Gray matter and white matter changes in non-demented amyotrophic lateral sclerosis patients with or without cognitive impairment: A combined voxel-based morphometry and tract-based spatial statistics whole-brain analysis
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The phenotypic heterogeneity in amyotrophic lateral sclerosis (ALS) implies that patients show structural changes within but also beyond the motor cortex and corticospinal tract and furthermore outside the frontal lobes, even if frank dementia is not detected. The aim of the present study was to investigate both gray matter (GM) and white matter (WM) changes in non-demented amyotrophic lateral sclerosis (ALS) patients with or without cognitive impairment (ALS-motor and ALS-plus, respectively). Nineteen ALS-motor, 31 ALS-plus and 25 healthy controls (HC) underwent 3D–T1-weighted and 30-directional diffusion-weighted imaging on a 3 T MRI scanner. Voxel-based morphometry and tract-based spatial-statistics analysis were performed to examine GM volume (GMV) changes and WM differences in fractional anisotropy (FA), axial and radial diffusivity (AD, RD, respectively). Compared to HC, ALS-motor patients showed decreased GMV in frontal and cerebellar areas and increased GMV in right supplementary motor area, while ALS-plus patients showed diffuse GMV reduction in primary motor cortex bilaterally, frontotemporal areas, cerebellum and basal ganglia. ALS-motor patients had increased GMV in left precuneus compared to ALS-plus patients. We also found decreased FA and increased RD in the corticospinal tract bilaterally, the corpus callosum and extra-motor tracts in ALS-motor patients, and decreased FA and increased AD and RD in motor and several WM tracts in ALS-plus patients, compared to HC. Multimodal neuroimaging confirms motor and extra-motor GM and WM abnormalities in non-demented cognitively-impaired ALS patients (ALS-plus) and identifies early extra-motor brain pathology in ALS patients without cognitive impairment (ALS-motor).
KeywordsAmyotrophic lateral sclerosis Multimodal neuroimaging Voxel-based morphometry Tract-based spatial statistics Cognition
Amyotrophic lateral sclerosis (ALS)
Gray matter volume
Motor neuron disorders
Central nervous system
Tract-based spatial statistics
Magnetic resonance imaging
Revised Amyotrophic Lateral Sclerosis Functional Rating Scale
T2-Fluid attenuation inversion recovery
Statistical Parametric Mapping
Total intracranial volume
Functional Magnetic Resonance Imaging of the Brain
FMRIB Software Library
Montreal Neurological Institute
Threshold-free cluster enhancement
Anterior cingulate cortex
Supplementary motor area
Superior longitudinal fasciculus
Inferior fronto-occipital fasciculus
Functional magnetic resonance imaging.
F.C. is supported by the IKY FELLOWSHIPS OF EXCELLENCE FOR POSTGRADUATE STUDIES IN GREECE - SIEMENS PROGRAM (SPHA:11118/13a) and IKY SHORT TERMS PROGRAM (2013-ΠΕ2-SHORT TERMS-18671). We acknowledge Odysseas Benekos, Giannis Spandonis and the Philips Medical System for providing all necessary research keys for MRI sequence acquisition. We also acknowledge the radiologists-technologists of Research Radiology & Medical Imaging Department (Ioannis Gkerles, Christos Lioulios, Anestis Passalis, Efstathios Xenos) for conducting and facilitating participants’ MR scanning. Finally, we would like to thank patients with ALS and their families, as well as healthy volunteers for their willingness to participate to the present study.
Compliance with ethical standards
The study did not receive any funding. F.C. is supported by the IKY FELLOWSHIPS OF EXCELLENCE FOR POSTGRADUATE STUDIES IN GREECE - SIEMENS PROGRAM (SPHA:11118/13a) and IKY SHORT TERMS PROGRAM (2013-ΠΕ2-SHORT TERMS-18671).
Conflict of interest
Author F.C., Author E.K., Author F.R., Author I.Z., Author P.F., Author G.V., Author S.X., Author I.Z., Author M.R., Author G.A., Author V.Z., Author T.Z., Author A.A., Author P.T., Author K.V., Author E.E., Author S.K., Author N.K., Author N.K., Author I.E. declares that she/he has no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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