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Histopathology of the cerebellar cortex in essential tremor and other neurodegenerative motor disorders: comparative analysis of 320 brains

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Abstract

In recent years, numerous morphologic changes have been identified in the essential tremor (ET) cerebellar cortex, distinguishing ET from control brains. These findings have not been fully contextualized within a broader degenerative disease spectrum, thus limiting their interpretability. Building off our prior study and now doubling the sample size, we conducted comparative analyses in a postmortem series of 320 brains on the severity and patterning of cerebellar cortex degenerative changes in ET (n = 100), other neurodegenerative disorders of the cerebellum [spinocerebellar ataxias (SCAs, n = 47, including 13 SCA3 and 34 SCA1, 2, 6, 7, 8, 14); Friedreich’s ataxia (FA, n = 13); multiple system atrophy (MSA), n = 29], and other disorders that may involve the cerebellum [Parkinson’s disease (PD), n = 62; dystonia, n = 19] versus controls (n = 50). We generated data on 37 quantitative morphologic metrics, grouped into 8 broad categories: Purkinje cell (PC) loss, heterotopic PCs, PC dendritic changes, PC axonal changes (torpedoes), PC axonal changes (other than torpedoes), PC axonal changes (torpedo-associated), basket cell axonal hypertrophy, and climbing fiber-PC synaptic changes. Principal component analysis of z scored raw data across all diagnoses (11,651 data items) revealed that diagnostic groups were not uniform with respect to pathology. Dystonia and PD each differed from controls in only 4/37 and 5/37 metrics, respectively, whereas ET differed in 21, FA in 10, SCA3 in 10, MSA in 21, and SCA1/2/6/7/8/14 in 27. Pathological changes were generally on the milder end of the degenerative spectrum in ET, FA and SCA3, and on the more severe end of that spectrum in SCA1/2/6/7/8/14. Comparative analyses across morphologic categories demonstrated differences in relative expression, defining distinctive patterns of changes in these groups. In summary, we present a robust and reproducible method that identifies somewhat distinctive signatures of degenerative changes in the cerebellar cortex that mark each of these disorders.

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References

  1. Babij R, Lee M, Cortes E, Vonsattel JP, Faust PL, Louis ED (2013) Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain 136:3051–3061. https://doi.org/10.1093/brain/awt238

    Article  PubMed  PubMed Central  Google Scholar 

  2. Beliveau E, Tremblay C, Aubry-Lafontaine E, Paris-Robidas S, Delay C, Robinson C et al (2015) Accumulation of amyloid-beta in the cerebellar cortex of essential tremor patients. Neurobiol Dis 82:397–408. https://doi.org/10.1016/j.nbd.2015.07.016

    Article  CAS  PubMed  Google Scholar 

  3. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404. https://doi.org/10.1007/s00401-006-0127-z

    Article  PubMed  PubMed Central  Google Scholar 

  4. Braak H, Braak E (1997) Diagnostic criteria for neuropathologic assessment of Alzheimer’s disease. Neurobiol Aging 18:S85-88

    Article  CAS  PubMed  Google Scholar 

  5. Choe M, Cortes E, Vonsattel JG, Kuo SH, Faust PL, Louis ED (2016) Purkinje cell loss in essential tremor: random sampling quantification and nearest neighbor analysis. Mov Disord 31:393–401. https://doi.org/10.1002/mds.26490

    Article  PubMed  PubMed Central  Google Scholar 

  6. Delay C, Tremblay C, Brochu E, Paris-Robidas S, Emond V, Rajput AH et al (2014) Increased LINGO1 in the cerebellum of essential tremor patients. Mov Disord 29:1637–1647. https://doi.org/10.1002/mds.25819

    Article  CAS  PubMed  Google Scholar 

  7. Erickson-Davis CR, Faust PL, Vonsattel JP, Gupta S, Honig LS, Louis ED (2010) “Hairy baskets” associated with degenerative Purkinje cell changes in essential tremor. J Neuropathol Exp Neurol 69:262–271. https://doi.org/10.1097/NEN.0b013e3181d1ad04

    Article  PubMed  Google Scholar 

  8. Fujishima K, Kurisu J, Yamada M, Kengaku M (2020) βIII spectrin controls the planarity of Purkinje cell dendrites by modulating perpendicular axon-dendrite interactions. Development 147:dev194530. https://doi.org/10.1242/dev.194530

    Article  CAS  PubMed  Google Scholar 

  9. Harasymiw JW, Bean P (2001) Identification of heavy drinkers by using the early detection of alcohol consumption score. Alcohol Clin Exp Res 25:228–235. https://doi.org/10.1111/j.1530-0277.2001.tb02203.x

    Article  CAS  PubMed  Google Scholar 

  10. Hirano A, Llena JF, French JH, Ghatak NR (1977) Fine structure of the cerebellar cortex in Menkes Kinky-hair disease. X-chromosome-linked copper malabsorption. Arch Neurol 34:52–56. https://doi.org/10.1001/archneur.1977.00500130072014

    Article  CAS  PubMed  Google Scholar 

  11. Ito H, Kawakami H, Wate R, Matsumoto S, Imai T, Hirano A et al (2006) Clinicopathologic investigation of a family with expanded SCA8 CTA/CTG repeats. Neurology 67:1479–1481. https://doi.org/10.1212/01.wnl.0000240256.13633.7b

    Article  CAS  PubMed  Google Scholar 

  12. Iwabuchi K, Koyano S, Yagishita S (2022) Simple and clear differentiation of spinocerebellar degenerations: overview of macroscopic and low-power view findings. Neuropathology 42:379–393. https://doi.org/10.1111/neup.12823

    Article  CAS  PubMed  Google Scholar 

  13. Koeppen AH (2018) The neuropathology of the adult cerebellum. Handb Clin Neurol 154:129–149. https://doi.org/10.1016/B978-0-444-63956-1.00008-4

    Article  PubMed  PubMed Central  Google Scholar 

  14. Koeppen AH (1991) The Purkinje cell and its afferents in human hereditary ataxia. J Neuropathol Exp Neurol 50:505–514. https://doi.org/10.1097/00005072-199107000-00010

    Article  CAS  PubMed  Google Scholar 

  15. Koeppen AH, Davis AN, Morral JA (2011) The cerebellar component of Friedreich’s ataxia. Acta Neuropathol 122:323–330. https://doi.org/10.1007/s00401-011-0844-9

    Article  PubMed  PubMed Central  Google Scholar 

  16. Koeppen AH, Mazurkiewicz JE (2013) Friedreich ataxia: neuropathology revised. J Neuropathol Exp Neurol 72:78–90. https://doi.org/10.1097/NEN.0b013e31827e5762

    Article  CAS  PubMed  Google Scholar 

  17. Kuo SH, Lin CY, Wang J, Sims PA, Pan MK, Liou JY et al (2017) Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases. Acta Neuropathol 133:121–138. https://doi.org/10.1007/s00401-016-1626-1

    Article  PubMed  Google Scholar 

  18. Kuo SH, Tang G, Louis ED, Ma K, Babji R, Balatbat M et al (2013) Lingo-1 expression is increased in essential tremor cerebellum and is present in the basket cell pinceau. Acta Neuropathol 125:879–889. https://doi.org/10.1007/s00401-013-1108-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lee PJ, Kerridge CA, Chatterjee D, Koeppen AH, Faust PL, Louis ED (2019) A quantitative study of empty baskets in essential tremor and other motor neurodegenerative diseases. J Neuropathol Exp Neurol 78:113–122. https://doi.org/10.1093/jnen/nly114

    Article  CAS  PubMed  Google Scholar 

  20. Lin CY, Louis ED, Faust PL, Koeppen AH, Vonsattel JP, Kuo SH (2014) Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain 137:3149–3159. https://doi.org/10.1093/brain/awu281

    Article  PubMed  PubMed Central  Google Scholar 

  21. Louis ED, Babij R, Cortes E, Vonsattel JP, Faust PL (2013) The inferior olivary nucleus: a postmortem study of essential tremor cases versus controls. Mov Disord 28:779–786. https://doi.org/10.1002/mds.25400

    Article  PubMed  PubMed Central  Google Scholar 

  22. Louis ED, Babij R, Lee M, Cortes E, Vonsattel JP (2013) Quantification of cerebellar hemispheric purkinje cell linear density: 32 ET cases versus 16 controls. Mov Disord 28:1854–1859. https://doi.org/10.1002/mds.25629

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Louis ED, Faust PL, Vonsattel JP, Honig LS, Rajput A, Pahwa R et al (2009) Torpedoes in Parkinson’s disease, Alzheimer’s disease, essential tremor, and control brains. Mov Disord 24:1600–1605. https://doi.org/10.1002/mds.22567

    Article  PubMed  PubMed Central  Google Scholar 

  25. Louis ED, Ford B, Bismuth B (1998) Reliability between two observers using a protocol for diagnosing essential tremor. Mov Disord 13:287–293. https://doi.org/10.1002/mds.870130215

    Article  CAS  PubMed  Google Scholar 

  26. Louis ED, Kerridge CA, Chatterjee D, Martuscello RT, Diaz DT, Koeppen AH et al (2019) Contextualizing the pathology in the essential tremor cerebellar cortex: a patholog-omics approach. Acta Neuropathol 138:859–876. https://doi.org/10.1007/s00401-019-02043-7

    Article  PubMed  PubMed Central  Google Scholar 

  27. Louis ED, Kuo SH, Tate WJ, Kelly GC, Gutierrez J, Cortes EP et al (2018) Heterotopic Purkinje cells: a comparative postmortem study of essential tremor and spinocerebellar ataxias 1, 2, 3, and 6. Cerebellum 17:104–110. https://doi.org/10.1007/s12311-017-0876-3

    Article  PubMed  PubMed Central  Google Scholar 

  28. Louis ED, Kuo SH, Vonsattel JP, Faust PL (2014) Torpedo formation and Purkinje cell loss: modeling their relationship in cerebellar disease. Cerebellum 13:433–439. https://doi.org/10.1007/s12311-014-0556-5

    Article  PubMed  PubMed Central  Google Scholar 

  29. Louis ED, Lee M, Babij R, Ma K, Cortes E, Vonsattel JP et al (2014) Reduced Purkinje cell dendritic arborization and loss of dendritic spines in essential tremor. Brain 137:3142–3148. https://doi.org/10.1093/brain/awu314

    Article  PubMed  PubMed Central  Google Scholar 

  30. Louis ED, McCreary M (2021) How common is essential tremor? Update on the worldwide prevalence of essential tremor. Tremor Other Hyperkinet Mov (NY) 11:28. https://doi.org/10.5334/tohm.632

    Article  Google Scholar 

  31. Louis ED, Ottman R (2014) How many people in the USA have essential tremor? Deriving a population estimate based on epidemiological data. Tremor Other Hyperkinet Mov (NY) 4:259. https://doi.org/10.7916/D8TT4P4B

    Article  Google Scholar 

  32. Louis ED, Ottman R, Ford B, Pullman S, Martinez M, Fahn S et al (1997) The Washington heights-inwood genetic study of essential tremor: methodologic issues in essential-tremor research. Neuroepidemiology 16:124–133. https://doi.org/10.1159/000109681

    Article  CAS  PubMed  Google Scholar 

  33. Louis ED, Vonsattel JP, Honig LS, Ross GW, Lyons KE, Pahwa R (2006) Neuropathologic findings in essential tremor. Neurology 66:1756–1759. https://doi.org/10.1212/01.wnl.0000218162.80315.b9

    Article  CAS  PubMed  Google Scholar 

  34. Louis ED, Wendt KJ, Albert SM, Pullman SL, Yu Q, Andrews H (1999) Validity of a performance-based test of function in essential tremor. Arch Neurol 56:841–846. https://doi.org/10.1001/archneur.56.7.841

    Article  CAS  PubMed  Google Scholar 

  35. Louis ED, Zheng W, Mao X, Shungu DC (2007) Blood harmane is correlated with cerebellar metabolism in essential tremor: a pilot study. Neurology 69:515–520. https://doi.org/10.1212/01.wnl.0000266663.27398.9f

    Article  PubMed  Google Scholar 

  36. Mavroudis I, Kazis D, Petridis F, Chatzikonstantinou S, Karantali E, Njau SN et al (2022) Morphological and morphometric changes in the Purkinje cells of patients with essential tremor. Exp Ther Med 23:167. https://doi.org/10.3892/etm.2021.11090

    Article  PubMed  Google Scholar 

  37. McKay BE, Turner RW (2005) Physiological and morphological development of the rat cerebellar Purkinje cell. J Physiol 567:829–850. https://doi.org/10.1113/jphysiol.2005.089383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mirra SS (1997) The CERAD neuropathology protocol and consensus recommendations for the postmortem diagnosis of Alzheimer’s disease: a commentary. Neurobiol Aging 18:S91-94. https://doi.org/10.1016/S0197-4580(97)00058-4

    Article  CAS  PubMed  Google Scholar 

  39. Paris-Robidas S, Brochu E, Sintes M, Emond V, Bousquet M, Vandal M et al (2012) Defective dentate nucleus GABA receptors in essential tremor. Brain 135:105–116. https://doi.org/10.1093/brain/awr301

    Article  PubMed  Google Scholar 

  40. Poewe W, Stankovic I, Halliday G, Meissner WG, Wenning GK, Pellecchia MT et al (2022) Multiple system atrophy. Nat Rev Dis Primers 8:56. https://doi.org/10.1038/s41572-022-00382-6

    Article  PubMed  Google Scholar 

  41. Sakai K, Ishida C, Morinaga A, Takahashi K, Yamada M (2015) Case study: somatic sprouts and halo-like amorphous materials of the purkinje cells in Huntington’s disease. Cerebellum 14:707–710. https://doi.org/10.1007/s12311-015-0678-4

    Article  CAS  PubMed  Google Scholar 

  42. Seidel K, Siswanto S, Brunt ER, den Dunnen W, Korf HW, Rub U (2012) Brain pathology of spinocerebellar ataxias. Acta Neuropathol 124:1–21. https://doi.org/10.1007/s00401-012-1000-x

    Article  CAS  PubMed  Google Scholar 

  43. Tanabe K, Kani S, Shimizu T, Bae YK, Abe T, Hibi M (2010) Atypical protein kinase C regulates primary dendrite specification of cerebellar Purkinje cells by localizing Golgi apparatus. J Neurosci 30:16983–16992. https://doi.org/10.1523/JNEUROSCI.3352-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang Q, Hashizume Y, Yoshida M, Wang Y, Goto Y, Mitsuma N et al (2000) Morphological Purkinje cell changes in spinocerebellar ataxia type 6. Acta Neuropathol 100:371–376. https://doi.org/10.1007/s004010000201

    Article  CAS  PubMed  Google Scholar 

  45. Yoshida K, Asakawa M, Suzuki-Kouyama E, Tabata K, Shintaku M, Ikeda S et al (2014) Distinctive features of degenerating Purkinje cells in spinocerebellar ataxia type 31. Neuropathology 34:261–267. https://doi.org/10.1111/neup.12090

    Article  CAS  PubMed  Google Scholar 

  46. Yu M, Ma K, Faust PL, Honig LS, Cortes E, Vonsattel JP et al (2012) Increased number of Purkinje cell dendritic swellings in essential tremor. Eur J Neurol 19:625–630. https://doi.org/10.1111/j.1468-1331.2011.03598.x

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Brain tissue was derived from: New York Brain Bank at Columbia University; Dr. Arnulf H. Koeppen, Veterans Affairs Medical Center, Albany, New York, USA; the National Institutes of Health NeuroBioBank (University of Maryland, Baltimore, MD, University of Miami, Miami, FL, and Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, MA); Dr. Laura Ranum, Center for NeuroGenetics Ataxia Brain Bank at the University of Florida, Gainesville FL; Dr. Todd Goldie, University of Florida Neuromedicine Human Brain and Tissue Bank, Gainesville FL; Dr. C. Dirk Keene, University of Washington, Seattle WA; and The Sheffield Biorepository at the University of Sheffield, Sheffield UK. We would like to thank all the patients and families that contributed to brain donation and the National Ataxia Foundation for providing funding to investigators for banking of brains from individuals with ataxia.

Funding

This work was supported by NINDS R01 NS088257 and NINDS R01 NS117745 (Drs. Louis and Faust, PIs) and R01 NS086736 (Dr. Louis, PI), which provide funding for the Essential Tremor Centralized Brain Repository.

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Authors and Affiliations

  1. Department of Neurology, University of Texas Southwestern, 5323 Harry Hines Blvd, Dallas, TX, 75390-8813, USA

    Elan D. Louis & Morgan McCreary

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

    Regina T. Martuscello, John T. Gionco, Whitney G. Hartstone, Jessica B. Musacchio, Marisa Portenti, Jean-Paul G. Vonsattel & Phyllis L. Faust

  3. Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Sheng-Han Kuo

  4. Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA

    Jean-Paul G. Vonsattel

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  1. Elan D. Louis
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  10. Phyllis L. Faust
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by EDL, RTM, JTG, WGH, JBM, MP, MM, S-HK, J-PGV, and PLF. The first draft of the manuscript was written by EDL and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Elan D. Louis.

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Louis, E.D., Martuscello, R.T., Gionco, J.T. et al. Histopathology of the cerebellar cortex in essential tremor and other neurodegenerative motor disorders: comparative analysis of 320 brains. Acta Neuropathol 145, 265–283 (2023). https://doi.org/10.1007/s00401-022-02535-z

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