Search

Introduction: Knowledge of the repeatability of quantitative parameters derived from [18F]FDG PET images is essential to define the group size and allow correct interpretation. Here we tested repeatability and accuracy of different [18F]FDG absolute and relative quantification parameters in a standardized preclinical setup in nonhuman primates (NHP). Material and methods: Repeated brain [18F]FDG scans were performed in 6 healthy NHP under controlled experimental factors likely to account for variability. Regional cerebral metabolic rate of glucose (CMRglu) was calculated using a Patlak plot with blood input function Semi-quantitative approaches measuring standard uptake values (SUV, SUV×glycemia and SUVR (SUV Ratio) using the pons or cerebellum as a reference region) were considered. Test-retest variability of all quantification parameters were compared in different brain regions in terms of absolute variability and intra-and-inter-subject variabilities. In an independent [18F]FDG PET experiment, robustness of these parameters was evaluated in 4 naive NHP. Results: Experimental conditions (injected dose, body weight, animal temperature) were the same at both imaging sessions (p >0.4). No significant difference in the [18F]FDG quantification parameters was found between test and retest sessions. Absolute variability of CMRglu, SUV, SUV×glycemia and normalized SUV ranged from 25 to 43%, 16 to 21%, 23 to 28%, and 7 to 14%, respectively. Intra-subject variability largely explained the absolute variability of all quantitative parameters. They were all significantly correlated to each other and they were all robust. Arterial and venous glycemia were highly correlated (r = 0.9691; p<0.0001). Conclusion: [18F]FDG test-retest studies in NHP protocols need to be conducted under well-standardized experimental conditions to assess and select the most reliable and reproducible quantification approach. Furthermore, the choice of the quantification parameter has to account for the transversal or follow-up study design. If pons and cerebellum regions are not affected, non-invasive SUVR is the most favorable approach for both designs. [ABSTRACT FROM AUTHOR]

The 18 kDa translocator protein (TSPO) is the main molecular target to image neuroinflammation by positron emission tomography (PET). However, TSPO-PET quantification is complex and none of the kinetic modelling approaches has been validated using a voxel-by-voxel comparison of TSPO-PET data with the actual TSPO levels of expression. Here, we present a single case study of binary classification of in vivo PET data to evaluate the statistical performance of different TSPO-PET quantification methods. To that end, we induced a localized and adjustable increase of TSPO levels in a non-human primate brain through a viral-vector strategy. We then performed a voxel-wise comparison of the different TSPO-PET quantification approaches providing parametric [18F]-DPA-714 PET images, with co-registered in vitro three-dimensional TSPO immunohistochemistry (3D-IHC) data. A data matrix was extracted from each brain hemisphere, containing the TSPO-IHC and TSPO-PET data for each voxel position. Each voxel was then classified as false or true, positive or negative after comparison of the TSPO-PET measure to the reference 3D-IHC method. Finally, receiver operating characteristic curves (ROC) were calculated for each TSPO-PET quantification method. Our results show that standard uptake value ratios using cerebellum as a reference region (SUVCBL) has the most optimal ROC score amongst all non-invasive approaches. [ABSTRACT FROM AUTHOR]

There is a great need for a non-invasive methodology enabling the quantification of translocator protein overexpression in PET clinical imaging. [18F]DPA-714 has emerged as a promising translocator protein radiotracer as it is fluorinated, highly specific and returned reliable quantification using arterial input function. Cerebellum gray matter was proposed as reference region for simplified quantification; however, this method cannot be used when inflammation involves cerebellum. Here we adapted and validated a supervised clustering (supervised clustering algorithm (SCA)) for [18F]DPA-714 analysis. Fourteen healthy subjects genotyped for translocator protein underwent an [18F]DPA-714 PET, including 10 with metabolite-corrected arterial input function and three for a test–retest assessment. Two-tissue compartmental modelling provided BPND AIF estimates that were compared to either BPND LoganSCA or BPND LoganCRB generated by Logan analysis (using supervised clustering algorithm extracted reference region or cerebellum gray matter). The supervised clustering algorithm successfully extracted a pseudo-reference region with similar reliability using classes that were defined using either all subjects, or separated into HAB and MAB subjects. BPND AIF, BPND LoganSCA and BPND LoganCRB were highly correlated (ICC of 0.91 ± 0.05) but BPND LoganSCA were ∼26% higher and less variable than BPND LoganCRB. Reproducibility was good with 5% variability in the test–retest study. The clustering technique for [18F]DPA-714 provides a simple, robust and reproducible technique that can be used for all neurological diseases. [ABSTRACT FROM AUTHOR]

Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease. [ABSTRACT FROM AUTHOR]

Astrocytes and microgha become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. It is widely considered that TSPO PET signal reveals reactive microglia, although a few studies suggested a potential contribution of reactive astrocytes. Because astrocytes and microglia play very different roles, it is crucial to determine whether reactive astrocytes can also overexpress TSPO and yield to a detectable TSPO PET signal in vivo. We used a model of selective astrocyte activation through lentiviral gene transfer of the cytokine ciliary neurotrophic factor (CNTF) into the rat striatum, in the absence of neurodegeneration. CNTF induced an extensive activation of astrocytes, which overexpressed GFAP and become hypertrophic, whereas microglia displayed minimal increase in reactive markers. Two TSPOradioligands,[18F]DPA-714[W,iV-diethyl-2-(2-(4-(2-[18F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[l, 5-a]pyrimidin-3-yl)acetamide] and [ 11C]SSR180575 (7-cHoro-N,N-dimethyl-5-[ 11ClmethyU-oxo-S-phenyl-3,5-dmydro-4H-pyridazinoKS-è]indole-l-acetamide), show eda significant binding in the lenti-CNTF-injected striatum that was saturated and displaced by PK11195 [iV-methyl-Af-(l-methylpropyl)-l-(2-chlorophenyl)-isoquinoline-3-carboxamide]. The volume of radioligand binding matched the GFAP immunopositive volume. TSPO mRNA levels were significantly increased, and TSPO protein was over expressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microgha. [ABSTRACT FROM AUTHOR]

18 F-DPA-714 is a second-generation tracer for PET imaging of the 18-kDa translocator protein (TSPO), a marker of neuroinflammation. Analysis and interpretation of TSPO PET are challenging, especially because of the basal expression of TSPO. The aim of this study was to evaluate a compartmental model that accounts for the effect of endothelial TSPO binding on the quantification of 18 F-DPA-714 PET scans from a cohort of healthy subjects. Methods: Fifteen healthy subjects (9 high-affinity binders and 6 mixed-affinity binders) underwent 18 F-DPA-714 PET scans with arterial blood sampling and metabolite analysis. The kinetic parameters were quantified using a 2-tissue compartmental model (2TC) as well as a 2TC with an extra, irreversible, compartment for endothelial binding (2TC-1K). These regional parameters and messenger RNA (mRNA) expression specific to endothelial cells were correlated with regional TSPO mRNA expression. Results: The 2TC-1K model was more appropriate than the 2TC for 81% of fits. The total volume of distribution was significantly reduced by 21% ± 12% across all regions with the 2TC-1K, compared with the 2TC. The endothelial binding parameter K b varied highly across brain regions. K b strongly and significantly correlated with all 3 probes extracted for TSPO mRNA expression ( r = 0.80, r = 0.79, and r = 0.90), but no correlation was seen with the other binding parameters from the 2TC-1K. For the 2TC, there was a lower but significant correlation between the volume of distribution and one of the TSPO mRNA probes ( r = 0.65). A strong, significant correlation was seen between mRNA for TSPO and genes specific to endothelial cells. Conclusion: Accounting for endothelial TSPO in the kinetic model improved the fit of PET data. The high correlation between K b and TSPO mRNA suggests that the 2TC-1K model reveals more biologic information about the regional density of TSPO than the 2TC. The correlation between TSPO and endothelial cell mRNA supports the relationship between the regional variation of K b and endothelial TSPO. These results can improve the estimation of binding parameter estimates from 18 F-DPA-714 PET, especially in diseases that induce vascular change., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Unlabelled: Translocator protein (TSPO) is expressed at a low level in healthy brain and is upregulated during inflammatory processes that may occur in neurodegenerative diseases. Thus, TSPO may be a suitable in vivo indicator of neurodegeneration. Here, we quantified the (18)F-DPA-714 radioligand in healthy TSPO-genotyped volunteers and developed a method to eliminate the need for invasive arterial blood sampling., Methods: Ten controls (7 high-affinity binders [HABs] and 3 mixed-affinity binders [MABs]) underwent (18)F-DPA-714 PET with arterial and venous sampling. (18)F-DPA-714 binding was quantified with a metabolite-corrected arterial plasma input function, using the 1- and 2-tissue-compartment models (TCMs) as well as the Logan analysis to estimate total volume distribution (V(T)) in the regions of interest. Alternative quantification methods were tested, including tissue-to-plasma ratio or population-based input function approaches normalized by late time points of arterial or venous samples., Results: The distribution pattern of (18)F-DPA-714 was consistent with the known distribution of TSPO in humans, with the thalamus displaying the highest binding and the cerebellum the lowest. The 2-TCM best described the regional kinetics of (18)F-DPA-714 in the brain, with good identifiability (percentage coefficient of variation < 5%). For each region of interest, V(T) was 47.6% ± 6.3% higher in HABs than in MABs, and estimates from the 2-TCM and the Logan analyses were highly correlated. Equilibrium was reached at 60 min after injection. V(T) calculated with alternative methods using arterial samples was strongly and significantly correlated with that calculated by the 2-TCM. Replacement of arterial with venous sampling in these methods led to a significant but lower correlation., Conclusion: Genotyping of subjects is a prerequisite for a reliable quantification of (18)F-DPA-714 PET images. The 2-TCM and the Logan analyses are accurate methods to estimate (18)F-DPA-714 V(T) in the human brain of both HAB and MAB individuals. Population-based input function and tissue-to-plasma ratio with a single arterial sample are promising alternatives to classic arterial plasma input function. Substitution with venous samples is promising but still requires methodologic improvements., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Objectives: This work includes (1) the characterization of a reproducible poly[lactide-coglycolide] (PLGA) microparticle preparation with an optimial mean diameter and size distribution and (2) the preliminary in vivo ultrasonographic investigation of PLGA microparticles., Methods: A first series of PLGA microparticle preparations (1 to 15 mum) was acoustically characterized on a hydrodynamic device to select the most appropriate for ultrasound contrast agent application. Preparations of 3-microm microparticles were selected, characterized at different doses, and then injected into 20 melanoma grafted mice for contrast-enhanced power Doppler ultrasonography evaluation., Results: The 3-microm microparticles (3.26-microm mean diameter with 0.41-microm standard deviation) led to in vitro enhancement of 18.3 dB at 0.62 mg/mL. In vivo experiments showed 47% enhancement of intratumoral vascularization detection after PLGA injection, significantly correlated (P < 0.0001) with preinjection intravascularization and tumoral volume. No toxicity was histologically observed., Conclusion: The 3-microm PLGA microparticles provided significant enhancement in vitro and in vivo without any toxicity.