title: Regional but not global brain damage contributes to fatigue in multiple sclerosis.
abstract: OBJECTIVE
  To use magnetic resonance (MR) imaging and advanced analysis to assess the role of lesions in normal-appearing white matter ( NAWM normal-appearing white matter ) and gray matter ( GM gray matter ) damage, global versus regional damage, and atrophy versus microstructural abnormalities in the pathogenesis of fatigue in multiple sclerosis ( MS multiple sclerosis ).
  
  
  METHODS
  Local ethics committee approval and written informed consent were obtained. Dual-echo, double inversion-recovery, high-resolution T1-weighted and diffusion-tensor ( DT diffusion tensor ) MR was performed in 31 fatigued patients, 32 nonfatigued patients, and 35 control subjects. Global and regional atrophy and DT diffusion tensor MR measures of damage to lesions, NAWM normal-appearing white matter , and GM gray matter were compared (analysis of variance).
  
  
  RESULTS
  Lesional, atrophy, and DT diffusion tensor MR measures of global damage to brain, white matter ( WM white matter ), and GM gray matter did not differ between fatigued and nonfatigued patients. Compared with nonfatigued patients and control subjects, fatigued patients experienced atrophy of the right side of the accumbens (mean volume ± standard deviation, 0.37 mL ± 0.09 in control subjects; 0.39 mL ± 0.1 in nonfatigued patients; and 0.33 mL ± 0.09 in fatigued patients), right inferior temporal gyrus ( ITG inferior temporal gyrus ) (Montreal Neurological Institute [ MNI Montreal Neurological Institute ] coordinates: 51, -51, -11; t value, 4.83), left superior frontal gyrus ( MNI Montreal Neurological Institute coordinates: -10, 49, 24; t value, 3.40), and forceps major ( MNI Montreal Neurological Institute coordinates: 11, -91, 18; t value, 3.37). They also had lower fractional anisotropy ( FA fractional anisotropy ) of forceps major ( MNI Montreal Neurological Institute coordinates: -17, -78, 6), left inferior fronto-occipital fasciculus ( MNI Montreal Neurological Institute coordinates: -25, 2, -11), and right anterior thalamic radiation ( ATR anterior thalamic radiation ) ( MNI Montreal Neurological Institute coordinates: 11, 2, -6) (P < .05, corrected). More lesions were found at T2-weighted imaging in fatigued patients. Multivariable model was used to identify right ITG inferior temporal gyrus atrophy (odds ratio, 0.83; 95% confidence interval [ CI confidence interval ]: 0.82, 0.97; P = .009) and right ATR anterior thalamic radiation FA fractional anisotropy (odds ratio, 0.74; 95% CI confidence interval : 0.61, 0.90; P = .003) as covariates independently associated with fatigue (C statistic, 0.85).
  
  
  CONCLUSIONS
  Damage to strategic brain WM white matter and GM gray matter regions, in terms of microstructural abnormalities and atrophy, contributes to pathogenesis of fatigue in MS multiple sclerosis , whereas global lesional, WM white matter , and GM gray matter damage does not seem to have a role.
authors.affiliation: From the Neuroimaging Research Unit (M.A.R., L.P., E.P., M.F.), Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience (M.A.R., M.R., B.C., G.C., M.F.), and Department of Neuroradiology (A.F.), CERMAC, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, Milan 20132, Italy; and Biostatistics Unit, IRCCS-Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (M.C.).
authors.forename: Maria A
authors.initials: MA
authors.lastname: Rocca
authors.forename: Laura
authors.initials: L
authors.lastname: Parisi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pagani
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Copetti
authors.forename: Mariaemma
authors.initials: M
authors.lastname: Rodegher
authors.forename: Bruno
authors.initials: B
authors.lastname: Colombo
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Andrea
authors.initials: A
authors.lastname: Falini
authors.forename: Massimo
authors.initials: M
authors.lastname: Filippi
mesh_terms: D000328:Adult; D016880:Anisotropy; D001921:Brain / Q000473:pathology*; D001931:Brain Mapping; D016022:Case-Control Studies; D004185:Disability Evaluation; D005221:Fatigue / Q000473:pathology* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology* / Q000503:physiopathology*