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O1 Neuroinflammation after disrupting the blood brain barrier with pulsed focused ultrasound and microbubbles imaged by 18F-DPA-714 PET and MRI Zsofia I. Kovacs, Georgios Z.
Papadakis, Tsang-Wei Tu, Sanhita Sinharay, William C. Reid, Bobbi Lewis, Dima A. Hammoud, Joseph A. Frank National Institutes of Health, Bethesda, Maryland, United States Correspondence: Zsofia I. Kovacs OBJECTIVES Blood brain barrier (BBB) disruption with MR-guided pulsed focused ultrasound (pFUS) and microbubbles (MB) has been advocated as a noninvasive adjuvant treatment for malignancies and neurodegenerative diseases.
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A sterile inflammatory reaction has been recently described in the brain as a result of pFUS+MB (Kovacs et al. However, one potential issue of weekly pFUS+MB treatments is the lack of data on the long-term effects on inflammation. The purpose of this study was to evaluate the effects of multiple weekly courses of pFUS+MB exposures in the rat brain using micro-Positron Emmision Tomography (PET) and 18F-DPA-714, a marker of translocator protein (TSPO) upregulation/microglial activation and an indication of neuroinflammation.
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METHODS Female rats were assigned to three different groups based on the number of weekly pFUS+MB: Group 1: pFUS+MB x1, PET scans performed 24 hours later (n=6); Group 2: pFUS+MB x2 with PET scans performed within 10 days after 2nd sonication (n=5); and Group 3: pFUS+MB x6 with PET scans performed 7-9 days later (n=5). The left striatum (str) and right hippocampus (hc) were targeted in all animals. 100 μl of MB (OptisonTM, GE Healthcare, Little Chalfont, UK) was administered intravenously over 1 minute starting 30 secs before pFUS.
Acoustic energy was delivered to the brain using “BBB configuration function” based on algorithm reported (O’Reilly et al. 2012) to determine optimal acoustic pressure for BBB opening via 1.5 f 0 and 2.5 f 0 ultra harmonic acoustic emission detection for every single pulse (9 focal points, 120 sec/9 focal points – striatum, 120 sec/4 focal points – hippocampus) using an 825 kHz hydrophone with a single-element spherical FUS transducer (center frequency: 589.636 kHz; focal number: 0.8; aperture: 7.5 cm; RK-100, FUS Instruments, Toronto, Ontario, Canada). T2. map were created from multiecho gradient echo sequence at 3T (Achieva, Philips Healthcare, Andover, MA) through the rat brain with TE=7 msec, echo train length 5 and echo spacing 7 and Tr=1500 msec. T2. maps were created by fitting signal intensity at each voxel to a single exponential fit with in-house software and histogram analysis was performed on volume of interests (VOI).
Static microPET/CT scans emission data was acquired 30-60 min after injection of 18F-DPA-714. VOIs were drawn in the targeted areas and uptake was compared to the contralateral unaffected side.
Uptake values were normalized to cerebellum. RESULTS 18F-DPA-714 uptake was increased at the sonication sites in all locations (Fig. The ratio of the percent increase in SUV between pFUS+MB treated striatum and hippocampus to contralateral side is depicted in graph (mean+/-SEM) clearly showing large increase in uptake for both regions compared to normal brain. The neuroinflammatory changes persisted for at least 14 days after 2 weekly sonications. The coefficient of variation for PET scans was. 2 (abstract O1). Mean normalized histograms derived from VOI from pFUS+MB treated cortex/striatum and hippocampus (ipsilateral) compared to contralateral brain forGroup 2 and 3 cohorts of rats.
There is clear shift to lower T2. values for sonicated regions for 2x v CONCLUSIONS Rats receiving pFUS+MB to open the BBB showed a clear upregulation of TSPO expression consistent with microglial activation/neuroinflammation, even after one sonication session.
Histograms derived from T2. maps MRI clearly shows that sonication with BBB algorithm results in left shift in T2. values that would be consistent with hypointense voxels on T2.w MRI and abnormatilies on histolology. These preliminary results contradict current assumptions that the effects of pFUS+MB are confined primarily to the endothelium and vessel wall.
Further assessment of the long-term effects of pFUS+MB is necessary before this approach can be widely implemented in clinical trials. References Kovacs, Z. 'Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation.' Proc Natl Acad Sci U S A 114(1): E75-E84. Hynynen (2012). 'Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller.' Radiology 263(1): 96-106.
O2 Long term effects of pulsed focused ultrasound and microbubbles detected by multivariate imaging modalities Zsofia I. Kovacs, Tsang-Wei Tu, Georgios Z. Papadakis, William C. Reid, Dima A. Hammoud, Joseph A. Frank National Institutes of Health, Bethesda, Maryland, United States Correspondence: Zsofia I.
Kovacs OBJECTIVES Blood brain barrier (BBB) opening by Guided Pulsed Focused Ultrasound (pFUS) and microbubbles (MB) is a non-invasive treatment of various central nervous system diseases. However, the potential adverse effects of repeated pFUS+MB exposure have not been thoroughly elucidated and may limit clinical translation. To date MRI scans of repeated BBB opening by pFUS+MB have been achieved without hemorrhage, edema and behavioral changes in non-human primates (Arvanitis, et al. 2016; Downs, et al. By incorporating detailed multimodal imaging, we characterized the long term effects of single or repeated pFUS+MB in the rat brain. The purpose of the study is to reveal the morphological and pathological changes following repeated BBB opening in the striatum and hippocampus as monitored by 3T and 9.4T MRI, FDG-positron emission tomography (PET) and histology over 13 weeks. METHODS pFUS+MB (Optison TM, GE Healthcare, Little Chalfont, UK) 0.3 – 0.5 MPa, 10 ms burst length, 1% duty cycle, 9 focal points, 120 sec/9 focal points – striatum, 120 sec/4 focal points – hippocampus, 589.636 kHz; focal number: 0.8; aperture: 7.5 cm; (FUS Instruments, Toronto, Ontario, Canada) was targeted in female rats (n=6/group) either once or six weekly to the striatum and the contralateral hippocampus.
100 μL of MB were administered intravenously over 1 minute starting 30 secs before pFUS. Rats received 3 daily doses of 300mg/kg 5-Bromo-2′-deoxy-uridine (BrdU, Sigma-Aldrich, St. Louis, MO) intraperitoneally before sonication to label proliferating cells in vivo.
T2, T2. and Gd-enhanced T1-weighted images were obtained by 3.0T MRI (Achieva, Philips Healthcare, Andover, MA), T2, T2. and diffusion tensor imaging (DTI) were performed by 9.4T MRI (Bruker, Billerica, MA). Parameters for DTI: 3D spin echo EPI; TR/TE 700 ms/37 msec; b-value 800 sec/mm 2 with 17 encoding directions; voxel size 200 μm (isotropic). Fractional anisotropy (FA) and the asymmetry of magnetization transfer ratio (MTRasym) were derived for mapping structural injury and glucose levels. Rats received 1.1 mCi of 18F-FDG via intravenously to quantitate glucose uptake by PET/CT (Inveon, Siemens, Munich, Germany).
PET emission data was acquired for 60 min. Dynamic images were reconstructed and image analyses was performed (PMOD Technologies Ltd., Zurich, Switzerland). Animals were euthanized 7 or 13 weeks after the first pFUS treatment. Histological evaluation of brain and tracking of BrdU tagged cells was performed. RESULTS Gd-enhanced T1-weighted images after each sonication demonstrated BBB disruption in the striatum and the hippocampus at 3T. Gd T1 enhancement, T2 and T2. abnormalities were not seen in the brain 1-day post pFUS+MB at 9.4T MRI.
Hypointense regions appeared on T2. MRI 2 weeks post pFUS+MB consistent with development of microhemorrhages within the parenchyma. White matter fiber structure- and gray matter-abnormalities on DTI MRI were detected in regions with the T2. abnormalities suggestive of increased astrogliosis and transient axonal damage. MRI findings following pFUS+MB x6 demonstrated more pronounced evidence of damage within the parenchyma and atrophy.
FDG-PET did not show differences between sonicated and contralateral cortex or hippocampus at any time point. BrdU showed evidence of increased neurogenesis in pFUS+MB treated regions. CONCLUSIONS The long term effects of pFUS+MB exposures in rats revealed that both single and repeated pFUS+MB cause structural injury at the location of sonication up to 13 weeks post treatment based on advanced imaging techniques. Histological evidence showed that associated with the pathological changes observed by MRI, there was evidence of neuronal damage and loss, neurogenesis and activated microglia. These results suggest the importance of long term monitor of the brain following low intensity pFUS+MB before its clinical translation. References Arvanitis, C. 'Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model.'
J Neurosurg 124(5): 1450-1459. 'Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task.' PLoS One 10(5): e0125911. 1 (abstract O6). See text for description CONCLUSIONS In this study, a stereotactic BBB opening system was extended to incorporate a feedback control algorithm based on the sub-/ultra-harmonic emissionsfrom microbubbles. The AUC responses were characterized and stable feedback control was demonstrated both in-vitro and in-vivo.
Using infusion injection instead ofbolus injection, combined with the real-time feedback control system, a more reliable BBB opening can be achieved across a larger brain region for applications focusedon drug delivery to peritumoral regions. O7 Unilateral focused ultrasound-induced blood-brain barrier opening redistributes hyperphosphorylated Tau in an Alzheimer's mouse model Maria Eleni Karakatsani 1, Tara Kugelman 1, Shutao Wang 1, Karen Duff 3, Elisa E. Konofagou 1,2 1Biomedical Engineering, Columbia University, New York, New York, USA; 2Radiology, Columbia University, New York, New York, USA; 3Pathology and Cell Biology, Columbia University, New York, New York, USA Correspondence: Maria Eleni Karakatsani OBJECTIVES Focused ultrasound has been shown to interact with Alzheimer’s pathology and particularly to trigger a mechanism that results in the reduction of the amyloid plaque load. However, a less studied interaction is that of ultrasound with the tangle formation that has been implicated in the cognitive decline of Alzheimer’s patients. Tau pathology can be characterized by increased density of the hyperphosphorylated tau protein that results in tangle formation.
At the early stages of Alzheimer’s disease, tau protein can be localized primarily in the axons while in late pathology, somatodendritic tau is more pronounced. With the current study we investigate the interaction of focused ultrasound-induced blood-brain barrier opening with the tau distribution. Moreover, the unilateral sonication of the transgenic brain provides a unique opportunity to explore potential bilateral effects. METHODS For this study the initial cohort included 10 mice of the rTg4510 line (3.5 months old), 5 of which were randomly assigned to the control group that did not receive any sonication and 5 to the treatment group. The treatment group received a double sonication covering almost the entire hippocampal region once per week for 4 consecutive weeks.
The day after the last sonication the mice were sacrificed. The brains were sectioned and counterstained for tau protein (AT8) as well as microglia activation (CD68). The images were acquired by means of confocal microscopy over a z-series to account for depth differences and enabling co-visualization of the tau protein and microglia distribution.
A custom algorithm was constructed to quantify the number of cells and the axonal distribution of the tau-marker. Background noise was automatically removed by color-based segmentation using k-means clustering and the cells were detected by the Hough transform. The axons were quantified based on their length marked by the tau protein. The same brain slices were utilized to quantify the hippocampal density of the CD68 marker by intensity-based quantification. RESULTS Figure 1 shows two representative examples of the control and the treatment group. Following the hippocampal formation of the control brain, it can be observed that both somatodendritic and axonal tau (red) are evident. In particular, the tau marker engulfs the cell bodies and the entire in-plane length of the axons can be detected.
Although the cell bodies affected by tau protein are also evident in the animals that received four sonications, the axonal tau was less pronounced. More specifically, the axonal distribution of the tau protein was not continuous. Differences across hemispheres were only detected in the treatment group. Moreover, the phagocytic microglia (green) seem almost absent in the control brains while they can be observed in both hemispheres of the treatment group. Quantification of the tau distribution and density are currently ongoing.
2 (abstract O10). Reproducibility experiments in pulsed sonication for the SC (subharmonic emission level) and IC (broadband noise level) indicators as a function of the applied voltage in open loop (2-a) and the SC target value in closed loop (2-c). 1 (abstract O12). (A) shows the block diagram of the proposed imagedguided dualtarget ultrasound brain stimulation system. Figure (B) demonstrates a Bmode image of a mousebrain for predetermining two different stimulation targets.
The exact positions of the targets can be selected by the computer mouse, and are pointed out by the arrows.