<scp>CSF</scp> glial markers are elevated in a subset of patients with genetic frontotemporal dementia
;
Georgia Peakman;
Caroline V Greaves;
Rhian Convery;
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Amanda Heslegrave;
James B Rowe;
Barbara Borroni ;
Daniela Galimberti ;
Pietro Tiraboschi ;
Mario Masellis;
Maria Carmela Tartaglia ;
Elizabeth Finger ;
John C van Swieten;
Harro Seelaar;
Lize Jiskoot;
Sandro Sorbi;
Chris R Butler;
Caroline Graff;
Alexander Gerhard;
Robert Laforce ;
Raquel Sanchez‐Valle ;
Alexandre de Mendonça;
Fermin Moreno;
Matthis Synofzik ;
Rik Vandenberghe;
Simon Ducharme ;
Isabelle Le Ber;
Johannes Levin;
Markus Otto ;
Florence Pasquier;
Isabel Santana;
Henrik Zetterberg;
Jonathan D Rohrer ;
Annabel Nelson;
Martina Bocchetta;
David Cash;
David L Thomas;
Emily Todd;
Hanya Benotmane;
Jennifer Nicholas ;
Kiran Samra;
Rachelle Shafei;
Carolyn Timberlake;
Thomas Cope;
Timothy Rittman;
Alberto Benussi;
Enrico Premi;
Roberto Gasparotti;
Silvana Archetti;
Stefano Gazzina;
Valentina Cantoni;
Andrea Arighi;
Chiara Fenoglio;
Elio Scarpini;
Giorgio Fumagalli;
Vittoria Borracci;
Giacomina Rossi;
Giorgio Giaccone;
Giuseppe Di Fede;
Paola Caroppo;
Sara Prioni;
Veronica Redaelli;
David Tang‐Wai;
Ekaterina Rogaeva;
Miguel Castelo‐Branco;
Morris Freedman;
Ron Keren;
Sandra Black;
Sara Mitchell;
Christen Shoesmith;
Robart Bartha;
Rosa Rademakers;
Jackie Poos;
Janne M Papma;
Lucia Giannini;
Rick van Minkelen;
Yolande Pijnenburg;
Benedetta Nacmias;
Camilla Ferrari;
Cristina Polito;
Gemma Lombardi;
Valentina Bessi;
Michele Veldsman;
Christin Andersson;
Hakan Thonberg;
Linn Öijerstedt;
Vesna Jelic;
Paul Thompson;
Tobias Langheinrich;
Albert Lladó;
Anna Antonell;
Jaume Olives;
Mircea Balasa;
Nuria Bargalló;
Sergi Borrego‐Ecija;
Ana Verdelho;
Carolina Maruta;
Catarina B Ferreira;
Gabriel Miltenberger;
Frederico Simões do Couto;
Alazne Gabilondo;
Ana Gorostidi;
Jorge Villanua;
Marta Cañada;
Mikel Tainta;
Miren Zulaica;
Myriam Barandiaran;
Patricia Alves;
Benjamin Bender;
Carlo Wilke;
Lisa Graf;
Annick Vogels;
Mathieu Vandenbulcke;
Philip Van Damme;
Rose Bruffaerts;
Koen Poesen;
Pedro Rosa‐Neto;
Serge Gauthier;
Agnès Camuzat;
Alexis Brice;
Anne Bertrand;
Aurélie Funkiewiez;
Daisy Rinaldi;
Dario Saracino;
Olivier Colliot;
Sabrina Sayah;
Catharina Prix;
Elisabeth Wlasich;
Olivia Wagemann;
Sandra Loosli;
Sonja Schönecker;
Tobias Hoegen;
Jolina Lombardi;
Sarah Anderl‐Straub;
Adeline Rollin;
Gregory Kuchcinski;
Maxime Bertoux;
Thibaud Lebouvier;
Vincent Deramecourt;
Beatriz Santiago;
Diana Duro;
Maria João Leitão;
Maria Rosario Almeida;
Miguel Tábuas‐Pereira;
Sónia Afonso;
(2022)
<scp>CSF</scp>
glial markers are elevated in a subset of patients with genetic frontotemporal dementia.
Annals of clinical and translational neurology, 9 (11).
pp. 1764-1777.
ISSN 2328-9503
DOI: 10.1002/acn3.51672
Background: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia-derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. Methods: We investigated the cerebrospinal fluid concentrations of TREM2, YKL-40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation-negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias-corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini-Mental State Examination (MMSE) score using non-parametric partial correlations adjusting for age. Age-adjusted z-scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Results: Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL-40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72, 25% of GRN, and 14% of MAPT mutation carriers had a concentration above the 95th percentile of controls. For YKL-40 this was 8% C9orf72, 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72, 50% GRN, and 29% MAPT mutation carriers. Conclusions: Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia-derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials.
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