initials: SJ
authors.lastname: Bonasera
authors.forename: K P
authors.initials: KP
authors.lastname: Rankin
authors.forename: M L
authors.initials: ML
authors.lastname: Gorno-Tempini
authors.forename: H J
authors.initials: HJ
authors.lastname: Rosen
authors.forename: J H
authors.initials: JH
authors.lastname: Kramer
authors.forename: M
authors.initials: M
authors.lastname: Weiner
authors.forename: B L
authors.initials: BL
authors.lastname: Miller
authors.forename: W W
authors.initials: WW
authors.lastname: Seeley
mesh_terms: D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology*; D003704:Dementia / Q000209:etiology / Q000473:pathology*; D004298:Dopamine / Q000235:genetics / Q000502:physiology*; D005260:Female; D057180:Frontotemporal Dementia / Q000209:etiology / Q000473:pathology; D057174:Frontotemporal Lobar Degeneration / Q000209:etiology / Q000473:pathology; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017397:Prefrontal Cortex / Q000378:metabolism / Q000473:pathology; D014633:Valine / Q000235:genetics
chemical_list: D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine; D004298:Dopamine