title: Frequency of cholinergic and caudate nucleus dopaminergic deficits across the predemented cognitive spectrum of Parkinson disease and evidence of interaction effects.
abstract: OBJECTIVE
  Little is known about the relative contributions of multisystem degenerative processes across the spectrum of predemented cognitive decline in Parkinson disease (PD).
  
  
  OBJECTIVE
  To investigate the relative frequency of caudate nucleus dopaminergic and forebrain cholinergic deficits across a spectrum of cognitively impaired patients with PD to explore their relative, individual, and combined contributions to cognitive impairment in PD.
  
  
  METHODS
  A cross-sectional study at an academic movement disorders clinic that included a predominantly nondemented cohort of 143 patients with PD. The mean (SD) age of patients was 65.5 (7.4) years and the mean (SD) Hoehn and Yahr stage was 2.4 (0.6).
  
  
  METHODS
  Binary classification of carbon 11-labeled [11C]PMP acetylcholinesterase and caudate nucleus [11C]DTBZ monoaminergic positron-emission tomography imaging based on normative data. The frequency of significant degenerative processes based on normative values was determined for consecutive intervals of cognitive impairment, ranging from no or minimal (z > -0.5) to more severe (z ≤ -2) cognitive impairment.
  
  
  RESULTS
  Across the spectrum from minimal (z > -0.5) to more severe (z ≤ -2) global cognitive impairment scores, caudate nucleus dopaminergic denervation was relatively frequent in individuals with minimal or no cognitive changes (51.1%) and increased in patients with more severe cognitive impairments (χ2 = 12.8; P = .01). Cortical cholinergic denervation frequency increased monotonically with increasing cognitive impairment from 24.7% (z > -0.5) to 85.7% (z ≤ -2); χ2 = 23.2; P = .001). Eighty-seven percent of patients with neocortical cholinergic deficits had caudate nucleus dopaminergic deficits. Multiple regression analysis (F = 7.51; P < .001) showed both independent cognitive predictions for caudate nucleus dopaminergic (F = 7.25; P = .008) and cortical cholinergic (F = 7.50; P = .007) degenerations as well as interaction effects (F = 5.40; P = .02).
  
  
  CONCLUSIONS
  Cortical cholinergic denervation is a major neurodegeneration associated with progressive declines across the spectrum of cognitive impairment in PD and typically occurs in the context of significant caudate nucleus dopaminergic denervation. Our findings imply that dopaminergic and cholinergic degenerations exhibit both independent and interactive contributions to cognitive impairment in PD.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor2Department of Neurology, University of Michigan, Ann Arbor3Neurology Service and Geriatric Research Education and Clinical Center, Veterans Administration Ann Arbor H.
authors.forename: Nicolaas I
authors.initials: NI
authors.lastname: Bohnen
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor3Neurology Service and Geriatric Research Education and Clinical Center, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, Michigan4Michigan Alzheimer Disease Center, Ann Arbor.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor.
authors.forename: Martijn L T M
authors.initials: ML
authors.lastname: Müller
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor.
authors.forename: Myria
authors.initials: M
authors.lastname: Petrou
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor.
authors.forename: Vikas
authors.initials: V
authors.lastname: Kotagal
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Koeppe
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor.
authors.forename: Peter J H
authors.initials: PJ
authors.lastname: Scott
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor2Department of Neurology, University of Michigan, Ann Arbor.
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Frey
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000368:Aged; D002421:Caudate Nucleus / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology*; D059329:Cholinergic Neurons / Q000473:pathology*; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000473:pathology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D049268:Positron-Emission Tomography / Q000379:methods*; D012720:Severity of Illness Index
chemical_list: D000109:Acetylcholine; D004298:Dopamine