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Microglia activation, an indicator of central nervous system inflammation, is believed to contribute to the pathology of Huntington’s disease. Laquinimod is capable of regulating microglia. By targeting the translocator protein, 11C-PBR28 PET-CT imaging can be used to assess the state of regional gliosis in vivo and explore the effects of laquinimod treatment. This study relates to the LEGATO-HD, multi-centre, double-blinded, Phase 2 clinical trial with laquinimod (US National Registration: NCT02215616). Fifteen patients of the UK LEGATO-HD cohort (mean age: 45.2 ± 7.4 years; disease duration: 5.6 ± 3.0 years) were treated with laquinimod (0.5 mg, N = 4; 1.0 mg, N = 6) or placebo (N = 5) daily. All participants had one 11C-PBR28 PET-CT and one brain MRI scan before laquinimod (or placebo) and at the end of treatment (12 months apart). PET imaging data were quantified to produce 11C-PBR28 distribution volume ratios. These ratios were calculated for the caudate and putamen using the reference Logan plot with the corpus callosum as the reference region. Partial volume effect corrections (Müller–Gartner algorithm) were applied. Differences were sought in Unified Huntington’s Disease Rating Scale scores and regional distribution volume ratios between baseline and follow-up and between the two treatment groups (laquinimod versus placebo). No significant change in 11C-PBR28 distribution volume ratios was found post treatment in the caudate and putamen for both those treated with laquinimod (N = 10) and those treated with placebo (N = 5). Over time, the patients treated with laquinimod did not show a significant clinical improvement. Data from the 11C-PBR28 PET-CT study indicate that laquinimod may not have affected regional translocator protein expression and clinical performance over the studied period.

Background Microglial activation contributes to both inflammatory damage and repair in experimental ischemic stroke. However, because of the logistical challenges, there have been few clinical imaging studies directly describing inflammatory activation and its resolution after stroke. The purpose of our pilot study was to describe the spatio-temporal profile of brain inflammation after stroke using 18kD translocator protein (TSPO) positron emission tomography (PET) with magnetic resonance (MR) co-registration in the subacute and chronic stage after stroke. Methods Three patients underwent magnetic resonance imaging (MRI) and PET scans with TSPO ligand [11C]PBR28 15 ± 3 and 90 ± 7 days after an ischaemic stroke. Regions of interest (ROI) were defined on MRI images and applied to the dynamic PET data to derive regional time-activity curves. Regional uptake was quantified as standardised uptake values (SUV) over 60 to 90 min post-injection. ROI analysis was applied to identify binding in the infarct, and in frontal, temporal, parietal, and occipital lobes and cerebellum excluding the infarcted area. Results The mean age of participants was 56 ± 20.4 years and mean infarct volume was 17.9 ± 18.1 ml. [11C]PBR28 showed increased tracer signal in the infarcted area compared to non-infarcted areas of the brain in the subacute phase of stroke (Patient 1 SUV 1.81; Patient 2 SUV 1.15; Patient 3 SUV 1.64). [11C]PBR28 uptake returned to the level of non-infarcted areas at 90 days Patient 1 SUV 0.99; Patient 3 SUV 0.80). No additional upregulation was detected elsewhere at either time point. Conclusions The neuroinflammatory reaction after ischaemic stroke is limited in time and circumscribed in space suggesting that post-ischaemic inflammation is tightly controlled but regulatory mechanisms.

Background: Saliva and tear flow rates and minor salivary gland biopsy are typically used to assess gland function and disease activity in primary Sjogren’s syndrome (pSS); however, these have limitations. Imaging methods can directly visualize and generate quantitative values in individual glands. 18F-FDG-PET/CT (18F-FDG) measures glucose metabolism, a potential surrogate for inflammation; 11C-methionine-PET/CT (11C-met) is an amino acid PET tracer that assesses protein synthesis, a potential surrogate for gland synthetic function. Objectives: Explore the potential of molecular imaging and multi-parametric MRI to characterize and quantify pSS disease manifestations. Methods: In this pilot imaging study (203818), patients with pSS diagnosed per AECG criteria, with a EULAR Sjogren’s syndrome disease activity index score ≥5, and basal salivary flow >0.0 mL/min or stimulated salivary flow rate ≥0.05 mL/min, underwent 18F-FDG and 11C–met and dynamic contrast-enhanced and diffusion-weighted MRI, followed by minor salivary gland biopsy for histological analysis. Age- and sex-matched healthy volunteers (HV) underwent MRI and 11C-met. HV-pSS mean differences (m-diff; 95% confidence intervals [CI]) were calculated and Pearson’s correlation coefficients (r) estimated. Peak PET standard uptake values (SUVpeak) were used in the correlations and SUVmax values were recorded. All methods were compared with routine clinical and laboratory tests. Results: 12 patients had MRI, 18F-FDG and 11C–met; while HV (n=12) had MRI (n=12) and 11C–met (n=8). A lower 11C-met SUVpeak was seen in the parotid (m-diff: 1.4 g/mL [0.4, 2.3]) and submandibular (m-diff: 2.0 g/mL [0.9, 3.2]) glands in pSS versus HV, as was a trend for lower lacrimal gland uptake (m-diff: 0.5 g/mL [-0.2, 1.3]) in patients with pSS. On structural MRI, the fat fraction (mean%) was higher in pSS vs HV in the submandibular glands (m-diff: -14.8 [CI: -29.3, -0.4]), with similar trends observed in the parotid glands (-11.2 [-24.3, 1.9]). There was a negative correlation between 11C-met uptake and fat fraction (r: -0.7 [-0.9, -0.4]) in the combined parotid glands. There was positive correlation between 11C-met uptake and stimulated salivary flow (r: 0.5 [0.03, 0.8]) and negative correlation for stimulated salivary flow and fat fraction (r: -0.5 (-0.8, -0.1)] in the parotid glands; similar correlations were also seen in the submandibular glands. There was negative correlation between the global lymphoid aggregation score on minor salivary gland biopsy and the combined salivary gland fat fraction (r: -0.7 [-0.9, -0.2]). Parotid gland SUVmax 18F-FDG uptake was higher than historical control values (mean: 1.9 g/ml, [SD: 0.5]1) in some patients (pSS mean SUVmax: 2.8 g/mL [SD: 0.8, range 1.7–4.6]), with positive correlation between 18F–FDG and 11C-met uptake (r: 0.7 [0.2, 0.9]) in the combined salivary glands. Conclusion: Imaging showed clear differences between pSS and HV and correlated with clinical endpoints. Low 11C-met uptake and high fat fraction on MRI may indicate poor residual gland function, while high 18F-FDG and stable 11C-met uptake may define a subpopulation that responds well to anti-inflammatory therapies. References [1] Basu S, et al. Nucl Med Commun 2008; 29:367–73. Acknowledgement: Study/editorial support by Fishawack Indicia Ltd, UK funded by GSK. Disclosure of Interests: Michele Bombardieri Grant/research support from: Celgene, Consultant for: Medimmune, Coziana Ciurtin: None declared, Michalis Kostapanos Consultant for: Is an NHS consultant seconded to the GSK Clinical Cambridge Unit (50%) and has nothing to disclose., Elisa Astorri: None declared, Anwar Tappuni: None declared, Natasha Jordan: None declared, Saleem Azeem Shareholder of: GSK, Teresa Fuller Shareholder of: GSK, Employee of: GSK, Kathleen Port Shareholder of: GSK, Employee of: GSK, Nirav Ratia Shareholder of: GSK, Employee of: GSK, Andre van Maurik Shareholder of: GSK, Employee of: GSK, Calum Gray: None declared, Lucy Kershaw: None declared, Rob Janiczek Shareholder of: GSK, Employee of: GSK, Graham Searle: None declared, Paul Galette Shareholder of: GSK, Employee of: GSK, Marius de Groot Shareholder of: GSK, Employee of: GSK, Neel Patel Shareholder of: GSK, Employee of: GSK, Nicolas Wisniacki Shareholder of: GSK, Employee of: GSK, Mats Bergstrom Shareholder of: GSK, Consultant for: acted as external consultant to GSK, Employee of: GSK, Pilar Jimenez-Royo Shareholder of: GSK, Employee of: GSK, Ruth Tarzi Shareholder of: GSK, Employee of: GSK

Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimer's Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD.