title: Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases.
abstract: Changes in climbing fiber-Purkinje cell (CF-PC) synaptic connections have been found in the essential tremor (ET) cerebellum, and these changes are correlated with tremor severity. Whether these postmortem changes are specific to ET remains to be investigated. We assessed CF-PC synaptic pathology in the postmortem cerebellum across a range of degenerative movement disorders [10 Parkinson's disease (PD) cases, 10 multiple system atrophy (MSA) cases, 10 spinocerebellar ataxia type 1 (SCA1) cases, and 20 ET cases] and 25 controls. We observed differences in terms of CF pathological features across these disorders. Specifically, PD cases and ET cases both had more CFs extending into the parallel fiber (PF) territory, but ET cases had more complex branching and increased length of CFs in the PF territory along with decreased CF synaptic density compared to PD cases. MSA cases and SCA1 cases had the most severely reduced CF synaptic density and a marked paucity of CFs extending into the PF territory. Furthermore, CFs in a subset of MSA cases formed collateral branches parallel to the PC layer, a feature not seen in other diagnostic groups. Using unsupervised cluster analysis, the cases and controls could all be categorized into four clusters based on the CF pathology and features of PC pathology, including counts of PCs and their axonal torpedoes. ET cases and PD cases co-segregated into two clusters, whereas SCA1 cases and MSA cases formed another cluster, separate from the control cluster. Interestingly, the presence of resting tremor seemed to be the clinical feature that separated the cases into the two ET-PD clusters. In conclusion, our study demonstrates that these degenerative movement disorders seem to differ with respect to the pattern of CF synaptic pathology they exhibit. It remains to be determined how these differences contribute to the clinical presentations of these diseases.
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, 650 West 168th Street, Room 305, New York, NY, 10032, USA. sk3295@columbia.edu.
authors.forename: Sheng-Han
authors.initials: SH
authors.lastname: Kuo
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, 650 West 168th Street, Room 305, New York, NY, 10032, USA.|Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Chi-Ying
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, 650 West 168th Street, Room 305, New York, NY, 10032, USA.|Department of Basic and Community Nursing, School of Nursing, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Departments of System Biology and Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sims
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, 650 West 168th Street, Room 305, New York, NY, 10032, USA.|Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ming-Kai
authors.initials: MK
authors.lastname: Pan
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, 10032, USA.
authors.forename: Jyun-You
authors.initials: JY
authors.lastname: Liou
authors.affiliation: Department of Neurology, College of Physicians and Surgeons, Columbia University, 650 West 168th Street, Room 305, New York, NY, 10032, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Tate
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Kelly
authors.affiliation: Department of Neurology, Yale School of Medicine, Yale University, New Haven, CT, USA.|Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT, USA.
authors.forename: Elan D
authors.initials: ED
authors.lastname: Louis
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Phyllis L
authors.initials: PL
authors.lastname: Faust
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D020329:Essential Tremor / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D009847:Olivary Nucleus / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology*; D012720:Severity of Illness Index; D020754:Spinocerebellar Ataxias / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D013569:Synapses / Q000378:metabolism / Q000473:pathology*; D014202:Tremor / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D000069558:Unsupervised Machine Learning; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: C493476:SLC17A6 protein, human; D050599:Vesicular Glutamate Transport Protein 2
keywords: Climbing fiber; Essential tremor; Multiple system atrophy; Parkinson’s disease; Purkinje cell; Spinocerebellar ataxia