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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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Abstract

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).

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Abbreviations

GM:

Gray matter

WM:

White matter

ALS:

Amyotrophic lateral sclerosis (ALS)

HC:

Healthy controls

GMV:

Gray matter volume

FA:

Fractional anisotropy

AD:

Axial diffusivity

RD:

Radial diffusivity

MND:

Motor neuron disorders

CNS:

Central nervous system

FTD:

Frontotemporal dementia

TBSS:

Tract-based spatial statistics

MRI:

Magnetic resonance imaging

VBM:

Voxel-based morphometry

ALSFRS-R:

Revised Amyotrophic Lateral Sclerosis Functional Rating Scale

HR_3DT1w:

3D–T1-weighted sequence;

DTI:

Diffusion-tensor imaging

T2-FLAIR:

T2-Fluid attenuation inversion recovery

SPM:

Statistical Parametric Mapping

CSF:

Cerebrospinal fluid

FWHM:

Full-width-at-half-maximum

TIV:

Total intracranial volume

FWE:

Family-wise error

FMRIB:

Functional Magnetic Resonance Imaging of the Brain

FSL:

FMRIB Software Library

MNI:

Montreal Neurological Institute

TFCE:

Threshold-free cluster enhancement

ACC:

Anterior cingulate cortex

SMA:

Supplementary motor area

CST:

Corticospinal tract

CC:

Corpus callosum

UF:

Uncinate fasciculus

SLF:

Superior longitudinal fasciculus

IFOF:

Inferior fronto-occipital fasciculus

SBM:

Surface-based morphometry

fMRI:

Functional magnetic resonance imaging.

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Acknowledgements

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.

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  1. Foteini Christidi and Efstratios Karavasilis shared first-authorship for equal contribution

Authors and Affiliations

  1. First Department of Neurology, Aeginition Hospital, Medical School, National & Kapodistrian University, Athens, Greece

    Foteini Christidi, Ioannis Zalonis, Sophia Xirou, Michalis Rentzos, Vasiliki Zouvelou, Thomas Zambelis, Nikolaos Karandreas & Ioannis Evdokimidis

  2. Second Department of Radiology, Attikon University Hospital, Medical School, National and Kapodistrian University, Athens, Greece

    Efstratios Karavasilis, Georgios Velonakis, Georgios Argiropoulos, Athanasios Athanasakos, Panagiotis Toulas, Efstathios Efstathopoulos & Nikolaos Kelekis

  3. Neurological Center Rosenhuegel and Karl Landsteiner Institute for Epilepsy Research and Cognitive Neurology, Vienna, Austria

    Franz Riederer

  4. Second Department of Psychiatry, Attikon University Hospital, Medical School, National & Kapodistrian University, Athens, Greece

    Panagiotis Ferentinos

  5. Department of Neurology, Demokritos University of Thrace, Alexandroupolis, Greece

    Konstantinos Vadikolias

  6. Clinic of Neuroradiology, University Hospital Zurich, Zurich, Switzerland

    Spyros Kollias

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  1. Foteini Christidi
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Correspondence to Foteini Christidi.

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Funding

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.

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

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Christidi, F., Karavasilis, E., Riederer, F. et al. 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. Brain Imaging and Behavior 12, 547–563 (2018). https://doi.org/10.1007/s11682-017-9722-y

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