[18F]FEPPA PET imaging for monitoring CD68-positive microglia/macrophage neuroinflammation in nonhuman primates

Abstract

The aim of this study was to examine whether the translocator protein 18-kDa (TSPO) PET ligand [ 18 F]FEPPA has the sensitivity for detecting changes in CD68-positive microglial/macrophage activation in hemiparkinsonian rhesus macaques treated with allogeneic grafts of induced pluripotent stem cell-derived midbrain dopaminergic neurons (iPSC-mDA). Methods: In vivo positron emission tomography (PET) imaging with [ 18 F]FEPPA was used in conjunction with postmortem CD68 immunostaining to evaluate neuroinflammation in the brains of hemiparkinsonian rhesus macaques (n = 6) that received allogeneic iPSC-mDA grafts in the putamen ipsilateral to MPTP administration. Results: Based on assessment of radiotracer uptake and confirmed by visual inspection of the imaging data, nonhuman primates with allogeneic grafts showed increased [ 18 F]FEPPA binding at the graft sites relative to the contralateral putamen. From PET asymmetry analysis of the images, the mean asymmetry index of the monkeys was AI = − 0.085 ± 0.018. Evaluation and scoring of CD68 immunoreactivity by an investigator blind to the treatment identified significantly more neuroinflammation in the grafted areas of the putamen compared to the contralateral putamen (p = 0.0004). [ 18 F]FEPPA PET AI showed a positive correlation with CD68 immunoreactivity AI ratings in the monkeys (Spearman's ρ = 0.94; p = 0.005). Conclusion: These findings reveal that [ 18 F]FEPPA PET is an effective marker for detecting increased CD68-positive microglial/macrophage activation and demonstrates sufficient sensitivity to detect changes in neuroinflammation in vivo following allogeneic cell engraftment.

Real‐time trajectory guide tracking for intraoperative MRI‐guided neurosurgery

“…The surgical procedure and equipment are described in our previous work, 18 as are the in vivo positron emission tomography and postmortem histology methods that were used to show successful implantation of similar cells after delivery to the putamen using this IMRI method. 9 The experiments were performed according to the federal guidelines on animal use and care 19 with approval of University of Wisconsin–Madison Institutional Animal Care and Use Committees.…”

“…In addition to in vitro experiments, we present in vivo targeting results from nonhuman primate (NHP) subjects undergoing preclinical gene and cell delivery experiments with postoperative observation periods of months to years. We have applied the proposed method during our NHP work on cell delivery for Parkinson's disease 8‐10 and viral vector gene delivery to study pathological anxiety 11,12 …”

The 18-kDa Translocator Protein PET Tracers as a Diagnostic Marker for Neuroinflammation: Development and Current Standing

“…From various studies of complete distribution in rats and athymic mice, a higher uptake in the peripheral parts like hearts and kidneys was reported when differentiated from the brain. − Initially, the in vitro consequence of polymorphism of FEPPA was not reported; only in vivo polymorphism has been considered. But recently, in vitro considerations for the polymorphism rs6971 in human colorectal cancer suggested a similar behavior of FEPPA to those of other TSPO PET tracers with respect to polymorphism rs6971. − …”

“…But recently, in vitro considerations for the polymorphism rs6971 in human colorectal cancer suggested a similar behavior of FEPPA to those of other TSPO PET tracers with respect to polymorphism rs6971. 62 − 64 …”

Inflaming the Brain with Iron

“…Microglia/macrophage activation can be followed during the progression of neurodegeneration by non-invasive techniques, such as positron emission tomography (PET), using radiotracers specifically designed for targeting the mitochondrial translocator protein 18-kDa (TSPO), which is a protein highly expressed in activated microglia/macrophages. Microglial/macrophage activation has been observed using PET in monkeys injected with the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is a toxin that selectively kills dopaminergic neurons [ 27 , 28 ], and in rats expressing human A53T mutated α-synuclein in SN [ 29 , 30 ] or injected with the highly oxidable dopamine analog 6-hydroxydopamine (6-OHDA) [ 31 , 32 ]. Altered glial immune responses have also been observed in animal models of familial PD [ 33 , 34 ] and in transgenic mice expressing AD-associated mutant proteins [ 35 , 36 ].…”