TY - JOUR
T1 - Contextualizing the pathology in the essential tremor cerebellar cortex
T2 - a patholog-omics approach
AU - Louis, Elan D.
AU - Kerridge, Chloë A.
AU - Chatterjee, Debotri
AU - Martuscello, Regina T.
AU - Diaz, Daniel Trujillo
AU - Koeppen, Arnulf H.
AU - Kuo, Sheng Han
AU - Vonsattel, Jean Paul G.
AU - Sims, Peter A.
AU - Faust, Phyllis L.
N1 - Funding Information:
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 Information:
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 Information:
This work was supported by NIH R01 NS088257.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
KW - Cerebellum
KW - Dystonia
KW - Essential tremor
KW - Parkinson’s disease
KW - Spinocerebellar ataxia
UR - http://www.scopus.com/inward/record.url?scp=85069001526&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069001526&partnerID=8YFLogxK
U2 - 10.1007/s00401-019-02043-7
DO - 10.1007/s00401-019-02043-7
M3 - Article
C2 - 31317229
AN - SCOPUS:85069001526
VL - 138
SP - 859
EP - 876
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 5
ER -