title: Prevalence of brain and spinal cord inclusions, including dipeptide repeat proteins, in patients with the C9ORF72 hexanucleotide repeat expansion: a systematic neuropathological review.
abstract: The current literature shows no consensus on the localization and number of characteristic neuronal inclusions [p62 and dipeptide repeat proteins (DRPs) positive, TDP-43-negative and TDP-43 positive] in the brain and spinal cord of patients with the hexanucleotide repeat expansion on chromosome 9 (C9ORF72-positive patients). This may be due to small sample sizes. A valid brain map of the inclusions in C9ORF72-positive patients may improve clinicopathological correlations and may serve as a reference for neuropathologists.
  
  
  
  We performed a systematic review on 42 pathological studies to assess the pooled prevalence rates and density (a measure of the number of inclusions per brain region) of (phosphorylated)-TDP-43, p62 and DRP neuronal inclusions in seven brain regions and the spinal cord of 261 C9ORF72-positive patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and ALS-FTD.
  
  
  
  In the cerebellum and hippocampus, the pooled prevalence rates of TDP-43 neuronal cytoplasmic inclusions (NCIs; cerebellum: 3.9%; hippocampus: 68.3%) were lower than those of DRP (cerebellum: 97.2%; hippocampus 97.1%). Moreover, TDP-43 inclusion density was lower compared with p62 inclusion density in these regions. The pooled prevalence rate of TDP-43 NCI in the substantia nigra was high (94.4%).
  
  
  
  The findings of this systematic review largely confirm findings of previous smaller studies on the localization and prevalence of inclusions in the central nervous system of C9ORF72-positive patients. The high prevalence of TDP-43 inclusions in the substantia nigra is a relatively new finding and is probably related to the relatively high prevalence of parkinsonism in C9ORF72-positive patients.
authors.affiliation: Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: L J
authors.initials: LJ
authors.lastname: Schipper
authors.affiliation: Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. joost.raaphorst@radboudumc.nl.|Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands. joost.raaphorst@radboudumc.nl.
authors.forename: J
authors.initials: J
authors.lastname: Raaphorst
authors.affiliation: Department of Neuropathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Baas
authors.affiliation: Clinical Research Unit, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: de Haan
authors.affiliation: Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: de Visser
authors.affiliation: Department of Neuropathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Troost
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D000073885:C9orf72 Protein / Q000235:genetics; D042622:DNA Repeat Expansion / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016601:RNA-Binding Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology*
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; C118585:P62 protein, human; D016601:RNA-Binding Proteins; C000598624:TARDBP protein, human
keywords: C9ORF72; TDP-43; amyotrophic lateral sclerosis; dipeptide repeat proteins; frontotemporal dementia; p62