Objective: The objective of this study is to examine the sub-regional differences in neuroinflammation (NI) in response to Lewy pathology (LP) within the hippocampus of autopsied Lewy body disease (LBD).

Background: LP is associated with an increase in NI derived from microglia (MG) but there is conflicting evidence to the role of MG in LBD pathogenesis. Progressive transsynaptic LP staging has been extensively studied in human autopsy tissue (i.e. Braak staging) but studies seldom account for neuroinflammation and often use sampling across multiple synaptic connections. Here we address these gaps in a focused digital histopathologic study of LP and NI within the human hippocampal subfields including cornu ammonis (CA) subfield 2 that is preferentially vulnerable to LP and the relatively spared dentate gyrus to test the hypothesis that NI within the hippocampus follows the same pattern of vulnerability to LP.

Method: We included autopsy-confirmed relatively pure LBD patients with limited age-related co-pathologies (n=68) and immunostained consecutive FFPE hippocampal sections for pathologic phosphorylated asyn (a marker of LP) and markers of MG derived NI, namely, IBA1 (pan MG marker), MHCII (antigen presentation), and CD68 (phagocytosis) by immunohistochemistry. We used QuPath v0.5.1 to measure percent area occupied (%AO) of these markers in each hippocampal subfield (Subiculum, CA1, 2, 3, 4, and DG). %AO was log2 transformed to obtain a normal distribution and Pearson correlation compared expression of MG markers with LP. Finally, we used linear-mixed effects (LME) models with subfield as a fixed factor to compare the %AO for each stain across subfields within patient groups while co-varying for age and sex.

Results: LME models for each MG marker consistently found CA2 with the highest density of MG markers and LP (B=-.146- -.41479, p<0.01). LP correlated with activated MG markers (MHCII: R=.27, p<0.05; CD68: R=0.27, p<0.05) but not the pan-MG marker (IBA1 P=0.17, p>0.05) in the CA2. Male sex was associated with increased CD68 %AO (B=0.246, p<0.01).

Conclusion: LP correlated with NI only in the CA2 indicating that NI may contribute to CA2 susceptibility to LP, and male sex may modulate this relationship. This study improves our understanding of NI development within the subregions of the hippocampus.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lewy-pathology-correlates-with-neuroinflammation-in-the-hippocampus-of-synucleinopathy-patients-in-a-subregion-specific-manner/