title: Progression of alpha-synuclein pathology in multiple system atrophy of the cerebellar type.
abstract: OBJECTIVE
  The aim of this study was to identify early foci of α-synuclein (α-syn pathology) accumulation, subsequent progression and neurodegeneration in multiple system atrophy of the cerebellar type (MSA-C).
  
  
  METHODS
  We analysed 70-μm-thick sections of 10 cases with MSA-C and 24 normal controls.
  
  
  RESULTS
  MSA-C cases with the lowest burden of pathology showed α-syn glial cytoplasmic inclusions (GCIs) in the cerebellum as well as in medullary and pontine cerebellar projections. Cerebellar pathology was highly selective and severely involved subcortical white matter, whereas deep white matter and granular layer were only mildly affected and the molecular layer was spared. Loss of Purkinje cells increased with disease duration and was associated with neuronal and axonal abnormalities. Neocortex, basal ganglia and spinal cord became consecutively involved with the increasing burden of α-syn pathology, followed by hippocampus, amygdala, and, finally, the visual cortex. GCIs were associated with myelinated axons, and the severity of GCIs correlated with demyelination.
  
  
  CONCLUSIONS
  Our findings indicate that cerebellar subcortical white matter and cerebellar brainstem projections are likely the earliest foci of α-syn pathology in MSA-C, followed by involvement of more widespread regions of the central nervous system and neurodegeneration with disease progression.
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Brettschneider
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA.|Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Irwin
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Boluda
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Byrne
authors.affiliation: Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical Research, University of Ulm, Ulm, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Fang
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: E B
authors.initials: EB
authors.lastname: Lee
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Robinson
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Suh
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Van Deerlin
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Toledo
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Grossman
authors.affiliation: Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Hurtig
authors.affiliation: Department of Neurology, Hanover Medical School, Hanover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Dengler
authors.affiliation: Department of Neurology, Hanover Medical School, Hanover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Petri
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: V M-Y
authors.initials: VM
authors.lastname: Lee
authors.affiliation: Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: J Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000368:Aged; D002490:Central Nervous System / Q000473:pathology; D002531:Cerebellum / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000473:pathology*; D009410:Nerve Degeneration / Q000473:pathology; D051844:alpha-Synuclein
chemical_list: D051844:alpha-Synuclein
keywords: cerebellum; multiple system atrophy; α-synuclein