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.
- Bailly, M., Destrieux, C., Hommet, C., Mondon, K., Cottier, J.P., Beaufils, E., et al. (2015). Precuneus and cingulate cortex atrophy and hypometabolism in patients with Alzheimer’s disease and mild cognitive impairment: MRI and (18)F-FDG PET quantitative analysis using FreeSurfer. Biomed Research International, 2015. doi: 10.1155/2012/473538.
- Bede, P., Bokde, A., Elamin, M., Byrne, S., McLaughlin, R. L., Jordan, N., et al. (2013a). Grey matter correlates of clinical variables in amyotrophic lateral sclerosis (ALS): A neuroimaging study of ALS motor phenotype heterogeneity and cortical focality. Journal of Neurology, Neurosurgery, and Psychiatry, 84, 766–773.PubMedCrossRefGoogle Scholar
- Brooks, B. R., Miller, R. G., Swash, M., Munsat, T. L., & World Federation of Neurology Research Group on Motor Neuron Diseases. (2000). El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders, 1, 293–299.PubMedCrossRefGoogle Scholar
- Christidi, F., Zalonis, I., Kyriazi, S., Rentzos, M., Karavasilis, E., Wilde, E. A., et al. (2014). Uncinate fasciculus microstructure and verbal episodic memory in amyotrophic lateral sclerosis: A diffusion tensor imaging and neuropsychological study. Brain Imaging and Behavior, 8, 497–505.PubMedCrossRefGoogle Scholar
- Kassubek, J., Unrath, A., Huppertz, H. J., Lulé, D., Ethofer, T., Sperfeld, A. D., et al. (2005). Global brain atrophy and corticospinal tract alterations in ALS, as investigated by voxel-based morphometry of 3-D MRI. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders, 6, 213–220.PubMedCrossRefGoogle Scholar
- Kew, J. J., Goldstein, L. H., Leigh, P. N., Abrahams, S., Cosgrave, N., Passingham, R. E., et al. (1993). The relationship between abnormalities of cognitive function and cerebral activation in amyotrophic lateral sclerosis. A neuropsychological and positron emission tomography study. Brain, 116, 1399–1423.PubMedGoogle Scholar
- Kilani, M., Micallef, J., Soubrouillard, C., Rey-Lardiller, D., Demattei, C., Dib, M., et al. (2004). A longitudinal study of the evolution of cognitive function and affective state in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders, 5, 46–54.PubMedCrossRefGoogle Scholar
- Lezak, M. D., Howieson, D. B., Bigler, E. D., & Tranel, D. (2004). Neuropsycholoical Assessment (5th ed.). NY: Oxford University Press.Google Scholar
- Menke, R. A., Proudfoot, M., Wuu, J., Andersen, P. M., Talbot, K., Benatar, M., et al. (2016). Increased functional connectivity common to symptomatic amyotrophic lateral sclerosis and those at genetic risk. Journal of Neurology, Neurosurgery, and Psychiatry, 87, 580–588.PubMedPubMedCentralCrossRefGoogle Scholar
- Meoded, A., Kwan, J. Y., Peters, T. L., Huey, E. D., Danielian, L. E., Wiggs, E., et al. (2013). Imaging findings associated with cognitive performance in primary lateral sclerosis and amyotrophic lateral sclerosis. Dementia and Geriatric Cognitive Disorders Extra, 3, 233–250.PubMedPubMedCentralCrossRefGoogle Scholar
- Rosskopf, J., Muller, H. P., Dreyhaupt, J., Gorges, M., Gorges, A. C., Ludolph, A. C., & Kassubek, J. (2015). Ex post facto assessment of diffusion tensor imaging metrics from different MRI protocols: Preparing for multicentre studies in ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 16, 92–101.PubMedCrossRefGoogle Scholar
- Rusina, R., Ridzon, P., Kulistak, P., Keller, O., Bartos, A., Buncova, M., et al. (2009). Relationship between ALS and the degree of cognitive impairment, markers of neurodegeneration and predictors for poor outcome: A prospective study. European Journal of Neurology, 17, 23–30.PubMedCrossRefGoogle Scholar
- Sarica, A., Cerasa, A., Vasta, R., Perrotta, P., Valentino, P., Mangone, G., et al. (2014). Tractography in amyotrophic lateral sclerosis using a novel probabilistic tool: A study with tract-based reconstruction compared to voxel-based approach. Journal of Neuroscience Methods, 224, 79–87.PubMedCrossRefGoogle Scholar
- Schuster, C., Hardiman, O., & Bede, P. (2016). Development of an automated MRI-based diagnostic protocol for amyotrophic lateral sclerosis using disease-specific pathognomonic features: A quantitative disease-state classification study. PloS One, 11, e0167331.PubMedPubMedCentralCrossRefGoogle Scholar
- Strauss, E., Sherman, E. M. S., & Spreen, O. (2002). A compendium of neuropsychological tests: Administration, norms, and commentary (3rd ed.). New York: Oxford University Press.Google Scholar
- Strong, M. J., Grace, G. M., Freedman, M., Lomen-Hoerth, C., Woolley, S., Goldstein, L. H., et al. (2009). Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis, 10, 131–146.PubMedCrossRefGoogle Scholar
- Thivard, L., Pradat, P. F., Lehéricy, S., Lacomblez, L., Dormont, D., Chiras, J., et al. (2007). Diffusion tensor imaging and voxel based morphometry study in amyotrophic lateral sclerosis: Relationships with motor disability. Journal of Neurology, Neurosurgery, and Psychiatry, 78, 889–892.PubMedPubMedCentralCrossRefGoogle Scholar
- Trojsi, F., Monsurrò, M. R., Esposito, F., & Tedeschi, G. (2012). Widespread structural and functional connectivity changes in amyotrophic lateral sclerosis: insights from advanced neuroimaging research. Neural Plasticity, 2012. doi: 10.1155/2015/583931.
- Verschueren, J., Vanhee, A., De Coster, L., van Damme, P., & van Laere, K. (2013). Impact of the C9orf72 expansion on brain glucose metabolism in ALS patients. The Journal of Nuclear Medicine, 54, 155.Google Scholar
- Xu, Z., Alruwaili, A. R. S., Henderson, R. D., & McCombe, P. A. (2017). Screening for cognitive and behavioural impairment in amyotrophic lateral sclerosis: Frequency of abnormality and effect on survival. Journal of the Neurological Sciences, 376, 16–23.Google Scholar
- Zalonis, I., Chritsidi, F., Paraskevas, G., et al. (2012). Can executive cognitive measures differentiate between patients with spinal- and bulbar-onset amyotrophic lateral sclerosis? Archives of Clinical Neuropsychology, 27, 348–354.Google Scholar