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Background: The resistance of glioblastoma stem cells (GSCs) to treatment is one of the causes of glioblastoma (GBM) recurrence. Endothelin A receptor (ETA) overexpression in GSCs constitutes an attractive biomarker for targeting this cell subpopulation, as illustrated by several clinical trials evaluating the therapeutic efficacy of endothelin receptor antagonists against GBM. In this context, we have designed an immunoPET radioligand combining the chimeric antibody targeting ETA, chimeric-Rendomab A63 (xiRA63), with 89Zr isotope and evaluated the abilities of xiRA63 and its Fab (ThioFab-xiRA63) to detect ETA+ tumors in a mouse model xenografted orthotopically with patient-derived Gli7 GSCs. Results: Radioligands were intravenously injected and imaged over time by µPET-CT imaging. Tissue biodistribution and pharmacokinetic parameters were analyzed, highlighting the ability of [89Zr]Zr-xiRA63 to pass across the brain tumor barrier and achieve better tumor uptake than [89Zr]Zr-ThioFab-xiRA63. Conclusions: This study shows the high potential of [89Zr]Zr-xiRA63 in specifically targeting ETA+ tumors, thus raising the possibility of detecting and treating ETA+ GSCs, which could improve the management of GBM patients. [ABSTRACT FROM AUTHOR]

The P-glycoprotein (P-gp/ABCB1) is a major efflux transporter which impedes the brain delivery of many drugs across the blood-brain barrier (BBB). Focused ultrasound with microbubbles (FUS) enables BBB disruption, which immediate and delayed impact on P-gp function remains unclear. Positron emission tomography (PET) imaging using the radiolabeled substrate [11C]metoclopramide provides a sensitive and translational method to study P-gp function at the living BBB. A FUS protocol was devised in rats to induce a substantial and targeted disruption of the BBB in the left hemisphere. BBB disruption was confirmed by the Evan ' s Blue extravasation test or the minimally-invasive contrast-enhanced MRI. The expression of P-gp was measured 24 h or 48 h after FUS using immunostaining and fluorescence microscopy. The brain kinetics of [11C]metoclopramide was studied by PET at baseline, and both immediately or 24 h after FUS, with or without half-maximum P-gp inhibition (tariquidar 1 mg/kg). In each condition (n = 4–5 rats per group), brain exposure of [11C]metoclopramide was estimated as the area-under-the-curve (AUC) in regions corresponding to the sonicated volume in the left hemisphere, and the contralateral volume. Kinetic modeling was performed to estimate the uptake clearance ratio (R 1) of [11C]metoclopramide in the sonicated volume relative to the contralateral volume. In the absence of FUS, half-maximum P-gp inhibition increased brain exposure (+135.0 ± 12.9%, p < 0.05) but did not impact R 1 (p > 0.05). Immediately after FUS, BBB integrity was selectively disrupted in the left hemisphere without any detectable impact on the brain kinetics of [11C]metoclopramide compared with the baseline group (p > 0.05) or the contralateral volume (p > 0.05). 24 h after FUS, BBB integrity was fully restored while P-gp expression was maximally down-regulated (−45.0 ± 4.5%, p < 0.001) in the sonicated volume. This neither impacted AUC nor R 1 in the FUS + 24 h group (p > 0.05). Only when P-gp was inhibited with tariquidar were the brain exposure (+130 ± 70%) and R 1 (+ 29.1 ± 15.4%) significantly increased in the FUS + 24 h/tariquidar group, relative to the baseline group (p < 0.001). We conclude that the brain kinetics of [11C]metoclopramide specifically depends on P-gp function rather than BBB integrity. Delayed FUS-induced down-regulation of P-gp function can be detected. Our results suggest that almost complete down-regulation is required to substantially enhance the brain delivery of P-gp substrates. [Display omitted] • P-glycoprotein (P-gp) hinders the blood-brain barrier (BBB) passage of many drugs. • BBB disruption induced by focused ultrasound (FUS) enables targeted brain delivery. • P-gp function at the BBB can be studied in vivo using [11C]metoclopramide PET imaging. • Immediately after FUS, BBB disruption did not impact the P-gp-mediated efflux in rats. • P-gp expression was decreased 24 h to 48 h after FUS, with limited impact on function. [ABSTRACT FROM AUTHOR]

[Display omitted] Glioblastoma (GBM) is the most common and deadly form of primary brain tumor. Between 30 % and 60 % of GBM are characterized by overexpression of the Epidermal Growth Factor Receptor (EGFR). The anti-EGFR antibody Cetuximab (CTX) showed a favorable effect for EGFR+ colorectal cancer but failed to demonstrate efficacy for GBM. Insufficient CTX passage through the blood–brain barrier (BBB) and the blood-tumor barrier (BTB) is assumed to be the primary determinant of the limited efficacy of this immunotherapy. Using positron emission tomography (PET) imaging, we have previously demonstrated that focused ultrasound (FUS) combined with microbubbles (µB) allowed significant and persistent delivery of CTX across the BBB in healthy mice. In the current study, we investigated by PET imaging the combination impact of CTX and FUS on orthotopic GBM preclinical model. After radiolabeling CTX with the long half-life isotope 89Zr, PET images have been acquired overtime in mice bearing U251 (EGFR+) with or without FUS treatment. Autoradiography combined with immunofluorescence staining was used to corroborate CTX delivery with EGFR expression. A survival study was conducted simultaneously to evaluate the therapeutic benefit of repeated CTX monotherapy associated or not with FUS. Ex vivo analysis confirmed that FUS enhanced and homogenized the delivery of CTX into all the FUS exposure area, including the tumor and the contralateral hemisphere at the early-time-point. Interestingly, FUS did not improve the long-term accumulation and retention of CTX in the tumor compared with the control group (no FUS). No significant difference in the CTX treatment efficacy, determined by the survival between FUS and non-FUS groups, has been either observed. This result is consistent with the absence of change in the CTX distribution through the GBM tumor after FUS. The neuroinflammation induced by FUS is not significant enough to explain the failure of the CTX delivery improvement. All together, these data suggest that the role of FUS combined with µB on the CTX distribution, even after multiple therapeutic sessions and glial cell activation is insufficient to improve survival of GBM mice compared with CTX treatment alone in this model. [ABSTRACT FROM AUTHOR]

Fifty million people worldwide are affected by dementia, a heterogeneous neurodegenerative condition encompassing diseases such as Alzheimer's, vascular dementia, and Parkinson's. For them, cognitive decline is often the first marker of the pathology after irreversible brain damage has already occurred. Researchers now believe that structural and functional alterations of the brain vasculature could be early precursors of the diseases and are looking at how functional imaging could provide an early diagnosis years before irreversible clinical symptoms. In this preclinical pilot study, we proposed using functional ultrasound (fUS) on the retina to assess neurovascular alterations non-invasively, bypassing the skull limitation. We demonstrated for the first time the use of functional ultrasound in the retina and applied it to characterize the retinal hemodynamic response function in vivo in rats following a visual stimulus. We then demonstrated that retinal fUS could measure robust neurovascular coupling alterations between wild-type rats and TgF344-AD rat models of Alzheimer's disease. We observed an average relative increase in blood volume of 21% in the WT versus 37% for the TG group (p = 0.019). As a portable, non-invasive and inexpensive technique, rfUS is a promising functional screening tool in clinics for dementia years before symptoms. [ABSTRACT FROM AUTHOR]

Deposits of different abnormal forms of tau in neurons and astrocytes represent key anatomo-pathological features of tauopathies. Although tau protein is highly enriched in neurons and poorly expressed by astrocytes, the origin of astrocytic tau is still elusive. Here, we used innovative gene transfer tools to model tauopathies in adult mouse brains and to investigate the origin of astrocytic tau. We showed in our adeno-associated virus (AAV)-based models and in Thy-Tau22 transgenic mice that astrocytic tau pathology can emerge secondarily to neuronal pathology. By designing an in vivo reporter system, we further demonstrated bidirectional exchanges of tau species between neurons and astrocytes. We then determined the consequences of tau accumulation in astrocytes on their survival in models displaying various status of tau aggregation. Using stereological counting of astrocytes, we report that, as for neurons, soluble tau species are highly toxic to some subpopulations of astrocytes in the hippocampus, whereas the accumulation of tau aggregates does not affect their survival. Thus, astrocytes are not mere bystanders of neuronal pathology. Our results strongly suggest that tau pathology in astrocytes may significantly contribute to clinical symptoms. [ABSTRACT FROM AUTHOR]

In many transcranial ultrasound studies on rats, the transmission factor is assumed to be independent of animal weight and losses resulting from non-normal incidence angles of the beam are not accounted for. In this study, we measured acoustic transmission factors through 13 excised skulls of male Sprague-Dawley rats weighing between 90 and 520g, at different positions on each skull and at 1, 1.25, 1.5, 1.75 and 2MHz. Our results revealed that insertion loss through rat skull increases linearly with both body mass and frequency and strongly depends on the position, decreasing from the front to the back and from the midline to the lateral sides. Skull thickness also scales linearly with body mass. Reflection explains the main part of the insertion loss compared with attenuation and aberration. These data are helpful in predicting the acoustic pressure at the focus in the brain. [ABSTRACT FROM AUTHOR]