Neural Regeneration Research ›› 2022, Vol. 17 ›› Issue (11): 2335-2341.doi: 10.4103/1673-5374.336139

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Cerebellar pathology in motor neuron disease: neuroplasticity and neurodegeneration

Rangariroyashe H. Chipika1, #, Grainne Mulkerrin1, #, Pierre-François Pradat2, Aizuri Murad1, Fabrice Ango3, Cédric Raoul3, Peter Bede1, 2, *   

  1. 1Computational Neuroimaging Group, Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; 2Pitié-Salpêtrière University Hospital, Sorbonne University, Paris, France; 3The Neuroscience Institute of Montpellier (INM), INSERM, CNRS, Montpellier, France
  • Online:2022-11-15 Published:2022-04-21
  • Contact: Peter Bede, MD, PhD, bedep@tcd.ie.
  • Supported by:
    This work was supported by the Spastic Paraplegia Foundation (SPF). Professor Peter Bede and the Computational Neuroimaging Group are also supported by the Health Research Board (HRB EIA-2017-019), the Irish Institute of Clinical Neuroscience (IICN), the EU Joint Programme-Neurodegenerative Disease Research (JPND), the Andrew Lydon scholarship, and the Iris O’Brien Foundation. 

Abstract: Amyotrophic lateral sclerosis is a relentlessly progressive multi-system condition. The clinical picture is dominated by upper and lower motor neuron degeneration, but extra-motor pathology is increasingly recognized, including cerebellar pathology. Post-mortem and neuroimaging studies primarily focus on the characterization of supratentorial disease, despite emerging evidence of cerebellar degeneration in amyotrophic lateral sclerosis. Cardinal clinical features of amyotrophic lateral sclerosis, such as dysarthria, dysphagia, cognitive and behavioral deficits, saccade abnormalities, gait impairment, respiratory weakness and pseudobulbar affect are likely to be exacerbated by co-existing cerebellar pathology. This review summarizes in vivo and post mortem evidence for cerebellar degeneration in amyotrophic lateral sclerosis. Structural imaging studies consistently capture cerebellar grey matter volume reductions, diffusivity studies readily detect both intra-cerebellar and cerebellar peduncle white matter alterations and functional imaging studies commonly report increased functional connectivity with supratentorial regions. Increased functional connectivity is commonly interpreted as evidence of neuroplasticity representing compensatory processes despite the lack of post-mortem validation. There is a scarcity of post-mortem studies focusing on cerebellar alterations, but these detect pTDP-43 in cerebellar nuclei. Cerebellar pathology is an overlooked facet of neurodegeneration in amyotrophic lateral sclerosis despite its contribution to a multitude of clinical symptoms, widespread connectivity to spinal and supratentorial regions and putative role in compensating for the degeneration of primary motor regions.

Key words: amyotrophic lateral sclerosis, ataxia, cerebellum, magnetic resonance imaging, motor neuron disease, neuroimaging, neuroplasticity, pathology, primary lateral sclerosis, pseudobulbar affect