Functional overlap and divergence between ALS and bvFTDby Francesca Trojsi, Fabrizio Esposito, Manuela de Stefano, Daniela Buonanno, Francesca L. Conforti, Daniele Corbo, Giovanni Piccirillo, Mario Cirillo, Maria Rosaria Monsurrò, Patrizia Montella, Gioacchino Tedeschi

Neurobiology of Aging

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Year
2015
DOI
10.1016/j.neurobiolaging.2014.06.025
Subject
Clinical Neurology / Neuroscience (all) / Ageing / Developmental Biology / Geriatrics and Gerontology

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Accepted Manuscript

Functional overlap and divergence between ALS and bvFTD

F. Trojsi, F. Esposito, M. de Stefano, D. Buonanno, F.L. Conforti, D. Corbo, G.

Piccirillo, M. Cirillo, M.R. Monsurrò, P. Montella, G. Tedeschi

PII: S0197-4580(14)00463-1

DOI: 10.1016/j.neurobiolaging.2014.06.025

Reference: NBA 8937

To appear in: Neurobiology of Aging

Received Date: 23 January 2014

Revised Date: 21 June 2014

Accepted Date: 24 June 2014

Please cite this article as: Trojsi, F, Esposito, F, de Stefano, M, Buonanno, D, Conforti, F., Corbo, D,

Piccirillo, G, Cirillo, M, Monsurrò, M., Montella, P, Tedeschi, G, Functional overlap and divergence between ALS and bvFTD, Neurobiology of Aging (2014), doi: 10.1016/j.neurobiolaging.2014.06.025.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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ACCEPTED MANUSCRIPT 1

Functional overlap and divergence between ALS and bvFTD

Trojsi Fa,b, Esposito Fb,c, de Stefano Ma, Buonanno Da, Conforti FLd, Corbo Db,e, Piccirillo Ga,b, Cirillo Ma,b, Monsurrò

MRa,b, Montella Pa,b, Tedeschi Ga,b* a Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, 80138

Naples, Italy b

MRI Research Center SUN-FISM – Second University of Naples, 80138 Naples, Italy c Department of Medicine and Surgery, University of Salerno, 84081 Baronissi (Salerno), Italy d

Institute of Neurological Sciences, National Research Council, 87050 Mangone (Cosenza), Italy e Neurological Institute for Diagnosis and Care “Hermitage Capodimonte”, 80131 Naples, Italy *Corresponding author:

Prof. Gioacchino Tedeschi

Second University of Naples, Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences

Piazza Miraglia 2, 80138 Naples (Italy) tel +390815665004; fax +390815665095 e-mail: gioacchino.tedeschi@unina2.it

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Abstract

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) lie on a clinical, pathological and genetic continuum. Neuroimaging techniques have proven to be potentially useful to unravel the shared features of these syndromes.

Using resting state functional magnetic resonance imaging (RS-fMRI), we investigated functional connectivity of brain networks in 15 ALS and 15 bvFTD patients in early stages of disease, and 15 healthy controls, looking expressly for connectivity pattern divergence or overlap between the two disorders.

Compared to controls, we found decreased RS-fMRI signals within sensorimotor, right fronto-parietal, salience and executive networks in both patient groups. Within the default mode network, divergent connectivity patterns were observed, with RS-fMRI signals in the posterior cingulate cortex enhanced in bvFTD patients and suppressed in ALS patients.

Our findings confirm that ALS and bvFTD broadly share common RS-fMRI connectivity patterns, probably representing different phenotypical expressions of the same neurodegenerative process, but also differ in the default mode network, probably reflecting a different stage of neurodegeneration.

Keywords: amyotrophic lateral sclerosis; behavioral variant frontotemporal dementia; RS-fMRI; connectivity; pathological continuum

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ACCEPTED MANUSCRIPT 3 1. Introduction

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are multisystem neurodegenerative disorders, which have been found highly related, occupying two poles of a disease spectrum, with a predominance of motor dysfunction at one end and cognitive symptoms at the other (Clark and Forman, 2006; Neumann et al., 2006). In fact, the two disorders have been recognized as representative of a neuropathological continuum since they share several clinical, genetic and pathogenetic characteristics (Lomen-Hoerth et al., 2002; Murphy et al., 2007; Ling et al., 2013).

Genetic and pathological analysis have demonstrated that mutations of TAR DNA binding protein 43 kD (TARDBP) (Benajiba et al., 2009), fused in sarcoma/translocated in liposarcoma (FUS/TLS) (Blair et al., 2010), ubiquilin-2 (UBQLN2) (Deng et al., 2011) and C9ORF72 (Renton et al., 2011; DeJesus-Hernandez et al., 2011) have a key role in the pathogenesis of the ALS-FTD spectrum. Notably, all these genes may share a common link to cellular RNA dynamics (Thomas et al., 2012; Ling et al., 2013). Furthermore, from the phenotypical point of view, up to 50% of sporadic ALS patients display some degree of cognitive impairment, whereas up to 15% of FTD patients display symptoms typical of motor neuron disease (MND) (Lomen-Hoerth et al., 2002; Ringholz et al., 2005), especially in the behavioural variant subtype of FTD (bvFTD) (Lomen-Hoerth et al., 2004).

Despite the broadly described clinical, genetic and pathological overlap between ALS and FTD, structural and functional magnetic resonance imaging (MRI) correlates across this continuum have been poorly explored. Specifically, structural MRI studies, using voxel-based morphometry (VBM), surface-based morphometry (SBM) and diffusion tensor imaging (DTI), have shown in several cohorts of ALS patients a distributed pattern of gray (GM) and white matter (WM) damage in the frontal and temporal lobes (Chang et al., 2005; Ellis et al., 2001; Cirillo et al., 2012;

Schuster et al., 2014; d'Ambrosio et al., 2013) revealing significant commonalities with GM and WM abnormalities described in FTD patients (Borroni et al., 2007; Whitwell et al., 2010; Lillo et al., 2012).

With regard to functional MRI (fMRI), only a few studies, exploring the whole-brain functional connectivity of the resting state (RS) [i.e., resting-state fMRI (RS-fMRI) (Biswal et al., 1995; van de Ven et al., 2004)], have been carried out in ALS (Mohammadi et al., 2009; Douaud et al., 2011; Tedeschi et al., 2012; Agosta et al., 2013) and bvFTD patients (Zhou et al., 2010; Whitwell et al., 2011; Filippi et al., 2013; Farb et al., 2013). Specifically, the most consistent