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Matching Asymmetry of Tremor with Asymmetry of Postmortem Cerebellar Hemispheric Changes in Essential Tremor

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Abstract

Although the number of postmortem studies in essential tremor (ET) has grown in recent years, clinical-pathological correlations remain limited. We are unaware of a study that has assessed whether the pathological changes in ET, if asymmetric, lateralize to the cerebellar hemisphere that is ipsilateral to the arm with more severe action tremor, as one would predict if the lesions were tremor producing. We compared postmortem changes in the right vs. left cerebellar hemispheres in ET and examined how these correlated with asymmetry of tremor on neurological examination. Action tremor in each arm was quantified using a reliable and valid clinical rating scale. Cases were divided into three clinical groups: tremor more severe on right, tremor more severe on left, and tremor symmetric. Calbindin D28k immunohistochemistry was performed on 100 μm vibrotome sections from a standard tissue block of both right and left neocerebellums to quantify Purkinje cell linear density, torpedo counts, and a group of previously described changes in Purkinje cell axonal shape (thickened axonal profiles) and connectivity (axon recurrent collaterals, axonal branching, terminal axonal sprouting, arciform axons, extent of recurrent collateral plexus). ET cases were divided into three postmortem groups: findings greatest on right, findings greatest on left, and findings symmetric. In 18 (72.0 %) of 25 ET cases, clinical and pathological features were concordant (i.e., both clinically and pathologically right-predominant (one case), both clinically and pathologically left-predominant (five cases), or both clinically and pathologically symmetric (12 cases), p = 0.007). In the remaining seven (28.0 %) ET cases, clinical and pathological data were not concordant, and in none were they completely discordant (i.e., tremor was more severe on the right, and postmortem cerebellar changes were paradoxically more severe on the left or vice versa). Among the seven ET cases with >20 % side-to-side difference in tremor severity, six cases (85.7 %) had the expected pathological asymmetry, with quantified postmortem cerebellar changes more marked ipsilateral to the more clinically affected side. We also created continuous measures of asymmetry. For the entire sample, there was a positive correlation between the clinical asymmetry index and the pathological asymmetry index = 0.52, p = 0.01 (i.e., the right-left difference in clinical asymmetry was correlated with the right-left difference in postmortem changes). For the seven ET cases with clear clinical asymmetry, the correlation was even more robust (r = 0.78, p = 0.039). Clinical-pathological correlations are important in terms of understanding the significance of observed pathological changes. The correlation between clinical laterality or symmetry of tremor and pathological changes in the majority of ET cases provides additional evidence that the pathological changes in the cerebellum in ET are of patho-mechanistic importance.

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References

  1. Louis ED. Re-thinking the biology of essential tremor: from models to morphology. Parkinsonism Relat Disord. 2014;20 Suppl 1:S88–93.

    Article  PubMed  Google Scholar 

  2. Louis ED. Essential tremor: evolving clinicopathological concepts in an era of intensive postmortem inquiry. Lancet Neurol. 2010;9:613–22.

    Article  PubMed  Google Scholar 

  3. 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(8):1003–4.

    Article  PubMed  Google Scholar 

  4. 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(Pt 12):3297–307.

    Article  PubMed  Google Scholar 

  5. 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(5):626–8.

    Article  CAS  PubMed  Google Scholar 

  6. Axelrad JE, Louis ED, Honig LS, et al. Reduced Purkinje cell number in essential tremor: a postmortem study. Arch Neurol. 2008;65(1):101–7.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Louis ED, Babij R, Lee M, Cortés E, Vonsattel JP. Quantification of cerebellar hemispheric purkinje cell linear density: 32 ET cases versus 16 controls. Mov Disord. 2013;28(13):1854–9.

    Article  PubMed  Google Scholar 

  8. Babij R, Lee M, Cortés E, Vonsattel JP, Faust PL, Louis ED. Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain. 2013;136(Pt 10):3051–61.

    Article  PubMed  Google Scholar 

  9. Yu M, Ma K, Faust PL, et al. Increased number of Purkinje cell dendritic swellings in essential tremor. Eur J Neurol. 2012;19(4):625–30.

    Article  CAS  PubMed Central  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(3):262–71.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Kuo SH, Tang G, Louis ED, et al. Lingo-1 expression is increased in essential tremor cerebellum and is present in the basket cell pinceau. Acta Neuropathol. 2013;125(6):879–89.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Paris-Robidas S, Brochu E, Sintes M, et al. Defective dentate nucleus GABA receptors in essential tremor. Brain. 2012;135(Pt 1):105–16.

    Article  PubMed  Google Scholar 

  13. Louis ED, Ford B, Bismuth B. Reliability between two observers using a protocol for diagnosing essential tremor. Mov Disord. 1998;13(2):287–93.

    Article  CAS  PubMed  Google Scholar 

  14. Louis ED, Pullman SL. Comparison of clinical vs. electrophysiological methods of diagnosing of essential tremor. Mov Disord. 2001;16(4):668–73.

    Article  CAS  PubMed  Google Scholar 

  15. Louis ED, Agnew A, Gillman A, Gerbin M, Viner AS. Estimating annual rate of decline: prospective, longitudinal data on arm tremor severity in two groups of essential tremor cases. J Neurol Neurosurg Psychiatry. 2011;82(7):761–5.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Fahn S, Elton R. Members of the UPDRS Development Committee. In: Fahn SMC, Goldtein M, Calne DB, editors. Recent developments in Parkinson's disease. Florham Park, NJ: Macmillan Health Care Information; 1987. p. 153–63.

    Google Scholar 

  17. Louis ED, Ottman R, Ford B, et al. The Washington Heights-Inwood Genetic Study of Essential Tremor: methodologic issues in essential-tremor research. Neuroepidemiology. 1997;16(3):124–33.

    Article  CAS  PubMed  Google Scholar 

  18. Harasymiw JW, Bean P. Identification of heavy drinkers by using the early detection of alcohol consumption score. Alcohol Clin Exp Res. 2001;25(2):228–35.

    Article  CAS  PubMed  Google Scholar 

  19. Vonsattel JP, Amaya MD, Cortés EP, Mancevska K, Keller CE. Twenty-first century brain banking: practical prerequisites and lessons from the past: the experience of New York Brain Bank, Taub Institute. C Univ Cell Tissue Bank. 2008;9(3):247–58.

    Article  CAS  Google Scholar 

  20. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006;112(4):389–404.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24(2):197–211.

    Article  PubMed  Google Scholar 

  22. Mirra SS. The CERAD neuropathology protocol and consensus recommendations for the postmortem diagnosis of Alzheimer's disease: a commentary. Neurobiol Aging. 1997;18(4 Suppl):S91–4.

    Article  CAS  PubMed  Google Scholar 

  23. Louis ED, Wendt KJ, Pullman SL, Ford B. Is essential tremor symmetric? Observational data from a community-based study of essential tremor. Arch Neurol. 1998;55(12):1553–9.

    Article  CAS  PubMed  Google Scholar 

  24. Bares M, Lungu OV, Husárová I, et al. Predictive motor timing performance dissociates between early diseases of the cerebellum and Parkinson's disease. Cerebellum. 2010;9(1):124–35.

    Article  PubMed  Google Scholar 

  25. Bares M, Husarova I, Lungu OV. Essential tremor, the cerebellum, and motor timing: towards integrating them into one complex entity. Tremor Other Hyperkinet Mov (N Y) 2012;2(pii):tre-02-93-653-1.

  26. Quattrone A, Cerasa A, Messina D, et al. Essential head tremor is associated with cerebellar vermis atrophy: a volumetric and voxel-based morphometry MR imaging study. AJNR. 2008;29(9):1692–7.

    Article  CAS  PubMed  Google Scholar 

  27. Louis ED. From neurons to neuron neighborhoods: the rewiring of the cerebellar cortex in essential tremor. Cerebellum 2014.

  28. Kempster PA, Gibb WR, Stern GM, Lees AJ. Asymmetry of substantia nigra neuronal loss in Parkinson’s disease and its relevance to the mechanism of levodopa related motor fluctuations. J Neurol Neurosurg Psychiatry. 1989;52(1):72–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Phibbs F, Fang JY, Cooper MK, Charles DP, Davis TL, Hedera P. Prevalence of unilateral tremor in autosomal dominant essential tremor. Mov Disord. 2009;24(1):108–11.

    Article  PubMed  Google Scholar 

  30. Symanski C, Shill HA, Dugger B. Essential tremor is not associated with cerebellar Purkinje cell loss. Mov Disord. 2014;29(4):496–500.

    Article  PubMed  Google Scholar 

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Acknowledgments

Dr. Vonsattel has received funding from the NINDS #R01 NS39422 (co-investigator), Dr. Faust has received funding from the NINDS #R21 NS077094 (principle investigator) and NINDS #R01 NS39422 (co-investigator), Dr. Louis has received research support from the National Institutes of Health: NINDS #R01 NS042859 (principal investigator), NINDS #R01 NS39422 (principal investigator), NINDS #R01 NS085136 (principal investigator), NINDS #T32 NS07153-24 (principal investigator), NINDS #R01 NS073872 (principal investigator), NINDS #R21 NS077094 (co-investigator), NINDS #R01 NS36630 (co-investigator), NIEHS P30 ES09089 (co-investigator), and CTSA grant number UL1 RR024156. He has also received support from the Parkinson’s Disease Foundation, the Arlene Bronstein Essential Tremor Research Fund (Columbia University), and the Claire O’Neil Essential Tremor Research Fund (Columbia University).

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There are no conflicts of interest or competing financial interests.

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Correspondence to Elan D. Louis.

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Louis, E.D., Lee, M., Cortés, E. et al. Matching Asymmetry of Tremor with Asymmetry of Postmortem Cerebellar Hemispheric Changes in Essential Tremor. Cerebellum 13, 462–470 (2014). https://doi.org/10.1007/s12311-014-0560-9

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