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Contextualizing the pathology in the essential tremor cerebellar cortex: a patholog-omics approach

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Abstract

Several morphological changes, centered in/around Purkinje cells (PCs), have been identified in the cerebellum of essential tremor (ET) patients. These changes have not been contextualized within a broader degenerative disease spectrum, limiting their interpretability. To address this, we compared the severity and patterning of degenerative changes within the cerebellar cortex in patients with ET, other neurodegenerative disorders of the cerebellum (spinocerebellar ataxias (SCAs), multiple system atrophy (MSA)], and other disorders that may involve the cerebellum [Parkinson’s disease (PD), dystonia]. Using a postmortem series of 156 brains [50 ET, 23 SCA (6 SCA3; 17 SCA 1, 2 or 6), 15 MSA, 29 PD, 14 dystonia, 25 controls], we generated data on 37 quantitative morphologic metrics, which were grouped into 8 broad categories: (1) PC loss, (2) heterotopic PCs, (3) PC dendritic changes, (4) PC axonal changes (torpedoes), (5) PC axonal changes (other than torpedoes), (6) PC axonal changes (torpedo-associated), (7) basket cell axonal hypertrophy, (8) climbing fiber-PC synaptic changes. Our analyses used z scored raw data for each metric across all diagnoses (5772 total data items). Principal component analysis revealed that diagnostic groups were not uniform with respect to cerebellar pathology. Dystonia and PD each differed from controls in only 2/37 metrics, whereas ET differed in 21, SCA3 in 8, MSA in 19, and SCA1/2/6 in 26 metrics. Comparing ET with primary disorders of cerebellar degeneration (i.e., SCAs), we observed a spectrum of changes reflecting differences of degree, being generally mild in ET and SCA3 and more severe in SCA1/2/6. Comparative analyses across morphologic categories demonstrated differences in relative expression, defining distinctive patterns of changes in these groups. Thus, the degree of cerebellar degeneration in ET aligns it with a milder end in the spectrum of cerebellar degenerative disorders, and a somewhat distinctive signature of degenerative changes marks each of these disorders.

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Acknowledgements

Brain tissue was derived from New York Brain Bank, Dr. Arnulf H. Koeppen, Veterans Affairs Medical Center, Albany, New York, USA, and the National Institutes of Health NeuroBioBank (University of Maryland Brain and Tissue Bank, Baltimore, MD, USA, University of Miami Brain Endowment Bank, Miami, FL, USA and Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, MA, USA). We would like to thank all the patients and families that contributed to brain donation. This work was supported by NINDS R01 NS088257 (Drs. Louis and Faust, PIs), which provides funding for the Essential Tremor Centralized Brain Repository. We obtained 15 MSA brains [6 from the New York Brain Bank and 9 from the National Institutes of Health NeuroBioBank (3 from University of Miami, Miami, FL, USA, 4 from University of Maryland, Baltimore, MD, USA, and 2 from the Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, MA, USA)] and 14 dystonia brains [2 from the New York Brain Bank and 12 from the National Institutes of Health NeuroBioBank (4 from University of Maryland, and 8 from the Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, MA, USA)].

Funding

This work was supported by NIH R01 NS088257.

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Authors and Affiliations

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

    Elan D. Louis & Daniel Trujillo Diaz

  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

  4. Department of Pathology and Cell Biology, Columbia University Irving Medical Center and the New York Presbyterian Hospital, 622 West 168th Street, PH Stem 1564, New York, NY, 10032, USA

    Chloë A. Kerridge, Debotri Chatterjee, Regina T. Martuscello, Jean-Paul G. Vonsattel & Phyllis L. Faust

  5. Research, Neurology, and Pathology Services, Veterans Affairs Medical Center and Departments of Neurology and Pathology, Albany Medical College, Albany, NY, USA

    Arnulf H. Koeppen

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

    Sheng-Han Kuo

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

    Jean-Paul G. Vonsattel

  8. Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA

    Peter A. Sims

  9. Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, NY, USA

    Peter A. Sims

  10. Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA

    Peter A. Sims

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  1. Elan D. Louis
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  2. Chloë A. Kerridge
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  3. Debotri Chatterjee
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  4. Regina T. Martuscello
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  7. Sheng-Han Kuo
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  8. Jean-Paul G. Vonsattel
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Correspondence to Elan D. Louis or Phyllis L. Faust.

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Louis, E.D., Kerridge, C.A., Chatterjee, D. et al. Contextualizing the pathology in the essential tremor cerebellar cortex: a patholog-omics approach. Acta Neuropathol 138, 859–876 (2019). https://doi.org/10.1007/s00401-019-02043-7

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