The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations
Abstract
Multiple system atrophy (MSA) has varying clinical (MSA-P versus MSA-C) and pathological [striatonigral degeneration (SND) versus olivopontocerebellar atrophy (OPCA)] phenotypes. To investigate the spectrum of clinicopathological correlations, we performed a semi-quantitative pathological analysis of 100 MSA cases with well-characterized clinical phenotypes. In 24 areas, chosen from both the striatonigral (StrN) and olivopontocerebellar (OPC) regions, the severity of neuronal cell loss and gliosis as well as the frequency of glial (oligodendroglial) cytoplasmic inclusions (GCIs) and neuronal cytoplasmic inclusions (NCIs) were determined. Clinical information was abstracted from the patients' medical records, and the severity of bradykinesia in the first year of disease onset and in the final stages of disease was graded retrospectively. The degree of levodopa responsiveness and the presence or absence of cerebellar ataxia and autonomic symptoms were also recorded. We report that 34% of the cases were SND- and 17% were OPCA-predominant, while the remainder (49%) had equivalent SND and OPCA pathology. We found a significant correlation between the frequency of GCIs and the severity of neuronal cell loss, and between these pathological changes and disease duration. Our data also suggest that GCIs may have more influence on the OPC than on the StrN pathology. Moreover, we raise the possibility that a rapid process of neuronal cell loss, which is independent of the accumulation of GCIs, occurs in the StrN region in MSA. There was no difference in the frequency of NCIs in the putamen, pontine nucleus and inferior olivary nucleus between the SND and OPCA subtypes of MSA, confirming that this pathological abnormality is not associated with a particular subtype of the disease. In the current large post-mortem series, 10% of the cases had associated Lewy body pathology, suggesting that this is not a primary process in MSA. As might be expected, there was a significant difference in the severity of bradykinesia and the presence of cerebellar signs between the pathological phenotypes: the SND phenotype demonstrates the most severe bradykinesia and the OPCA phenotype the more frequent occurrence of cerebellar signs, confirming that the clinical phenotype is dependent on the distribution of pathology within the basal ganglia and cerebellum. Putaminal involvement correlated with a poor levodopa response in MSA. Our finding that relatively mild involvement of the substantia nigra is associated clinically with manifest parkinsonism, while more advanced cerebellar pathology is required for ataxia, may explain why the parkinsonian presentation is predominant over ataxia in MSA.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
There is a positive correlation between GCI density and neuronal loss, highlighting the importance of α-syn in the disease process.
“While the precise pathological mechanism(s) remain unknown, the positive correlation between GCI density and neuronal loss highlight the importance of α-syn in the disease process [40].”
From Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates (2017) · cites this paper as [40]
Cites
Consensus statement on the diagnosis of multiple system atrophy
Gilman, S., Low, P. A., Quinn, N. P., Albanese, A., Ben‐Shlomo, Y., Fowler, C. J., Kaufmann, H., Klockgether, T., Lang, A. E., Lantos, P. L., et al. (1998) · Clinical Autonomic Research · doi:10.1007/bf02309628 · Cited by 1,316 · see citing works
Papp, M. I., Kahn, J. E., & Lantos, P. L. (1989) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(89)90219-0 · Cited by 991 · see citing works
Clinical features and natural history of multiple system atrophy
Wenning, G. K., Ben‐Shlomo, Y., Magalhães, M., Danie, S. E., & Quinn, N. P. (1994) · Brain · doi:10.1093/brain/117.4.835 · Cited by 788 · see citing works
Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy.
Graham, J. G., & Oppenheimer, D. R. (1969) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.32.1.28 · Cited by 561 · see citing works
Papp, M. I., & Lantos, P. L. (1994) · Brain · doi:10.1093/brain/117.2.235 · Cited by 389 · cited 1× · see citing works
“Papp and Lantos observed no direct correlation between the density of GCIs and the severity of neuronal loss in most anatomical sites, and they suggested that GCIs generally appear before neuronal cell loss (Papp and Lantos, 1994).”
BackgroundClinicopathological study of 35 cases of multiple system atrophy.
Wenning, G. K., Ben‐Shlomo, Y., Magalhaes, M., Daniel, S. E., & Quinn, N. P. (1995) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.58.2.160 · Cited by 244 · see citing works
Arima, K., Uéda, K., Sunohara, N., Arakawa, K., Hirai, S., Nakamura, M., Tonozuka-Uehara, H., & Kawai, M. (1998) · Acta Neuropathologica · doi:10.1007/s004010050917 · Cited by 239 · see citing works
Dystonia in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy
Rivest, J., Quinn, N. P., & MARSDEN, C. D. (1990) · Neurology · doi:10.1212/wnl.40.10.1571 · Cited by 108 · see citing works
Olivopontocerebellar pathology in multiple system atrophy
Wenning, G. K., Tison, F., Elliott, L., Quinn, N. P., & Daniel, S. E. (1996) · Movement Disorders · doi:10.1002/mds.870110207 · Cited by 106 · see citing works
Lewy bodies are not increased in progressive supranuclear palsy compared with normal controls
Tsuboi, Y., Ahlskog, J. E., Apaydın, H., Parisi, J. E., & Dickson, D. W. (2001) · Neurology · doi:10.1212/wnl.57.9.1675 · Cited by 48 · see citing works
Pathology of the inferior olivary nucleus in patients with multiple system atrophy
Sakurai, A., Okamoto, K., Yaguchi, M., et al. (2002) · Acta Neuropathologica · doi:10.1007/s00401-001-0500-x · Cited by 44 · see citing works
Progression and prognosis in multiple system atrophy : An analysis of 230 Japanese patients
渡邉, 宏. (2003) · 名古屋大学 eBooks · Cited by 43 · see citing works
WIDESPREAD ALTERATIONS IN ALPHA-SYNUCLEIN IN MULTIPLE SYSTEM ATROPHY
Dickson, D. W., Liu, W. K., & Yen, S. H. (1999) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199905000-00191 · Cited by 12 · see citing works
AGING AND PARKINSONS-DISEASE - SUBSTANTIA-NIGRA REGIONAL SELECTIVITY
FEARNLEY, J., & LEES, A. (1991) · UCL Discovery (University College London) · Cited by 10 · see citing works
Idiopathic Parkinson's disease combined with multiple system atrophy.
LEES, A., Hughes, A., & Sa, D. S. (1991) · UCL Discovery (University College London) · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Second consensus statement on the diagnosis of multiple system atrophy
Gilman, S., Wenning, G. K., Low, P. A., Brooks, D. J., Mathias, C. J., Trojanowski, J. Q., Wood, N. W., Colosimo, C., Dürr, A., Fowler, C. J., et al. (2008) · Neurology · doi:10.1212/01.wnl.0000324625.00404.15 · Cited by 3,140 · see citing works
Parkinson's Disease and Parkinsonism: Neuropathology
Dickson, D. W. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009258 · Cited by 847 · see citing works
Toll‐like receptor 4 is required for α‐synuclein dependent activation of microglia and astroglia
Fellner, L., Irschick, R., Schanda, K., Reindl, M., Klimaschewski, L., Poewe, W., Wenning, G. K., & Stefanova, N. (2013) · Glia · doi:10.1002/glia.22437 · Cited by 697 · see citing works
McCann, H., Stevens, C. H., Cartwright, H., & Halliday, G. M. (2014) · Parkinsonism & Related Disorders · doi:10.1016/s1353-8020(13)70017-8 · Cited by 364 · see citing works
Proposed neuropathological criteria for the <i>post mortem</i> diagnosis of multiple system atrophy
Trojanowski, J. Q., Revesz, T., & the Neuropathology Working Group on MSA (2007) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2007.00907.x · Cited by 349 · see citing works
Expanding the spectrum of neuronal pathology in multiple system atrophy
Cykowski, M. D., Coon, E. A., Powell, S. Z., Jenkins, S. M., Benarroch, E. E., Low, P. A., Schmeichel, A. M., & Parisi, J. E. (2015) · Brain · doi:10.1093/brain/awv114 · Cited by 241 · see citing works
Neuropathology of multiple system atrophy: New thoughts about pathogenesis
Jellinger, K. A. (2014) · Movement Disorders · doi:10.1002/mds.26052 · Cited by 181 · see citing works
Oligodendroglia and Myelin in Neurodegenerative Diseases: More Than Just Bystanders?
Ettle, B., Schlachetzki, J. C. M., & Winkler, J. (2016) · Molecular Neurobiology · doi:10.1007/s12035-015-9205-3 · Cited by 160 · see citing works
Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy
Martinez-Valbuena, I., Visanji, N. P., Kim, A., Lau, H. H. C., So, R. W. L., Alshimemeri, S., Gao, A., Seidman, M. A., Luquin, M. R., Watts, J. C., et al. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00283-4 · Cited by 103 · see citing works
Neuroinflammation in Multiple System Atrophy: Response to and Cause of α-Synuclein Aggregation
Vieira, B. D. M., Radford, R. A., Chung, R. S., Guillemin, G. J., & Pountney, D. L. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00437 · Cited by 93 · see citing works
Salvesen, L., Ullerup, B. H., Sunay, F. B., Brudek, T., Løkkegaard, A., Agander, T. K., Winge, K., & Pakkenberg, B. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.11.008 · Cited by 85 · see citing works
Oligodendroglial α‐synucleinopathy‐driven neuroinflammation in multiple system atrophy
Hoffmann, A., Ettle, B., Battis, K., Reiprich, S., Schlachetzki, J. C. M., Masliah, E., Wegner, M., Kuhlmann, T., Riemenschneider, M. J., & Winkler, J. (2019) · Brain Pathology · doi:10.1111/bpa.12678 · Cited by 83 · see citing works
Chronic traumatic encephalopathy pathology in multiple system atrophy
Koga, S., Dickson, D. W., & Bieniek, K. F. (2016) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw073 · Cited by 58 · see citing works
Mandel, R. J., Marmion, D. J., Kirik, D., Chu, Y., Heindel, C., McCown, T., Gray, S. J., & Kordower, J. H. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0451-7 · Cited by 56 · see citing works
Changes in the cell population in brain white matter in multiple system atrophy
Nykjær, C. H., Brudek, T., Salvesen, L., & Pakkenberg, B. (2017) · Movement Disorders · doi:10.1002/mds.26979 · Cited by 51 · see citing works
Zhao, P., Zhang, B., Gao, S., & Li, X. (2020) · Brain and Behavior · doi:10.1002/brb3.1827 · Cited by 37 · see citing works
Animal modeling an oligodendrogliopathy – multiple system atrophy
Bleasel, J. M., Halliday, G. M., & Kim, W. S. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0279-6 · Cited by 19 · see citing works
- Authors
- Ozawa, T.
- Affiliations
- National Hospital for Neurology and Neurosurgery (GB)
- Corresponding author
- Ozawa, T.
- ORCID
- Ozawa, T.
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-11-10
- Volume
- 127
- Issue
- 12
- Pages
- 2657-2671
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W1500851319
- Cited by
- 515
- References
- 15
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 26 · 2023: 21 · 2022: 25 · 2021: 34 · 2020: 32 · 2019: 28 · 2018: 24 · 2017: 31 · 2016: 19 · 2015: 34 · 2014: 26 · 2013: 33 · 2012: 20
- FWCI
- 8.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Parkinson's UK (G-4029)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, clinicopathological correlation, glial cytoplasmic inclusions, neuronal cytoplasmic inclusions, neuronal loss, gliosis, bradykinesia, cerebellar ataxia, Lewy body pathology, autonomic dysfunction, disease duration, MSA-P, MSA-C
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Neurons, Olivopontocerebellar Atrophies, Phenotype, Severity of Illness Index, Time Factors, Lewy Bodies, Cell Death, Age Distribution, Sex Distribution, Multiple System Atrophy, Striatonigral Degeneration
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
