title: Structural brain signature of FTLD driven by Granulin mutation.
abstract: Several causative gene mutations have been identified in frontotemporal lobar degeneration (FTLD), including mutations within Granulin (GRN) genes. It was recently shown that FTLD patients carriers of GRN Thr272fs mutation [FTLD-GRN(m+)] exhibit more severe abnormalities, as assessed by magnetic resonance imaging (MRI), than those with sporadic FTLD [FTLD-GRN(m-)]. The aim of this study was to investigate the relationship between grey (GM) and white matter (WM) microstructural damage in FTLD patients, carriers and non-carriers of the mutation. Twenty-three FTLD patients [6 GRN(m+) and 17 GRN(m-)] and 12 healthy subjects received an MRI scan including volumetric and diffusion imaging. GM was assessed using voxel-based morphometry, while the corpus callosum was reconstructed using diffusion tractography. Mean diffusivity and fractional anisotropy of the corpus callosum were compared between groups. FTLD patients showed widespread GM atrophy and altered diffusion indices in the corpus callosum when compared to healthy subjects. When contrasting GRN(m+) against GRN(m-) patients, the former group had more atrophy in the left frontal GM, and reduced fractional anisotropy and increased mean diffusivity in the left anterior part of the corpus callosum. Significant correlations between the GM and WM damage were found in GRN(m+) patients. This pattern of damage was able to predict some of the additional neuropsychological deficits observed in GRN(m+) as compared to GRN(m-) patients. A more prominent involvement of WM in GRN(m+) patients is consistent with the knowledge that GRN genes are expressed in the microglia. This involvement might be responsible for the accrual of additional GM atrophy via disconnection mechanisms.
authors.affiliation: Neuroimaging Laboratory, Santa Lucia Foundation IRCCS, Rome, Italy. m.bozzali@hsantalucia.it
authors.forename: Marco
authors.initials: M
authors.lastname: Bozzali
authors.forename: Valentina
authors.initials: V
authors.lastname: Battistoni
authors.forename: Enrico
authors.initials: E
authors.lastname: Premi
authors.forename: Antonella
authors.initials: A
authors.lastname: Alberici
authors.forename: Giovanni
authors.initials: G
authors.lastname: Giulietti
authors.forename: Silvana
authors.initials: S
authors.lastname: Archetti
authors.forename: Marinella
authors.initials: M
authors.lastname: Turla
authors.forename: Roberto
authors.initials: R
authors.lastname: Gasparotti
authors.forename: Mara
authors.initials: M
authors.lastname: Cercignani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
mesh_terms: D000368:Aged; D001284:Atrophy / Q000235:genetics / Q000473:pathology; D001921:Brain / Q000473:pathology*; D003337:Corpus Callosum / Q000473:pathology*; D056324:Diffusion Tensor Imaging; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D017628:Microglia / Q000473:pathology; D008875:Middle Aged; D009474:Neurons / Q000473:pathology; D009483:Neuropsychological Tests; D017354:Point Mutation; D011237:Predictive Value of Tests; D000077153:Progranulins
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins