title: Cerebrospinal Fluid Progranulin, but Not Serum Progranulin, Is Reduced in GRN-Negative Frontotemporal Dementia.
abstract: Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD.
  
  
  
  Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls). All FTD patients were assessed by whole-exome sequencing for GRN mutations, yielding a target cohort of 34 patients without pathogenic mutations in GRN (GRN-negative cohort) and 3 GRN mutation carriers (2 LoF variants and 1 novel missense variant).
  
  
  
  Not only the GRN mutation carriers but also the GRN-negative patients showed decreased CSF levels of progranulin (serum levels in GRN-negative patients were normal). The decreased CSF progranulin levels were unrelated to patients' increased CSF levels of total tau, possibly indicating different destructive neuronal processes within FTD neurodegeneration. The patient with the novel GRN missense variant (c.1117C>T, p.P373S) showed substantially decreased CSF levels of progranulin, comparable to the 2 patients with GRN LoF mutations, suggesting a pathogenic effect of this missense variant.
  
  
  
  Our results indicate that central nervous progranulin reduction is not restricted to the relatively rare cases of FTD caused by GRN LoF mutations, but also contributes to the more common GRN-negative forms of FTD. Central nervous progranulin reduction might reflect a partially distinct pathogenic mechanism underlying FTD neurodegeneration and is not directly linked to tau alterations.
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), University of Tübingen, Tübingen, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Wilke
authors.forename: Frank
authors.initials: F
authors.lastname: Gillardon
authors.forename: Christian
authors.initials: C
authors.lastname: Deuschle
authors.forename: Markus A
authors.initials: MA
authors.lastname: Hobert
authors.forename: Iris E
authors.initials: IE
authors.lastname: Jansen
authors.forename: Florian G
authors.initials: FG
authors.lastname: Metzger
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Walter
authors.initials: W
authors.lastname: Maetzler
authors.forename: Cornelis
authors.initials: C
authors.lastname: Blauwendraat
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
mesh_terms: D000368:Aged; D005260:Female; D057180:Frontotemporal Dementia / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D000077153:Progranulins; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000378:metabolism
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D000077153:Progranulins; D016875:tau Proteins