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Prolonged hematopoietic and myeloid cellular response in patients after an acute coronary syndrome measured with 18F-DPA-714 PET/CT.

ABSTRACT: PURPOSE:An acute coronary syndrome (ACS) is characterized by a multi-level inflammatory response, comprising activation of bone marrow and spleen accompanied by augmented release of leukocytes into the circulation. The duration of this response after an ACS remains unclear. Here, we assessed the effect of an ACS on the multi-level inflammatory response in patients both acutely and after 3 months. METHODS:We performed 18F-DPA-714 PET/CT acutely and 3 months post-ACS in eight patients and eight matched healthy controls. DPA-714, a PET tracer binding the TSPO receptor and highly expressed in myeloid cells, was used to assess hematopoietic activity. We also characterized circulating monocytes and hematopoietic stem and progenitor cells (HSPCs) by flow cytometry in 20 patients acutely and 3 months post-ACS and in 19 healthy controls. RESULTS:In the acute phase, patients displayed a 1.4-fold and 1.3-fold higher 18F-DPA-714 uptake in, respectively, bone marrow (p?=?0.012) and spleen (p?=?0.039) compared with healthy controls. This coincided with a 2.4-fold higher number of circulating HSPCs (p?=?0.001). Three months post-ACS, 18F-DPA-714 uptake in bone marrow decreased significantly (p?=?0.002), but no decrease was observed for 18F-DPA-714 uptake in the spleen (p?=?0.67) nor for the number of circulating HSPCs (p?=?0.75). CONCLUSIONS:18F-DPA-714 PET/CT reveals an ACS- triggered hematopoietic organ activation as initiator of a prolonged cellular inflammatory response beyond 3 months, characterized by a higher number of circulating leukocytes and their precursors. This multi-level inflammatory response may provide an attractive target for novel treatment options aimed at reducing the high recurrence rate post-ACS.

SUBMITTER: Verweij SL

PROVIDER: S-EPMC6132543 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Prolonged hematopoietic and myeloid cellular response in patients after an acute coronary syndrome measured with <sup>18</sup>F-DPA-714 PET/CT.

Verweij Simone L SL Stiekema Lotte C A LCA Delewi Ronak R Zheng Kang H KH Bernelot Moens Sophie J SJ Kroon Jeffrey J Stroes Charlotte I CI Versloot Miranda M Piek Jan J JJ Verberne Hein J HJ Stroes Erik S G ESG

European journal of nuclear medicine and molecular imaging 20180504 11

<h4>Purpose</h4>An acute coronary syndrome (ACS) is characterized by a multi-level inflammatory response, comprising activation of bone marrow and spleen accompanied by augmented release of leukocytes into the circulation. The duration of this response after an ACS remains unclear. Here, we assessed the effect of an ACS on the multi-level inflammatory response in patients both acutely and after 3 months.<h4>Methods</h4>We performed <sup>18</sup>F-DPA-714 PET/CT acutely and 3 months post-ACS in e ...[more]

PMID: 29728748

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Project description:Aim(18)F-DPA-714 is a PET tracer that recognizes macrophage translocator protein (TSPO), and (18)F-Alfatide II ((18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2) is specific for integrin αvβ3. This study aims to apply these two tracers for longitudinal PET imaging of muscular inflammation, and evaluate the value of (18)F-DPA-714 in differentiating inflammation from tumor.MethodsRAW264.7 mouse macrophage cells were used for cell uptake analysis of (18)F-DPA-714. A mouse hind limb muscular inflammation model was established by intramuscular injection of turpentine oil. For the inflammation model, PET imaging was performed at different days using (18)F-DPA-714 and (18)F-Alfatide II. The specificity of the imaging probes was tested by co- or pre-injection of PK11195 or unlabeled RGD (Arg-Gly-Asp) peptide. PET imaging using (18)F-DPA-714 was performed in A549, HT29, U87MG, INS-1, and 4T1 xenograft models. Immunofluorescence staining was performed to evaluate infiltrated macrophages and angiogenesis in inflammation and/or tumors.ResultsUptake of (18)F-DPA-714 in RAW264.7 cells was 45.5% at 1 h after incubation, and could be blocked by PK11195. PET imaging showed increased (18)F-DPA-714 and (18)F-Alfatide II uptake at inflammatory muscles. Peak uptake of (18)F-DPA-714 was seen on day 6 (4.02 ± 0.64 %ID/g), and peak uptake of (18)F-Alfatide II was shown on day 12 (1.87 ± 0.35 %ID/g) at 1 h p.i.. Tracer uptakes could be inhibited by PK11195 for (18)F-DPA-714 or cold RGD for (18)F-Alfatide II. Moreover, macrophage depletion with liposomal clodronate also reduced the local accumulation of both tracers. A549, HT29, U87MG, INS-1, and 4T1 tumor uptakes of (18)F-DPA-714 (0.46 ± 0.28, 0.91 ± 0.08, 1.69 ± 0.67, 1.13 ± 0.33, 1.22 ± 0.55 %ID/g at 1 h p.i., respectively) were significantly lower than inflammation uptake (All P < 0.05).ConclusionPET imaging using (18)F-DPA-714 as a TSPO targeting tracer could evaluate the dynamics of macrophage activation and infiltration in different stages of inflammatory diseases. The concomitant longitudinal PET imaging with both (18)F-DPA-714 and (18)F-Alfatide II matched the causal relationship between macrophage infiltration and angiogenesis. Moreover, we found (18)F-DPA-714 uptake in several types of tumors is significantly lower than that in inflammatory muscles, suggesting (18)F-DPA-714 PET has the potential for better differentiation of tumor and non-tumor inflammation.

Project description:PurposeNeuroinflammation is involved in several brain disorders and can be monitored through expression of the translocator protein 18 kDa (TSPO) on activated microglia. In recent years, several new PET radioligands for TSPO have been evaluated in disease models. [(18)F]DPA-714 is a TSPO radiotracer with great promise; however results vary between different experimental models of neuroinflammation. To further examine the potential of [(18)F]DPA-714, it was compared directly to [(11)C]PK11195 in experimental cerebral ischaemia in rats.MethodsUnder anaesthesia, the middle cerebral artery of adult rats was occluded for 60 min using the filament model. Rats were allowed recovery for 5 to 7 days before one hour dynamic PET scans with [(11)C]PK11195 and/or [(18)F]DPA-714 under anaesthesia.ResultsUptake of [(11)C]PK11195 vs [(18)F]DPA-714 in the ischemic lesion was similar (core/contralateral ratio: 2.84±0.67 vs 2.28±0.34 respectively), but severity of the brain ischemia and hence ligand uptake in the lesion appeared to vary greatly between animals scanned with [(11)C]PK11195 or with [(18)F]DPA-714. To solve this issue of inter-individual variability, we performed a direct comparison of [(11)C]PK11195 and [(18)F]DPA-714 by scanning the same animals sequentially with both tracers within 24 h. In this direct comparison, the core/contralateral ratio (3.35±1.21 vs 4.66±2.50 for [(11)C]PK11195 vs [(18)F]DPA-714 respectively) showed a significantly better signal-to-noise ratio (1.6 (1.3-1.9, 95%CI) fold by linear regression) for [(18)F]DPA-714.ConclusionsIn a clinically relevant model of neuroinflammation, uptake for both radiotracers appeared to be similar at first, but a high variability was observed in our model. Therefore, to truly compare tracers in such models, we performed scans with both tracers in the same animals. By doing so, our result demonstrated that [(18)F]DPA-714 displayed a higher signal-to-noise ratio than [(11)C]PK11195. Our results suggest that, with the longer half-life of [(18)F] which facilitates distribution of the tracer across PET centre, [(18)F]DPA-714 is a good alternative for TSPO imaging.

Project description:BackgroundMagnetic resonance imaging (MRI)-guided pulsed focused ultrasound combined with the infusion of microbubbles (pFUS+MB) induces transient blood-brain barrier opening (BBBO) in targeted regions. pFUS+MB, through the facilitation of neurotherapeutics' delivery, has been advocated as an adjuvant treatment for neurodegenerative diseases and malignancies. Sterile neuroinflammation has been recently described following pFUS+MB BBBO. In this study, we used PET imaging with [18F]-DPA714, a biomarker of translocator protein (TSPO), to assess for neuroinflammatory changes following single and multiple pFUS+MB sessions.MethodsThree groups of Sprague-Dawley female rats received MRI-guided pFUS+MB (Optison™; 5-8 × 107 MB/rat) treatments to the left frontal cortex and right hippocampus. Group A rats were sonicated once. Group B rats were sonicated twice and group C rats were sonicated six times on weekly basis. Passive cavitation detection feedback (PCD) controlled the peak negative pressure during sonication. We performed T1-weighted scans immediately after sonication to assess efficiency of BBBO and T2*-weighted scans to evaluate for hypointense voxels. [18F]DPA-714 PET/CT scans were acquired after the BBB had closed, 24 h after sonication in group A and within an average of 10 days from the last sonication in groups B and C. Ratios of T1 enhancement, T2* values, and [18F]DPA-714 percent injected dose/cc (%ID/cc) values in the targeted areas to the contralateral brain were calculated. Histological assessment for microglial activation/astrocytosis was performed.ResultsIn all groups, [18F]DPA-714 binding was increased at the sonicated compared to non-sonicated brain (%ID/cc ratios > 1). Immunohistopathology showed increased staining for microglial and astrocytic markers in the sonicated frontal cortex compared to contralateral brain and to a lesser extent in the sonicated hippocampus. Using MRI, we documented BBB disruption immediately after sonication with resolution of BBBO 24 h later. We found more T2* hypointense voxels with increasing number of sonications. In a longitudinal group of animals imaged after two and after six sonications, there was no cumulative increase of neuroinflammation on PET.ConclusionUsing [18F]DPA-714 PET, we documented in vivo neuroinflammatory changes in association with pFUS+MB. Our protocol (utilizing PCD feedback to minimize damage) resulted in neuroinflammation visualized 24 h post one sonication. Our findings were supported by immunohistochemistry showing microglial activation and astrocytosis. Experimental sonication parameters intended for BBB disruption should be evaluated for neuroinflammatory sequelae prior to implementation in clinical trials.

Dataset Information

Prolonged hematopoietic and myeloid cellular response in patients after an acute coronary syndrome measured with 18F-DPA-714 PET/CT.

Publications

Prolonged hematopoietic and myeloid cellular response in patients after an acute coronary syndrome measured with <sup>18</sup>F-DPA-714 PET/CT.

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