Changes in total cell numbers of the basal ganglia in patients with multiple system atrophy — A stereological study
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Total numbers of neurons, oligodendrocytes, astrocytes, and microglia in the basal ganglia and red nucleus were estimated in brains from 11 patients with multiple system atrophy (MSA) and 11 age- and gender-matched control subjects with unbiased stereological methods. Compared to the control subjects, the MSA patients had a substantially lower number of neurons in the substantia nigra (p=0.001), putamen (p=0.001), and globus pallidus (p<0.001), and, to a lesser extent in the caudate nucleus (p=0.03). A significantly lower number of oligodendrocytes were only observed in the putamen (p=0.04) and globus pallidus (p=0.01). In the MSA brains the total number of astrocytes was significantly higher in the putamen (p=0.04) and caudate nucleus (p=0.01). In all examined regions a higher number of microglia were found in the MSA brains with the greatest difference observed in the otherwise unaffected red nucleus (p=0.001). The results from the stereological study were supported by cell marker expression analyses showing increased markers for activated microglia. Our results suggest that microgliosis is a consistent and severe neuropathological feature of MSA, whereas no widespread and substantial loss of oligodendrocytes was observed. We have demonstrated significant neuronal loss in the substantia nigra, striatum, and globus pallidus of patients with MSA, while neurons in other basal ganglia nuclei were spared, supporting the region-specific patterns of neuropathological changes in MSA.
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Drastic demyelination observed in MSA patients is not accompanied by a severe loss of mature oligodendrocytes.
“The drastic demyelination observed in MSA patients is not accompanied by a severe loss of mature oligodendrocytes [49, 14]”
From Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates (2017) · cites this paper as [49]
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“changes in the PUT but more variable changes in other basal ganglia regions.(4,36) This varying pathology may contribute partly to the in-”
BackgroundJucaite, A., Cselényi, Z., Kreisl, W. C., Rabiner, E. A., Varrone, A., Carson, R. E., Rinne, J. O., Savage, A., Schou, M., Johnström, P., et al. (2022) · Movement Disorders · doi:10.1002/mds.28814 · Cited by 43 · see citing works
“9,10 A glia response in vivo has been reported in a small group of patients with MSA, using positron emission tomography (PET) imaging of the translocator protein (TSPO), a marker for microglia and astrocytes.”
BackgroundMultiple System Atrophy - State of the Art
Laurens, B., Vergnet, S., Cuina, M. L., Foubert‐Samier, A., Tison, F., Fernagut, P., & Meissner, W. G. (2017) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-017-0751-0 · Cited by 34 · see citing works
Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy
Mészáros, L., Hoffmann, A., Wihan, J., & Winkler, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21082775 · Cited by 32 · see citing works
Terao, Y., Fukuda, H., Tokushige, S., Inomata‐Terada, S., Yugeta, A., Hamada, M., Ichikawa, Y., Hanajima, R., & Ugawa, Y. (2015) · Clinical Neurophysiology · doi:10.1016/j.clinph.2015.07.035 · Cited by 30 · see citing works
“The preferential involvement of the putamen with less prominent neuronal loss in the caudate (Salvesen et al., 2015) in MSA-P may provide an explanation for the preserved MGS performance, since the caudate is more involved in oculomotor control, whereas the putamen is more involved in somatomotor control (Alexander an…”
BackgroundResultBroad white matter impairment in multiple system atrophy
del Campo, N., Phillips, O., Ory‐Magne, F., Brefel‐Courbon, C., Galitzky, M., Thalamas, C., Narr, K. L., Joshi, S. H., Singh, M. K., Péran, P., et al. (2020) · Human Brain Mapping · doi:10.1002/hbm.25227 · Cited by 28 · see citing works
“…in MSA patients comparable to our own in terms of age and disease duration shows largely preserved oligodendrocyte numbers in the presence of significant microgliosis, astrocytosis and neuronal loss, both sub-cortically (Salvesen et al., 2015a) and in the neocortex (Salvesen et al., 2015b).”
BackgroundInfluentialRusholt, E. H. L., Salvesen, L., Brudek, T., Tesfay, B., Pakkenberg, B., & Olesen, M. V. (2019) · Brain Pathology · doi:10.1111/bpa.12806 · Cited by 28 · see citing works
“© 2019 International Society of Neuropathology 577 substantial and region-specific loss of neurons in the basal ganglia, cortex, and white matter of MSA brains (34, 44, 45).”
BackgroundResultSelf-citationNeuronal α-synuclein toxicity is the key driver of neurodegeneration in multiple system atrophy
Wiseman, J. A., Halliday, G. M., & Dieriks, B. V. (2025) · Brain · doi:10.1093/brain/awaf030 · Cited by 27 · see citing works
“2,3,24 Although GCIs generally represent the highest proportion of lesion type across degenerating brain regions, oligodendroglial cell loss in MSA is minimal, 11,25 despite myelin dysfunction.”
Rydbirk, R., Folke, J., Busato, F., Roché, E., Chauhan, A. S., Løkkegaard, A., Hejl, A., Bode, M., Blaabjerg, M., Møller, M., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00908-7 · Cited by 27 · see citing works
“Of interest, both MSA [65 – 67] and HDLS [68] share pathological astro-and microgliosis.”
BackgroundSelf-citationMultiple System Atrophy: Pathology, Pathogenesis, and Path Forward
Ndayisaba, A., Halliday, G. M., & Khurana, V. (2024) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-051122-104528 · Cited by 26 · see citing works
Nigral Neuroinflammation and Dopaminergic Neurons in Parkinson's Disease and Atypical Parkinsonisms
Backman, E. A., Gardberg, M., Saari, L., Peurla, M., Vahlberg, T. J., Borghammer, P., Stefanova, N., Wenning, G. K., & Kaasinen, V. (2025) · Annals of Neurology · doi:10.1002/ana.27202 · Cited by 26 · see citing works
“18 Furthermore, a recent PET imaging study revealed increased translocator protein expression by glia in the lentiform nucleus and cerebellar white matter in individuals with MSA compared to those with PD. 39 However, the interpretation of microglial activation using the PET signal for translocator…”
Marmion, D. J., Rutkowski, A., Chatterjee, D., Hiller, B. M., Werner, M. H., Bézard, E., Kirik, D., McCown, T. J., Gray, S. J., & Kordower, J. H. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105184 · Cited by 26 · see citing works
“Despite the disruption of myelin observed in regions of GCI formation, the presence of aSyn inclusions in oligodendroglia is believed to disrupt the normal function of oligodendrocytes, but not oligodendroglial degeneration, as only minor changes to oligodendrocyte numbers have been reported in post-mortem MSA cases […”
BackgroundBrain injections of glial cytoplasmic inclusions induce a multiple system atrophy-like pathology
Teil, M., Doveró, S., Bourdenx, M., Arotçarena, M.-L., Camus, S. M. J., Porras, G., Thiolat, M.-L., Trigo‐Damas, I., Perier, C., Estrada, C. M., et al. (2021) · Brain · doi:10.1093/brain/awab374 · Cited by 26 · see citing works
Sanfilippo, C., Nunnari, G., Calcagno, A., Malaguarnera, L., Blennow, K., Zetterberg, H., & Rosa, M. D. (2016) · Virus Research · doi:10.1016/j.virusres.2016.10.012 · Cited by 25 · see citing works
Neuropathological findings in multiple system atrophy with cognitive impairment
Jellinger, K. A. (2020) · Journal of Neural Transmission · doi:10.1007/s00702-020-02201-2 · Cited by 24 · see citing works
The Hidden Life of the Basal Ganglia
Bergman, H. (2021) · The MIT Press eBooks · doi:10.7551/mitpress/14075.001.0001 · Cited by 21 · see citing works
Kang, S., Hong, S., Kang, S., Song, M. R., Yang, M. A., Essa, H., Baker, M. R., Lee, J., Bruce, R. A., Lee, S. W., et al. (2023) · Science Advances · doi:10.1126/sciadv.adh9239 · Cited by 21 · see citing works
Multiple system atrophy - a clinicopathological update
Jellinger, K. A. (2020) · Free Neuropathology · doi:10.17879/freeneuropathology-2020-2813 · Cited by 20 · see citing works
“Multiple system atrophy: experimental models and reality”.
Overk, C., Rockenstein, E., Valera, E., Stefanova, N., Wenning, G., & Masliah, E. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1772-0 · Cited by 22 · see citing works
“did not observe any significant oligodendrocyte degeneration in MSA patients compared to controls [91], while another study reported a loss in the putamen and globus pallidus [108].”
ResultAstrocyte-neuron interaction in the dorsal striatum-pallidal circuits and alcohol-seeking behaviors
Hong, S., Kang, S., Baker, M. R., & Choi, D. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108759 · Cited by 19 · see citing works
Tong, J., Williams, B., Rusjan, P., Mizrahi, R., Lacapere, J., McCluskey, T., Furukawa, Y., Guttman, M., Ang, L., Boileau, I., et al. (2020) · Journal of Cerebral Blood Flow and Metabolism · doi:10.1177/0271678x19858003 · Cited by 14 · see citing works
Nuccio, F. D., Kashyrina, M., Serinelli, F. C., Laferrière, F., Lofrumento, D. D., Giorgi, F. D., & Ichas, F. (2023) · Biomolecules · doi:10.3390/biom13020269 · Cited by 17 · see citing works
“matter takes place with a loss of myelinated fibers without major change in the number of OLs [56].”
BackgroundMészáros, L., Riemenschneider, M. J., Gaßner, H., Marxreiter, F., von Hörsten, S., Hoffmann, A., & Winkler, J. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01166-x · Cited by 15 · see citing works
“However, our and other previous studies indicate no reduction of the number of oligodendrocytes or only subtle in the putamen and caudate nucleus of MSA patients [11, 18, 21, 39].”
ResultTNFα inhibitors as targets for protective therapies in MSA: a viewpoint
Ndayisaba, A., Jellinger, K. A., Berger, T., & Wenning, G. K. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1477-5 · Cited by 13 · see citing works
Renovascular hypertension associated with neurofibromatosis: two cases and review of the literature.
Nakhoul, F. M., Green, J., Angel, A., Ofer, A., Ben‐Izhak, O., & Lewin, M. (2001) · PubMed · Cited by 13 · see citing works
Battis, K., Florio, J. B., Mante, M., Lana, A. J., Naumann, I., Gauer, C., Lambrecht, V., Müller, S. J., Cobo, I., Fixsen, B. R., et al. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.0417-22.2022 · Cited by 11 · see citing works
The Stereological Analysis and Spatial Distribution of Neurons in the Human Subthalamic Nucleus
Bokulić, E., Medenica, T., Knezović, V., Štajduhar, A., Almahariq, F., Baković, M., Judáš, M., & Sedmak, G. (2021) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2021.749390 · Cited by 10 · see citing works
Henkel, L. M., Kankowski, S., Möllenkamp, T. M., Smandzich, N. J., Schwarz, S. C., Fonzo, A. D., Göhring, G., Höglinger, G. U., & Wegner, F. (2023) · Cells · doi:10.3390/cells12020223 · Cited by 8 · see citing works
“Severe neuronal losses in various brain regions, such as the putamen, pons, cerebellum, inferior olive, and substantia nigra, are characteristic of MSA, while the number of oligodendrocytes seems to be preserved, despite myelin loss [6].”
Multiple System Atrophy - A Synucleinopathy with Specific Glioneuronal Degeneration
Ka, J., & Jellinger, K. A. (2015) · Cited by 8 · see citing works
Stereological Quantification of Plaques and Tangles in Neocortex from Alzheimer’s Disease Patients
Madsen, J. B., Folke, J., & Pakkenberg, B. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180105 · Cited by 8 · see citing works
“As described elsewhere [64–66] and schematized in Fig.”
Self-citationJellinger, K. A. (2022) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2022.105273 · Cited by 7 · see citing works
Carmona‐Abellán, M., Pino, R. D., Murueta‐Goyena, A., Acera, M., Tijero, B., Berganzo, K., Gabilondo, I., & Gómez‐Esteban, J. C. (2021) · Neurología · doi:10.1016/j.nrl.2021.04.007 · Cited by 7 · see citing works
Quantitative cellular changes in multiple system atrophy brains
Andersen, A. M., Kaalund, S. S., Marner, L., Salvesen, L., Pakkenberg, B., & Olesen, M. V. (2023) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12941 · Cited by 6 · see citing works
“To add further information, we performed cluster and principal component analysis (PCA) on the combined data-sets from Salvesen et al [49], Salvesen et al [50] and Vigen et al [54] where the same MSA brains were used.”
BackgroundMethodInfluentialSelf-citationTheory of Mind in multiple system atrophy: comparison with Parkinson’s disease and healthy subjects
Santangelo, G., Cuoco, S., Picillo, M., Erro, R., Squillante, M., Volpe, G., Cozzolino, A., Cicarelli, G., Barone, P., & Pellecchia, M. T. (2020) · Journal of Neural Transmission · doi:10.1007/s00702-020-02181-3 · Cited by 6 · see citing works
Quantitative Cellular Changes in the Thalamus of Patients with Multiple System Atrophy
Vigen, T. R., Brudek, T., Pakkenberg, B., & Olesen, M. V. (2021) · Neuroscience · doi:10.1016/j.neuroscience.2021.02.003 · Cited by 6 · see citing works
Self-citationSharma, P. K., Gentleman, S., Dexter, D. T., & Pienaar, I. S. (2025) · Brain Pathology · doi:10.1111/bpa.70011 · Cited by 5 · see citing works
“In this regard, a study attributed function to neuronal density variation in the subthalamic nucleus, postulating that lower neuronal density may represent motor function output [53].”
Johnson, M. L., Lewis, M. M., Wang, E. W., Jellen, L. C., Du, G., Jesus, S. D., Kong, L., Pu, C., & Huang, X. (2024) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2024.107043 · Cited by 5 · see citing works
Changes of Amide Proton Transfer Imaging in Multiple System Atrophy Parkinsonism Type
Li, S., Chan, P., Li, C., Chen, H., Chen, M., Su, W., Li, K., Lü, N., Lu, Y., Chu, D., et al. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.572421 · Cited by 5 · see citing works
“Previous work had reported that there were extensive microgliosis in the RN, putamen, and globus pallidus with neuronal loss in the putamen and globus pallidus (Salvesen et al., 2015).”
BackgroundMultiparametric MRI for Characterization of the Basal Ganglia and the Midbrain
Schneider, T. M., Ma, J., Wagner, P., Behl, N. G. R., Nagel, A. M., Ladd, M. E., Heiland, S., Bendszus, M., & Straub, S. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.661504 · Cited by 5 · see citing works
Li, X., Pang, H., Bu, S., Li, Y., Zhao, M., Wang, J., Liu, Y., Yu, H., & Fan, G. (2025) · Brain Imaging and Behavior · doi:10.1007/s11682-025-00984-0 · Cited by 4 · see citing works
“Pathophysiological inquiries have indicated that MSA patients exhibit more pronounced and distinct neuronal loss in the putamen compared to the caudate nucleus (Salvesen et al., 2015).”
Gauer, C., Battis, K., Schneider, Y., Florio, J. B., Mante, M., Kim, H. Y., Rissman, R. A., Hoffmann, A., & Winkler, J. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114706 · Cited by 3 · see citing works
“…revealing regional differences in the number and morphology of microglial cells and the levels of proinflammatory cytokines across brain regions (Ishizawa et al., 2004, Salvesen et al., 2015, Salvesen et al., 2017) suggest the presence of functional heterogenous microglial populations in MSA.”
BackgroundRecent advances in multiple system atrophy
Jellinger, K. A. (2016) · Journal of Neurology and Neuromedicine · doi:10.29245/2572.942x/2016/1.1002 · Cited by 3 · see citing works
Astrocytes in the external globus pallidus coordinate flexibility of action strategyPreprint
Hong, S., Kang, S., Song, M. R., Yang, M. A., Baker, M. R., Kang, S., Lee, J., Lee, S. W., & Choi, D. (2021) · Research Square · doi:10.21203/rs.3.rs-845991/v1 · Cited by 3 · see citing works
Glial Cells as Key Orchestrators of Neural Degeneration in Basal Ganglia Disorders
Bhaduri, B., & Alladi, P. A. (2022) · Springer eBooks · doi:10.1007/978-981-16-8313-8_15 · Cited by 2 · see citing works
Astrocytes and the Synucleinopathies
Koob, A. O., & Sacchetti, P. (2018) · Springer eBooks · doi:10.1007/978-981-13-0944-1_8 · Cited by 1 · see citing works
Carmona‐Abellán, M., Pino, R. D., Murueta‐Goyena, A., Acera, M., Tijero, B., Berganzo, K., Gabilondo, I., & Gómez‐Esteban, J. C. (2023) · Neurología (English Edition) · doi:10.1016/j.nrleng.2021.04.008 · Cited by 1 · see citing works
Huang, J., Zhang, L., Jiang, Q., Wang, S., Xiao, Y., Che, N.-N., Lin, J., Zhao, B., Cheng, Y., Li, C., et al. (2026) · Movement Disorders · doi:10.1002/mds.70289 · Cited by 1 · see citing works
Single-nucleus brain transcriptomics reveals microglia dysfunction in multiple system atrophy
Rydbirk, R., Sørensen, F. N. F., Folke, J., Haukedal, H., Asenjo-Martínez, A., Vargas, I. L., McGarry, S., Hollmann, O. C., Gherardelli, C., Sepulveda, S. E., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-71525-6 · Cited by 2 · see citing works
“4c, pathways are selected based on their relevance to disease etiology from the full list of signi fi cant pathways in Supplementary Dataset 8).”
InfluentialSelf-citationCognitive functions of the GPe
O'Berry, K., & Gittis, A. H. (2026) · Trends in Neurosciences · doi:10.1016/j.tins.2026.05.005 · Cited by 1 · see citing works
The external pallidum: think locally, act globallyPreprint
Courtney, C. D., Pamukcu, A., & Chan, C. S. (2021) · arXiv (Cornell University) · doi:10.48550/arxiv.2104.10795 · Cited by 1 · see citing works
Stereology of the Human Caudate Nucleus
Delgado‐González, J., & Artacho‐Pérula, E. (2024) · Neuromethods · doi:10.1007/978-1-0716-3977-1_4
Rydbirk, R., Folke, J., Busato, F., Roché, E., Chauhan, A. S., Løkkegaard, A., Hejl, A.-M., Bode, M., Blaabjerg, M., Møller, M. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.11960322
Self-citationMészáros, L., Riemenschneider, M. J., Gassner, H., Marxreiter, F., von Hörsten, S., Hoffmann, A., & Winkler, J. (2021) · Figshare · doi:10.6084/m9.figshare.14418353
Rydbirk, R., Folke, J., Busato, F., Roché, E., Chauhan, A. S., Løkkegaard, A., Hejl, A.-M., Bode, M., Blaabjerg, M., Møller, M. L., et al. (2020) · Figshare · doi:10.6084/m9.figshare.11960316
Self-citationWu, C., Lin, J., Chen, Y., Takahashi, N., Chen, Q., Liu, B., Dai, F., Zhao, W., Finkelstein, D. I., Kawahata, K., et al. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104150
“C), partially supported by previous reports showing profound glial remodeling in MSA white matter [33,34].”
Basellini, M. J., Calogero, A. M., Mazzetti, S., Cagni, E., Calandrella, D., Isaias, I. U., Cappelletti, G., Pezzoli, G., & Contaldi, E. (2026) · Research Square · doi:10.21203/rs.3.rs-10762754/v1
- Authors
- Salvesen, L., Ullerup, B. H., Sunay, F. B., Brudek, T., Løkkegaard, A., Agander, T. K., Winge, K., & Pakkenberg, B.
- Affiliations
- Bispebjerg Hospital (DK)
- Balıkesir University (TR)
- Rigshospitalet (DK)
- Corresponding author
- Salvesen, Lisette
- ORCID
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 74
- Pages
- 104-113
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W1969219907
- Cited by
- 85
- References
- 52
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 13 · 2020: 11 · 2019: 7 · 2018: 4 · 2017: 9 · 2016: 8 · 2015: 7
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- green
- doaj.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Lundbeckfonden (R126-2012-12359)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- multiple system atrophy, basal ganglia, neuronal loss, microglial activation, oligodendrocytes, astrocytes, microglia, substantia nigra, putamen, globus pallidus, caudate nucleus, red nucleus, stereology, cell number
- MeSH terms
- Aged, Aged, 80 and over, Astrocytes, Basal Ganglia, Cell Count, Female, Humans, Male, Middle Aged, Neurons, Oligodendroglia, Organ Size, Red Nucleus, Substantia Nigra, Microglia, Multiple System Atrophy, Subthalamic Nucleus, Real-Time Polymerase Chain Reaction
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