title: Inflammatory molecules in Frontotemporal Dementia: cerebrospinal fluid signature of progranulin mutation carriers.
abstract: Mutations in progranulin gene (GRN) are one of the major causes of autosomal dominant Frontotemporal Lobar Degeneration (FTLD). Progranulin displays anti-inflammatory properties and is likely a ligand of Tumor Necrosis Factor (TNF) receptor 2, expressed on microglia. A few cytokines and chemokines are altered in cerebrospinal fluid (CSF) from patients with sporadic FTLD, whereas no information is available in familial cases. We evaluated, through BioPlex, levels of 27 inflammatory molecules, including cytokines, chemokines, and related receptors, in CSF and matched serum, from FTLD patients carrying GRN mutations as compared with sporadic FTLD with no GRN mutations and controls. Mean±SD Monocyte Chemoattractant Protein-1 (MCP-1) levels were significantly increased in CSF from sporadic FTLD patients as compared with controls (334.27±151.5 versus 159.7±49pg/ml; P⩽0.05). In GRN mutation carriers versus controls, CSF levels of MCP-1 were unchanged, whereas Interferon-γ-inducible protein-10 (IP-10) levels were increased (809.17±240.0 versus 436.61±202.5pg/ml; P=0.012). In the same group, TNFα and Interleukin (IL)-15 levels were decreased (3.18±1.41 versus 35.68±30.5pg/ml; P=0.013 and 9.34±5.54 versus 19.15±10.03pg/ml; P=0.023, respectively). Conversely, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) levels were decreased in patients, with or without mutations, as compared with controls (4.63±3.30 and 2.58±20 versus 87.57±70pg/ml, respectively; P<0.05). Moreover, IP-10, IL-15 and RANTES CSF levels were not influenced by age, whereas MCP-1 levels increased with age (ρ=0.48; P=0.007). In conclusion, inflammatory de-regulation was observed in both sporadic FTLD and GRN carriers compared to controls, with a specific inflammatory profile for the latter group.
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy. Electronic address: daniela.galimberti@unimi.it.
authors.forename: D
authors.initials: D
authors.lastname: Galimberti
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bonsi
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Fenoglio
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Serpente
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: S M G
authors.initials: SM
authors.lastname: Cioffi
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Fumagalli
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Arighi
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Ghezzi
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Arcaro
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mercurio
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Rotondo
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Scarpini
mesh_terms: D000368:Aged; D018932:Chemokine CCL2 / Q000097:blood / Q000134:cerebrospinal fluid; D054357:Chemokine CXCL10 / Q000097:blood / Q000134:cerebrospinal fluid; D005260:Female; D057180:Frontotemporal Dementia / Q000134:cerebrospinal fluid* / Q000150:complications / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000134:cerebrospinal fluid* / Q000150:complications / Q000235:genetics*; D018836:Inflammation Mediators / Q000097:blood / Q000134:cerebrospinal fluid*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D019409:Interleukin-15 / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000077153:Progranulins; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000134:cerebrospinal fluid
chemical_list: C111835:CCL2 protein, human; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; C492314:GRN protein, human; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D019409:Interleukin-15; D000077153:Progranulins; D014409:Tumor Necrosis Factor-alpha
keywords: Cerebrospinal fluid; Chemokines; Cytokines; Frontotemporal Dementia (FTD); Frontotemporal Lobar Degeneration (FTLD); Inflammation; Pick dementia; Progranulin (GRN)