title: C9ORF72 expansions, parkinsonism, and Parkinson disease: a clinicopathologic study.
abstract: OBJECTIVE
  To determine the histopathologic bases for the observed incidence of parkinsonism in families with C9ORF72 expansions, which typically cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia.
  
  
  METHODS
  DNA was extracted from 377 brains with the histopathologic diagnosis of idiopathic Parkinson disease or related disorders and analyzed for C9ORF72 expansions. α-Synuclein and p62 immunohistochemistry of the substantia nigra (SN) was undertaken in brains of 17 ALS cases with (C9ORF72+) and 51 without (C9ORF72-) the C9ORF72 expansion.
  
  
  RESULTS
  Only 1 of 338 cases with pathologically confirmed idiopathic Parkinson disease had a C9ORF72 expansion. Similarly, only 1 of 17 C9ORF72+ brains displayed features suggestive of α-synucleinopathy. In contrast, p62-positive, TDP-43-negative neuronal cytoplasmic inclusions within the SN were considerably more frequent in C9ORF72+ brain tissue than in the C9ORF72- brains (p = 0.005). Furthermore, there was a more marked loss of dopaminergic neurons in the SN of C9ORF72+ ALS brains than C9ORF72- ALS brains (p = 0.029).
  
  
  CONCLUSIONS
  SN involvement is common in C9ORF72+ ALS but can be clearly distinguished from Parkinson disease-related mechanisms by the presence of p62-positive inclusions and the absence of α-synuclein-positive Lewy bodies or Lewy neurites.
authors.affiliation: Sheffield Institute for Translational Neuroscience, Sheffield Children's NHS Foundation Trust, Western Bank, UK.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Cooper-Knock
authors.forename: Antonina
authors.initials: A
authors.lastname: Frolov
authors.forename: J Robin
authors.initials: JR
authors.lastname: Highley
authors.forename: Gavin
authors.initials: G
authors.lastname: Charlesworth
authors.forename: Janine
authors.initials: J
authors.lastname: Kirby
authors.forename: Antonio
authors.initials: A
authors.lastname: Milano
authors.forename: Judith
authors.initials: J
authors.lastname: Hartley
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McDermott
authors.forename: Tammaryn
authors.initials: T
authors.lastname: Lashley
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Oliver
authors.initials: O
authors.lastname: Bandmann
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000166:cytology; D010300:Parkinson Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D011506:Proteins / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; D051844:alpha-Synuclein