Quantitative Measurement Of Cerebral Blood Flow Research Articles

Multi-Tracer Studies of Brain Oxygen and Glucose Metabolism Using a Time-of-Flight Positron Emission Tomography - Computed Tomography Scanner.

The authors have developed a paradigm using positron emission tomography (PET) with multiple radiopharmaceutical tracers that combines measurements of cerebral metabolic rate of glucose (CMRGlc), cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and cerebral blood volume (CBV), culminating in estimates of brain aerobic glycolysis (AG). These in vivo estimates of oxidative and non-oxidative glucose metabolism are pertinent to the study of the human brain in health and disease. The latest positron emission tomography-computed tomography (PET-CT) scanners provide time-of-flight (TOF) imaging and critical improvements in spatial resolution and reduction of artifacts. This has led to significantly improved imaging with lower radiotracer doses. Optimized methods for the latest PET-CT scanners involve administering a sequence of inhaled 15O-labeled carbon monoxide (CO) and oxygen (O2), intravenous 15O-labeled water (H2O), and 18F-deoxyglucose (FDG)-all within 2-h or 3-h scan sessions that yield high-resolution, quantitative measurements of CMRGlc, CMRO2, CBF, CBV, and AG. This methods paper describes practical aspects of scanning designed for quantifying brain metabolism with tracer kinetic models and arterial blood samples and provides examples of imaging measurements of human brain metabolism.

Image-derived input functions from dynamic 15O–water PET scans using penalised reconstruction

BackgroundQuantitative positron emission tomography (PET) scans of the brain typically require arterial blood sampling but this is complicated and logistically challenging. One solution to remove the need for arterial blood sampling is the use of image-derived input functions (IDIFs). Obtaining accurate IDIFs, however, has proved to be challenging, mainly due to the limited resolution of PET. Here, we employ penalised reconstruction alongside iterative thresholding methods and simple partial volume correction methods to produce IDIFs from a single PET scan, and subsequently, compare these to blood-sampled input curves (BSIFs) as ground truth. Retrospectively we used data from sixteen subjects with two dynamic 15O-labelled water PET scans and continuous arterial blood sampling: one baseline scan and another post-administration of acetazolamide.ResultsIDIFs and BSIFs agreed well in terms of the area under the curve of input curves when comparing peaks, tails and peak-to-tail ratios with R2 values of 0.95, 0.70 and 0.76, respectively. Grey matter cerebral blood flow (CBF) values showed good agreement with an average difference between the BSIF and IDIF CBF values of 2% ± and a coefficient of variation (CoV) of 7.3%.ConclusionOur results show promising results that a robust IDIF can be produced for dynamic 15O–water PET scans using only the dynamic PET scan images with no need for a corresponding MRI or complex analytical techniques and thereby making routine clinical use of quantitative CBF measurements with 15O–water feasible.

Test–retest reliability of arterial spin labelling for cerebral blood flow in older adults with small vessel disease

Cerebral small vessel disease (SVD) is common in older people and is associated with lacunar stroke, white matter hyperintensities (WMH) and vascular cognitive impairment. Cerebral blood flow (CBF) is reduced in SVD, particularly within white matter.Here we quantified test–retest reliability in CBF measurements using pseudo-continuous arterial spin labelling (pCASL) in older adults with clinical and radiological evidence of SVD (N=54, mean (SD): 66.9 (8.7) years, 15 females/39 males). We generated whole-brain CBF maps on two visits at least 7 days apart (mean (SD): 20 (19), range 7-117 days).Test–retest reliability for CBF was high in all tissue types, with intra-class correlation coefficient [95%CI]: 0.758 [0.616, 0.852] for whole brain, 0.842 [0.743, 0.905] for total grey matter, 0.771 [0.636, 0.861] for deep grey matter (caudate-putamen and thalamus), 0.872 [0.790, 0.923] for normal-appearing white matter (NAWM) and 0.780 [0.650, 0.866] for WMH (all p<0.001). ANCOVA models indicated significant decline in CBF in total grey matter, deep grey matter and NAWM with increasing age and diastolic blood pressure (all p<0.001). CBF was lower in males relative to females (p=0.013 for total grey matter, p=0.004 for NAWM).We conclude that pCASL has high test–retest reliability as a quantitative measure of CBF in older adults with SVD. These findings support the use of pCASL in routine clinical imaging and as a clinical trial endpoint.All data come from the PASTIS trial, prospectively registered at: https://eudract.ema.europa.eu (2015-001235-20, registered 13/05/2015), http://www.clinicaltrials.gov (NCT02450253, registered 21/05/2015).

Laminar perfusion imaging with zoomed arterial spin labeling at 7 Tesla

Laminar fMRI based on BOLD and CBV contrast at ultrahigh magnetic fields has been applied for studying the dynamics of mesoscopic brain networks. However, the quantitative interpretations of BOLD/CBV fMRI results are confounded by different baseline physiology across cortical layers. Here we introduce a novel 3D zoomed pseudo-continuous arterial spin labeling (pCASL) technique at 7T that offers the capability for quantitative measurements of laminar cerebral blood flow (CBF) both at rest and during task activation with high spatial specificity and sensitivity. We found arterial transit time in superficial layers is ∼100 ms shorter than in middle/deep layers revealing the time course of labeled blood flowing from pial arteries to downstream microvasculature. Resting state CBF peaked in the middle layers which is highly consistent with microvascular density measured from human cortex specimens. Finger tapping induced a robust two-peak laminar profile of CBF increases in the superficial (somatosensory and premotor input) and deep (spinal output) layers of M1, while finger brushing task induced a weaker CBF increase in superficial layers (somatosensory input). This observation is highly consistent with reported laminar profiles of CBV activation on M1. We further demonstrated that visuospatial attention induced a predominant CBF increase in deep layers and a smaller CBF increase on top of the lower baseline CBF in superficial layers of V1 (feedback cortical input), while stimulus driven activity peaked in the middle layers (feedforward thalamic input). With the capability for quantitative CBF measurements both at baseline and during task activation, high-resolution ASL perfusion fMRI at 7T provides an important tool for in vivo assessment of neurovascular function and metabolic activities of neural circuits across cortical layers.

PET and SPECT imaging of the brain: a review on the current status of nuclear medicine in Japan.

Radiolabeled tracers allow visualization of not only perfusion, but receptors, function, and metabolism as well. Although spatial resolution is lower than that of computed tomography and magnetic resonance imaging, positron emission tomography (PET) and single photon emission computed tomography (SPECT) have great potential for target-specific imaging. In this review, we discuss several SPECT and PET tracers used in brain imaging, specifically focusing on tracers currently available, or developed, in Japan. Several important and sophisticated methods exist for analysis of brain PET and SPECT images. Two of them, quantitative cerebral blood flow measurement and voxel-based statistical analysis are discussed in this review. The former method, which employs acetazolamide loading, is useful for evaluation of the brain perfusion reserve for ischemic brain diseases. The latter is useful in diagnosing dementing diseases. Additionally, great strides have been made in the development of the technology used in the scanners. New SPECT systems based on cadmium-zinc-telluride, PET/MRI, and semiconductor PET/CT may provide higher spatial resolution with an acquisition time shorter than ever before. Such developments of both tracers and scanners can be integrated for unprecedented imagery of the brain, providing valuable insight into underlying causes of some fatal brain disorders.

Significance of Quantitative Cerebral Blood Flow Measurement in the Acute Stage after Revascularization Surgery for Adult Moyamoya Disease: Implication for the Pathological Threshold of Local Cerebral Hyperperfusion

Objective: Superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis is a standard surgical procedure for adult patients with moyamoya disease (MMD) and plays a role in preventing ischemic and/or hemorrhagic stroke. Cerebral hyperperfusion (CHP) syndrome is a potential complication of this procedure that can result in deleterious outcomes, such as delayed intracerebral hemorrhage, but the exact threshold of the pathological increase in postoperative cerebral blood flow (CBF) is unclear. Thus, we analyzed local CBF in the acute stage after revascularization surgery for adult MMD to predict CHP syndrome under modern perioperative management. Materials and Methods: Fifty-nine consecutive adult MMD patients, aged 17–66 years old (mean 43.1), underwent STA-MCA anastomosis with indirect pial synangiosis for 65 affected hemispheres. All patients were perioperatively managed by strict blood pressure control (systolic pressure of 110–130 mm Hg) to prevent CHP syndrome. Local CBF at the site of anastomosis was quantitatively measured using the autoradiographic method by N-isopropyl-p-[¹²³I] iodoamphetamine single-photon emission computed tomography 1 and 7 days after surgery, in addition to the preoperative CBF value at the corresponding area. We defined CHP phenomenon as a local CBF increase over 150% compared to the preoperative value. Then, we investigated the correlation between local hemodynamic change and the development of CHP syndrome. Results: After 65 surgeries, 5 patients developed CHP syndrome, including 2 patients with delayed intracerebral hemorrhage (3.0%), 1 with symptomatic subarachnoid hemorrhage (1.5%), and 2 with focal neurological deterioration without hemorrhage. The CBF increase ratio was significantly higher in patients with CHP syndrome (270.7%) than in patients without CHP syndrome (135.2%, p = 0.003). Based on receiver operating characteristic analysis, the cutoff value for the pathological postoperative CBF increase ratio was 184.5% for CHP syndrome (sensitivity = 83.3%, specificity = 94.2%, area under the curve [AUC] value = 0.825) and 241.3% for hemorrhagic CHP syndrome (sensitivity = 75.0%, specificity = 97.2%, AUC value = 0.742). Conclusion: Quantitative measurement of the local CBF value in the early postoperative period provides essential information to predict CHP syndrome after STA-MCA anastomosis in patients with adult MMD. The pathological threshold of hemorrhagic CHP syndrome was as high as 241.3% by the local CBF increase ratio, but 2 patients (3.0%) developed delayed intracerebral hemorrhage in this series that were managed following the intensive perioperative management protocol. Thus, we recommend routine CBF measurement in the acute stage after direct revascularization surgery for adult MMD and satisfactory blood pressure control to avoid the deleterious effects of CHP.

Assessment of cerebral blood perfusion reserve with acetazolamide using 3D spiral ASL MRI: Preliminary experience in pediatric patients

PurposeTo demonstrate the clinical feasibility of a new non-Cartesian cylindrically-distributed spiral 3D pseudo-continuous arterial spin labeling (pCASL) magnetic resonance imaging (MRI) pulse sequence in pediatric patients in quantifying cerebral blood flow (CBF) response to an acetazolamide (ACZ) vasodilator challenge. Materials and methodsMRI exams were performed on two 3 Tesla Philips Ingenia systems using 32 channel head coil arrays. After local institutional review board approval, the 3D spiral-based pCASL technique was added to a standard brain MRI exam and evaluated in 13 pediatric patients (average age: 11.7±6.4years, range: 1.4–22.2years). All patients were administered ACZ for clinically indicated reasons. Quantitative whole-brain CBF measurements were computed pre- and post-ACZ to assess cerebrovascular reserve. Results3D spiral pCASL data were successfully reconstructed in all 13 cases. In 11 patients, CBF increased 2.8% to 93.2% after administration of ACZ. In the two remaining patients, CBF decreased by 2.4 to 6.0% after ACZ. The group average change in CBF due to ACZ was approximately 25.0% and individual changes were statistically significant (p<0.01) in all patients using a paired t-test analysis. CBF perfusion data were diagnostically useful in supporting conventional MR angiography and clinical findings. Conclusion3D cylindrically-distributed spiral pCASL MRI provides a robust approach to assess cerebral blood flow and reserve in pediatric patients.

Acousto-Optic Cerebral Blood Flow Monitoring During Induction of Anesthesia in Humans.

Past transcranial Doppler (TCD) studies have documented the effects of the sequence of anesthesia induction followed by intubation on cerebral blood flow (CBF) velocity. The purpose of this study was to determine whether acousto-optic CBF monitoring would detect changes in CBF which are known to occur with propofol and subsequent endotracheal intubation. Seventy-two patients scheduled for elective non-intracranial surgery were evaluated. A Cerox 3215F (Ornim Medical) acousto-optic CBF monitor was used. The acousto-optic transducers were applied bifrontally prior to induction. Baseline cerebral flow index (CFI) values were obtained for at least 2min prior to induction, set to a unitless value of 100. Subsequent relative changes in CFI from baseline were determined at the lowest value over 3min after propofol injection but before laryngoscopy; and the highest value over 5min after the start of laryngoscopy. CFI data were evaluated using Friedman's test. The median dose of propofol [interquartile range] given was 200mg [160-250]. CFI decreased to 84% of baseline after propofol and increased to 147% of baseline after endotracheal intubation (both p<0.001); MAP decreased after intravenous induction of anesthesia from 103±15 to 86±15mmHg (p<0.001) and then returned following endotracheal intubation to 104±20mmHg. Our data are congruent with previous observations made with TCD under similar experimental conditions. Such observations support the notion that acousto-optic monitoring yields valid real-time measures of changes in CBF in humans. Further validation against other quantitative measures of CBF would be appropriate.

Sonochemical internalization using 5-aminolevulinic acid enhances the cytotoxic effect of bleomycin

s / Photodiagnosis and Photodynamic Therapy 12 (2015) 325–375 343 Results: The few treated cases for the moment show fading lesions in an average of 4 sessions, including an immunocompromised patient had a very quick recovery. Conclusions:Fora country likeEcuador is very important search new cheaper and efficient alternatives for the treatment of health public problems. The results do not present major problems to raise a medical guideline, however this study will be continued and should be replicated in different demographic areas throughout the country collecting statistical data over types of patients, sessions conducted and recurrences. http://dx.doi.org/10.1016/j.pdpdt.2015.07.073 Examining the effect of liposomal lapatinib in combination with PDT for the treatment of malignant gliomas Carl Fisher1,2,3,4, Carolyn Niu1,2,3,4, Warren Foltz1,2,3,4, Girgis Obaid1,2,3,4, Tayyaba Hasan1,2,3,4, Lothar Lilge1,2,3,4 1 Department of Medical Biophysics, University of Toronto, Canada 2 Department of Radiation Oncology, University Health Network, Canada 3 Wellman Center for Photomedicine, Massachusetts General Hospital, USA 4 Division of Molecular Imaging, Princess Margaret Cancer Centre, Canada Malignant gliomas are invasive and difficult to treat tumours. Of this group of tumours, Glioblastoma Multiforme (GBM) is the most common and the most aggressive. Of proposed GBM treatments, ALA-PpIX mediated Photodynamic Therapy (PDT) has been explored and researched into. The goal of our group is to examine whether combining PDT with EGFR kinase inhibitors leads to greater outcomes compared to PDT or EGFR inhibitors alone. The study proposed utilized the human cell line U87 (EGFR positive) in combination with a liposomal based EGFR inhibitor (lapatinib) that was combined with PDT treatment. Pre-PDT animals were scannedwithaBruker7T small animalMRI systemtomeasure cerebral blood flow (CBF) and tumor vascular permeability and began treatment with the liposomal lapatinib conjugation. Post-PDT animal were scanned at regular intervals to measure CBF and tumour size between the two groups. In the initial pilot study, liposomal lapatinib combined with PDT lead to significant increases in survival compared to PDT alone and demonstrated differences in both CBF and tumour response to PDT. Ongoing studies are focused on increasing the number of animals and get quantitativemeasures of CBF and cerebral blood volume both preand post-PDT. http://dx.doi.org/10.1016/j.pdpdt.2015.07.074 Sonochemical internalization using 5-aminolevulinic acid enhances the cytotoxic effect of bleomycin Tomohiro Osaki1, Yoshihiro Uto2, Masahiro Ishizuka3, Toru Tanaka3, Nobuyasu Yamanaka4, Tsukasa Kurahashi4, Kazuo Azuma1, Yusuke Murahata1, Takeshi Tsuka1, Norihiko Ito1, Tomohiro Imagawa1, Yoshiharu Okamoto1 1 Department of Veterinary Clinical Medicine, School of Veterinary Medicine, Tottori University, Japan 2 Department of Life System, Institute of Technology and Science, Graduate School, Tokushima University, Japan 3 SBI Pharmaceuticals Co., Ltd., Japan 4 ITO Physiotherapy & Rehabilitation, Japan Photochemical internalization (PCI) is a technology to improve the intracellular delivery ofmacromolecules andbasedon the same principle as photodynamic therapy (PDT). PCI is based on the use of photosensitizers located in endocytic vesicles that upon activation by light induce rupture of endocytic vesicles and release the macromolecules into cytosol. Bleomycin (BLM) is used for chemotherapeutic agent for PCI. The limitation of PDT and PCI is the penetration of light in the tissue. It is difficult to treat deepseated tumor with PDT and PCI. Sonodynamic therapy (SDT) is also an antitumor strategy that kills tumor cells by ultrasound and photosensitizer. Ultrasound can penetrate deep tissue and excite photosensitizer. We hypothesized that ultrasound could excite photosensitizers used for PCI, and this newmethod could improve the intracellular delivery of macromolecules. We defined this new method as sonochemical internalization (SCI). In this study, we examined whether internalization of BLM by ultrasound and 5aminolevulinic acid (5-ALA) was able to destroy tumors. In vitro and in vivo study, a significant cytotoxic effect of SCI of BLM using 5-ALA was observed. It was considered that SCI might act as an ultrasound-directed drug-delivery system by triggered release of endocytosed macromolecules into cytosol as PCI. http://dx.doi.org/10.1016/j.pdpdt.2015.07.075 Acridine orange as radiosensitizer to improve cell damage caused by radiotherapy in breast cancer cells line Cintia Teles de Andrade, Jose Dirceu Vollet-Filho, Layla Pires, Vanderlei Salvador Bagnato, Cristina Kurachi Sao Carlos Institute of Physics, University of Sao

Examining the effect of liposomal lapatinib in combination with PDT for the treatment of malignant gliomas

s / Photodiagnosis and Photodynamic Therapy 12 (2015) 325–375 343 Results: The few treated cases for the moment show fading lesions in an average of 4 sessions, including an immunocompromised patient had a very quick recovery. Conclusions:Fora country likeEcuador is very important search new cheaper and efficient alternatives for the treatment of health public problems. The results do not present major problems to raise a medical guideline, however this study will be continued and should be replicated in different demographic areas throughout the country collecting statistical data over types of patients, sessions conducted and recurrences. http://dx.doi.org/10.1016/j.pdpdt.2015.07.073 Examining the effect of liposomal lapatinib in combination with PDT for the treatment of malignant gliomas Carl Fisher1,2,3,4, Carolyn Niu1,2,3,4, Warren Foltz1,2,3,4, Girgis Obaid1,2,3,4, Tayyaba Hasan1,2,3,4, Lothar Lilge1,2,3,4 1 Department of Medical Biophysics, University of Toronto, Canada 2 Department of Radiation Oncology, University Health Network, Canada 3 Wellman Center for Photomedicine, Massachusetts General Hospital, USA 4 Division of Molecular Imaging, Princess Margaret Cancer Centre, Canada Malignant gliomas are invasive and difficult to treat tumours. Of this group of tumours, Glioblastoma Multiforme (GBM) is the most common and the most aggressive. Of proposed GBM treatments, ALA-PpIX mediated Photodynamic Therapy (PDT) has been explored and researched into. The goal of our group is to examine whether combining PDT with EGFR kinase inhibitors leads to greater outcomes compared to PDT or EGFR inhibitors alone. The study proposed utilized the human cell line U87 (EGFR positive) in combination with a liposomal based EGFR inhibitor (lapatinib) that was combined with PDT treatment. Pre-PDT animals were scannedwithaBruker7T small animalMRI systemtomeasure cerebral blood flow (CBF) and tumor vascular permeability and began treatment with the liposomal lapatinib conjugation. Post-PDT animal were scanned at regular intervals to measure CBF and tumour size between the two groups. In the initial pilot study, liposomal lapatinib combined with PDT lead to significant increases in survival compared to PDT alone and demonstrated differences in both CBF and tumour response to PDT. Ongoing studies are focused on increasing the number of animals and get quantitativemeasures of CBF and cerebral blood volume both preand post-PDT. http://dx.doi.org/10.1016/j.pdpdt.2015.07.074 Sonochemical internalization using 5-aminolevulinic acid enhances the cytotoxic effect of bleomycin Tomohiro Osaki1, Yoshihiro Uto2, Masahiro Ishizuka3, Toru Tanaka3, Nobuyasu Yamanaka4, Tsukasa Kurahashi4, Kazuo Azuma1, Yusuke Murahata1, Takeshi Tsuka1, Norihiko Ito1, Tomohiro Imagawa1, Yoshiharu Okamoto1 1 Department of Veterinary Clinical Medicine, School of Veterinary Medicine, Tottori University, Japan 2 Department of Life System, Institute of Technology and Science, Graduate School, Tokushima University, Japan 3 SBI Pharmaceuticals Co., Ltd., Japan 4 ITO Physiotherapy & Rehabilitation, Japan Photochemical internalization (PCI) is a technology to improve the intracellular delivery ofmacromolecules andbasedon the same principle as photodynamic therapy (PDT). PCI is based on the use of photosensitizers located in endocytic vesicles that upon activation by light induce rupture of endocytic vesicles and release the macromolecules into cytosol. Bleomycin (BLM) is used for chemotherapeutic agent for PCI. The limitation of PDT and PCI is the penetration of light in the tissue. It is difficult to treat deepseated tumor with PDT and PCI. Sonodynamic therapy (SDT) is also an antitumor strategy that kills tumor cells by ultrasound and photosensitizer. Ultrasound can penetrate deep tissue and excite photosensitizer. We hypothesized that ultrasound could excite photosensitizers used for PCI, and this newmethod could improve the intracellular delivery of macromolecules. We defined this new method as sonochemical internalization (SCI). In this study, we examined whether internalization of BLM by ultrasound and 5aminolevulinic acid (5-ALA) was able to destroy tumors. In vitro and in vivo study, a significant cytotoxic effect of SCI of BLM using 5-ALA was observed. It was considered that SCI might act as an ultrasound-directed drug-delivery system by triggered release of endocytosed macromolecules into cytosol as PCI. http://dx.doi.org/10.1016/j.pdpdt.2015.07.075 Acridine orange as radiosensitizer to improve cell damage caused by radiotherapy in breast cancer cells line Cintia Teles de Andrade, Jose Dirceu Vollet-Filho, Layla Pires, Vanderlei Salvador Bagnato, Cristina Kurachi Sao Carlos Institute of Physics, University of Sao

Treatment of condyloma acuminatum using methyl-aminolaevulinic acid for introduce a medical guideline on health public system

s / Photodiagnosis and Photodynamic Therapy 12 (2015) 325–375 343 Results: The few treated cases for the moment show fading lesions in an average of 4 sessions, including an immunocompromised patient had a very quick recovery. Conclusions:Fora country likeEcuador is very important search new cheaper and efficient alternatives for the treatment of health public problems. The results do not present major problems to raise a medical guideline, however this study will be continued and should be replicated in different demographic areas throughout the country collecting statistical data over types of patients, sessions conducted and recurrences. http://dx.doi.org/10.1016/j.pdpdt.2015.07.073 Examining the effect of liposomal lapatinib in combination with PDT for the treatment of malignant gliomas Carl Fisher1,2,3,4, Carolyn Niu1,2,3,4, Warren Foltz1,2,3,4, Girgis Obaid1,2,3,4, Tayyaba Hasan1,2,3,4, Lothar Lilge1,2,3,4 1 Department of Medical Biophysics, University of Toronto, Canada 2 Department of Radiation Oncology, University Health Network, Canada 3 Wellman Center for Photomedicine, Massachusetts General Hospital, USA 4 Division of Molecular Imaging, Princess Margaret Cancer Centre, Canada Malignant gliomas are invasive and difficult to treat tumours. Of this group of tumours, Glioblastoma Multiforme (GBM) is the most common and the most aggressive. Of proposed GBM treatments, ALA-PpIX mediated Photodynamic Therapy (PDT) has been explored and researched into. The goal of our group is to examine whether combining PDT with EGFR kinase inhibitors leads to greater outcomes compared to PDT or EGFR inhibitors alone. The study proposed utilized the human cell line U87 (EGFR positive) in combination with a liposomal based EGFR inhibitor (lapatinib) that was combined with PDT treatment. Pre-PDT animals were scannedwithaBruker7T small animalMRI systemtomeasure cerebral blood flow (CBF) and tumor vascular permeability and began treatment with the liposomal lapatinib conjugation. Post-PDT animal were scanned at regular intervals to measure CBF and tumour size between the two groups. In the initial pilot study, liposomal lapatinib combined with PDT lead to significant increases in survival compared to PDT alone and demonstrated differences in both CBF and tumour response to PDT. Ongoing studies are focused on increasing the number of animals and get quantitativemeasures of CBF and cerebral blood volume both preand post-PDT. http://dx.doi.org/10.1016/j.pdpdt.2015.07.074 Sonochemical internalization using 5-aminolevulinic acid enhances the cytotoxic effect of bleomycin Tomohiro Osaki1, Yoshihiro Uto2, Masahiro Ishizuka3, Toru Tanaka3, Nobuyasu Yamanaka4, Tsukasa Kurahashi4, Kazuo Azuma1, Yusuke Murahata1, Takeshi Tsuka1, Norihiko Ito1, Tomohiro Imagawa1, Yoshiharu Okamoto1 1 Department of Veterinary Clinical Medicine, School of Veterinary Medicine, Tottori University, Japan 2 Department of Life System, Institute of Technology and Science, Graduate School, Tokushima University, Japan 3 SBI Pharmaceuticals Co., Ltd., Japan 4 ITO Physiotherapy & Rehabilitation, Japan Photochemical internalization (PCI) is a technology to improve the intracellular delivery ofmacromolecules andbasedon the same principle as photodynamic therapy (PDT). PCI is based on the use of photosensitizers located in endocytic vesicles that upon activation by light induce rupture of endocytic vesicles and release the macromolecules into cytosol. Bleomycin (BLM) is used for chemotherapeutic agent for PCI. The limitation of PDT and PCI is the penetration of light in the tissue. It is difficult to treat deepseated tumor with PDT and PCI. Sonodynamic therapy (SDT) is also an antitumor strategy that kills tumor cells by ultrasound and photosensitizer. Ultrasound can penetrate deep tissue and excite photosensitizer. We hypothesized that ultrasound could excite photosensitizers used for PCI, and this newmethod could improve the intracellular delivery of macromolecules. We defined this new method as sonochemical internalization (SCI). In this study, we examined whether internalization of BLM by ultrasound and 5aminolevulinic acid (5-ALA) was able to destroy tumors. In vitro and in vivo study, a significant cytotoxic effect of SCI of BLM using 5-ALA was observed. It was considered that SCI might act as an ultrasound-directed drug-delivery system by triggered release of endocytosed macromolecules into cytosol as PCI. http://dx.doi.org/10.1016/j.pdpdt.2015.07.075 Acridine orange as radiosensitizer to improve cell damage caused by radiotherapy in breast cancer cells line Cintia Teles de Andrade, Jose Dirceu Vollet-Filho, Layla Pires, Vanderlei Salvador Bagnato, Cristina Kurachi Sao Carlos Institute of Physics, University of Sao

Highly accurate thermal flow microsensor for continuous and quantitative measurement of cerebral blood flow.

Cerebral blood flow (CBF) plays a critical role in the exchange of nutrients and metabolites at the capillary level and is tightly regulated to meet the metabolic demands of the brain. After major brain injuries, CBF normally decreases and supporting the injured brain with adequate CBF is a mainstay of therapy after traumatic brain injury. Quantitative and localized measurement of CBF is therefore critically important for evaluation of treatment efficacy and also for understanding of cerebral pathophysiology. We present here an improved thermal flow microsensor and its operation which provides higher accuracy compared to existing devices. The flow microsensor consists of three components, two stacked-up thin film resistive elements serving as composite heater/temperature sensor and one remote resistive element for environmental temperature compensation. It operates in constant-temperature mode (~2°C above the medium temperature) providing 20ms temporal resolution. Compared to previous thermal flow microsensor based on self-heating and self-sensing design, the sensor presented provides at least two-fold improvement in accuracy in the range from 0 to 200ml/100g/min. This is mainly achieved by using the stacked-up structure, where the heating and sensing are separated to improve the temperature measurement accuracy by minimization of errors introduced by self-heating.

Abstract W P399: Magnetic Resonance Imaging Based Cerebral Blood Flow Changes in Asymptomatic Human Immunodeficiency Virus Infected Subjects

Background: Human Immunodeficiency Virus (HIV) infected individuals are at high risk for ischemic stroke. Magnetic resonance imaging (MRI) method of measurement of cerebral blood flow (CBF) and oxygen extraction fraction (OEF) may help assess the stroke risk in asymptomatic HIV subjects. Objectives: To evaluate MR measured CBF and OEF in treatment naïve asymptomatic HIV+ subjects and HIV- controls. Methods: Treatment naïve asymptomatic HIV+ subjects and age-gender-race matched HIV- controls were assessed for CBF using a pulsed arterial spin labeling (PASL) approach and Oxygen Extraction Fraction (OEF) using MRI T2*-weighted echo-planar imaging (EPI) sequences. All images were acquired using a Siemens 3T MR scanner (Treo, Siemens Medical Systems Inc). Quantitative CBF and OEF measurements were made in the whole-brain, gray matter and white matter and compared between the groups using unpaired t-test. Results: A total of 65 subjects of who, 35 treatment naïve HIV+ subjects (Mean age ± SD=30±7,89% male, 31% white, 49% black and 20% others) and 30 age-gender-race matched HIV- controls (Mean age± SD= 31±8,93% male, 37% white, 53% black and 10% others) consented to the protocol. HIV+ subjects compared to HIV- controls had significantly higher whole brain CBF (58.0 ± 13.8 ml/100g/min vs. 51.3 ± 9.0 ml/100g/min; p=0.03) and gray matter CBF (72.9 ± 16.2 ml/100g/min vs. 63.9 ± 9.9 ml/100g/min; p=0.01). However, values for whole brain OEF (0.4 ± 0.04) and gray matter OEF (0.4 ± 0.05) were similar for both groups. White matter CBF in HIV+ subjects (41.5 ± 13.1 ml/100g/min) compared to HIV- controls (37.2 ± 9.2 ml/100g/min) was not significantly higher (p=0.16) while white matter OEF (0.4 ± 0.04 HIV+ subjects vs. 0.4 ± 0.03 HIV-controls) showed no changes. Conclusions: The observed increase of whole brain CBF in treatment naïve HIV + subjects compared to HIV- matched controls, without corresponding changes in the OEF appears to be driven by a pronounced significant change in the gray matter compared with the white matter. These changes in CBF without corresponding changes in OEF suggest increase in metabolic activity, and may explain the higher stroke risk in asymptomatic HIV subjects.

OP04 * QUANTITATIVE MEASUREMENT OF BLOOD FLOW IN PAEDIATRIC BRAIN TUMOURS - A COMPARATIVE STUDY OF DYNAMIC SUSCEPTIBILITY CONTRAST AND MULTI-TIMEPOINT ARTERIAL SPIN LABEL IMAGING

INTRODUCTION: Arterial spin labeling (ASL) is a MR technique that allows for noninvasive quantification of cerebral blood flow (CBF). This technique, predominately used in research, has seen significant technical developments in the last few years that have led to more clinical applications. Currently, the main MR method used to provide perfusion measures in brain tumours is dynamic susceptibility contrast (DSC). DSC traces the signal changes caused by the transit of a bolus of gadolinium contrast agent. ASL has the advantage of not requiring bolus injection of contrast. We have performed a comparative study of DSC and multi-timepoint ASL in paediatric brain tumours (PBT). METHOD: Data from a total of 19 PBT patients (mean age: 9 ± 5 years; 10 females, 9 males) were included in the analyses for this study. Data used were from first presentation scans performed before any surgical intervention. Comparisons of the quantitative measures of CBF and blood arrival time between the two techniques were carried out to test the feasibility of ASL to provide useful quantification measures of CBF in PBT. RESULTS: DSC measurements of tumour blood flow showed a significant decrease in flow in comparison with normal brain, but this is not seen with ASL. There was a strong correlation between ASL and DSC measures of blood flow in normal brain (r = 0.65, p = 0.009), but not in tumour blood flow (r = 0.33, p = 0.2). CONCLUSION: This study demonstrates the feasibility and potential utility of ASL as a non-invasive technique for measuring blood flow in PBT. However, there is a discrepancy between ASL and DSC measures, that may be due to leakage of gadolinium contrast, reflecting the abnormal characteristics of tumour blood vessels in PBT.

Imaging of cerebral blood flow in patients with severe traumatic brain injury in the neurointensive care.

Ischemia is a common and deleterious secondary injury following traumatic brain injury (TBI). A great challenge for the treatment of TBI patients in the neurointensive care unit (NICU) is to detect early signs of ischemia in order to prevent further advancement and deterioration of the brain tissue. Today, several imaging techniques are available to monitor cerebral blood flow (CBF) in the injured brain such as positron emission tomography (PET), single-photon emission computed tomography, xenon computed tomography (Xenon-CT), perfusion-weighted magnetic resonance imaging (MRI), and CT perfusion scan. An ideal imaging technique would enable continuous non-invasive measurement of blood flow and metabolism across the whole brain. Unfortunately, no current imaging method meets all these criteria. These techniques offer snapshots of the CBF. MRI may also provide some information about the metabolic state of the brain. PET provides images with high resolution and quantitative measurements of CBF and metabolism; however, it is a complex and costly method limited to few TBI centers. All of these methods except mobile Xenon-CT require transfer of TBI patients to the radiological department. Mobile Xenon-CT emerges as a feasible technique to monitor CBF in the NICU, with lower risk of adverse effects. Promising results have been demonstrated with Xenon-CT in predicting outcome in TBI patients. This review covers available imaging methods used to monitor CBF in patients with severe TBI.

Accuracy and precision of pseudo-continuous arterial spin labeling perfusion during baseline and hypercapnia: A head-to-head comparison with 15O H2O positron emission tomography

Measurements of the cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) provide useful information about cerebrovascular condition and regional metabolism. Pseudo-continuous arterial spin labeling (pCASL) is a promising non-invasive MRI technique to quantitatively measure the CBF, whereas additional hypercapnic pCASL measurements are currently showing great promise to quantitatively assess the CVR. However, the introduction of pCASL at a larger scale awaits further evaluation of the exact accuracy and precision compared to the gold standard. 15O H2O positron emission tomography (PET) is currently regarded as the most accurate and precise method to quantitatively measure both CBF and CVR, though it is one of the more invasive methods as well. In this study we therefore assessed the accuracy and precision of quantitative pCASL-based CBF and CVR measurements by performing a head-to-head comparison with 15O H2O PET, based on quantitative CBF measurements during baseline and hypercapnia. We demonstrate that pCASL CBF imaging is accurate during both baseline and hypercapnia with respect to 15O H2O PET with a comparable precision. These results pave the way for quantitative usage of pCASL MRI in both clinical and research settings.

Quantitative CBF measurement using an integrated SPECT/CT system: validation of three-dimensional ordered-subset expectation maximization and CT-based attenuation correction by comparing with O-15 water PET

As spreading integrated SPECT/CT scanners, reconstruction method based on three-dimensional ordered-subset expectation maximization (3D-OSEM) with attenuation correction (AC) using an X-ray CT image (CTAC) is easily available in brain imaging. For quantitative cerebral blood flow (CBF) measurements, however, the accuracy of this method has not been fully evaluated clinically. To validate this new algorithm, we sequentially studied quantitative PET-CBF and SPECT-CBF measurements in the same healthy volunteers and compared CBF values. Ten healthy subjects underwent quantitative PET-CBF and SPECT-CBF measurements on the same day. PET-CBF data were obtained by the intravenous injection of O-15 water and the quantitative IMP-ARG method followed. Three types of SPECT images were reconstructed: (1) filtered back projection (FBP) with Chang's AC (FBP+Chang's AC), (2) 3D-OSEM with Chang's AC (3D-OSEM+Chang's AC), and (3) 3D-OSEM with CTAC (3D-OSEM+CTAC). The mean CBF difference, the linearity, and the correlation between the PET-CBF and SPECT-CBF values were compared among the SPECT reconstruction algorithms. The mean SPECT-CBF values of all the algorithms were significantly lower in the pons (P=0.000-0.007) and higher in the frontal lobe (P=0.002-0.022). All the SPECT-CBF values were significantly correlated with the PET-CBF values (r=0.749-0.829, P<0.001). The SPECT-CBF values obtained using the 3D-OSEM+CTAC method showed the best regression with the PET-CBF values. The present clinical study validated accuracy of CBF image reconstructed by the 3-D OSEM method with CTAC and the integrated SPECT/CT system.

Quantitative Evaluation of Cerebral Blood Flow and Oxygen Metabolism in Normal Anesthetized Rats: 15O-Labeled Gas Inhalation PET with MRI Fusion

PET with (15)O gas has been used for the quantitative measurement of cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO(2)), oxygen extraction fraction (OEF), and cerebral blood volume (CBV) in humans. However, several technical difficulties limit its use in experiments on small animals. Herein, we describe the application of the (15)O gas steady-state inhalation method for normal anesthetized rats. Eight normal male Sprague-Dawley rats (mean body weight ± SD, 268 ± 14 g) under anesthesia were investigated by (15)O-labeled gas PET. After tracheotomy, an airway tube was placed in the trachea, and the animals were connected to a ventilator (tidal volume, 3 cm(3); frequency, 60/min). The CBF and OEF were measured according to the original steady-state inhalation technique under artificial ventilation with (15)O-CO(2) and (15)O-O(2) gases delivered through the radioactive gas stabilizer. CBV was measured by (15)O-CO gas inhalation and corrected for the intravascular hemoglobin-bound (15)O-O(2). Arterial blood sampling was performed during each study to measure the radioactivity of the whole blood and plasma. MR image was performed with the same acrylic animal holder immediately after the PET. Regions of interest were placed on the whole brain of the PET images with reference to the semiautomatically coregistered PET/MR fused images. The data acquisition time for the whole PET experiment in each rat was 73.3 ± 5.8 (range, 68-85) min. In both the (15)O-CO(2) and the (15)O-O(2) studies, the radioactivity count of the brain reached a steady state by approximately 10 min after the start of continuous inhalation of the gas. The quantitative PET data of the whole brain were as follows: CBF, 32.3 ± 4.5 mL/100 mL/min; CMRO(2), 3.23 ± 0.42 mL/100 mL/min; OEF, 64.6% ± 9.1%; and CBV, 5.05 ± 0.45 mL/100 mL. Although further technical improvements may be needed, this study demonstrated the feasibility of quantitative PET measurement of CBF, OEF, and CMRO(2) using the original steady-state inhalation method of (15)O-CO(2) and (15)O-O(2) gases and measurement of CBV using the (15)O-CO gas inhalation method in the brain of normal anesthetized rats.

Cortical responses to amphetamine exposure studied by pCASL MRI and pharmacokinetic/pharmacodynamic dose modeling

Perfusion measurement by arterial spin labeling (ASL) techniques is well suited for pharmaceutical magnetic resonance imaging (phMRI) studies to investigate how drugs change the cerebral perfusion status and further, neuronal activity. Twelve healthy normal male volunteers participated in the study which was based on a double blinded design. Six subjects were randomly selected to receive a single oral dose of 20mg d-amphetamine and six were given placebo. Perfusion measurements by pseudo-continuous ASL (pCASL) technique were repeatedly performed at 10 different time points with a 3T clinical MRI scanner during a 10 hour period after dose together with physiologic data and blood sample collections. The dynamic changes in cerebral perfusion in response to the plasma concentration variations of d-amphetamine were analyzed at voxel-level and for regions of interest. Compared to the placebo group a 20% reduction in cerebral blood flow (CBF) was observed in gray matter for the subjects that received d-amphetamine. The most significant reduction of regional CBF (rCBF) was detected in the basal ganglia, frontal region and insular cortex using voxel based analysis. A relation between d-amphetamine exposure and CBF response was found using PK/PD modeling, which predicted on average a 15% decrease of the CBF in gray matter at a plasma concentration of 30 ng/ml. In this study we have demonstrated that repeated perfusion measurements by pCASL technique was sufficiently robust to differentiate the neurological response between the groups that received d-amphetamine and placebo. Quantitative and repetitive CBF measurements can be used for PK/PD modeling of CNS drug responses in humans.

Cerebral Blood Flow and Metabolism Measurement Using Positron Emission Tomography before and during Internal Carotid Artery Test Occlusions: Feasibility of Rapid Quantitative Measurement of CBF and OEF/CMRO2

Balloon test occlusion (BTO) of the internal carotid artery (ICA) combined with cerebral blood flow (CBF) study is a sensitive test for predicting the outcome of permanent ICA occlusion. However, false negative results sometimes occur using single photon emission tomography (SPECT). We have recently developed a rapid positron emission tomography (PET) protocol that measures not only the CBF but also the cerebral oxygen metabolism before and during BTO in succession. We measured acute changes in regional CBF and OEF/CMRO(2) before and during BTO in three cases with large or giant cerebral aneurysms using the rapid PET protocol. Although no patients showed ischemic symptoms during BTO, PET studies exhibited mildly to moderately decreased CBF (9∼34%) compared to the values obtained before BTO in all cases. The average OEF during BTO was significantly increased (21% and 43%) than that of before BTO in two cases. The two cases were considered to be non-tolerant for permanent ICA occlusion and treated without ICA sacrifice. Measurement of the CBF and OEF/CMRO(2) using a rapid PET protocol before and during BTO is feasible and can be used for accurate assessment of tolerance prediction in ICA occlusion.