Abstract
PurposeOver the past 20 years, neuroinflammation (NI) has increasingly been recognised as having an important role in many neurodegenerative diseases, including Alzheimer’s disease. As such, being able to image NI non-invasively in patients is critical to monitor pathological processes and potential therapies targeting neuroinflammation. The translocator protein (TSPO) has proven a reliable NI biomarker for positron emission tomography (PET) imaging. However, if TSPO imaging in acute conditions such as stroke provides strong and reliable signals, TSPO imaging in neurodegenerative diseases has proven more challenging. Here, we report results comparing the recently developed TSPO tracers [18F]GE-180 and [18F]DPA-714 with (R)-[11C]PK11195 in a rodent model of subtle focal inflammation.ProceduresAdult male Wistar rats were stereotactically injected with 1 μg lipopolysaccharide in the right striatum. Three days later, animals underwent a 60-min PET scan with (R)-[11C]PK11195 and [18F]GE-180 (n = 6) or [18F]DPA-714 (n = 6). Ten animals were scanned with either [18F]GE-180 (n = 5) or [18F]DPA-714 (n = 5) only. Kinetic analysis of PET data was performed using the simplified reference tissue model (SRTM) with a contralateral reference region or a novel data-driven input to estimate binding potential BPND. Autoradiography and immunohistochemistry were performed to confirm in vivo results.ResultsAt 40–60 min post-injection, [18F]GE-180 dual-scanned animals showed a significantly increased core/contralateral uptake ratio vs. the same animals scanned with (R)-[11C]PK11195 (3.41 ± 1.09 vs. 2.43 ± 0.39, p = 0.03); [18]DPA-714 did not (2.80 ± 0.69 vs. 2.26 ± 0.41). Kinetic modelling with a contralateral reference region identified significantly higher binding potential (BPND) in the core of the LPS injection site with [18F]GE-180 but not with [18F]DPA-714 vs. (R)-[11C]PK11195. A cerebellar reference region and novel data-driven input to the SRTM were unable to distinguish differences in tracer BPND.ConclusionsSecond-generation TSPO-PET tracers are able to accurately detect mild-level NI. In this model, [18F]GE-180 shows a higher core/contralateral ratio and BPND when compared to (R)-[11C]PK11195, while [18F]DPA-714 did not.
Highlights
Inflammation is known to play a role in the development and progression of a wide variety of neuropathological conditions, including stroke [1], multiple sclerosis [2] and neurodegenerative diseases [3, 4]
There were no significant differences between animals scanned with [18F]GE-180only (n = 5) and [18F]GE180 (n = 6), nor with [18F]DPA-714only (n = 5) and [18F]DPA-714 (n = 6) (Table 1)
Published work has shown that both F-18 labelled tracers have an improved SNR over (R)-[11C]PK11195 in models of acute inflammation [17, 22, 23, 28], but to date, there is neither reported investigation comparing these new tracers nor looking at their performance in a model producing a lower level inflammation (∼2-fold increase in translocator protein (TSPO) positron emission tomography (PET) signal), which is more similar to the levels observed in neurodegenerative diseases than stroke [17, 23], excitotoxic lesions [16, 48] or high doses of LPS [28, 34] (∼4–6-fold increase in TSPO PET signal)
Summary
Inflammation is known to play a role in the development and progression of a wide variety of neuropathological conditions, including stroke [1], multiple sclerosis [2] and neurodegenerative diseases [3, 4]. Microglia, which are resident immune cells of the brain, are in a state of ramification and constantly probing against potential insult or injury, even in the healthy brain [5,6,7] Once activated, they begin to alter their morphology, becoming increasingly macrophage-like and releasing pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor-α (TNF-α). They begin to alter their morphology, becoming increasingly macrophage-like and releasing pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor-α (TNF-α) Whether this cytokine cascade exacerbates damage or helps to restore equilibrium conditions varies depending on the nature of the insult and with time [8]. The true role of TSPO in NI remains to be fully understood, an increase in expression of the protein is well established as a correlate with the level of microglial activation, proliferation and/or level of infiltrated macrophages, and to some extent astrogliosis [2, 10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
