Structural Brain Signature of FTLD Driven by Granulin Mutation

Article type: Research Article

Authors: Bozzali, Marco^{a; *} | Battistoni, Valentina^a | Premi, Enrico^b | Alberici, Antonella^b | Giulietti, Giovanni^a | Archetti, Silvana^c | Turla, Marinella^d | Gasparotti, Roberto^e | Cercignani, Mara^{a; f} | Padovani, Alessandro^b | Borroni, Barbara^b

Affiliations: [a] Neuroimaging Laboratory, Santa Lucia Foundation IRCCS, Rome, Italy | [b] Neurology Unit, Centre for Aging Brain and Neurodegenerative Disorder, University of Brescia, Brescia, Italy | [c] Laboratories of Analysis, Brescia Hospital, Brescia, Italy | [d] Neurology Unit, Valle Camonica Hospital, Esine, Brescia, Italy | [e] Neuroradiology Unit, University of Brescia, Brescia, Italy | [f] Clinical Imaging Science Centre, Brighton and Sussex Medical School, University of Sussex, Falmer, UK

Correspondence: [*] Correspondence to: Dr. Marco Bozzali, Neuroimaging Laboratory, Santa Lucia Foundation, Via Ardeatina 306, 00179 Rome, Italy. Tel.: +39 06 5150 1324; Fax: +39 06 5150 1213; E-mail: m.bozzali@hsantalucia.it.

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.

Keywords: Corpus callosum, diffusion tensor magnetic resonance imaging, frontotemporal lobar degeneration, granulin, GRN, tractography, voxel-based morphometry

DOI: 10.3233/JAD-2012-121273

Journal: Journal of Alzheimer's Disease, vol. 33, no. 2, pp. 483-494, 2013