In vivo Assessment of Neuroinflammation in 4-Repeat Tauopathies

Objective: The aim of this cross-sectional single center study was to investigate 18kDa translocator protein (TSPO)-PET as a biomarker for microglial activation in the 4-repeat tauopathies corticobasal degeneration and progressive supranuclear palsy (PSP). Methods: Specific binding of the TSPO tracer 18F-GE-180 was determined by serial PET during pharmacological depletion of microglia in a 4-repeat tau mouse model. TSPO-PET was performed in 30 patients with corticobasal syndrome (CBS, 68{+/-}9 years, 16 female) and 14 patients with PSP (69{+/-}9 years, 8 female), and 13 control subjects (70{+/-}7 years, 7 female). Group comparisons and associations with parameters of disease progression and sTREM2 were assessed by region-based and voxel-wise analyses. Results: Tracer binding was significantly reduced after pharmacological depletion of microglia in 4-repeat tau mice. Elevated TSPO labeling (standardized-uptake-value-ratios) was observed in subcortical brain areas of CBS and PSP patients when compared to controls, most pronounced in the globus pallidus internus (CBS: 1.039 [95%CI 1.000-1.078, p<0.001], PSP: 1.046 [95%CI: 0.990-1.101, p<0.001], controls: 0.861 [95%CI 0.802-0.921]), whereas only CBS patients showed additionally elevated tracer binding in motor and supplemental motor areas. TSPO labeling was only correlated weakly with parameters of disease progression in CBS and PSP but allowed sensitive detection of 4-repeat tauopathy patients. sTREM2 did not differ between patients with CBS and controls. Interpretation: Our data indicate a potential of 18F-GE-180 PET to detect microglial activation in the brain of 4-repeat tauopathy patients, fitting to predilection sites of the phenotype. TSPO-PET may serve as a sensitive early disease stage biomarker in 4-repeat tauopathies.