Distinct neuroinflammatory profiles in progressive supranuclear palsy associated with HLA haplotypes

Progressive supranuclear palsy (PSP) is a neurodegenerative four-repeat tauopathy characterized by atypical parkinsonism or cognitive behavioral changes and a relatively uniform neuropathology. Building on prior identification of rare HLA (human leukocyte antigen) haplotypes in PSP, this study investigates whether these haplotypes correlate with distinct clinical and immunopathological phenotypes. In addition to retrospective collection of clinical data, we evaluated T and B cells, microglia, and phosphorylated-tau (p-Tau) cytopathologies in 32 PSP cases. Machine learning was used to analyze whether pathological variables and their ratios, or the sequence of clinical symptoms are different HLA-defined groups, including one linked to narcolepsy (DRB1*15:01-DQB1*06:02). Neuropathology revealed regional differences in the severity of microglia load, density of cytotoxic T cells, and p-Tau cytopathologies between groups. Machine learning revealed that specific ratios of neuroinflammatory markers reliably distinguished HLA haplotypes. Additionally, symptom progression sequences varied by HLA haplotype, suggesting a potential effect of neuroinflammatory profiles on disease trajectory. These findings support the notion that PSP pathology might be associated with various etiological-pathogenic events rarely including targetable autoimmune mechanisms as well. The HLA-haplotype dependent diversity of neuroinflammatory markers should be evaluated in clinical and biomarker studies in, and beyond, PSP to understand its relevance for patient stratification in disease modifying therapy trials.