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Extra-motor cerebral changes and manifestations in primary lateral sclerosis

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Abstract

Primary lateral sclerosis (PLS) is classically considered a ‘pure’ upper motor neuron disorder. Motor cortex atrophy and pyramidal tract degeneration are thought to be pathognomonic of PLS, but extra-motor cerebral changes are poorly characterized. In a prospective neuroimaging study, forty PLS patients were systematically evaluated with a standardised imaging, genetic and clinical protocol. Patients were screened for ALS and HSP associated mutations, as well as C9orf72 hexanucleotide repeats. Clinical assessment included composite reflex scores, spasticity scales, functional rating scales, and screening for cognitive and behavioural deficits. The neuroimaging protocol evaluated cortical atrophy patterns, subcortical grey matter changes and white matter alterations in whole-brain and region-of-interest analyses. PLS patients tested negative for known ALS- and HSP-associated mutations and C9orf72 repeat expansions. Voxel-wise analyses revealed anterior cingulate, dorsolateral prefrontal, insular, opercular, orbitofrontal and bilateral mesial temporal grey matter changes and white matter alterations in the fornix, brainstem, temporal lobes, and cerebellum. Significant thalamus, caudate, hippocampus, putamen and accumbens nucleus volume reductions were also identified. Extra-motor clinical manifestations were dominated by verbal fluency deficits, language deficits, apathy and pseudobulbar affect. Our clinical and radiological evaluation confirms considerable extra-motor changes in a population-based cohort of PLS patients. Our data suggest that PLS should no longer be considered a neurodegenerative disorder selectively affecting the pyramidal system. PLS is associated with widespread extra-motor changes and manifestations which should be carefully considered in the multidisciplinary management of this low-incidence condition.

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Acknowledgements

We acknowledge all patients with primary lateral sclerosis and all healthy controls who have kindly participated in this research study. Without their contribution, this study would have not been possible. This work was sponsored by the Spastic Paraplegia Foundation, Inc. (SPF). Professor Peter Bede is also supported by the Health Research Board (HRB EIA-2017-019), the EU Joint Programme – Neurodegenerative Disease Research (JPND), the Andrew Lydon scholarship, the Irish Institute of Clinical Neuroscience (IICN), the Iris O’Brien Foundation, and the Research Motor Neuron (RMN-Ireland) Foundation. Professor Russell L. McLaughlin and Ms. Jennifer C. Hengeveld are supported by Science Foundation Ireland (17/CDA/4737). The genetic aspects of this study were supported in part by a research grant from Science Foundation Ireland (SFI) under Grant Number 16/RC/3948, co-funded under the European Regional Development Fund and by FutureNeuro industry partners. The sponsors of the authors had no role in the study design, analyses or the interpretation of our research findings.

Funding sources

Spastic Paraplegia Foundation, Inc. (SPF), Health Research Board (HRB EIA-2017-019), the EU Joint Programme – Neurodegenerative Disease Research (JPND), the Andrew Lydon scholarship, the Irish Institute of Clinical Neuroscience (IICN), the Iris O’Brien Foundation, the Research Motor Neuron (RMN-Ireland) Foundation, Science Foundation Ireland (17/CDA/4737 and 16/RC/3948), European Regional Development Fund and FutureNeuro.

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Authors and Affiliations

  1. Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland

    Eoin Finegan, Stacey Li Hi Shing, Rangariroyashe H. Chipika, Kai Ming Chang, Mary Clare McKenna, Orla Hardiman & Peter Bede

  2. Electronics and Computer Science, University of Southampton, Southampton, UK

    Kai Ming Chang

  3. Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland

    Mark A. Doherty, Jennifer C. Hengeveld, Alice Vajda & Russell L. McLaughlin

  4. Department of Psychology, Beaumont Hospital, Dublin, Ireland

    Niall Pender

  5. Department of Neurology, Belfast, Western Health & Social Care Trust, Belfast, Northern Ireland

    Colette Donaghy

  6. Department of Neurology, St James’s Hospital, Dublin, Ireland

    Siobhan Hutchinson

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  1. Eoin Finegan
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Contributions

Imaging analyses: EF, SLHS, RC, KMC, MCMcK, PB.

Genetic analyses: MD, JH, AV, RMcL.

Clinical characterization: EF, OH, NP, SH, CD.

Drafting the paper: EF, PB.

Corresponding author

Correspondence to Peter Bede.

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none declared.

Ethical approval

The study was approved by the Ethics Committee of Beaumont Hospital, Dublin, Ireland and all participants provided written informed consent prior to inclusion.

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Finegan, E., Shing, S.L.H., Chipika, R.H. et al. Extra-motor cerebral changes and manifestations in primary lateral sclerosis. Brain Imaging and Behavior 15, 2283–2296 (2021). https://doi.org/10.1007/s11682-020-00421-4

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