Brain Imaging and Behavior

, Volume 12, Issue 2, pp 547–563 | Cite as

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

  • Foteini Christidi
  • Efstratios Karavasilis
  • Franz Riederer
  • Ioannis Zalonis
  • Panagiotis Ferentinos
  • Georgios Velonakis
  • Sophia Xirou
  • Michalis Rentzos
  • Georgios Argiropoulos
  • Vasiliki Zouvelou
  • Thomas Zambelis
  • Athanasios Athanasakos
  • Panagiotis Toulas
  • Konstantinos Vadikolias
  • Efstathios Efstathopoulos
  • Spyros Kollias
  • Nikolaos Karandreas
  • Nikolaos Kelekis
  • Ioannis Evdokimidis
Original Research


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).


Amyotrophic lateral sclerosis Multimodal neuroimaging Voxel-based morphometry Tract-based spatial statistics Cognition 



Gray matter


White matter


Amyotrophic lateral sclerosis (ALS)


Healthy controls


Gray matter volume


Fractional anisotropy


Axial diffusivity


Radial diffusivity


Motor neuron disorders


Central nervous system


Frontotemporal dementia


Tract-based spatial statistics


Magnetic resonance imaging


Voxel-based morphometry


Revised Amyotrophic Lateral Sclerosis Functional Rating Scale


3D–T1-weighted sequence;


Diffusion-tensor imaging


T2-Fluid attenuation inversion recovery


Statistical Parametric Mapping


Cerebrospinal fluid




Total intracranial volume


Family-wise error


Functional Magnetic Resonance Imaging of the Brain


FMRIB Software Library


Montreal Neurological Institute


Threshold-free cluster enhancement


Anterior cingulate cortex


Supplementary motor area


Corticospinal tract


Corpus callosum


Uncinate fasciculus


Superior longitudinal fasciculus


Inferior fronto-occipital fasciculus


Surface-based morphometry


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.

Ethical approval

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

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Foteini Christidi
    • 1
  • Efstratios Karavasilis
    • 2
  • Franz Riederer
    • 3
  • Ioannis Zalonis
    • 1
  • Panagiotis Ferentinos
    • 4
  • Georgios Velonakis
    • 2
  • Sophia Xirou
    • 1
  • Michalis Rentzos
    • 1
  • Georgios Argiropoulos
    • 2
  • Vasiliki Zouvelou
    • 1
  • Thomas Zambelis
    • 1
  • Athanasios Athanasakos
    • 2
  • Panagiotis Toulas
    • 2
  • Konstantinos Vadikolias
    • 5
  • Efstathios Efstathopoulos
    • 2
  • Spyros Kollias
    • 6
  • Nikolaos Karandreas
    • 1
  • Nikolaos Kelekis
    • 2
  • Ioannis Evdokimidis
    • 1
  1. 1.First Department of Neurology, Aeginition Hospital, Medical SchoolNational & Kapodistrian UniversityAthensGreece
  2. 2.Second Department of Radiology, Attikon University Hospital, Medical SchoolNational and Kapodistrian UniversityAthensGreece
  3. 3.Neurological Center Rosenhuegel and Karl Landsteiner Institute for Epilepsy Research and Cognitive NeurologyViennaAustria
  4. 4.Second Department of Psychiatry, Attikon University Hospital, Medical SchoolNational & Kapodistrian UniversityAthensGreece
  5. 5.Department of NeurologyDemokritos University of ThraceAlexandroupolisGreece
  6. 6.Clinic of NeuroradiologyUniversity Hospital ZurichZurichSwitzerland

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