Expanding the spectrum of neuronal pathology in multiple system atrophy
Open accessAbstract
Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients with multiple system atrophy, including a patient with visual hallucinations. Further, the presence of Lewy body-like inclusions in neocortex, but not hippocampal alpha-synuclein pathology, was associated with cognitive impairment (P = 0.002). However, several cases had the presence of isolated Lewy body-like inclusions at atypical sites (e.g. thalamus, deep cerebellar nuclei) that are not typical for Lewy body-spectrum disease. Finally, interregional correlations (rho ≥ 0.6) in pathologic glial and neuronal lesion burden suggest shared mechanisms of disease progression between both discrete anatomic regions (e.g. basal forebrain and hippocampus) and cell types (neuronal and glial inclusions in frontal cortex and white matter, respectively). These findings suggest that in addition to glial inclusions, neuronal pathology plays an important role in the developmental and progression of multiple system atrophy.
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The pathological hallmark of MSA is abnormal accumulation of α-syn in the cytoplasm of oligodendrocytes, named glial cytoplasmic inclusions (GCIs).
“The pathological hallmark of MSA is the abnormal accumulation of α-syn in the cytoplasm of oligodendrocytes, named glial cytoplasmic inclusions (GCIs).271–275”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [273]
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- Reyes JF, Rey NL, Bousset L, Melki R, Brundin P, Angot E. Alphasynuclein transfers from neurons to oligodendrocytes. Glia 2014; 62: 387-98.
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- Authors
- Cykowski, M. D., Coon, E. A., Powell, S. Z., Jenkins, S. M., Benarroch, E. E., Low, P. A., Schmeichel, A. M., & Parisi, J. E.
- Affiliations
- Houston Methodist (US)
- Mayo Clinic (US)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-05-16
- Volume
- 138
- Issue
- 8
- Pages
- 2293-2309
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC4840945
- OpenAlex
- W1955567615
- Cited by
- 241
- References
- 50
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 22 · 2023: 20 · 2022: 24 · 2021: 28 · 2020: 22 · 2019: 29 · 2018: 22 · 2017: 19 · 2016: 16 · 2015: 5
- FWCI
- 14.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mayo Clinic
- Mayo Foundation for Medical Education and Research
- Houston Methodist Hospital
- National Institutes of Health
- U.S. Public Health Service (U54NSO65736)
- National Institute of Neurological Disorders and Stroke (P01NS044233, U54NS065736)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- multiple system atrophy, neuronal inclusions, synucleinopathies, Lewy body-like inclusions, glial cytoplasmic inclusions, cognitive impairment, visual hallucinations, anterior cingulate cortex, amygdala, entorhinal cortex, striatum, substantia nigra, disease progression
- MeSH terms
- Aged, Aged, 80 and over, Brain, Inclusion Bodies, Female, Humans, Male, Middle Aged, Neuroglia, Neurons, Multiple System Atrophy, Lewy Body Disease, alpha-Synuclein
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