TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat

EJNMMI Research

Alexander Levit¹  Brian L. Allman¹  Austyn D. Roseborough¹  Shawn N. Whitehead¹  Jonathan D. Thiessen²  Qi Qi²  Nassir U. Al-Khishman²  Udunna C. Anazodo³  Matthew S. Fox⁴ 

[1] Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada;Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada;Lawson Health Research Institute, P.O. Box 5777, B5-003a, 268 Grosvenor St, Stn. B, N6A 4V2, London, ON, Canada;Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada;Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada;Department of Physics and Astronomy, Western University, London, ON, Canada;Lawson Health Research Institute, P.O. Box 5777, B5-003a, 268 Grosvenor St, Stn. B, N6A 4V2, London, ON, Canada;

关键词: TSPO;    Major histocompatibility complex class II;    White matter inflammation;    Ischemic stroke;    Alzheimer’s disease;   

DOI  :  10.1186/s13550-020-00699-x

来源: Springer

【 摘 要 】

BackgroundAccurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) inflammation in neurodegenerative diseases. Radioligands targeting the translocator protein (TSPO) are considered sensitive indicators of neuroinflammation, but it is not clear how well the expression of TSPO coincides with major histocompatibility complex class II (MHCII) molecules in WM. This study aimed to test the ability of TSPO to detect activated WM microglia that are immunohistochemically positive for MHCII in rat models of prodromal Alzheimer’s disease and acute subcortical stroke.MethodsFischer 344 wild-type (n = 12) and TgAPP21 (n = 11) rats were imaged with [18F]FEPPA PET and MRI to investigate TSPO tracer uptake in the corpus callosum, a WM region known to have high levels of MHCII activated microglia in TgAPP21 rats. Wild-type rats subsequently received an endothelin-1 (ET1) subcortical stroke and were imaged at days 7 and 28 post-stroke before immunohistochemistry of TSPO, GFAP, iNOS, and the MHCII rat antigen, OX6.Results[18F]FEPPA PET was not significantly affected by genotype in WM and only detected increases near the ET1 infarct (P = 0.033, infarct/cerebellum uptake ratio: baseline = 0.94 ± 0.16; day 7 = 2.10 ± 0.78; day 28 = 1.77 ± 0.35). Immunohistochemistry confirmed that only the infarct (TSPO cells/mm2: day 7 = 555 ± 181; day 28 = 307 ± 153) and WM that is proximal to the infarct had TSPO expression (TSPO cells/mm2: day 7 = 113 ± 93; day 28 = 5 ± 7). TSPO and iNOS were not able to detect the chronic WM microglial activation that was detected with MHCII in the contralateral corpus callosum (day 28 OX6% area: saline = 0.62 ± 0.38; stroke = 4.30 ± 2.83; P = .029).ConclusionTSPO was only expressed in the stroke-induced insult and proximal tissue and therefore was unable to detect remote and non-insult-related chronically activated microglia overexpressing MHCII in WM. This suggests that research in neuroinflammation, particularly in the WM, would benefit from MHCII-sensitive radiotracers.

【 授权许可】

CC BY