Peripheral and central inflammation associated with progressive cognitive decline in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia, pathologically defined by the presence of Lewy bodies. Peripheral and central inflammation are increasingly recognised in DLB in clinical, post-mortem, and animal studies. Finding clinically relevant biomarkers of inflammation in DLB will support identification of novel pathways for disease modifying therapies or use in clinical trials of immunomodulatory agents. Whilst there are cross-sectional studies of inflammation markers in DLB, there is limited evidence on the association between these markers and cognitive decline over time. Twenty participants with DLB underwent blood sampling for serum inflammatory markers, paired with PET imaging of the translocator protein (TSPO) and up to four years of longitudinal cognitive testing. Thirty participants with Alzheimer’s disease—comprising both Alzheimer’s dementia and/or Mild Cognitive Impairment with biomarker evidence of amyloid pathology (AD/MCI+) and twenty-eight controls were also recruited for group comparisons. Data from forty-two baseline cytokine immunoassays and TSPO PET were used as predictors of longitudinal cognitive scores in linear mixed effects models. Partial least squares regression was used to test the association between peripheral and central inflammation. Using peripheral inflammatory markers as single predictors we identified fourteen associated with either slower or faster rate of cognitive decline in DLB, whilst no single marker was predictive of decline in AD/MCI+. As many inflammatory markers were highly correlated, we used principal components analysis to identify a cytokine component associated with reduced cognitive decline in both DLB and AD/MCI+, which overlapped with the single markers identified in the previous analysis. A separate component was associated with cognitive decline in AD/MCI+, or DLB with Alzheimer’s dementia co-pathology (ascertained by amyloid PET). Widespread TSPO binding was associated with reduced cognitive decline in DLB, whilst a fronto-temporal pattern was associated with more rapid cognitive decline in both DLB and AD/MCI+. There were associations between peripheral cytokines and TSPO PET in AD/MCI+, but these were not significant in DLB. Overall peripheral and central inflammation predicted cognitive decline in DLB. Specific patterns associated with both faster and slower rates of decline were identified. These profiles had both overlapping and contrasting associations when compared to AD/MCI+. Collectively, these data add to a body of evidence suggesting clinically relevant levels of inflammation in DLB. Future studies in larger, multi-site cohorts with multiple biomarker sampling points are required to understand the impact and dynamics of inflammation across all stages of disease. Swann et al report patterns of peripheral and neuroinflammation associated with different rates of cognitive decline in dementia with Lewy bodies. The authors conclude that inflammation may be clinically relevant in dementia with Lewy bodies and explored as a future treatment target. Graphical Abstract