Abstract
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.
Highlights
Diffuse inflammation of brain white matter (WM) has been clinically implicated in the pathology of neurodegenerative diseases including schizophrenia, traumatic brain injury, and Alzheimer’s Disease [1,2,3]
We further demonstrated the importance of diffuse major histocompatibility complex class II (MHCII) activated microglia by detecting them in WM remote to an ischemic subcortical stroke in an endothelin-1 (ET1) rat model that exhibits executive dysfunction [14, 15]
standardized uptake value (SUV) was not significantly affected by genotype, ET1, or interaction between ET1 and timepoints (P = ns for two-way and three-way analyses of variance (ANOVA))
Summary
Diffuse inflammation of brain white matter (WM) has been clinically implicated in the pathology of neurodegenerative diseases including schizophrenia, traumatic brain injury, and Alzheimer’s Disease [1,2,3]. We further demonstrated the importance of diffuse MHCII activated microglia by detecting them in WM remote to an ischemic subcortical stroke in an endothelin-1 (ET1) rat model that exhibits executive dysfunction [14, 15]. Overall, these observations motivate the need to detect MHCII activated microglia in vivo. 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.
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