Neuroinflammation distinguishes HLA haplotypes in progressive supranuclear palsy

ObjectivesProgressive supranuclear palsy (PSP) is a neurodegenerative 4R tauopathy clinically presenting with atypical parkinsonism or cognitive behavioral changes and a relatively uniform neuropathology. We recently identified rare HLA haplotypes in PSP and now examine whether HLA haplotypes are associated with different cytopathological and clinical phenotypes. MethodsRetrospective collection of clinical data and mapping of 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 cluster or predict HLA haplotypes. ResultsFour groups were defined based on HLA haplotypes: i) 12 cases with the haplotype associated with narcolepsy (DRB1*15:01-DQB1*06:02); ii) 11 cases with other DQ5-DQ6 haplotypes; iii) 8 cases with various haplotypes frequent in the general population; and iv) one case with the haplotype frequent in IgLON5-disease (DRB1*10:01-DQB1*05:01). Neuropathology revealed regional differences in the severity of microglia load, density of cytotoxic T cells, and p-Tau cytopathologies between groups. HLA haplotypes were most distinguishable using machine learned features of inflammatory markers and ratios of neuropathological variables (clustering accuracy: 86.96% and 91.30%, respectively). The sequence of clinical symptoms and the ratios of neuropathological variables were the strongest predictors of HLA haplotypes (prediction accuracy=80.00% and 71.43%, respectively). InterpretationPSP pathology might be associated with various etiological-pathogenic events including targetable autoimmune mechanisms. 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.