Wijeyekoon RS, Kronenberg-Versteeg D, Scott KM, et al. - Given the involvement of innate immune system in Parkinson disease (PD) but existing poor knowledge on peripheral in-vivo clinical proof of the components and driving mechanisms implicated and their link with clinical heterogeneity and progression to dementia, researchers assessed alterations in peripheral innate immune-associated markers in PD cases (n = 41) stratified by risk of developing early dementia. Based on neuropsychological predictors and MAPT H1/H2 genotype, experts described ‘Higher Risk’ (n = 23) and ‘Lower Risk’ (n = 18) groups, which were contrasted to age, gender, and genotype-matched controls. The presence of systemic innate immune alterations in PD was revealed, and those carrying a higher risk of rapid progression to dementia exhibited the greatest systemic innate immune changes. A difference was evident between markers related to PD per-se (alpha-synuclein, caspase-1) and those associated with cognitive progression and clinical heterogeneity (endotoxin, Triggering Receptor Expressed on Myeloid cells-2, TLR4, classical monocytes, HLA-DR), with mechanistic as well as therapeutic implications. Alpha-synuclein and caspase-1 were found to be connected, implying inflammasome involvement common to all PD, while bacterial translocation related changes were suggested to likely contribute to progression to Parkinson dementia. Likely modulation of existing clinical disease by HLA-DR-related variations in antigen presentation/clearance was also suggested.