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Quantification of [11C]PBR28 data after systemic lipopolysaccharide challenge.

ABSTRACT: BACKGROUND:Lipopolysaccharide (LPS) is a classic immune stimulus. LPS combined with positron emission tomography (PET) 18?kDa translocator protein (TSPO) brain imaging provides a robust human laboratory model to study neuroimmune signaling. To evaluate optimal analysis of these data, this work compared the sensitivity of six quantification approaches. METHODS:[11C]PBR28 data from healthy volunteers (N = 8) were collected before and 3?h after LPS challenge (1.0?ng/kg IV). Quantification approaches included total volume of distribution estimated with two tissue, and two tissue plus irreversible uptake in whole blood, compartment models (2TCM and 2TCM-1k, respectively) and multilinear analysis-1 (MA-1); binding potential estimated with simultaneous estimation (SIME); standardized uptake values (SUV); and SUV ratio (SUVR). RESULTS:The 2TCM, 2TCM-1k, MA-1, and SIME approaches each yielded substantive effect sizes for LPS effects (partial ?2 = 0.56-0.89, ps <. 05), whereas SUV and SUVR did not. CONCLUSION:These findings highlight the importance of incorporating AIF measurements to quantify LPS-TSPO studies.

SUBMITTER: Woodcock EA

PROVIDER: S-EPMC7067964 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Quantification of [<sup>11</sup>C]PBR28 data after systemic lipopolysaccharide challenge.

Woodcock Eric A EA Schain Martin M Cosgrove Kelly P KP Hillmer Ansel T AT

EJNMMI research 20200312 1

<h4>Background</h4>Lipopolysaccharide (LPS) is a classic immune stimulus. LPS combined with positron emission tomography (PET) 18 kDa translocator protein (TSPO) brain imaging provides a robust human laboratory model to study neuroimmune signaling. To evaluate optimal analysis of these data, this work compared the sensitivity of six quantification approaches.<h4>Methods</h4>[<sup>11</sup>C]PBR28 data from healthy volunteers (N = 8) were collected before and 3 h after LPS challenge (1.0 ng/kg IV) ...[more]

PMID: 32166497

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Project description:[(11)C] PBR28 binding to translocator protein (TSPO) was evaluated for imaging of acute and chronic inflammation using two established rat models.Acute inflammation was induced by local carrageenan injection into the paw of Fisher 344 rats (model A). T-cell mediated adjuvant arthritis was induced by heat-inactivated Mycobacterium butyricum injection in Lewis rats (model B). Micro-PET scan was performed after injection of approximately 35 MBq [(11)C]PBR28. In model A, volumes of interest (VOIs) were defined in the paw of Fisher 344 rats (n=6) with contralateral sham treatment as control. For model B, VOIs were defined in the tail, sacroiliac joints, hips, knees and thigh muscles of M. butyricum treated animals (n=8) and compared with sham-treated controls (n=4). The peak (11)C-PBR28 SUV (SUVpeak) and area under the curve (AUCSUV) of 60-minute time-activity data were calculated. Immunohistochemistry for CD68, a macrophage stain, was performed from paw tissues. In addition, the [(11)C]PBR28 cell uptake was measured in lipopolysaccharide (LPS)-stimulated and non-stimulated macrophage cultures.LPS-stimulated macrophages displayed dose-dependent increased [(11)C]PBR28 uptake, which was blocked by non-labeled PBR28. In both models, radiotracer uptake of treated lesions increased rapidly within minutes and displayed overall accumulative kinetics. The SUVpeak and AUCSUV of carrageenan-treated paws was significantly increased compared to controls. Also, the [(11)C]PBR28 uptake ratio of carrageenan-treated vs. sham-treated paw correlated significantly with CD68 staining ratios of the same animals. In adjuvant arthritis, significantly increased [(11)C]PBR28 SUVpeak and AUCSUV values were identified at the tail, knees, and sacroiliac joints, while no significant differences were identified in the lumbar spine and hips.Based on our initial data, [(11)C]PBR28 PET appears to have potential for imaging of various inflammatory processes involving macrophage activation.

Project description:BackgroundThe standard reference region (RR) for amyloid-beta (A?) PET studies is the cerebellar grey matter (GMCB), while alternative RRs have mostly been utilized without prior validation against the gold standard. This study compared five commonly used RRs to gold standard plasma input-based quantification using the GMCB.MethodsThirteen subjects from a test-retest (TRT) study and 30 from a longitudinal study were retrospectively included (total: 17 Alzheimer's disease, 13 mild cognitive impairment, 13 controls). Dynamic [11C]PiB PET (90 min) and T1-weighted MR scans were co-registered and time-activity curves were extracted for cortical target regions and the following RRs: GMCB, whole cerebellum (WCB), white matter brainstem/pons (WMBS), whole brainstem (WBS) and eroded subcortical white matter (WMES). A two-tissue reversible plasma input model (2T4k_Vb) with GMCB as RR, reference Logan and the simplified reference tissue model were used to derive distribution volume ratios (DVRs), and standardized uptake value (SUV) ratios were calculated for 40-60 min and 60-90 min intervals. Parameter variability was evaluated using TRT scans, and correlations and agreements with the gold standard (DVR from 2T4k_Vb with GMCB RR) were also assessed. Next, longitudinal changes in SUVs (both intervals) were assessed for each RR. Finally, the ability to discriminate between visually A? positive and A? negative scans was assessed.ResultsAll RRs yielded stable TRT performance (max 5.1% variability), with WCB consistently showing lower variability. All approaches were able to discriminate between A? positive and A? negative scans, with highest effect sizes obtained for GMCB (range?-?0.9 to?-?0.7), followed by WCB (range?-?0.8 to?-?0.6). Furthermore, all approaches provided good correlations with the gold standard (r???0.78), while the highest bias (as assessed by the regression slope) was observed using WMES (range slope 0.52-0.67), followed by WBS (range slope 0.58-0.92) and WMBS (range slope 0.62-0.91). Finally, RR SUVs were stable across a period of 2.6 years for all except WBS and WMBS RRs (60-90 min interval).ConclusionsGMCB and WCB are considered the best RRs for quantifying amyloid burden using [11C]PiB PET.

Dataset Information

Quantification of [11C]PBR28 data after systemic lipopolysaccharide challenge.

Publications

Quantification of [<sup>11</sup>C]PBR28 data after systemic lipopolysaccharide challenge.

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