The role of intelligence in PTSD treatment outcomes: evidence from a multicenter TF-CBT trial with youth.

Intraneuronal protein aggregates predominantly made up of α-synuclein, termed neuronal α-synuclein pathology (n-asyn), pathologically define Lewy body diseases (LBDs) that clinically encompass Parkinson’s disease (PD) without and with dementia (PDD) and dementia with Lewy bodies [, , ]. Braak and colleagues initially proposed a topographical pattern of n-asyn split into progressive stages for PD from the olfactory bulb and dorsal medulla with hypothesized spreading rostrally from the brainstem to limbic and neocortical regions [, ]. Subsequent postmortem staging systems define additional patterns of progressive n-asyn transsynaptic spread in the human brain and peripheral nervous system, but thus far, these schemata do not account for non-neuronal aspects of disease pathophysiology or provide detailed analysis within the anatomic framework of local circuits to model these intercellular interactions [–, , , , ]. Indeed, genome-wide association studies in LBD have found risk variants in microglia-associated genes and genes with relative enriched expression in microglia over neurons [, , ]. Moreover, postmortem studies have found significant morphologic, transcriptional, and molecular changes in microglia within specific disease-relevant brain regions, such as the Substantia nigra pars compacta, suggesting a microglial component to disease pathogenesis [, , ]. Limited existing studies find a relatively modest increase in activated microglial phenotypes in LBD compared to the microglial response in Alzheimer’s disease (AD), suggesting an altered microglial response in LBD vs. AD [, , , , , ]. There is an established link between the development of activated microglial phenotypes and n-asyn within key vulnerable brain regions like the substantia nigra pars compacta, where n-asyn burden is associated with activated microglial states typified by increased phagocytic activity and antigen presentation through an increase in CD68 and HLA-DR, respectively [, , , ]. Despite this, the relationship between LBD clinical progression and these activated microglial phenotypes within the key vulnerable non-motor brain regions that develop n-asyn is unclear. The hippocampus provides an ideal anatomic model to test the association of activated microglial phenotypes that occur in response to progressive n-asyn burden in LBD because the subfields form part of the well-defined intra-hippocampal circuit that is critical to memory encoding and affected in LBD [, ]. The hippocampus develops n-asyn in dementia with Lewy bodies and in stage V of classical Braak staging of PD/PDD [, ]. The cornu ammonis 2 (CA2) hippocampal subfield is particularly vulnerable to forming n-asyn compared to other hippocampal subfields in LBD [, , ]. One study found that the CA2 develops increasing microglial phagocytic activity with increasing Parkinson’s Braak stage by measuring staining to CD68, and another found increased antigen presentation measured by HLA-DR in the CA2 of PD patients compared to controls [, ]. Despite this, detailed anatomic studies to model the relationship of activated microglial phenotypes with subregional n-asyn burden in the hippocampus are limited, and this is a crucial knowledge gap that could provide critical clues in elucidating the role of microglia in LBD pathogenesis. Here, we tested the hypothesis that activated microglial phenotypes are associated with n-asyn burden within the hippocampal subfields in LBD. To do this, we selected a unique cohort of LBD patients with n-asyn and limited potentially confounding Alzheimer’s Disease Neuropathologic Change (ADNC) [, ]. We compared this select well-defined LBD cohort to a well-characterized control cohort of healthy adults diagnosed post-mortem with primary age-related tauopathy (PART), defined as limited age-related tau pathology within the CA2 with minimal amyloid plaques and carefully accounted for other age-related pathologies in our models [, ]. We used rigorously validated digital histopathology methods to measure the percent area occupied (%AO) of n-asyn and markers of activated microglial phenotypes including total microglial area, phagocytic activity, and antigen presentation with Iba1, CD68, and HLA-DR, respectively [, , , , ]. We found that LBD patients exhibit greater CD68 and HLA-DR signal in almost all hippocampal sub-regions compared to PART controls, despite only the CA2 and subiculum sub-regions showing a slightly increased Iba1%AO, suggestive of an enrichment of activated microglial phenotypes due to n-asyn. Moreover, we found that LBD patients with widespread hippocampal n-asyn throughout the hippocampal subfields demonstrate increased activated microglial phenotypes specifically within the CA2 and worse cognition compared to those with limited hippocampal n-asyn in the CA2–3 subfields alone. Activated microglial phenotypes in the CA2 correlated with n-asyn burden in distal subfields with retrograde connectivity to CA2–3 region but not anterograde activity w