The positron emission tomography radioligand [ 11 C]PBR28 targets translocator protein (18 kDa) (TSPO) and is a potential marker of neuroinflammation. [ 11 C]PBR28 binding is commonly quantified using a two-tissue compartment model and an arterial input function. Previous studies with [ 11 C]-(R)-PK11195 demonstrated a slow irreversible binding component to the TSPO proteins localized in the endothelium of brain vessels, such as venous sinuses and arteries. However, the impact of this component on the quantification of [ 11 C]PBR28 data has never been investigated. In this work we propose a novel kinetic model for [ 11 C]PBR28. This model hypothesizes the existence of an additional irreversible component from the blood to the endothelium. The model was tested on a data set of 19 healthy subjects. A simulation was also performed to quantify the error generated by the standard twotissue compartmental model when the presence of the irreversible component is not taken into account. Our results show that when the vascular component is included in the model the estimates that include the vascular component (2TCM-1K) are more than three-fold smaller, have a higher time stability and are better correlated to brain mRNA TSPO expression than those that do not include the model (2TCM).

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Objectives:To explore in-vivo innate immune cell activation as a function of the distance from ventricular CSF in patients with Multiple Sclerosis (MS) using [18F]-DPA714 PET, and to investigate its relationship with periventricular microstructural damage, evaluated by magnetization transfer ratio (MTR), and with trajectories of disability worsening.Methods:Thirty-seven MS patients and nineteen healthy controls underwent MRI and [18F]-DPA714 TSPO dynamic PET, from which individual maps of voxels characterized by innate immune cell activation (DPA+) were generated. White matter (WM) was divided in 3mm-thick concentric rings radiating from the ventricular surface toward the cortex, and the percentage of DPA+ voxels and mean MTR were extracted from each ring. Two-year trajectories of disability worsening were collected to identify patients with and without recent disability worsening.Results:The percentage of DPA+ voxels was higher in patients compared to controls in the periventricular WM (p=6.10e-6), and declined with increasing distance from ventricular surface, with a steeper gradient in patients compared to controls (p=0.001). This gradient was found both in periventricular lesions and normal-appearing WM. In the total WM, it correlated with a gradient of microstructural tissue damage measured by MTR (rs=-0.65, p=1.0e-3). When compared to clinically stable patients, patients with disability worsening were characterized by a higher percentage of DPA+ voxels in the periventricular normal-appearing WM (p=0.025).Conclusions:Our results demonstrate that in MS the innate immune cell activation predominates in periventricular regions and associates with microstructural damage and disability worsening. This could result from the diffusion of pro-inflammatory CSF-derived factors into surrounding tissues.

Increasing evidence suggests that neuroinflammation is active in Parkinson disease (PD) and contributes to neurodegeneration. This process can be studied in vivo with PET and radioligands targeting TSPO, upregulated in activated microglia. Initial PET studies investigating microglial activation in PD with the [ 11 C]-PK11195 have provided inconclusive results. Here we assess the presence and distribution of neuroinflammatory response in PD patients using [ 18 F]-DPA714 and to correlate imaging biomarkers to dopamine transporter imaging and clinical status. Methods: PD patients (n = 24, Hoehn and Yahr I-III) and 28 healthy controls were scanned with [ 18 F]-DPA714 and [ 11 C]-PE2I and analyzed. They were all genotyped for TSPO polymorphism. Regional binding parameters were estimated (reference Logan graphical approach with supervised cluster analysis). Impact of TSPO genotype was analyzed using Wilcoxon signed-rank test. Differences between groups were investigated using a two-way ANOVA and Tukey post hoc tests. Results: PD patients showed significantly higher [ 18 F]-DPA714 binding compared to healthy controls bilaterally in the midbrain (p < 0.001), the frontal cortex (p = 0.001), and the putamen contralateral to the more clinically affected hemibody (p = 0.038). Microglial activation in these regions did not correlate with the severity of motor symptoms, disease duration nor putaminal [ 11 C]-PE2I uptake. However, there was a trend toward a correlation between cortical TSPO binding and disease duration (p = 0.015 uncorrected, p = 0.07 after Bonferroni correction). Conclusion: [ 18 F]-DPA714 binding confirmed that there is a specific topographic pattern of microglial activation in the nigro-striatal pathway and the frontal cortex of PD patients.

To develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using 18 F-DPA-714 translocator protein (TSPO) positron emission tomography (PET), and to explore the relationship between these maps and individual trajectories of disability worsening in patients with multiple sclerosis (MS). Methods: Patients with MS (n=37), whose trajectories of disability worsening over the 2 years preceding study entry were calculated, and healthy controls (n=19) underwent magnetic resonance magnetic and 18 F-DPA-714 PET. A threshold of significant activation of 18 F-DPA-714 binding was calculated with a voxel-wise randomized permutation-based comparison between patients and controls, and used to classify each WM voxel in patients as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were employed to calculate the extent of activation in WM regions-of-interests and to classify each WM lesion as "DPA-active", "DPA-inactive" or "unclassified". Results: Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM, (NAWM in patients=24.99.7%; WM in controls=14.07.8%, p<0.001). In patients with MS, the percentage of DPA+ voxels showed a significant increase from NAWM, to perilesional areas, T2 hyperintense lesions and T1 hypointense lesions (38.113.5%, 45.017.9%, and 51.922.9%, respectively, p<0.001). Among the 1379 T2 lesions identified, 512 were defined as DPAactive and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (OR=1.13, p=0.009), a higher percentage of DPA+ voxels in the NAWM (OR=1.16, p=0.009) and in T1-spin-echo lesions (OR=1.06, p=0.036), were significantly associated by Imperial College London Library on February 11, 2020. For personal use only. jnm.snmjournals.org Downloaded from 2 with a retrospective more severe clinical trajectory in patients with MS. Conclusion: A more severe trajectory of disability worsening in MS is associated with an innate immune cells activation inside and around WM lesions. 18 F-DPA-714 PET may provide a promising biomarker to identify patients at risk of severe clinical trajectory.

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The 18 kDa translocator protein (TSPO) is a marker of microglia activation and the main target of positron emission tomography (PET) ligands for neuroinflammation. Previous works showed that accounting for TSPO endothelial binding improves PET quantification for [C]PBR28, [F]DPA714 and [C]-R-PK11195. It is still unclear, however, whether the vascular signal is tracer-dependent. This work aims to explore the relationship between the TSPO vascular and tissue components for PET tracers with varying affinity, also assessing the impact of affinity towards the differentiability amongst kinetics and the ensuing ligand amenability to cluster analysis for the extraction of a reference region. First, we applied the compartmental model accounting for vascular binding to [C]-R-PK11195 data from six healthy subjects. Then, we compared the [C]-R-PK11195 vascular binding estimates with previously published values for [F]DPA714 and [C]PBR28. Finally, we determined the suitability for reference region extraction by calculating the angle between grey and white matter kinetics. Our results showed that endothelial binding is common to all TSPO tracers and proportional to their affinity. By consequence, grey and white matter kinetics were most similar for the radioligand with the highest affinity (i.e. [C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering.

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