Divergent brain network connectivity in amyotrophic lateral sclerosis Federica Agosta a , Elisa Canu a , Paola Valsasina a , Nilo Riva b , Alessandro Prelle c , Giancarlo Comi b , Massimo Filippi a,b, * a Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, via Olgettina 60, Milan, Italy b Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, via Olgettina 60, Milan, Italy c Neurology Unit, Ospedale Maggiore di Crema, Largo Ugo Dossena, 2, Crema, Cremona, Italy Received 9 January 2012; received in revised form 23 April 2012; accepted 28 April 2012 Abstract Using resting state (RS) functional magnetic resonance imaging and independent component analysis, the integrity of brain networks related to cognition and behavior was investigated in 20 nondemented patients with amyotrophic lateral sclerosis (ALS). The association between RS functional connectivity and executive functions was assessed in 16 patients with neuropsychological assessment. ALS patients compared with control subjects showed a decreased connectivity of the right orbitofrontal cortex, and an enhanced connectivity of the left precuneus in the default mode network; a decreased connectivity of the left inferior frontal cortex, and an increased connectivity of the right angular gyrus in the right frontoparietal network; and an increased connectivity of the parietal cortex in the left frontoparietal network. The enhanced parietal connectivity was associated with the clinical and cognitive deficits of the patients. In ALS, an alteration of large-scale functional brain networks associated with cognition does occur, even in the absence of overt dementia. The increased parietal connectivity may have a role in an attempt to maintain cognitive efficiency in the presence of structural frontotemporal injury. © 2013 Elsevier Inc. All rights reserved. Keywords: Amyotrophic lateral sclerosis; Resting state functional MRI; Executive functions; Cognitive impairment 1. Introduction Although amyotrophic lateral sclerosis (ALS) is charac- terized primarily by degeneration of the motor neurons and the corticospinal tracts (CST), it is well known that there is a clinical, pathological, and genetic overlap between this condition and frontotemporal lobar degeneration (FTLD) (Phukan et al., 2007). ALS co-occurs clinically with fron- totemporal dementia (FTD) in 5 to 15% of cases, whereas approximately 35% of nondemented ALS patients show a mild to moderate cognitive impairment (Phukan et al., 2007). The most consistently reported cognitive changes in ALS patients relate to dysfunction of components of the executive system. Behavioral impairment is also recognized as another feature of ALS (Phukan et al., 2007). The analysis of functional connectivity of the resting state (RS) (i.e., RS functional magnetic resonance imaging [fMRI]) has allowed a remarkable advancement of our un- derstanding of the complex interactions among distributed neural networks underlying brain functioning (Biswal et al., 1995). Using RS fMRI, multiple networks of temporally correlated brain regions have been identified that are related to specific sensory, motor, and cognitive functions (Smith et al., 2009). In ALS, the results about connectivity of RS network (RSN) other than the sensorimotor have been poorly con- sistent (Mohammadi et al., 2009; Tedeschi et al., 2012), with some investigators (Mohammadi et al., 2009) showing an altered connectivity of the default mode network (DMN), which has been linked to high-order cognitive processes * Corresponding author at: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scien- tific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy. Tel.: +39 02 26433033; fax: +39 02 26435972. E-mail address: m.filippi@hsr.it (M. Filippi). Neurobiology of Aging 34 (2013) 419 – 427 www.elsevier.com/locate/neuaging 0197-4580/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2012.04.015