Effect of a multinutrient intervention after ischemic stroke in female C57Bl/6 mice.

Stroke can affect females very differently from males, and therefore preclinical research on underlying mechanisms and the effects of interventions should not be restricted to male subjects, and treatment strategies for stroke should be tailored to benefit both sexes. Previously, we demonstrated that a multinutrient intervention (Fortasyn) improved impairments after ischemic stroke induction in male C57Bl/6 mice, but the therapeutic potential of this dietary treatment remained to be investigated in females. We now induced a transient middle cerebral artery occlusion (tMCAo) in C57Bl/6 female mice and immediately after surgery switched to either Fortasyn or an isocaloric Control diet. The stroke females performed several behavioral and motor tasks before and after tMCAo and were scanned in an 11.7 Tesla MRI scanner to assess brain perfusion, integrity and functional connectivity. To assess brain plasticity, inflammation and vascular integrity, immunohistochemistry was performed after sacrifice of the mice. We found that the multinutrient intervention had diverse effects on the stroke-induced impairments in females. Similar to previous observations in male stroke mice, brain integrity, sensorimotor integration and neurogenesis benefitted from Fortasyn, but impairments in activity and motor skills were not improved in female stroke mice. Overall, Fortasyn effects in the stroked females seem more modest in comparison to previously investigated stroked male mice. We suggest that with further optimization of treatment protocols more information on the efficacy of specific interventions in stroked females can be gathered. This in turn will help with the development of (gender-specific) treatment regimens for cerebrovascular diseases such as stroke

Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state

Microglia are potential targets for therapeutic intervention in neurological and neurodegenerative diseases affecting the central nervous system. In order to assess the efficacy of therapies aimed to reduce the tissue damaging activities of microglia and/or to promote the protective potential of these cells, suitable pre-clinical and clinical tools for the in vivo analysis of microglia activities and dynamics are required. The aim of this work was to identify new translational markers of the anti-inflammatory / protective state of microglia for the development of novel PET tracers. Methods: New translational markers of the anti-inflammatory/protective activation state of microglia were selected by bioinformatic approaches and were in vitro and ex vivo validated by qPCR and immunohistochemistry in rodent and human samples. Once a viable marker was identified, a novel PET tracer was developed. This tracer was subsequently confirmed by autoradiography experiments in murine and human brain tissues. Results: Here we provide evidence that P2RY12 expression increases in murine and human microglia following exposure to anti-inflammatory stimuli, and that its expression is modulated in the reparative phase of experimental and clinical stroke. We then synthesized a novel carbon-11 labeled tracer targeting P2RY12, showing increased binding in brain sections of mice treated with IL4, and low binding to brain sections of a murine stroke model and of a stroke patient. Conclusion: This study provides new translational targets for PET tracers for the anti-inflammatory/protective activation state of microglia and shows the potential of a rationale-based approach. It therefore paves the way for the development of novel non-invasive methodologies aimed to monitor the success of therapeutic approaches in various neurological diseases

Multimodal imaging reveals temporal and spatial microglia and matrix metalloproteinase activity after experimental stroke

Stroke is the most common cause of death and disability from neurologic disease in humans. Activation of microglia and matrix metalloproteinases (MMPs) is involved in positively and negatively affecting stroke outcome. Novel, noninvasive, multimodal imaging methods visualizing microglial and MMP alterations were employed. The spatio-temporal dynamics of these parameters were studied in relation to blood flow changes. Micro positron emission tomography (μPET) using [F]BR-351 showed MMP activity within the first days after transient middle cerebral artery occlusion (tMCAo), followed by increased [F]DPA-714 uptake as a marker for microglia activation with a maximum at 14 days after tMCAo. The inflammatory response was spatially located in the infarct core and in adjacent (penumbral) tissue. For the first time, multimodal imaging based on PET, single photon emission computed tomography, and magnetic resonance imaging revealed insight into the spatio-temporal distribution of critical parameters of poststroke inflammation. This allows further evaluation of novel treatment paradigms targeting the postischemic inflammation.Peer Reviewe

P09.05 177Lu-DOTATATE therapy in progressive meningioma

Abstract BACKGROUND Progressive meningioma is a challenging condition with a decreasing number of treatment options over the course of disease. Neurovascular involvement and multifocal disease often complicate surgical management. In addition, repeated radiotherapy carriers a risk of side effects. In somatostatin receptor expressing meningioma, peptide receptor radiotherapy (PPRT) with 177Lu-DOTATATE poses a promising alternative. However, current evidence is scarce. Hereby we present our single center experience of (PPRT) with 177Lu-DOTATATE in progressive meningioma. METHODS Eight patients (median age: 71 years; range 56–77) with progressive meningioma underwent PRRT using 177Lu-DOTATATE were included in this retrospective analysis. Response to therapy was assessed by interim and post-therapy 68Ga-DOTATATE-PET-CT and MRI. 177Lu-DOTATATE scintigraphies 48h p.i. were evaluated according to Krenning scale. Additionally, clinical outcome and follow up imaging were analyzed for progression free interval times. RESULTS Eight patients were included: Six patients with grade II and two patients with grade I meningiomas, according to the 2016 WHO classification. Six of eight patients harbored multifocal disease. One patients suffered systemic metastatic disease. Patients received a median of three cycles (range: 1 - 5) of PRRT with 177Lu-DOTATATE (mean injected dose 7.1 GBq) between 1/2015 and 1/2019. Tumor uptake in 48h p.i. 177Lu-Scintigraphies was heterogeneous (Krenning scale; median: 3; range: 1–4). Post-therapy imaging scheduled eight weeks after completion of therapy showed progressive disease in five patients, three patients had stable disease. Median follow-up post therapy response evaluation was 24 months in patients with stable disease. Median time to progression was 10 months. CONCLUSION In this cohort of eight progressive meningioma patients 177Lu-DOTATATE therapy showed heterogeneous efficacy. </jats:sec

Impact of hydroxytyrosol on stroke: tracking therapy response on neuroinflammation and cerebrovascular parameters using PET-MR imaging and on functional outcomes

Contains fulltext : 232256.pdf (Publisher’s version ) (Open Access

P14.67 Somatostatin receptor targeted radioligand therapyin head and neck paraganglioma

Abstract BACKGROUND Surgical resection is the therapy of choice in head and neck paraganglioma. However, surgery is associated with significant morbidity depending on tumor size and localization. In case of progressive residual or recurrent disease, new and less aggressive therapeutic options are warranted. Somatostatin receptor (SSTR) targeted therapies pose a promising alternative, as SSTRs are upregulated in paragangliomas. Only few studies provide evidence on efficacy of 177Lu-DOTATATE therapy in these patients. The aim of this study was to evaluate the efficacy of peptide receptor radiotherapy (PPRT) with 177Lu-DOTATATE for head and neck paragangliomas. METHODS A total of seven consecutive patients (mean age: 60 years, range: 14–84) with progressive head and neck paragangliomas (3 carotid body tumors, 4 jugulotympanic paragangliomas), treated with PRRT using 177Lu-DOTATATE, were included in this retrospective analysis. Therapy response was assessed by interim and post-therapy 68Ga-DOTATATE-PET-CT and MRI according to morphological and SSTR imaging parameters. Therapeutic uptake was classified on177Lu-DOTATATE scintigraphies 48h p.i. according to the Krenning scale. Longer-term clinical and imaging-based outcome were evaluated. RESULTS Patients received a median of 4 cycles (range: 3 to 5) of PRRT with 177Lu-DOTATATE (mean injected dose 7.3 GBq). Interim and post-therapy staging showed at least stable disease in all patients. Tumor uptake in 48h p.i. 177Lu-scintigraphies was moderate to high in all patients (Krenning scale; median: 3; range: 2–4). Furthermore, none of the patients showed progressive disease during the median follow-up time of 28 months (range: 6–37 months). CONCLUSION SSTR targeted therapy using 177Lu-DOTATATE shows promising efficacy and may lead to long lasting stable disease. </jats:sec