Objective: To investigate the role of Th17 pathway in systemic and central inflammation in PSP and to identify signatures of inflammation-induced neurodegeneration in PSP.

Background: Progressive Supranuclear Palsy (PSP) is the third most common neurodegenerative disorder. Emerging evidence suggests immune dysfunction and neuroinflammation, particularly microglial activation; however, the underlying mechanism of microglial activation remains unknown. Among the mediators of inflammation, Th17 cells have gained wide recognition for their high encephalitogenic potential and association with various disorders of the nervous system. However, the role of systemic inflammation mediated by Th17 cells and its impact on neuroinflammation/microglia remains unexplored in PSP.

Method: A prospective case-control study was conducted at NIMHANS, with 56 patients with PSP, 56 age-gender-matched controls, and 11 disease controls. Expressions of NF-κB (Nfkb1, Nfkb2), inflammasome (Nlrp3, Casp1, and Il18), Th17 (Il1b, Il6, IL17, Tnfa, Il22, Il23, Rorc, Stat3) and anti-inflammatory (Tgfb, Il10) genes were quantified. Cytokines (IL-6, IL-1β, IL-4, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ sCD40L, TNF-α) were measured in both plasma and CSF. Neuroinflammation was assessed using ¹¹C-PBR28 PET/MRI.

Results: Gene expression levels of Il6 (p=0.026), Il1b (p=0.037), Casp1 (p=0.038), Il18 (p<0.001) and Nfkb1 (p=0.047) were upregulated in PSP as compared to healthy controls. Higher plasma levels of IL-1β (p=0.041), IL-6 (p=0.014) and IL-17A (p=0.031) and decreased levels of IL-25 (p=0.043) and IL-33 (p=0.015) were observed in patients with PSP. Plasma levels of IL-1β were correlated (rho=0.602, p=0.004) with CSF levels of IL-1β in PSP. Increased microglial activation in white matter (WM) (p=0.018), cerebellar WM (p=0.014), and higher atrophy in twelve brain regions as well as whole brain were observed in the PSP compared to disease controls. Additionally, plasma and CSF levels of cytokines were significantly correlated with the disease onset, cognitive function and motor severity.

Conclusion: Elevated expression of genes, plasma cytokines, strong correlations between gene expression and plasma cytokine levels with CSF cytokines and microglial activation highlight the interplay between systemic and neuroinflammation, which may provide important insights into the immunopathogenic basis of PSP.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evidence-of-systemic-and-neuro-inflammation-in-progressive-supranuclear-palsy-insight-from-an-imaging-inflammation-study/