Multiple system atrophy variant with severe hippocampal pathology

Area of Science:

• Neuropathology
• Neurodegenerative Diseases
• Alpha-synucleinopathies

Background:

• Multiple system atrophy (MSA) typically affects the striatonigral and olivopontocerebellar systems, characterized by neuronal loss, astrogliosis, and alpha-synuclein inclusions.
• Rare variants of MSA involve neuronal cytoplasmic inclusions (NCIs) outside these typical regions.
• The clinical and pathological spectrum of MSA continues to expand, necessitating detailed characterization of atypical presentations.

Purpose of the Study:

• To investigate the clinical and pathological features of MSA patients with prominent hippocampal involvement.
• To determine the prevalence and characteristics of alpha-synuclein pathology within the hippocampus in MSA.
• To explore potential correlations between severe hippocampal pathology and clinical phenotypes in MSA.

Main Methods:

• Retrospective analysis of 146 consecutively autopsied MSA patients.
• Semi-quantitative immunohistochemistry for alpha-synuclein to assess NCIs in specific brain regions, including the hippocampus.
• Clinical data review, including disease duration, cognitive status, and brain weight.
• Statistical analysis (Fisher's exact test, Mann-Whitney U-test) to compare patient groups.

Main Results:

• Twelve out of 146 MSA patients (8.2%) exhibited severe NCIs in hippocampal regions (granule cells, cornu ammonis, parahippocampal gyrus, amygdala).
• Patients with severe hippocampal involvement showed a higher prevalence of women, longer disease duration, increased cognitive impairment, and lower brain weight.
• NCIs in the hippocampus were often ring-shaped or neurofibrillary tangle-like; a subset displayed Pick body-like morphology. Minimal tau and TDP-43 pathology was observed.

Conclusions:

• A distinct pathological variant of MSA characterized by severe hippocampal neuron involvement is identified.
• This hippocampal MSA phenotype is associated with specific demographic and clinical features, including cognitive impairment.
• The findings underscore the significance of alpha-synucleinopathy in the hippocampus for MSA pathogenesis and suggest this variant may represent a unique clinicopathological entity.