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Linking Essential Tremor to the Cerebellum: Neuropathological Evidence

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Abstract

A fundamental question about essential tremor (ET) is whether its associated pathological changes and disease mechanisms are linkable to a specific brain region. To that end, recent tissue-based studies have made significant strides in elucidating changes in the ET brain. Emerging from these studies is increasing neuropathological evidence linking ET to the cerebellum. These studies have systematically identified a broad range of structural, degenerative changes in the ET cerebellum, spanning across all Purkinje cell compartments. These include the dendritic compartment (where there is an increase in number of Purkinje cell dendritic swellings, a pruning of the dendritic arbor, and a reduction in spine density), the cell body (where, aside from reductions in Purkinje cell linear density in some studies, there is an increase in the number of heterotopic Purkinje cell soma), and the axonal compartment (where a plethora of changes in axonal morphology have been observed, including an increase in the number of thickened axonal profiles, torpedoes, axonal recurrent collaterals, axonal branching, and terminal axonal sprouting). Additional changes, possibly due to secondary remodeling, have been observed in neighboring neuronal populations. These include a hypertrophy of basket cell axonal processes and changes in the distribution of climbing fiber-Purkinje cell synapses. These changes all distinguish ET from normal control brains. Initial studies further indicate that the profile (i.e., constellation) of these changes may separate ET from other diseases of the cerebellum, thereby serving as a disease signature. With the discovery of these changes, a new model of ET has arisen, which posits that it may be a neurodegenerative disorder centered in the cerebellar cortex. These newly emerging neuropathological studies pave the way for anatomically focused, hypothesis-driven, molecular mechanistic studies of disease pathogenesis.

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References

  1. Louis ED, Vonsattel JP, Honig LS, Ross GW, Lyons KE, Pahwa R. Neuropathologic findings in essential tremor. Neurology. 2006;66:1756–9.

    Article  CAS  PubMed  Google Scholar 

  2. Rajput A, Robinson CA, Rajput AH. Essential tremor course and disability: a clinicopathologic study of 20 cases. Neurology. 2004;62:932–6.

    Article  PubMed  Google Scholar 

  3. Rajput AH, Robinson CA, Rajput ML, Robinson SL, Rajput A. Essential tremor is not dependent upon cerebellar Purkinje cell loss. Parkinsonism Relat Disord. 2012;18:626–8.

    Article  CAS  PubMed  Google Scholar 

  4. Louis ED, Faust PL, Vonsattel JP. Purkinje cell loss is a characteristic of essential tremor: towards a more mature understanding of pathogenesis. Parkinsonism Relat Disord. 2012;18:1003–4.

    Article  PubMed  Google Scholar 

  5. Yu M, Ma K, Faust PL, Honig LS, Cortes E, Vonsattel JP, et al. Increased number of Purkinje cell dendritic swellings in essential tremor. Eur J Neurol. 2012;19:625–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Louis ED, Lee M, Babij R, Ma K, Cortes E, Vonsattel JP, et al. Reduced Purkinje cell dendritic arborization and loss of dendritic spines in essential tremor. Brain. 2014;137:3142–8.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Axelrad JE, Louis ED, Honig LS, Flores I, Ross GW, Pahwa R, et al. Reduced Purkinje cell number in essential tremor: a postmortem study. Arch Neurol. 2008;65:101–7.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Louis ED, Faust PL, Vonsattel JP, Honig LS, Rajput A, Robinson CA, et al. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain. 2007;130:3297–307.

    Article  PubMed  Google Scholar 

  9. Kuo SH, Erickson-Davis C, Gillman A, Faust PL, Vonsattel JP, Louis ED. Increased number of heterotopic Purkinje cells in essential tremor. J Neurol Neurosurg Psychiatry. 2011;82:1038–40.

    Article  PubMed  Google Scholar 

  10. Erickson-Davis CR, Faust PL, Vonsattel JP, Gupta S, Honig LS, Louis ED. “Hairy baskets” associated with degenerative Purkinje cell changes in essential tremor. J Neuropathol Exp Neurol. 2010;69:262–71.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kuo SH, Tang G, Louis ED, Ma K, Babji R, Balatbat M, et al. Lingo-1 expression is increased in essential tremor cerebellum and is present in the basket cell pinceau. Acta Neuropathol. 2013;125:879–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lin CY, Louis ED, Faust PL, Koeppen AH, Vonsattel JP, Kuo SH. Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain. 2014;137:3149–59.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lee M, Cheng MM, Lin CY, Louis ED, Faust PL, Kuo SH. Decreased EAAT2 protein expression in the essential tremor cerebellar cortex. Acta Neuropathol Commun. 2014;2:157.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Grimaldi G, Manto M. Is essential tremor a Purkinjopathy? The role of the cerebellar cortex in its pathogenesis. Mov Disord. 2013;28:1759–61.

    Article  PubMed  Google Scholar 

  15. Louis ED. From neurons to neuron neighborhoods: the rewiring of the cerebellar cortex in essential tremor. Cerebellum. 2014;13:501–12.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Louis E. Re-thinking the biology of essential tremor: from models to morphology. Parkinsonism Relat Disord. 2014;20(Suppl1):S88–93.

    Article  PubMed  Google Scholar 

  17. Dusart I, Morel MP, Wehrle R, Sotelo C. Late axonal sprouting of injured Purkinje cells and its temporal correlation with permissive changes in the glial scar. J Comp Neurol. 1999;408:399–418.

    Article  CAS  PubMed  Google Scholar 

  18. Louis ED, Lee M, Cortes E, Vonsattel JP, Faust PL. Matching asymmetry of tremor with asymmetry of postmortem cerebellar hemispheric changes in essential tremor. Cerebellum. 2014;13:462–70.

    Article  PubMed  Google Scholar 

  19. Rajput AH, Adler CH, Shill HA, Rajput A. Essential tremor is not a neurodegenerative disease. Neurodegener Dis Manag. 2012;2:259–68.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Symanski C, Shill HA, Dugger B, Hentz JG, Adler CH, Jacobson SA, et al. Essential tremor is not associated with cerebellar Purkinje cell loss. Mov Disord. 2014;29:496–500.

    Article  PubMed  Google Scholar 

  21. Louis ED, Faust PL, Vonsattel JP. Purkinje cell loss is a characteristic of essential tremor. Parkinsonism Relat Disord. 2011;17:406–9.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord. 2010;25:534–41.

    Article  PubMed  Google Scholar 

  23. Babij R, Lee M, Cortes E, Vonsattel JP, Faust PL, Louis ED. Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain. 2013;136:3051–61.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Rossi F, Jankovski A, Sotelo C. Target neuron controls the integrity of afferent axon phenotype: a study on the Purkinje cell-climbing fiber system in cerebellar mutant mice. J Neurosci. 1995;15:2040–56.

    CAS  PubMed  Google Scholar 

  25. Shill HA, Adler CH, Sabbagh MN, Connor DJ, Caviness JN, Hentz JG, et al. Pathologic findings in prospectively ascertained essential tremor subjects. Neurology. 2008;70:1452–5.

    Article  CAS  PubMed  Google Scholar 

  26. Louis ED, Honig LS, Vonsattel JP, Maraganore DM, Borden S, Moskowitz CB. Essential tremor associated with focal nonnigral Lewy bodies: a clinicopathologic study. Arch Neurol. 2005;62:1004–7.

    PubMed  Google Scholar 

  27. Louis ED. Understanding essential tremor: progress on the biological front. Curr Neurol Neurosci Rep. 2014;14:450.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hubble JP, Busenbark KL, Pahwa R, Lyons K, Koller WC. Clinical expression of essential tremor: effects of gender and age. Mov Disord. 1997;12:969–72.

    Article  CAS  PubMed  Google Scholar 

  29. Parisi SL, Heroux ME, Culham EG, Norman KE. Functional mobility and postural control in essential tremor. Arch Phys Med Rehabil. 2006;87:1357–64.

    Article  PubMed  Google Scholar 

  30. Louis ED, Rios E, Rao AK. Tandem gait performance in essential tremor: clinical correlates and association with midline tremors. Mov Disord. 2010;25:1633–8.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Rao AK, Gillman A, Louis ED. Quantitative gait analysis in essential tremor reveals impairments that are maintained into advanced age. Gait Posture. 2011;34:65–70.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Louis ED. Essential tremor and other forms of kinetic tremor. In: Grimaldi G, Manto M, editors. Mechanisms and emerging therapies of tremor disorders. Humana Press; 2012. p. 219–234.

  33. Louis ED, Galecki M, Rao AK. Four essential tremor cases with moderately impaired gait: how impaired can gait be in this disease? Tremor Other Hyperkinet Mov (N Y) 2013;3. pii: tre-03-200-4597-1.

  34. Deuschl G, Wenzelburger R, Loffler K, Raethjen J, Stolze H. Essential tremor and cerebellar dysfunction clinical and kinematic analysis of intention tremor. Brain. 2000;123:1568–80.

    Article  PubMed  Google Scholar 

  35. Leegwater-Kim J, Louis ED, Pullman SL, Floyd AG, Borden S, Moskowitz CB, et al. Intention tremor of the head in patients with essential tremor. Mov Disord. 2006;21:2001–5.

    Article  PubMed  Google Scholar 

  36. Gitchel GT, Wetzel PA, Baron MS. Slowed saccades and increased square wave jerks in essential tremor. Tremor Other Hyperkinet Mov (N Y) 2013;3. pii: tre-03-178-4116-2.

  37. Helmchen C, Hagenow A, Miesner J, Sprenger A, Rambold H, Wenzelburger R, et al. Eye movement abnormalities in essential tremor may indicate cerebellar dysfunction. Brain. 2003;126:1319–32.

    Article  CAS  PubMed  Google Scholar 

  38. Avanzino L, Bove M, Tacchino A, Ruggeri P, Giannini A, Trompetto C, et al. Cerebellar involvement in timing accuracy of rhythmic finger movements in essential tremor. Eur J Neurosci. 2009;30:1971–9.

    Article  PubMed  Google Scholar 

  39. Trillenberg P, Fuhrer J, Sprenger A, Hagenow A, Kompf D, Wenzelburger R, et al. Eye-hand coordination in essential tremor. Mov Disord. 2006;21:373–9.

    Article  PubMed  Google Scholar 

  40. Bares M, Lungu OV, Husarova I, Gescheidt T. Predictive motor timing performance dissociates between early diseases of the cerebellum and Parkinson’s disease. Cerebellum. 2010;9:124–35.

    Article  PubMed  Google Scholar 

  41. Farkas Z, Szirmai I, Kamondi A. Impaired rhythm generation in essential tremor. Mov Disord. 2006;21:1196–9.

    Article  PubMed  Google Scholar 

  42. Dupuis MJ, Delwaide PJ, Boucquey D, Gonsette RE. Homolateral disappearance of essential tremor after cerebellar stroke. Mov Disord. 1989;4:183–7.

    Article  CAS  PubMed  Google Scholar 

  43. Rajput AH, Maxood K, Rajput A. Classic essential tremor changes following cerebellar hemorrhage. Neurology. 2008;71:1739–40.

    Article  PubMed  Google Scholar 

  44. Schuurman PR, Bosch DA, Bossuyt PM, Bonsel GJ, van Someren EJ, de Bie RM, et al. A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. N Engl J Med. 2000;342:461–8.

    Article  CAS  PubMed  Google Scholar 

  45. Benabid AL, Pollak P, Seigneuret E, Hoffmann D, Gay E, Perret J. Chronic VIM thalamic stimulation in Parkinson’s disease, essential tremor and extra-pyramidal dyskinesias. Acta Neurochir Suppl (Wien). 1993;58:39–44.

    CAS  Google Scholar 

  46. Passamonti L, Cerasa A, Quattrone A. Neuroimaging of essential tremor: what is the evidence for cerebellar involvement? Tremor Other Hyperkinet Mov (N Y) 2012;2. pii: 02-67-421-3.

  47. Louis ED, Huang CC, Dyke JP, Long Z, Dydak U. Neuroimaging studies of essential tremor: how well do these studies support/refute the neurodegenerative hypothesis? Tremor Other Hyperkinet Mov (N Y) 2014;4:235.

  48. Bucher SF, Seelos KC, Dodel RC, Reiser M, Oertel WH. Activation mapping in essential tremor with functional magnetic resonance imaging. Ann Neurol. 1997;41:32–40.

    Article  CAS  PubMed  Google Scholar 

  49. Jenkins IH, Bain PG, Colebatch JG, Thompson PD, Findley LJ, Frackowiak RS, et al. A positron emission tomography study of essential tremor: evidence for overactivity of cerebellar connections. Ann Neurol. 1993;34:82–90.

    Article  CAS  PubMed  Google Scholar 

  50. Wills AJ, Jenkins IH, Thompson PD, Findley LJ, Brooks DJ. Red nuclear and cerebellar but no olivary activation associated with essential tremor: a positron emission tomographic study. Ann Neurol. 1994;36:636–42.

    Article  CAS  PubMed  Google Scholar 

  51. Colebatch JG, Findley LJ, Frackowiak RS, Marsden CD, Brooks DJ. Preliminary report: activation of the cerebellum in essential tremor. Lancet. 1990;336:1028–30.

    Article  CAS  PubMed  Google Scholar 

  52. Louis ED, Shungu DC, Chan S, Mao X, Jurewicz EC, Watner D. Metabolic abnormality in the cerebellum in patients with essential tremor: a proton magnetic resonance spectroscopic imaging study. Neurosci Lett. 2002;333:17–20.

    Article  CAS  PubMed  Google Scholar 

  53. Pagan FL, Butman JA, Dambrosia JM, Hallett M. Evaluation of essential tremor with multi-voxel magnetic resonance spectroscopy. Neurology. 2003;60:1344–7.

    Article  PubMed  Google Scholar 

  54. Shin DH, Han BS, Kim HS, Lee PH. Diffusion tensor imaging in patients with essential tremor. AJNR Am J Neuroradiol. 2008;29:151–3.

    Article  CAS  PubMed  Google Scholar 

  55. Klein JC, Lorenz B, Kang JS, Baudrexel S, Seifried C, van de Loo S, et al. Diffusion tensor imaging of white matter involvement in essential tremor. Hum Brain Mapp. 2011;32:896–904.

    Article  PubMed  Google Scholar 

  56. Nicoletti G, Manners D, Novellino F, Condino F, Malucelli E, Barbiroli B, et al. Diffusion tensor MRI changes in cerebellar structures of patients with familial essential tremor. Neurology. 2010;74:988–94.

    Article  CAS  PubMed  Google Scholar 

  57. Benito-Leon J, Alvarez-Linera J, Hernandez-Tamames JA, Alonso-Navarro H, Jimenez-Jimenez FJ, Louis ED. Brain structural changes in essential tremor: voxel-based morphometry at 3-Tesla. J Neurol Sci. 2009;287:138–42.

    Article  PubMed  Google Scholar 

  58. Quattrone A, Cerasa A, Messina D, Nicoletti G, Hagberg GE, Lemieux L, et al. Essential head tremor is associated with cerebellar vermis atrophy: a volumetric and voxel-based morphometry MR imaging study. Am J Neuroradiol. 2008;29:1692–7.

    Article  CAS  PubMed  Google Scholar 

  59. Gironell A. The GABA hypothesis in essential tremor: lights and shadows. Tremor Other Hyperkinet Mov. 2014;4:254. doi:10.7916/D8SF2T9C. eCollection 2014.

    Google Scholar 

  60. Louis ED, Kuo SH, Vonsattel JP, Faust PL. Torpedo formation and Purkinje cell loss: modeling their relationship in cerebellar disease. Cerebellum. 2014;13:433–9.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Louis RJ, Lee M, Kuo SH, Vonsattel JP, Louis ED, Faust PL. Cellular density in the cerebellar molecular layer in essential tremor, spinocerebellar ataxia, and controls. Parkinsonism Relat Disord. 2014;20:1270–3.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Louis ED. Essential tremors: a family of neurodegenerative disorders? Arch Neurol. 2009;66:1202–8.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Louis ED. ‘Essential tremor’ or ‘the essential tremors’: is this one disease or a family of diseases? Neuroepidemiology. 2014;42:81–9.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Deuschl G, Elble R. Essential tremor—neurodegenerative or nondegenerative disease towards a working definition of ET. Mov Disord. 2009;24:2033–41.

    Article  PubMed  Google Scholar 

  65. Louis ED, Vonsattel JP, Honig LS, Lawton A, Moskowitz C, Ford B, et al. Essential tremor associated with pathologic changes in the cerebellum. Arch Neurol. 2006;63:1189–93.

    Article  PubMed  Google Scholar 

  66. Louis ED, Mazzoni P, Ma KJ, Moskowitz CB, Lawton A, Garber A, et al. Essential tremor with ubiquitinated intranuclear inclusions and cerebellar degeneration. Clin Neuropathol. 2012;31:119–26.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Elble RJ. Animal models of action tremor. Mov Disord. 1998;13 Suppl 3:35–9.

    PubMed  Google Scholar 

  68. Testa CM. Key issues in essential tremor genetics research: where are we now and how can we move forward? Tremor Other Hyperkinet Mov (N Y) 2013;3. pii: tre-03-105-1843-1.

  69. Tan EK, Schapira AH. Hunting for genes in essential tremor. Eur J Neurol. 2008;15:889–90.

    Article  CAS  PubMed  Google Scholar 

  70. Paris-Robidas S, Brochu E, Sintes M, Emond V, Bousquet M, Vandal M, et al. Defective dentate nucleus GABA receptors in essential tremor. Brain. 2012;135:105–16.

    Article  PubMed  Google Scholar 

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Acknowledgments

Dr. Louis has received research support from the National Institutes of Health: NINDS #R01 NS042859 (principal investigator), NINDS #R01 NS39422 (principal investigator), NINDS #R01 NS086736 (principal investigator), NINDS #R01 NS073872 (principal investigator), NINDS #R01 NS085136 (principal investigator), and NINDS #R01 NS088257 (principal investigator). He has also received support from the Claire O’Neil Essential Tremor Research Fund (Yale University). The author declares that there are no additional disclosures to report.

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There are no conflicts of interest or competing financial interests.

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Authors and Affiliations

  1. Division of Movement Disorders, Department of Neurology, Yale School of Medicine, Yale University, LCI 710, 15 York Street, PO Box 208018, New Haven, CT, 06520-8018, USA

    Elan D. Louis

  2. Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, USA

    Elan D. Louis

  3. Center for Neuroepidemiology and Clinical Neurological Research, Yale School of Medicine, Yale University, New Haven, CT, USA

    Elan D. Louis

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Louis, E.D. Linking Essential Tremor to the Cerebellum: Neuropathological Evidence. Cerebellum 15, 235–242 (2016). https://doi.org/10.1007/s12311-015-0692-6

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  • DOI: https://doi.org/10.1007/s12311-015-0692-6

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