Objective: To describe a pathologically unusual case of Multiple systems atrophy (MSA) with severe widespread gliosis and neuronal loss with scant alpha-synuclein (aSyn) pathology.

Background: MSA is clinically marked by parkinsonism, cerebellar ataxia and autonomic failure. Neuropathologically, MSA is readily identified by florid aSyn positive glial cytoplasmic inclusions (GCIs) and neuronal species that are present throughout striato-nigral, olivo-ponto-cerebellar, and neocortical areas[1].

Method: A 45-year-old woman presented with left upper extremity rigidity and lightheadedness on standing. Orthostatic hypotension, parkinsonism, and urinary incontinence were confirmed, meeting criteria for MSA[2]. Two years after disease onset, she started falling and was wheelchair bound three years later. At seven years disease duration she required tracheostomy for vocal cord paralysis and inspiratory stridor and gastrostomy tube placement. ‘Hot crossed buns’ sign and putaminal rim signs were present on MRI. She survived with anarthria and severe rigidity for another 14 years, passing away 21 years into her disease course at age 66.

Results: Formalin fixed brain weight was 852g. Severe atrophy of the cerebellum, midbrain, pallidum, striatum, and pons was present with complete hypopigmentation of the substantia nigra and locus coeruleus. Severe gliosis, rarefied neuropil and neuronal loss was noted throughout all regions of the neocortex, basal ganglia, and brainstem. Amyloid-β plaques were observed in the neocortex, basal ganglia, and midbrain (Thal 4, A3, CERAD 3). Tau positive neurofibrillary tangles were seen in the entorhinal cortex only (Braak III/VI, B2). Scant aSyn positive GCIs were noted in the cingulate gyrus, entorhinal cortex, and basal ganglia but were absent from the pons, midbrain, and cerebellum. There were no pathological TDP-43 or TAF-15 inclusions.

Conclusion: This unusual case of MSA was clinically marked by rapid decline followed by very long duration of severe disease. Pathologically, the case exhibits extremely severe gliosis and neuronal loss, with very scant classic glial aSYN accumulations which suggests the possibility that aSYN inclusions in MSA could be cleared in severe disease of long duration, though further investigation is required. This observation has ramifications for the development of aSyn specific biomarkers in MSA and other synucleinopathies.

References: [1] G.K. Wenning, F. Tison, Y. Ben Shlomo, S.E. Daniel, N.P. Quinn, Multiple system atrophy: A review of 203 pathologically proven cases, Mov. Disord. 12 (1997) 133–147. https://doi.org/10.1002/mds.870120203. [2] S. Gilman, G.K. Wenning, P.A. Low, D.J. Brooks, C.J. Mathias, J.Q. Trojanowski, N.W. Wood, C. Colosimo, A. Dürr, C.J. Fowler, Second consensus statement on the diagnosis of multiple system atrophy, Neurology. 71 (2008) 670–676.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/an-unusual-case-of-multiple-systems-atrophy-with-long-disease-duration-severe-gliosis-and-scant-synuclein-pathology/