In vivo Assessment of Neuroinflammation in 4-Repeat Tauopathies

Abstract

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.

Multi-omics and 3D-imaging reveal bone heterogeneity and unique calvaria cells in neuroinflammation

“…Next, we assessed whether TSPO imaging of skull would give any hints on underlying brain pathologies in human. To this end, we assessed the TSPO-PET signal in the skull of stroke, relapsing remitting multiple sclerosis (RRMS) ( 43 ) and primary progressive multiple sclerosis (PPMS) patients as well as 4-repeat tauopathy (4RT) patients ( 44 ). Our data demonstrated elevated skull inflammation in each cohort of patients with different patterns ( Fig.…”

PET Imaging of Neuroinflammation in Alzheimer’s Disease

“…Clinical trial of PET using [ 11 C]ER176 for accessing microglia activation in patients with MCI and AD is still ongoing (NCT03744312). Microglial activation assessed by using [ 18 F]GE-180 in different amyloidosis, tauopathy rodent models have been reported ( 47 , 50 , 53 , 89 , 90 , 92 – 102 ) ( Table 1 ). López-Picón et al showed that [ 18 F]GE-180 signal reached plateaus at an early stage, while the Aβ load detected by [ 11 C]PIB was still increasing in APP23 mice ( 90 ).…”

Have (R)-[11C]PK11195 challengers fulfilled the promise? A scoping review of clinical TSPO PET studies

“…In the case of [ 18 F]PBR111, two independent research groups conducted studies in multiple sclerosis [103,230,231] (Imperial College London, UK) and schizophrenia/psychosis [115,232] (University of Antwerp, Belgium). Among the 6 remaining challengers, 2 were restricted to specific groups of pathologies: [ 11 [81], rheumatoid arthritis [200] and stroke [26]). However, [ 18 F]GE-180 was shown to have slow/poor brain uptake in human [233], and the consequences on quantification and modelling have abundantly debated [234][235][236].…”

“…Among the 6 remaining challengers, 2 were restricted to specific groups of pathologies: [ 11 C]DAA1106 and [ 18 F]FEPPA were used only in neurodegenerative diseases and mental disorders ([ 11 C]DAA1106: 20 and 91 patients respectively; [ 18 F]FEPPA: 77 and 337 patients respectively). [ 18 F]GE-180, initially mainly used in patients with multiple sclerosis (45 patients) and brain tumour (68 patients), was recently tested in other pathologies (tauopathies [ 81 ], rheumatoid arthritis [ 200 ] and stroke [ 26 ]). However, [ 18 F]GE-180 was shown to have slow/poor brain uptake in human [ 233 ], and the consequences on quantification and modelling have abundantly debated [ 234 – 236 ].…”

“…Other taupathies (corticobasal degeneration, progressive supranuclear palsy) were studied with (R)-[ 11 C]PK11195 (4 publications, 25 patients [77][78][79][80]), and in one very recent study with [ 18 F]GE-180 (combining 30 CBD and 14 PSP [81]). All studies reported a consensual increased binding in the striatum (CBD and PSP) and cortical areas (CBD > PSP).…”