title: Structural brain correlates of cognitive and behavioral impairment in MND.
abstract: OBJECTIVE
  To assess the structural correlates of cognitive and behavioral impairment in motor neuron diseases (MND) using multimodal MRI.
  
  
  METHODS
  One hundred one patients with sporadic MND (56 classic amyotrophic lateral sclerosis, 31 upper motor neuron phenotype, and 14 lower motor neuron phenotype) and 51 controls were enrolled. Patients were classified into MND with a pure motor syndrome (MND-motor) and with cognitive/behavioral symptoms (MND-plus). Cortical thickness measures and diffusion tensor (DT) metrics of white matter (WM) tracts were assessed. A random forest approach was used to explore the independent role of cortical and WM abnormalities in explaining major cognitive and behavioral symptoms.
  
  
  RESULTS
  There were 48 MND-motor and 53 MND-plus patients. Relative to controls, both patient groups showed a distributed cortical thinning of the bilateral precentral gyrus, insular and cingulate cortices, and frontotemporal regions. In all regions, there was a trend toward a more severe involvement in MND-plus cases, particularly in the temporal lobes. Both patient groups showed damage to the motor callosal fibers, which was more severe in MND-plus. MND-plus patients also showed a more severe involvement of the extra-motor WM tracts. The best predictors of executive and non-executive deficits and behavioral symptoms in MND were diffusivity abnormalities of the corpus callosum and frontotemporal tracts, including the uncinate, cingulum, and superior longitudinal fasciculi.
  
  
  CONCLUSIONS
  Cortical thinning and WM degeneration are highly associated with neuropsychological and behavioral symptoms in patients with MND. DT MRI metrics seem to be the most sensitive markers of extra-motor deficits within the MND spectrum.
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Agosta
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Pilar M
authors.initials: PM
authors.lastname: Ferraro
authors.affiliation: Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Nilo
authors.initials: N
authors.lastname: Riva
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.|Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Edoardo G
authors.initials: EG
authors.lastname: Spinelli
authors.affiliation: 'Rita Levi Montalcini' Department of Neuroscience, ALS Center, University of Torino, Torino, Italy.
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Canu
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Valsasina
authors.affiliation: Serena Onlus Foundation, NEuroMuscular Omnicenter, Milan, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Lunetta
authors.affiliation: Department of Clinical Neurosciences, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Iannaccone
authors.affiliation: Biostatistics Unit, IRCCS-Ospedale Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Copetti
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.|Department of Neuroradiology and CERMAC, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Evelina
authors.initials: E
authors.lastname: Prudente
authors.affiliation: Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Serena Onlus Foundation, NEuroMuscular Omnicenter, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Falini
authors.affiliation: Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.|Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Filippi
mesh_terms: D000368:Aged; D002540:Cerebral Cortex / Q000000981:diagnostic imaging*; D003072:Cognition Disorders / Q000000981:diagnostic imaging* / Q000523:psychology; D003430:Cross-Sectional Studies; D056324:Diffusion Tensor Imaging / Q000379:methods; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D001523:Mental Disorders / Q000000981:diagnostic imaging* / Q000523:psychology; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000000981:diagnostic imaging* / Q000523:psychology
keywords: amyotrophic lateral sclerosis; cognitive and behavioral impairment; cortical thinning; diffusion tensor MRI; motor neuron disease
references.citation: Magn Reson Imaging. 1999 Nov;17(9):1335-45
references.pmid: 10576719
references.citation: Neurology. 2012 Sep 25;79(13):1377-83
references.pmid: 22972650
references.citation: Amyotroph Lateral Scler. 2011 Jan;12(1):52-8
references.pmid: 21271791
references.citation: Neurology. 2008 Oct 28;71(18):1396-401
references.pmid: 18784377
references.citation: PLoS One. 2013 Dec 05;8(12):e82017
references.pmid: 24349172
references.citation: Neuroimage. 1999 Feb;9(2):179-94
references.pmid: 9931268
references.citation: Amyotroph Lateral Scler. 2009 Jun;10(3):131-46
references.pmid: 19462523
references.citation: Neurobiol Aging. 2014 Jan;35(1):240-6
references.pmid: 23992619
references.citation: Neuron. 2011 Oct 20;72(2):257-68
references.pmid: 21944779
references.citation: PLoS One. 2013;8(2):e57584
references.pmid: 23460879
references.citation: J Neurol Neurosurg Psychiatry. 2012 Jan;83(1):102-8
references.pmid: 21836033
references.citation: Neurology. 2015 Oct 13;85(15):1301-9
references.pmid: 26385880
references.citation: J Affect Disord. 2013 Sep 5;150(2):384-8
references.pmid: 23759278
references.citation: Neurology. 2010 Nov 2;75(18):1645-52
references.pmid: 21041787
references.citation: AJNR Am J Neuroradiol. 2011 Nov-Dec;32(10):1866-72
references.pmid: 22016410
references.citation: Ann Neurol. 2013 Jul;74(1):20-38
references.pmid: 23686809
references.citation: Neurology. 2013 Jul 23;81(4):361-9
references.pmid: 23771489
references.citation: Neurol Sci. 2000 Oct;21(5):279-91
references.pmid: 11286040
references.citation: J Neurol Sci. 1999 Oct 31;169(1-2):13-21
references.pmid: 10540002
references.citation: Neurobiol Dis. 2004 Apr;15(3):601-9
references.pmid: 15056468
references.citation: Neuropsychologia. 1997 Apr;35(4):399-408
references.pmid: 9106269
references.citation: Amyotroph Lateral Scler. 2006 Sep;7(3):150-60
references.pmid: 16963404
references.citation: J Neurol Neurosurg Psychiatry. 2012 Apr;83(4):383-8
references.pmid: 21965521
references.citation: Brain. 2011 Sep;134(Pt 9):2502-12
references.pmid: 21785117
references.citation: J Neurol. 2014 Oct;261(10):1871-80
references.pmid: 25022938
references.citation: J Neurol. 2014 Feb;261(2):412-21
references.pmid: 24452838
references.citation: Lancet Neurol. 2013 Mar;12(3):310-22
references.pmid: 23415570
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9
references.pmid: 11464847
references.citation: PLoS One. 2014 Aug 21;9(8):e105632
references.pmid: 25144223
references.citation: Neurology. 2015 Nov 17;85(20):1780-8
references.pmid: 26497991
references.citation: Neuropsychologia. 2000;38(6):734-47
references.pmid: 10689049
references.citation: Brain. 2013 Jun;136(Pt 6):1692-707
references.pmid: 23649697
references.citation: Brain. 2011 Oct;134(Pt 10):3011-29
references.pmid: 21666264
references.citation: Neurobiol Aging. 2010 Mar;31(3):512-22
references.pmid: 18495298
references.citation: Brain Lang. 2013 Nov;127(2):157-66
references.pmid: 23890877
references.citation: J Neurol Neurosurg Psychiatry. 2011 Feb;82(2):170-5
references.pmid: 20562407
references.citation: Arch Neurol. 2012 Nov;69(11):1493-9
references.pmid: 22910997
references.citation: BMC Neurol. 2013 Oct 18;13:148
references.pmid: 24138960
references.citation: Neuropsychology. 2012 Jul;26(4):422-9
references.pmid: 22612577
references.citation: PLoS One. 2013 Nov 20;8(11):e80748
references.pmid: 24278317
references.citation: Neurol Sci. 2013 May;34(5):749-54
references.pmid: 22689311
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11050-5
references.pmid: 10984517
references.citation: Neuroimage. 2007 Jan 1;34(1):144-55
references.pmid: 17070705
references.citation: Neuroimage. 2006 Jul 1;31(3):968-80
references.pmid: 16530430
references.citation: Amyotroph Lateral Scler Frontotemporal Degener. 2013 Dec;14(7-8):507-15
references.pmid: 23889583
references.citation: Eur Neurol. 1996;36(6):378-84
references.pmid: 8954307
references.citation: PLoS One. 2012;7(8):e42816
references.pmid: 22880116
references.citation: PLoS One. 2014 Dec 11;9(12):e114543
references.pmid: 25501028
references.citation: Funct Neurol. 1987 Apr-Jun;2(2):189-94
references.pmid: 3666548
references.citation: Neurol Sci. 2007 Apr;28(2):80-6
references.pmid: 17464470
references.citation: Brain. 2011 Apr;134(Pt 4):1211-28
references.pmid: 21362631
references.citation: AJNR Am J Neuroradiol. 2014 Feb;35(2):304-10
references.pmid: 24113470
references.citation: J Neurol Neurosurg Psychiatry. 2015 Mar;86(3):288-94
references.pmid: 25121571
references.citation: Behav Neurol. 2008;19(4):169-75
references.pmid: 19096141
references.citation: Neurol Sci. 2003 Apr;24(1):10-5
references.pmid: 12754651
references.citation: Hum Brain Mapp. 2007 Dec;28(12):1430-8
references.pmid: 17370339
references.citation: Clin Neuropsychol. 2012;26(6):926-41
references.pmid: 22809061
references.citation: Neurol Sci. 2014 Jun;35(6):911-8
references.pmid: 24435432
references.citation: Neurology. 2006 Nov 14;67(9):1718-9
references.pmid: 17101922
references.citation: Brain. 2014 Sep;137(Pt 9):2546-55
references.pmid: 24951638
references.citation: Brain. 2013 Nov;136(Pt 11):3290-304
references.pmid: 24056536
references.citation: Ital J Neurol Sci. 1987 Dec;8(6):539-48
references.pmid: 3429213
references.citation: Neurology. 2005 Jul 12;65(1):75-80
references.pmid: 16009889
references.citation: Hum Brain Mapp. 2014 Apr;35(4):1710-22
references.pmid: 23633431
references.citation: J Neurol Neurosurg Psychiatry. 2011 Jul;82(7):740-6
references.pmid: 21402743
references.citation: PLoS One. 2012;7(8):e43993
references.pmid: 22952843
references.citation: J Neurol Neurosurg Psychiatry. 2015 Feb;86(2):168-73
references.pmid: 24769471