MRI evaluation of cerebral metabolic rate of oxygen (CMRO2) in obstructive sleep apnea.

Patients with obstructive sleep apnea (OSA) are at elevated risk of developing systemic vascular disease and cognitive dysfunction. Here, cerebral oxygen metabolism was assessed in patients with OSA by means of a magnetic resonance-based method involving simultaneous measurements of cerebral blood flow rate and venous oxygen saturation in the superior sagittal sinus for a period of 10 minutes at an effective temporal resolution of 1.3 seconds before, during, and after repeated 24-second breath-holds mimicking spontaneous apneas, yielding, along with pulse oximetry-derived arterial saturation, whole-brain CMRO2 via Fick's Principle. Enrolled subjects were classified based on their apnea-hypopnea indices into OSA (N = 31) and non-sleep apnea reference subjects (NSA = 21), and further compared with young healthy subjects (YH, N = 10). OSA and NSA subjects were matched for age and body mass index. CMRO2 was lower in OSA than in the YH group during normal breathing (105.6 ± 14.1 versus 123.7 ± 22.8 µmol O2/min/100g, P = 0.01). Further, the fractional change in CMRO2 in response to a breath-hold challenge was larger in OSA than in the YH group (15.2 ± 9.2 versus 8.5 ± 3.4%, P = 0.04). However, there was no significant difference in CMRO2 between OSA and NSA subjects. The data suggest altered brain oxygen metabolism in OSA and possibly in NSA as well.

Endogenous T1ρ cardiovascular magnetic resonance in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by increased left ventricular wall thickness, cardiomyocyte hypertrophy, and fibrosis. Adverse cardiac risk characterization has been performed using late gadolinium enhancement (LGE), native T1, and extracellular volume (ECV). Relaxation time constants are affected by background field inhomogeneity. T1ρ utilizes a spin-lock pulse to decrease the effect of unwanted relaxation. The objective of this study was to study T1ρ as compared to T1, ECV, and LGE in HCM patients. METHODS: HCM patients were recruited as part of the Novel Markers of Prognosis in Hypertrophic Cardiomyopathy study, and healthy controls were matched for comparison. In addition to cardiac functional imaging, subjects underwent T1 and T1ρ cardiovascular magnetic resonance imaging at short-axis positions at 1.5T. Subjects received gadolinium and underwent LGE imaging 15-20 min after injection covering the entire heart. Corresponding basal and mid short axis LGE slices were selected for comparison with T1 and T1ρ. Full-width half-maximum thresholding was used to determine the percent enhancement area in each LGE-positive slice by LGE, T1, and T1ρ. Two clinicians independently reviewed LGE images for presence or absence of enhancement. If in agreement, the image was labeled positive (LGE + +) or negative (LGE --); otherwise, the image was labeled equivocal (LGE + -). RESULTS: In 40 HCM patients and 10 controls, T1 percent enhancement area (Spearman's rho = 0.61, p < 1e-5) and T1ρ percent enhancement area (Spearman's rho = 0.48, p < 0.001e-3) correlated with LGE percent enhancement area. T1 and T1ρ percent enhancement areas were also correlated (Spearman's rho = 0.28, p = 0.047). For both T1 and T1ρ, HCM patients demonstrated significantly longer relaxation times compared to controls in each LGE category (p < 0.001 for all). HCM patients also showed significantly higher ECV compared to controls in each LGE category (p < 0.01 for all), and LGE -- slices had lower ECV than LGE + + (p = 0.01). CONCLUSIONS: Hyperenhancement areas as measured by T1ρ and LGE are moderately correlated. T1, T1ρ, and ECV were elevated in HCM patients compared to controls, irrespective of the presence of LGE. These findings warrant additional studies to investigate the prognostic utility of T1ρ imaging in the evaluation of HCM patients.

Co-delivery of etoposide and cisplatin in dual-drug loaded nanoparticles synergistically improves chemoradiotherapy in non-small cell lung cancer models.

Chemoradiotherapy with cisplatin and etoposide is a curative management regimen for both small and non-small cell lung cancers. While the treatment regimen is effective, it also has a high toxicity profile. One potential strategy to improve the therapeutic ratio of chemoradiation is to utilize nanotherapeutics. Nanoparticle formulation of cisplatin and etoposide, however, is challenging due to the significant mismatch in chemical properties of cisplatin and etoposide. Herein we report the formulation of a polymeric nanoparticle formulation of cisplatin and etoposide using a prodrug approach. We synthesized a hydrophobic platinum prodrug, which was then co-delivered with etoposide using a nanoparticle. Using mouse models of lung cancer, we demonstrated that dual-drug loaded nanoparticles are significantly more effective than small molecule chemotherapy in chemoradiotherapy. These results support further investigation of nanoparticle-based drug formulations of combination chemotherapies and the use of nanotherapeutics in chemoradiotherapy. STATEMENT OF SIGNIFICANCE: The treatment of lung cancer often involves a combination of chemotherapy and radiation. While it can be effective, it also has a high toxicity profile. Preferential delivery of chemotherapeutics to the tumor while avoiding normal tissue would improve efficacy and lower toxicity. While this is challenging with conventional drug delivery technologies, nanotechnology offers a unique opportunity. In this study, we have engineered nanoparticles that are loaded with combination chemotherapeutics and showed such nanotherapeutics are more effective and less toxic than free chemotherapeutics in chemoradiotherapy. Our work highlights the importance and potential of nanoformulations of combination chemotherapy in chemoradiotherapy and cancer treatment. This approach can be translated clinically and it can have a significant impact on cancer treatment.

MRI evaluation of cerebrovascular reactivity in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by intermittent obstruction of the airways during sleep. Cerebrovascular reactivity (CVR) is an index of cerebral vessels' ability to respond to a vasoactive stimulus, such as increased CO2. We hypothesized that OSA alters CVR, expressed as a breath-hold index (BHI) defined as the rate of change in CBF or BOLD signal during a controlled breath-hold stimulus mimicking spontaneous apneas by being both hypercapnic and hypoxic. In 37 OSA and 23 matched non sleep apnea (NSA) subjects, we obtained high temporal resolution CBF and BOLD MRI data before, during, and between five consecutive BH stimuli of 24 s, each averaged to yield a single BHI value. Greater BHI was observed in OSA relative to NSA as derived from whole-brain CBF (78.6 ± 29.6 vs. 60.0 ± 20.0 mL/min2/100 g, P = 0.010) as well as from flow velocity in the superior sagittal sinus (0.48 ± 0.18 vs. 0.36 ± 0.10 cm/s2, P = 0.014). Similarly, BOLD-based BHI was greater in OSA in whole brain (0.19 ± 0.08 vs. 0.15 ± 0.03%/s, P = 0.009), gray matter (0.22 ± 0.09 vs. 0.17 ± 0.03%/s, P = 0.011), and white matter (0.14 ± 0.06 vs. 0.10 ± 0.02%/s, P = 0.010). The greater CVR is not currently understood but may represent a compensatory mechanism of the brain to maintain oxygen supply during intermittent apneas.

Calibrated fMRI for dynamic mapping of CMRO2 responses using MR-based measurements of whole-brain venous oxygen saturation.

Functional MRI (fMRI) can identify active foci in response to stimuli through BOLD signal fluctuations, which represent a complex interplay between blood flow and cerebral metabolic rate of oxygen (CMRO2) changes. Calibrated fMRI can disentangle the underlying contributions, allowing quantification of the CMRO2 response. Here, whole-brain venous oxygen saturation (Yv) was computed alongside ASL-measured CBF and BOLD-weighted data to derive the calibration constant, M, using the proposed Yv-based calibration. Data were collected from 10 subjects at 3T with a three-part interleaved sequence comprising background-suppressed 3D-pCASL, 2D BOLD-weighted, and single-slice dual-echo GRE (to measure Yv via susceptometry-based oximetry) acquisitions while subjects breathed normocapnic/normoxic, hyperoxic, and hypercapnic gases, and during a motor task. M was computed via Yv-based calibration from both hypercapnia and hyperoxia stimulus data, and results were compared to conventional hypercapnia or hyperoxia calibration methods. Mean M in gray matter did not significantly differ between calibration methods, ranging from 8.5 ± 2.8% (conventional hyperoxia calibration) to 11.7 ± 4.5% (Yv-based calibration in response to hyperoxia), with hypercapnia-based M values between (p = 0.56). Relative CMRO2 changes from finger tapping were computed from each M map. CMRO2 increased by ∼20% in the motor cortex, and good agreement was observed between the conventional and proposed calibration methods.

Nanoparticle co-delivery of wortmannin and cisplatin synergistically enhances chemoradiotherapy and reverses platinum resistance in ovarian cancer models.

Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum-sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic.

High-speed whole-brain oximetry by golden-angle radial MRI.

PURPOSE: To determine whole-brain cerebral metabolic rate of oxygen (CMRO2 ), an improved imaging approach, based on radial encoding, termed radial OxFlow (rOxFlow), was developed to simultaneously quantify draining vein venous oxygen saturation (SvO2 ) and total cerebral blood flow (tCBF). METHODS: To evaluate the efficiency and precision of the rOxFlow sequence, 10 subjects were studied during a paradigm of repeated breath-holds with both rOxFlow and Cartesian OxFlow (cOxFlow) sequences. CMRO2 was calculated at baseline from OxFlow-measured data assuming an arterial O2 saturation of 97%, and the SvO2 and tCBF breath-hold responses were quantified. RESULTS: Average neurometabolic-vascular parameters across the 10 subjects for cOxFlow and rOxFlow were, respectively: SvO2 (%) baseline: 64.6 ± 8.0 versus 64.2 ± 6.6; SvO2 peak: 70.5 ± 8.5 versus 72.6 ± 5.4; tCBF (mL/min/100 g) baseline: 39.2 ± 3.8 versus 40.6 ± 8.0; tCBF peak: 53.2 ± 5.1 versus 56.1 ± 11.7; CMRO2 (µmol O2 /min/100 g) baseline: 111.5 ± 26.8 versus 120.1 ± 19.6. The above measures were not significantly different between sequences (P > 0.05). CONCLUSION: There was good agreement between the two methods in terms of the physiological responses measured. Comparing the two, rOxFlow provided higher temporal resolution and greater flexibility for reconstruction while maintaining high SNR. Magn Reson Med 79:217-223, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Simultaneous measurement of macro- and microvascular blood flow and oxygen saturation for quantification of muscle oxygen consumption.

PURPOSE: To investigate the relationship between blood flow and oxygen consumption in skeletal muscle, a technique called "Velocity and Perfusion, Intravascular Venous Oxygen saturation and T2*" (vPIVOT) is presented. vPIVOT allows the quantification of feeding artery blood flow velocity, perfusion, draining vein oxygen saturation, and muscle T2*, all at 4-s temporal resolution. Together, the measurement of blood flow and oxygen extraction can yield muscle oxygen consumption ( V˙O2) via the Fick principle. METHODS: In five subjects, vPIVOT-derived results were compared with those obtained from stand-alone sequences during separate ischemia-reperfusion paradigms to investigate the presence of measurement bias. Subsequently, in 10 subjects, vPIVOT was applied to assess muscle hemodynamics and V˙O2 following a bout of dynamic plantar flexion contractions. RESULTS: From the ischemia-reperfusion paradigm, no significant differences were observed between data from vPIVOT and comparison sequences. After exercise, the macrovascular flow response reached a maximum 8 ± 3 s after relaxation; however, perfusion in the gastrocnemius muscle continued to rise for 101 ± 53 s. Peak V˙O2 calculated based on mass-normalized arterial blood flow or perfusion was 15.2 ± 6.7 mL O2 /min/100 g or 6.0 ± 1.9 mL O2 /min/100 g, respectively. CONCLUSIONS: vPIVOT is a new method to measure blood flow and oxygen saturation, and therefore to quantify muscle oxygen consumption. Magn Reson Med 79:846-855, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Co-delivery of paclitaxel and cisplatin with biocompatible PLGA-PEG nanoparticles enhances chemoradiotherapy in non-small cell lung cancer models.

Chemoradiotherapy (CRT) with paclitaxel (PTX) and cisplatin (CP) is part of the standard of care for patients with locally advanced non-small cell lung cancer (NSCLC). Despite the high treatment intensity, many patients still develop local recurrence after treatment. Thus, there is a strong need to further improve CRT for lung cancer. One strategy is to co-deliver cytotoxic chemotherapy agents using biocompatible nanoparticles (NPs) which can limit off-target tissue toxicity and improve therapeutic efficacy. Herein, we report the development of dual-drug loaded nanoformulations that improve the efficacy of CRT for NSCLC by co-encapsulation of cisplatin (CP) and PTX in PLGA-PEG NPs. Mice bearing NSCLC xenografts given the dual-drug loaded NPs during CRT showed greater inhibition of tumor growth than free drug combinations or combinations of single-drug loaded NPs. These results indicate that using a NP co-delivery strategy for this common CRT regimen may improve clinical responses in NSCLC patients.

Susceptibility-based time-resolved whole-organ and regional tissue oximetry.

The magnetism of hemoglobin - being paramagnetic in its deoxy and diamagnetic in its oxy state - offers unique opportunities to probe oxygen metabolism in blood and tissues. The magnetic susceptibility χ of blood scales linearly with blood oxygen saturation, which can be obtained by measuring the magnetic field ΔB of the intravascular MR signal relative to tissue. In contrast to χ, the induced field ΔB is non-local. Therefore, to obtain the intravascular susceptibility Δχ relative to adjoining tissue from the measured ΔB demands solution of an inverse problem. Fortunately, for ellipsoidal structures, to which a straight, cylindrically shaped blood vessel segment conforms, the solution is trivial. The article reviews the principle of MR susceptometry-based blood oximetry. It then discusses applications for quantification of whole-brain oxygen extraction - typically on the basis of a measurement in the superior sagittal sinus - and, in conjunction with total cerebral blood flow, the cerebral metabolic rate of oxygen (CMRO2 ). By simultaneously measuring flow and venous oxygen saturation (SvO2 ) a temporal resolution of a few seconds can be achieved, allowing the study of the response to non-steady-state challenges such as volitional apnea. Extensions to regional measurements in smaller cerebral veins are also possible, as well as voxelwise quantification of venous blood saturation in cerebral veins accomplished by quantitative susceptibility mapping (QSM) techniques. Applications of susceptometry-based oximetry to studies of metabolic and degenerative disorders of the brain are reviewed. Lastly, the technique is shown to be applicable to other organ systems such as the extremities using SvO2 as a dynamic tracer to monitor the kinetics of the microvascular response to induced ischemia. Copyright © 2016 John Wiley & Sons, Ltd.

Nanoparticle delivery of chemotherapy combination regimen improves the therapeutic efficacy in mouse models of lung cancer.

The combination chemotherapy regimen of cisplatin (CP) and docetaxel (DTX) is effective against a variety of cancers. However, combination therapies present unique challenges that can complicate clinical application, such as increases in toxicity and imprecise exposure of tumors to specific drug ratios that can produce treatment resistance. Drug co-encapsulation within a single nanoparticle (NP) formulation can overcome these challenges and further improve combinations' therapeutic index. In this report, we employ a CP prodrug (CPP) strategy to formulate poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs carrying both CPP and DTX. The dually loaded NPs display differences in drug release kinetics and in vitro cytotoxicity based on the structure of the chosen CPP. Furthermore, NPs containing both drugs showed a significant improvement in treatment efficacy versus the free drug combination in vivo.

Phototriggered Secretion of Membrane Compartmentalized Bioactive Agents.

A strategy for the light-activated release of bioactive compounds (BODIPY, colchicine, paclitaxel, and methotrexate) from membrane-enclosed depots is described. We have found that membrane-permeable bioagents can be rendered membrane impermeable by covalent attachment to cobalamin (Cbl) through a photocleavable linker. These Cbl-bioagent conjugates are imprisoned within lipid-enclosed compartments in the dark, as exemplified by their retention in the interior of erythrocytes. Subsequent illumination drives the secretion of the bioactive species from red blood cells. Photorelease is triggered by wavelengths in the red, far-red, and near-IR regions, which can be pre-assigned by affixing a fluorophore with the desired excitation wavelength to the Cbl-bioagent conjugate. Pre-assigned wavelengths allow different biologically active compounds to be specifically and unambiguously photoreleased from common carriers.

Calibrated bold fMRI with an optimized ASL-BOLD dual-acquisition sequence.

Calibrated fMRI techniques estimate task-induced changes in the cerebral metabolic rate of oxygen (CMRO2) based on simultaneous measurements of cerebral blood flow (CBF) and blood-oxygen-level-dependent (BOLD) signal changes evoked by stimulation. To determine the calibration factor M (corresponding to the maximum possible BOLD signal increase), BOLD signal and CBF are measured in response to a gas breathing challenge (usually CO2 or O2). Here we describe an ASL dual-acquisition sequence that combines a background-suppressed 3D-GRASE readout with 2D multi-slice EPI. The concatenation of these two imaging sequences allowed separate optimization of the acquisition for CBF and BOLD data. The dual-acquisition sequence was validated by comparison to an ASL sequence with a dual-echo EPI readout, using a visual fMRI paradigm. Results showed a 3-fold increase in temporal signal-to-noise ratio (tSNR) of the ASL time-series data while BOLD tSNR was similar to that obtained with the dual-echo sequence. The longer TR of the proposed dual-acquisition sequence, however, resulted in slightly lower T-scores (by 30%) in the BOLD activation maps. Further, the potential of the dual-acquisition sequence for M-mapping on the basis of a hypercapnia gas breathing challenge and for quantification of CMRO2 changes in response to a motor activation task was assessed. In five subjects, an average gray matter M-value of 8.71±1.03 and fractional changes of CMRO2 of 12.5±5% were found. The new sequence remedies the deficiencies of prior combined BOLD-ASL acquisition strategies by substantially enhancing perfusion tSNR, which is essential for accurate BOLD calibration.

Measurement of skeletal muscle perfusion dynamics with pseudo-continuous arterial spin labeling (pCASL): Assessment of relative labeling efficiency at rest and during hyperemia, and comparison to pulsed arterial spin labeling (PASL).

PURPOSE: To compare calf skeletal muscle perfusion measured with pulsed arterial spin labeling (PASL) and pseudo-continuous arterial spin labeling (pCASL) methods, and to assess the variability of pCASL labeling efficiency in the popliteal artery throughout an ischemia-reperfusion paradigm. MATERIALS AND METHODS: At 3T, relative pCASL labeling efficiency was experimentally assessed in five subjects by measuring the signal intensity of blood in the popliteal artery just distal to the labeling plane immediately following pCASL labeling or control preparation pulses, or without any preparation pulses throughout separate ischemia-reperfusion paradigms. The relative label and control efficiencies were determined during baseline, hyperemia, and recovery. In a separate cohort of 10 subjects, pCASL and PASL sequences were used to measure reactive hyperemia perfusion dynamics. RESULTS: Calculated pCASL labeling and control efficiencies did not differ significantly between baseline and hyperemia or between hyperemia and recovery periods. Relative to the average baseline, pCASL label efficiency was 2 ± 9% lower during hyperemia. Perfusion dynamics measured with pCASL and PASL did not differ significantly (P > 0.05). Average leg muscle peak perfusion was 47 ± 20 mL/min/100g or 50 ± 12 mL/min/100g, and time to peak perfusion was 25 ± 3 seconds and 25 ± 7 seconds from pCASL and PASL data, respectively. Differences of further metrics parameterizing the perfusion time course were not significant between pCASL and PASL measurements (P > 0.05). CONCLUSION: No change in pCASL labeling efficiency was detected despite the almost 10-fold increase in average blood flow velocity in the popliteal artery. pCASL and PASL provide precise and consistent measurement of skeletal muscle reactive hyperemia perfusion dynamics. J. MAGN. RESON. IMAGING 2016;44:929-939.

MRI-based methods for quantification of the cerebral metabolic rate of oxygen.

The brain depends almost entirely on oxidative metabolism to meet its significant energy requirements. As such, the cerebral metabolic rate of oxygen (CMRO2) represents a key measure of brain function. Quantification of CMRO2 has helped elucidate brain functional physiology and holds potential as a clinical tool for evaluating neurological disorders including stroke, brain tumors, Alzheimer's disease, and obstructive sleep apnea. In recent years, a variety of magnetic resonance imaging (MRI)-based CMRO2 quantification methods have emerged. Unlike positron emission tomography - the current "gold standard" for measurement and mapping of CMRO2 - MRI is non-invasive, relatively inexpensive, and ubiquitously available in modern medical centers. All MRI-based CMRO2 methods are based on modeling the effect of paramagnetic deoxyhemoglobin on the magnetic resonance signal. The various methods can be classified in terms of the MRI contrast mechanism used to quantify CMRO2: T2*, T2', T2, or magnetic susceptibility. This review article provides an overview of MRI-based CMRO2 quantification techniques. After a brief historical discussion motivating the need for improved CMRO2 methodology, current state-of-the-art MRI-based methods are critically appraised in terms of their respective tradeoffs between spatial resolution, temporal resolution, and robustness, all of critical importance given the spatially heterogeneous and temporally dynamic nature of brain energy requirements.

Fluorophore Assisted Photolysis of Thiolato-Cob(III)alamins.

Cobalamins are known to react with thiols to yield stable ß-axial Co(III)-S bonded thiolato-cobalamin complexes. However, in stark contrast to the Co-C bond in alkylcobalamins, the photolability of the Co-S bond in thiolato-cobalamins remains undetermined. We have investigated the photolysis of N-acetylcysteinyl cob(III)alamin at several wavelengths within the ultraviolet and visible spectrum. To aid in photolysis, we show that attaching fluorophore "antennae" to the cobalamin scaffold can improve photolytic efficiency by up to an order of magnitude. Additionally, electron paramagnetic resonance confirms previous conjectures that the photolysis of thiolato-cobalamins at wavelengths as long as 546 nm produces thiyl radicals.

Cerebral metabolic rate of oxygen in obstructive sleep apnea at rest and in response to breath-hold challenge.

Obstructive sleep apnea (OSA) is associated with extensive neurologic comorbidities. It is hypothesized that the repeated nocturnal apneas experienced in patients with OSA may inhibit the normal apneic response, resulting in hypoxic brain injury and subsequent neurologic dysfunction. In this study, we applied the recently developedOxFlowMRI method for rapid quantification of cerebral metabolic rate of oxygen (CMRO2) during a volitional apnea paradigm. MRI data were analyzed in 11 OSA subjects and 10 controls (mean ± SD apnea-hypopnea index (AHI): 43.9 ± 18.1 vs. 2.9 ± 1.6 events/hour,P < 0.0001; age: 53.8 ± 8.2 vs. 45.3 ± 8.5 years,P = 0.027; BMI: 36.6 ± 4.4 vs. 31.9 ± 2.2 kg/m(2),P = 0.0064). Although total cerebral blood flow and arteriovenous oxygen difference were not significantly different between apneics and controls (P > 0.05), apneics displayed reduced baseline CMRO2(117.4 ± 37.5 vs. 151.6 ± 29.4 µmol/100 g/min,P = 0.013). In response to apnea, CMRO2decreased more in apneics than controls (-10.9 ± 8.8 % vs. -4.0 ± 6.7 %,P = 0.036). In contrast, group differences in flow-based cerebrovascular reactivity were not significant. Results should be interpreted with caution given the small sample size, and future studies with larger independent samples should examine the observed associations, including potential independent effects of age or BMI. Overall, these data suggest that dysregulation of the apneic response may be a mechanism for OSA-associated neuropathology.

Method for rapid MRI quantification of global cerebral metabolic rate of oxygen.

A recently reported quantitative magnetic resonance imaging (MRI) method denoted OxFlow has been shown to be able to quantify whole-brain cerebral metabolic rate of oxygen (CMRO2) by simultaneously measuring oxygen saturation (SvO2) in the superior sagittal sinus and cerebral blood flow (CBF) in the arteries feeding the brain in 30 seconds, which is adequate for measurement at baseline but not necessarily in response to neuronal activation. Here, we present an accelerated version of the method (referred to as F-OxFlow) that quantifies CMRO2 in 8 seconds scan time under full retention of the parent method's capabilities and compared it with its predecessor at baseline in 10 healthy subjects. Results indicate excellent agreement between both sequences, with mean bias of 2.2% (P=0.18, two-tailed t-test), 3.4% (P=0.08, two-tailed t-test), and 2.0% (P=0.56, two-tailed t-test) for SvO2, CBF, and CMRO2, respectively. F-OxFlow's potential to monitor dynamic changes in SvO2, CBF, and CMRO2 is illustrated in a paradigm of volitional apnea applied to five of the study subjects. The sequence captured an average increase in SvO2, CBF, and CMRO2 of 10.1±2.5%, 43.2±9.2%, and 7.1±2.2%, respectively, in good agreement with literature values. The method may therefore be suited for monitoring alterations in CBF and SvO2 in response to neurovascular stimuli.

B(12)-mediated, long wavelength photopolymerization of hydrogels.

Medical hydrogel applications have expanded rapidly over the past decade. Implantation in patients by noninvasive injection is preferred, but this requires hydrogel solidification from a low viscosity solution to occur in vivo via an applied stimuli. Transdermal photo-cross-linking of acrylated biopolymers with photoinitiators and lights offers a mild, spatiotemporally controlled solidification trigger. However, the current short wavelength initiators limit curing depth and efficacy because they do not absorb within the optical window of tissue (600-900 nm). As a solution to the current wavelength limitations, we report the development of a red light responsive initiator capable of polymerizing a range of acrylated monomers. Photoactivation occurs within a range of skin type models containing high biochromophore concentrations.

Cerebrovascular reactivity measured with arterial spin labeling and blood oxygen level dependent techniques.

PURPOSE: To compare cerebrovascular reactivity (CVR) quantified with pseudo-continuous arterial spin labeling (pCASL) and blood oxygen level dependent (BOLD) fMRI techniques. MATERIALS AND METHODS: Sixteen healthy volunteers (age: 37.8±14.3years; 6 women and 10 men; education attainment: 17±2.1years) were recruited and completed a 5% CO2 gas-mixture breathing paradigm at 3T field strength. ASL and BOLD images were acquired for CVR determination assuming that mild hypercapnia does not affect the cerebral metabolic rate of oxygen. Both CVR quantifications were derived as the ratio of the fractional cerebral blood flow (CBF) or BOLD signal change over the change in end-tidal CO2 pressure. RESULTS: The absolute CBF, BOLD and CVR measures were consistent with literature values. CBF derived CVR was 5.11±0.87%/mmHg in gray matter (GM) and 4.64±0.37%/mmHg in parenchyma. BOLD CVR was 0.23±0.04%/mmHg and 0.22±0.04%/mmHg for GM and parenchyma respectively. The most significant correlations between BOLD and CBF-based CVRs were also in GM structures, with greater vascular response in occipital cortex than in frontal and parietal lobes (6.8%/mmHg versus 4.5%/mmHg, 50% greater). Parenchymal BOLD CVR correlated significantly with the fractional change in CBF in response to hypercapnia (r=0.61, P=0.01), suggesting the BOLD response to be significantly flow driven. GM CBF decreased with age in room air (-5.58mL/100g/min per decade for GM; r=-0.51, P=0.05), but there was no association of CBF with age during hypercapnia. A trend toward increased pCASL CVR with age was observed, scaling as 0.64%/mmHg per decade for GM. CONCLUSION: Consistent with previously reported CVR values, our results suggest that BOLD and CBF CVR techniques are complementary to each other in evaluating neuronal and vascular underpinning of hemodynamic processes.