A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study
Authors: Bergström Sofia , Öijerstedt Linn , Remnestål Julia , Olofsson Jennie , Ullgren Abbe , Seelaar Harro , van Swieten John C. , Synofzik Matthis , Sanchez-Valle Raquel , Moreno Fermin , Finger Elizabeth , Masellis Mario , Tartaglia Carmela , Vandenberghe Rik , Laforce Robert , Galimberti Daniela , Borroni Barbara , Butler Chris R. , Gerhard Alexander , Ducharme Simon , Rohrer Jonathan D. , Månberg Anna , Graff Caroline , Nilsson Peter ,   on behalf of the Genetic Frontotemporal Dementia Initiative (GENFI), Jiskoot Lize , Rowe James B. , de Mendonça Alexandre , Tagliavini Fabrizio , Santana Isabel , Le Ber Isabelle , Levin Johannes , Danek Adrian , Otto Markus , Frisoni Giovanni , Ghidoni Roberta , Sorbi Sandro , Pasquier Florence , Jelic Vesna , Andersson Christin , Afonso Sónia , Almeida Maria Rosario , Anderl-Straub Sarah , Antonell Anna , Archetti Silvana , Arighi Andrea , Balasa Mircea , Barandiaran Myriam , Bargalló Nuria , Bartha Robart , Bender Benjamin , Benussi Alberto , Benussi Luisa , Bessi Valentina , Binetti Giuliano , Black Sandra , Bocchetta Martina , Borrego-Ecija Sergi , Bras Jose , Bruffaerts Rose , Cañada Marta , Cantoni Valentina , Caroppo Paola , Cash David , Castelo-Branco Miguel , Convery Rhian , Cope Thomas , Di Fede Giuseppe , Díez Alina , Duro Diana , Fenoglio Chiara , Ferrari Camilla , Ferreira Catarina B. , Fox Nick , Freedman Morris , Fumagalli Giorgio , Gabilondo Alazne , Gasparotti Roberto , Gauthier Serge , Gazzina Stefano , Giaccone Giorgio , Gorostidi Ana , Greaves Caroline , Guerreiro Rita , Heller Carolin , Hoegen Tobias , Indakoetxea Begoña , Jiskoot Lize , Karnath Hans-Otto , Keren Ron , Langheinrich Tobias , Leitão Maria João , Lladó Albert , Lombardi Gemma , Loosli Sandra , Maruta Carolina , Mead Simon , Meeter Lieke , Miltenberger Gabriel , van Minkelen Rick , Mitchell Sara , Moore Katrina , Nacmias Benedetta , Nicholas Jennifer , Olives Jaume , Ourselin Sebastien , Padovani Alessandro , Panman Jessica , Papma Janne M. , Peakman Georgia , Pievani Michela , Pijnenburg Yolande , Polito Cristina , Premi Enrico , Prioni Sara , Prix Catharina , Rademakers Rosa , Redaelli Veronica , Rittman Tim , Rogaeva Ekaterina , Rosa-Neto Pedro , Rossi Giacomina , Rosser Martin , Santiago Beatriz , Scarpini Elio , Schönecker Sonja , Semler Elisa , Shafei Rachelle , Shoesmith Christen , Tábuas-Pereira Miguel , Tainta Mikel , Taipa Ricardo , Tang-Wai David , Thomas David L. , Thompson Paul , Thonberg Håkan , Timberlake Carolyn , Tiraboschi Pietro , Todd Emily , Van Damme Philip , Vandenbulcke Mathieu , Veldsman Michele , Verdelho Ana , Villanua Jorge , Warren Jason , Wilke Carlo , Woollacott Ione , Wlasich Elisabeth , Zetterberg Henrik , Zulaica Miren 
Published: November 2021

Abstract
Background
A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers.

Methods
A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest.

Results
When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN).

Conclusion
In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.