Assessing reactive astrogliosis in Parkinson’s brain with astroglial tracers BU99008 and deprenyl

Abstract

AbstractBackgroundThe knowledge regarding the role of reactive astrogliosis in Parkinson’s disease (PD) is still at the surface level, however, a few in vivo PET studies have speculated that reactive astrogliosis could be an early event in PD pathology. Moreover, a direct link between a‐synuclein pathology and astrocytes in PD has been also shown, where astrocytes play a key role in a‐synuclein propagation by shuttling a‐synuclein between neurons and astrocytes. The PET imaging field is advancing very fast and different astrocytic‐tracers are now available, such as 11C‐Deprenyl (DED) (targeting MAO‐B) and 11C‐BU99008 (detect imidazoline‐2‐binding sites (I2Bs)), which we believe is crucial to explore the role of reactive astrogliosis, including astrocytic heterogeneity in PD. Hence, we used a multi‐tracer approach to understand the role of reactive astrogliosis and to validate its reliability as a potential biomarker in PD and related synucleinopathies.MethodWe used specialized postmortem saturation radioligand binding assay and small frozen human brain section autoradiography in PD and controls (CN) brains.ResultThe 3H‐BU99008 and 3H‐DED saturation binding studies in the frontal cortex (FC) brain homogenate (BH) of PD (n = 2‐3) and CN (n = 2) cases demonstrated relatively higher 3H‐DED binding as compared to 3H‐BU99008 with following Bmax (binding‐density) and Kd values: 3H‐BU99008 CNBmax – 59.1fmol/mg, Kd‐ 2.9nM vs. PDBmax – 51.6fmol/mg, 2.3nM; 3H‐DED CNBmax – 190.6fmol/mg, Kd‐ 2.7nM and PDBmax –244.2fmol/mg, Kd‐ 6.7nM. 3H‐BU99008 binding in the Cau in PD was ∼3‐fold higher than in CN. In contrast, the 3H‐DED binding between CN and PD brains in the Cau BH was almost comparable. Interestingly, qualitative, and semi‐quantitative assessment of small frozen brain section autoradiographies showed increased specific binding of 3H‐BU99008 and 3H‐DED in PD (n = 4) frontal & temporal cortices as compared to CN (n = 2‐3). In Cau, 3H‐BU99008 again showed higher binding than CN whereas 3H‐DED binding was comparable to CN, further complementing our saturation data.ConclusionThe first study to assess reactive astrogliosis signature in postmortem PD brains with astroglial tracers BU99008 and DED. The findings clearly highlight regional differences in BU99008 and DED binding in PD brains and suggest increased reactive astrogliosis at the end stages of the disease warrants further investigation.