Impaired glymphatic system in genetic frontotemporal dementia: a GENFI study
Authors: Premi Enrico , Diano Matteo , Mattioli Irene , Altomare Daniele , Cantoni Valentina , Bocchetta Martina , Gasparotti Roberto , Buratti Emanuele , Pengo Marta , Bouzigues Arabella , Russell Lucy L , Foster Phoebe H , Ferry-Bolder Eve , Heller Carolin , van Swieten John C , Jiskoot Lize C , Seelaar Harro , Moreno Fermin , Sanchez-Valle Raquel , Galimberti Daniela , Laforce Robert , Graff Caroline , Masellis Mario , Tartaglia Maria Carmela , Rowe James B , Finger Elizabeth , Vandenberghe Rik , de Mendonça Alexandre , Butler Chris R , Gerhard Alexander , Ducharme Simon , Le Ber Isabelle , Tiraboschi Pietro , Santana Isabel , Pasquier Florence , Synofzik Matthis , Levin Johannes , Otto Markus , Sorbi Sandro , Rohrer Jonathan D , Borroni Barbara ,   Coinvestigators GENFI Consortium, Thomas David L , Todd Emily , Greaves Caroline V , Nicholas Jennifer , Samra Kiran , Convery Rhian , Timberlake Carolyn , Cope Thomas , Rittman Timothy , Arighi Andrea , Fenoglio Chiara , Scarpini Elio , Fumagalli Giorgio , Borracci Vittoria , Rossi Giacomina , Giaccone Giorgio , Di Fede Giuseppe , Caroppo Paola , Prioni Sara , Redaelli Veronica , Tang-Wai David , Rogaeva Ekaterina , Castelo-Branco Miguel , Freedman Morris , Keren Ron , Black Sandra , Mitchell Sara , Shoesmith Christen , Bartha Robart , Rademakers Rosa , Poos Jackie , Papma Janne M , Giannini Lucia , van Minkelen Rick , Pijnenburg Yolande , Nacmias Benedetta , Ferrari Camilla , Polito Cristina , Lombardi Gemma , Bessi Valentina , Veldsman Michele , Andersson Christin , Thonberg Hakan , Öijerstedt Linn , Jelic Vesna , Thompson Paul , Langheinrich Tobias , Lladó Albert , Antonell Anna , Olives Jaume , Balasa Mircea , Bargalló Nuria , Borrego-Ecija Sergi , Verdelho Ana , Maruta Carolina , Costa-Coelho Tiago , Miltenberger Gabriel , Gabilondo Alazne , Gorostidi Ana , Villanua Jorge , Cañada Marta , Tainta Mikel , Zulaica Miren , Barandiaran Myriam , Alves Patricia , Bender Benjamin , Wilke Carlo , Graf Lisa , Vogels Annick , Vandenbulcke Mathieu , Van Damme Philip , Bruffaerts Rose , Poesen Koen , Rosa-Neto Pedro , Gauthier Serge , Camuzat Agnès , Brice Alexis , Bertrand Anne , Funkiewiez Aurélie , Rinaldi Daisy , Saracino Dario , Colliot Olivier , Sayah Sabrina , Prix Catharina , Wlasich Elisabeth , Wagemann Olivia , Loosli Sandra , Schönecker Sonja , Hoegen Tobias , Lombardi Jolina , Anderl-Straub Sarah , Rollin Adeline , Kuchcinski Gregory , Bertoux Maxime , Lebouvier Thibaud , Deramecourt Vincent , Santiago Beatriz , Duro Diana , Leitão Maria João , Almeida Maria Rosario , Tábuas-Pereira Miguel , Afonso Sónia 
Published: June 2024

Abstract
The glymphatic system is an emerging target in neurodegenerative disorders. Here, we investigated the activity of the glymphatic system in genetic frontotemporal dementia with a diffusion-based technique called diffusion tensor image analysis along the perivascular space. We investigated 291 subjects with symptomatic or presymptomatic frontotemporal dementia (112 with chromosome 9 open reading frame 72 [C9orf72] expansion, 119 with granulin [GRN] mutations and 60 with microtubule-associated protein tau [MAPT] mutations) and 83 non-carriers (including 50 young and 33 old non-carriers). We computed the diffusion tensor image analysis along the perivascular space index by calculating diffusivities in the x-, y- and z-axes of the plane of the lateral ventricle body. Clinical stage and blood-based markers were considered. A subset of 180 participants underwent cognitive follow-ups for a total of 640 evaluations. The diffusion tensor image analysis along the perivascular space index was lower in symptomatic frontotemporal dementia (estimated marginal mean ± standard error, 1.21 ± 0.02) than in old non-carriers (1.29 ± 0.03, P = 0.009) and presymptomatic mutation carriers (1.30 ± 0.01, P &lt; 0.001). In mutation carriers, lower diffusion tensor image analysis along the perivascular space was associated with worse disease severity (β = −1.16, P &lt; 0.001), and a trend towards a significant association between lower diffusion tensor image analysis along the perivascular space and higher plasma neurofilament light chain was reported (β = −0.28, P = 0.063). Analysis of longitudinal data demonstrated that worsening of disease severity was faster in patients with low diffusion tensor image analysis along the perivascular space at baseline than in those with average (P = 0.009) or high (P = 0.006) diffusion tensor image analysis along the perivascular space index. Using a non-invasive imaging approach as a proxy for glymphatic system function, we demonstrated glymphatic system abnormalities in the symptomatic stages of genetic frontotemporal dementia. Such measures of the glymphatic system may elucidate pathophysiological processes in human frontotemporal dementia and facilitate early phase trials of genetic frontotemporal dementia.