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Published on: August 16, 2020
Clinicopathologic and genetic features of multiple system atrophy with Lewy body disease
Shunsuke Koga1, Fuyao Li1, Na Zhao1
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL.
Background:
Abnormal aggregates of α-synuclein are pathologic hallmarks of multiple system atrophy (MSA) and Lewy body disease (LBD). LBD sometimes coexists with MSA, but the impact of co-pathology, particularly diffuse LBD, on presentation of MSA has not been studied. We aimed to determine the frequency and clinicopathologic features of MSA with LBD (MSA+LBD).
Methods:
Using hematoxylin & eosin and α-synuclein-immunostained slides, we assessed the distribution and severity of LBD in 230 autopsy-confirmed MSA patients collected from 1998 to 2018. Alzheimer-type pathology was assessed to assign the likelihood of clinical presentations of dementia with Lewy body (DLB) using the consensus criteria for DLB. We reviewed medical records to characterize clinicopathologic features of MSA+LBD. Genetic risk factors for LBD, including APOE ε4 allele and mutations in GBA, SNCA, LRRK2, and VPS35, were analyzed.
Results:
LBD was observed in 11 MSA patients (5%); seven were brainstem type, three were transitional type, and one was diffuse type. The latter four had an intermediate or high likelihood of DLB. Three of the four had an antemortem diagnosis of Parkinson's disease with dementia (PDD) or clinically probable DLB. Two patients had neuronal loss in the substantia nigra, but not in striatal or olivocerebellar systems with widespread glial cytoplasmic inclusions, consistent with minimal change MSA. In these cases, LBD was considered the primary pathology, and MSA was considered coincidental. APOE ε4 allele frequency was not different between MSA+LBD and MSA without LBD. Two of nine MSA+LBD patients had a risk variant of GBA (p.T408M and p.E365K).
Conclusions:
Although rare, MSA with transitional or diffuse LBD can develop clinical features of PDD or DLB. Minimal change MSA can be interpreted as a coincidental, but distinct, α-synucleinopathy in a subset of patients with diffuse LBD.
Insights
Multiple system atrophy (MSA) with Lewy body disease (LBD) is rare but can present as dementia with Lewy body (DLB) or Parkinson's disease with dementia (PDD). Minimal change MSA may be a distinct alpha-synucleinopathy alongside diffuse LBD.
Area of Science:
- Neuropathology
- Neurodegenerative Diseases
- α-synucleinopathies
Background:
- Abnormal α-synuclein aggregates define multiple system atrophy (MSA) and Lewy body disease (LBD).
- Co-occurrence of LBD and MSA, particularly diffuse LBD, is not well-studied regarding its impact on MSA presentation.
- The clinicopathologic features of MSA with LBD (MSA+LBD) require investigation.
Purpose of the Study:
- To determine the frequency of Lewy body disease (LBD) in autopsy-confirmed multiple system atrophy (MSA) cases.
- To characterize the clinicopathologic features of patients with coexisting MSA and LBD (MSA+LBD).
- To assess the clinical presentation and potential overlap between MSA+LBD and dementia with Lewy body (DLB) or Parkinson's disease with dementia (PDD).
Main Methods:
- Analysis of α-synuclein-immunostained slides from 230 autopsy-confirmed MSA patients.
- Assessment of Lewy body disease (LBD) distribution and severity using consensus criteria for dementia with Lewy body (DLB).
- Review of medical records for clinical characterization and genetic analysis of risk factors (APOE ε4, GBA, SNCA, LRRK2, VPS35).
Main Results:
- Lewy body disease (LBD) was found in 5% of MSA cases (11/230), with transitional or diffuse types in four patients.
- These four patients had intermediate or high likelihood of dementia with Lewy body (DLB) and three were diagnosed antemortem with PDD or probable DLB.
- Minimal change MSA cases with diffuse LBD suggested LBD as the primary pathology and MSA as coincidental; GBA risk variants were found in two patients.
Conclusions:
- Multiple system atrophy (MSA) with transitional or diffuse Lewy body disease (LBD) can clinically mimic dementia with Lewy body (DLB) or Parkinson's disease with dementia (PDD).
- Minimal change MSA in the context of diffuse LBD may represent a distinct, coincidental α-synucleinopathy.
- Understanding these overlapping pathologies is crucial for accurate diagnosis and management of neurodegenerative disorders.
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