Objective: To report a patient with MSA with concomitant occurrence of TDP-43-labeled and a-synuclein labeled inclusions in oligodendrocytes.

Background: The pathologic hallmark in multiple system atrophy (MSA) is oligodendrocytic glial cytoplasmic inclusions (GCI) containing a-synuclein, in addition to neuronal loss and astrogliosis especially involving the striatonigral and olivopontocerebellar systems.(1) Rarely, TAR DNA-binding protein of 43 kDa (TDP-43), a component of ubiquitinated inclusions seen mainly in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) has been demonstrated in cases of MSA and more recently, was shown to colocalize with a-synuclein pathology in GCIs in two patients.(2,3) Due to a relative lack of TDP-43 in GCIs in younger patients, it is not clear if this is a pathologic finding or an age-related change.

Method: A 66-year-old woman presented with a syndrome characterized by spasticity, dysautonomia, bulbar dysfunction, and Parkinsonism, responsive to Carbidopa/Levodopa. Symptoms progressed until her death at age 74. Neuropathologic evaluation was performed at the New York Brain Bank at Columbia University.

Results: Macroscopically, there was striking severe volume loss of the left striatum compared to mild involvement of the right striatum. The caudal level of the left putamen was severely atrophic and the globus pallidus was markedly smaller than normal. Microscopically, the neuronal loss and gliosis of the putamen and globus pallidus were severe on the left side, in contrast to the mild involvement on the right side. Immunohistochemistry for a-synuclein revealed widespread GCIs. The sections subjected to TDP-43 antibodies showed a few lenticular GCIs with definite nucleo-cytoplasmic translocation of the labeling as well as within the paracentral cortex.

Conclusion: This report adds to the evidence that TDP-43 anda-synuclein do occur in GCIs.  Whether the coexistence of the synucleinopathic burden and the TDP-43 findings contributes to the pathogenesis of a subset of MSA patients or is coincidental is not known. More cases with these peculiar pathologic hallmarks might help determine whether or not there is a pathogenic interaction between these two proteins, and whether TDP-43 contributes to neurodegeneration in a subset of patients with MSA.

References: 1. Ramirez EP, Vonsattel JP. Neuropathologic changes of multiple system atrophy and diffuse Lewy body disease. Semin Neurol. 2014 Apr;34(2):210-6 2. Geser F, Malunda JA, Hurtig HI, Duda JE, Wenning GK, Gilman S, Low PA, Lee VM, Trojanowski JQ. TDP-43 pathology occurs infrequently in multiple system atrophy. Neuropathol Appl Neurobiol. 2011 Jun;37(4):358-65 3. Koga S, Lin WL, Walton RL, Ross OA, Dickson DW. TDP-43 pathology in multiple system atrophy: colocalization of TDP-43 and α-synuclein in glial cytoplasmic inclusions. Neuropathol Appl Neurobiol. 2018 Dec;44(7):707-721

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MDS Abstracts - https://www.mdsabstracts.org/abstract/multiple-system-atrophy-with-predominant-striato-nigral-degeneration-msa-p-and-tdp-43-pathology-an-unusual-pathologic-variant-of-msa/