title: Microstructural changes across different clinical milestones of disease in amyotrophic lateral sclerosis.
abstract: Neurodegenerative process in amyotrophic lateral sclerosis (ALS) has been proven to involve several cortical and subcortical brain regions within and beyond motor areas. However, how ALS pathology spreads progressively during disease evolution is still unknown. In this cross-sectional study we investigated 54 ALS patients, divided into 3 subsets according to the clinical stage, and 18 age and sex-matched healthy controls, by using tract-based spatial statistics (TBSS) diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses. We aimed to identify white (WM) and gray matter (GM) patterns of disease distinctive of each clinical stage, corresponding to specific clinical milestones. ALS cases in stage 2A (i.e., at diagnosis) were characterized by GM and WM impairment of left motor and premotor cortices and brainstem at ponto-mesenchephalic junction. ALS patients in clinical stage 2B (with impairment of two functional regions) exhibited decreased fractional anisotropy (FA) (p<0.001, uncorrected) and increased mean (MD) and radial diffusivity (RD) (p<0.001, uncorrected) in the left cerebellar hemisphere and brainstem precerebellar nuclei, as well as in motor areas, while GM atrophy (p<0.001, uncorrected) was detected only in the left inferior frontal gyrus and right cuneus. Finally, ALS patients in stage 3 (with impairment of three functional regions) exhibited decreased FA and increased MD and RD (p<0.05, corrected) within WM underneath bilateral pre and postcentral gyri, corpus callosum midbody, long associative tracts and midbrain, while no significant clusters of GM atrophy were observed. Our findings reinforce the hypothesis that the neurodegenerative process propagates along the axonal pathways and develops beyond motor areas from early stages, involving progressively several frontotemporal regions and their afferents and efferents, while the detection of GM atrophy in earlier stages and its disappearance in later stages may be the result of reactive gliosis.
authors: Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy; MRI Research Center SUN-FISM-Second University of Naples, 80138 Naples, Italy.
authors: Francesca
authors: F
authors: Trojsi
authors: Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy; MRI Research Center SUN-FISM-Second University of Naples, 80138 Naples, Italy.
authors: Giuseppina
authors: G
authors: Caiazzo
authors: Department of Neuroscience, University of Parma, 43100 Parma, Italy.
authors: Daniele
authors: D
authors: Corbo
authors: Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy.
authors: Giovanni
authors: G
authors: Piccirillo
authors: Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy.
authors: Viviana
authors: V
authors: Cristillo
authors: Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy.
authors: Cinzia
authors: C
authors: Femiano
authors: Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy.
authors: Teresa
authors: T
authors: Ferrantino
authors: Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy; MRI Research Center SUN-FISM-Second University of Naples, 80138 Naples, Italy.
authors: Mario
authors: M
authors: Cirillo
authors: Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy; MRI Research Center SUN-FISM-Second University of Naples, 80138 Naples, Italy.
authors: Maria Rosaria
authors: MR
authors: Monsurrò
authors: MRI Research Center SUN-FISM-Second University of Naples, 80138 Naples, Italy; Department of Medicine and Surgery, University of Salerno, 84081 Baronissi (Salerno), Italy.
authors: Fabrizio
authors: F
authors: Esposito
authors: Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, Second University of Naples, Naples, Italy; MRI Research Center SUN-FISM-Second University of Naples, 80138 Naples, Italy.
authors: Gioacchino
authors: G
authors: Tedeschi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000473:pathology*; D001284:Atrophy; D001921:Brain / Q000473:pathology; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged