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Essential tremor pathology: neurodegeneration and reorganization of neuronal connections

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From Nature Reviews Neurology

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Abstract

Essential tremor (ET) is the most common tremor disorder globally and is characterized by kinetic tremor of the upper limbs, although other clinical features can also occur. Postmortem studies are a particularly important avenue for advancing our understanding of the pathogenesis of ET; however, until recently, the number of such studies has been limited. Several recent postmortem studies have made important contributions to our understanding of the pathological changes that take place in ET. These studies identified abnormalities in the cerebellum, which primarily affected Purkinje cells (PCs), basket cells and climbing fibres, in individuals with ET. We suggest that some of these pathological changes (for example, focal PC axonal swellings, swellings in and regression of the PC dendritic arbor and PC death) are likely to be primary and degenerative. By contrast, other changes, such as an increase in PC recurrent axonal collateral formation and hypertrophy of GABAergic basket cell axonal processes, could be compensatory responses to restore cerebellar GABAergic tone and cerebellar cortical inhibitory efficacy. Such compensatory responses are likely to be insufficient, enabling the disease to progress. Here, we review the results of recent postmortem studies of ET and attempt to place these findings into an anatomical–physiological disease model.

Key points

  • Several groups have identified pathological changes in the cerebellum of individuals with essential tremor (ET).

  • Cerebellar abnormalities in ET include changes to Purkinje cell (PC) axons and dendrites, displacement and loss of PCs, changes to basket cell axonal processes, abnormal distribution of climbing fibre connections to PCs and changes in GABA receptors in the dentate nucleus.

  • Some of the observed changes (for example, loss of PCs) could result in reduced GABAergic output from the cerebellum.

  • Some pathological changes in ET are likely to be primary and degenerative, whereas others could be regarded as compensatory responses aimed at restoring cerebellar GABAergic tone.

  • In the brains of individuals with ET, both PCs themselves and neighbouring GABAergic neurons (basket cells) might increase their connections with PCs, resulting in rewiring and reorganization of neuronal connections within the cerebellum.

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Fig. 1: The degenerative cascade in essential tremor: a provisional model.
Fig. 2: Putative ‘early’ pathological changes in essential tremor.
Fig. 3: Putative ‘middle’ pathological changes in ET.
Fig. 4: Putative ‘late’ pathological changes in ET.
Fig. 5: The ‘perfect storm’ of decreased cerebellar GABAergic output in essential tremor.

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Acknowledgements

The work of E.D.L. and P.L.F. is supported by the NIH National Institute of Neurological Disorders and Stroke (grant number R01 NS088257).

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In January 2019, the authors searched PubMed using the keyword “essential tremor” in combination with “biology” (101 results), “mechanisms” (247 results), “pathophysiology” (187 results), “post-mortem” (61 results), “cerebellum” (326 results), “Purkinje” (92 results), “inferior olive” (33 results), “thalamus” (513 results), “motor loop” (5 results) or “degeneration” (118 results). During the initial screening of the abstracts and full texts, publications that were not relevant to this Review, duplicates, and those that were published in languages other than English were removed. The references from these articles as well as full-text articles and abstracts from the authors’ personal collections were also thoroughly searched for additional articles.

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  1. Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA

    Elan D. Louis

  2. Department of Pathology and Cell Biology, Columbia University Irving Medical Center and the New York Presbyterian Hospital, New York, NY, USA

    Phyllis L. Faust

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Both authors contributed equally to discussion of the content of the article, writing, and reviewing and/or editing of the manuscript before submission. E.D.L. also researched data for the article.

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Glossary

Kinetic tremor

A tremor that occurs during voluntary movement.

Bielschowsky stain

A silver stain that is useful for staining neuronal filamentous structures, including axons, neurofibrillary tangles and amyloid plaques.

Golgi–Kopsch method

A silver staining technique that is useful to visualize nerve processes belonging to individual neurons.

Arciform axons

Purkinje cell axons that gradually curve back towards the Purkinje cell layer.

Enhanced physiological tremor

A generally low-amplitude, upper-limb action tremor that is observed in the large majority of healthy individuals and can be exacerbated by stress or drugs.

Pinceau structure

Resembling a pincer.

Complex spike

A Purkinje cell action potential generated from a single excitatory climbing fibre, originating in the inferior olive, through hundreds of synapses across the proximal Purkinje cell dendritic tree. Complex spikes occur at low frequency with a characteristic burst of small spikelets and produce a prolonged depolarization.

Vibrissal movements

Movement of the facial whiskers of rodents.

Ephaptic coupling

Electrical conduction that involves adjacent nerve fibres, distinct from direct neuron to neuron communication through synapses.

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Louis, E.D., Faust, P.L. Essential tremor pathology: neurodegeneration and reorganization of neuronal connections. Nat Rev Neurol 16, 69–83 (2020). https://doi.org/10.1038/s41582-019-0302-1

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