J Brettschneider1, D J Irwin1,2, S Boluda1, M D Byrne1, L Fang3, E B Lee1,4, J L Robinson1, E Suh1,4, V M Van Deerlin1,4, J B Toledo1, M Grossman2, H Hurtig2, R Dengler5, S Petri5, V M-Y Lee1,4, J Q Trojanowski1,4. 1. Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, Philadelphia, PA, USA. 2. Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. 3. Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical Research, University of Ulm, Ulm, Germany. 4. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. 5. Department of Neurology, Hanover Medical School, Hanover, Germany.
Abstract
AIMS: 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.
AIMS: 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: Jon B Toledo; Vivianna M Van Deerlin; Edward B Lee; EunRan Suh; Young Baek; John L Robinson; Sharon X Xie; Jennifer McBride; Elisabeth M Wood; Theresa Schuck; David J Irwin; Rachel G Gross; Howard Hurtig; Leo McCluskey; Lauren Elman; Jason Karlawish; Gerard Schellenberg; Alice Chen-Plotkin; David Wolk; Murray Grossman; Steven E Arnold; Leslie M Shaw; Virginia M-Y Lee; John Q Trojanowski Journal: Alzheimers Dement Date: 2013-08-24 Impact factor: 21.566
Authors: Jaeho Hwang; Anna M Bank; Farzad Mortazavi; Derek H Oakley; Matthew P Frosch; Jeremy D Schmahmann Journal: Neurology Date: 2019-08-13 Impact factor: 9.910
Authors: Johannes Brettschneider; EunRan Suh; John L Robinson; Lubin Fang; Edward B Lee; David J Irwin; Murray Grossman; Vivianna M Van Deerlin; Virginia M-Y Lee; John Q Trojanowski Journal: J Neuropathol Exp Neurol Date: 2018-11-01 Impact factor: 3.685
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