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Background: Influenza virus infection (IVI) was reported to be associated with minor cardiac changes, mostly those detected on electrocardiogram with and without elevated blood markers of myocardial injury; however, the characteristics of myocardial involvement in association with IVI are poorly understood. This study used echocardiographic tissue imaging (tissue Doppler, strain, and strain rate) to evaluate changes in left atrial (LA) and left ventricular (LV) myocardial function after IVI. Methods and results: We examined 20 adult individuals (mean age, 43 years) at 2 and 4 weeks after diagnosis of IVI. For myocardial functional variables, we obtained LV global longitudinal strain (GLS), LV early diastolic strain rate (e'sr), LA strain, and LA stiffness (E/e’/LA strain), in addition to data on tissue Doppler (s’, e’, and a’) and myocardial performance index. Blood markers of myocardial injury were also examined. During follow-up, there were no significant changes in global chamber function such as LV ejection fraction, E/e’, and LA volume. However, significant changes in myocardial function were observed, namely, in s’ (8.0 ± 1.6 cm/s to 9.3 ± 1.5 cm/s; p = 0.01), e’ (10.2 ± 2.8 cm/s to 11.4 ± 3.0 cm/s; p < 0.001), e’sr (1.43 ± 0.44 1/s to 1.59 ± 0.43 1/s; p = 0.005), and LA strain (35 ± 8% to 40 ± 12%; p = 0.025), and the myocardial performance index (0.52 ± 0.20 to 0.38 ± 0.09; p = 0.009), but not in a’, LA stiffness, or GLS. Cardiac troponin T and creatinine kinase isoenzyme MB were not elevated significantly at any examination. Conclusions: Myocardial dysfunction during IVI recovery appeared to be transient particularly in the absence of myocardial injury. Echocardiographic tissue imaging may be useful to detect subclinical cardiac changes in association with IVI. [ABSTRACT FROM AUTHOR]

Proteasome primarily degrades the unneeded or damaged proteins by proteolysis. Disruption of the brain barrier and its resulting meningoencephalitis caused by Angiostrongylus cantonensis are important pathological events in non-permissive hosts. In this study, the results showed upregulated proteasome during A. cantonensis infection. Occludin degradation and matrix metalloproteinase-9 (MMP-9) activity were significantly increased in infected mice than in uninfected mice. Moreover, confocal immunoflourescence microscopy showed that occludin was co-localized with MMP-9. The infected-mice were treated with proteasomal activity inhibitor MG132 by 1.5 and 3.0 mg/kg/day, which resulted in significantly reduced protein levels of phosphorylated IκBα (P<0.05) compared with the untreated control. The phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) showed similar result. In addition, MMP-9 activity and occludin degradation were reduced because of MG132 treatment. These results suggested that the proteasome in A. cantonensis infection degraded phosphorylated IκBα, modulated phosphorylated NF-κB, and then regulated the activation of MMP-9 and occludin degradation. Proteasome alterations were presented in eosinophilic meningitis of BALB/c mice and may contribute to the pathophysiology of eosinophilic meningitis by increasing occludin degradation. This molecule would serve as pivotal regulator in A. cantonensis-induced eosinophilic meningoencephalitis. [ABSTRACT FROM AUTHOR]

Background: Currently, there are many studies on the application of the 3D pseudocontinuous arterial spin-labeled (3D-pcASL) perfusion MRI technique for adult brain examinations, but few studies exist on the application of the technique for child brain examinations. Purpose: To explore the application of a 3D-pcASL perfusion MRI scan combined with postlabeling delay (PLD) for assessing neonatal hypoxic-ischemic encephalopathy (HIE). Materials and methods: Two-hundred neonates diagnosed with neonatal HIE were equally divided into five groups (40/group): 0- to <24-hour-old HIE group, 1- to <3-day-old HIE group, 3- to <7-day-old HIE group, 7- to <15-day-old HIE group and 15- to 28-day-old HIE group; 200 healthy neonates were equivalently divided. All 10 groups received a conventional and a 3D-pcASL perfusion MRI scan. For groups <3 days old, PLD values for the 3D-pcASL cerebral perfusion MRI scan were preset at 1025 ms; in all other groups, PLD values were preset at 1525 ms. CBF values for the 3D-pcASL cerebral perfusion MRI were compared between the HIE and corresponding control groups to determine the distinguishing characteristics of CBF values in HIE neonates. Results: On the 3D-pcASL cerebral perfusion MRI scan, in the 1- to <3-day-old groups, HIE neonate CBF values were higher than those of controls in all brain regions (excluding the frontal lobe); in the 0- to <24-hour-old and 3- to <7-day-old groups, HIE neonate CBF values were lower than those of corresponding controls in all brain regions; in the 7- to <15-day-old and 15- to 28-day-old groups, there were no significant differences in the CBF values between groups in any brain regions. Conclusions: The 3D-pcASL perfusion MRI scan combined with a PLD can assist in the early diagnosis of neonatal HIE, as this method more comprehensively reflects the HIE pathological process. [ABSTRACT FROM AUTHOR]

Reductions in cerebral oxygen saturation (ScO2) measured by near infra-red spectroscopy have been found during compensated hypovolemia in the lower body negative pressure (LBNP)-model, which may reflect reduced cerebral blood flow. However, ScO2 may also be contaminated from extracranial (scalp) tissues, mainly supplied by the external carotid artery (ECA), and it is possible that a ScO2 reduction during hypovolemia is caused by reduced scalp, and not cerebral, blood flow. The aim of the present study was to explore the associations between blood flow in precerebral arteries and ScO2 during LBNP-induced hypovolemia. Twenty healthy volunteers were exposed to LBNP 20, 40, 60 and 80 mmHg. Blood flow in the internal carotid artery (ICA), ECA and vertebral artery (VA) was measured by Doppler ultrasound. Stroke volume for calculating cardiac output was measured by suprasternal Doppler. Associations of changes within subjects were examined using linear mixed-effects regression models. LBNP reduced cardiac output, ScO2 and ICA and ECA blood flow. Changes in flow in both ICA and ECA were associated with changes in ScO2 and cardiac output. Flow in the VA did not change during LBNP and changes in VA flow were not associated with changes in ScO2 or cardiac output. During experimental compensated hypovolemia in healthy, conscious subjects, a reduced ScO2 may thus reflect a reduction in both cerebral and extracranial blood flow. [ABSTRACT FROM AUTHOR]

Aquaporin-4 (AQP4) plays an important role in regulating water exchange across the blood-brain barrier (BBB) and brain-cerebrospinal fluid interface. Studies on AQP-4 knockout mice (AQP4-KO) have reported considerable protection from brain edema induced by acute water intoxication and ischemic stroke, identifying AQP4 as a potential target for therapeutic interventions. However, the long-term effects of chronic AQP4 suppression are yet to be elucidated. In the current study, we evaluated the physiological and structural changes in adult AQP4-KO mice using magnetic resonance imaging (MRI) and immunohistochemical analysis. Water exchange across BBB was assessed by tracking an intravenous bolus injection of oxygen-17 (17O) water (H217O) using 17O-MRI. Cerebral blood flow (CBF) was quantified using arterial spin-labeling (ASL) MRI. Capillary density was determined by immunohistochemical staining for glucose transporter-1 (GLUT1). Compared to wildtype control mice, AQP4-KO mice showed a significant reduction in peak and steady-state H217O uptake despite unaltered CBF. Interestingly, a 22% increase in cortical capillary density was observed in AQP4-KO mice. These results suggest that increased cerebral vascularization may be an adaptive response to chronic reduction in water exchange across BBB in AQP4-KO mice. [ABSTRACT FROM AUTHOR]

Different pediatric physiologically-based pharmacokinetic (PBPK) models have been described incorporating developmental changes that influence plasma drug concentrations. Drug disposition into cerebrospinal fluid (CSF) is also subject to age-related variation and can be further influenced by brain diseases affecting blood-brain barrier integrity, like meningitis. Here, we developed a generic pediatric brain PBPK model to predict CSF concentrations of drugs that undergo passive transfer, including age-appropriate parameters. The model was validated for the analgesics paracetamol, ibuprofen, flurbiprofen and naproxen, and for a pediatric meningitis population by empirical optimization of the blood-brain barrier penetration of the antibiotic meropenem. Plasma and CSF drug concentrations derived from the literature were used to perform visual predictive checks and to calculate ratios between simulated and observed area under the concentration curves (AUCs) in order to evaluate model performance. Model-simulated concentrations were comparable to observed data over a broad age range (3 months– 15 years postnatal age) for all drugs investigated. The ratios between observed and simulated AUCs (AUCo/AUCp) were within 2-fold difference both in plasma (range 0.92–1.09) and in CSF (range 0.64–1.23) indicating acceptable model performance. The model was also able to describe disease-mediated changes in neonates and young children (<3m postnatal age) related to meningitis and sepsis (range AUCo/AUCp plasma: 1.64–1.66, range AUCo/AUCp CSF: 1.43–1.73). Our model provides a new computational tool to predict CSF drug concentrations in children with and without meningitis and can be used as a template model for other compounds that passively enter the CNS. [ABSTRACT FROM AUTHOR]

Background and purpose: Aging leads to alterations in cerebrovascular function, and these are thought to contribute to cognitive decline/dementia. Disturbances to cerebral blood flow regulation have been reported, but the findings are inconsistent and to date no study has comprehensively tested the collective and independent contribution of these parameters in the same age range. Such lines of enquiry are vital since aging is a heterogeneous and complex process, with cerebrovascular parameters being differentially affected depending on the individual. A multicomponent comprehensive measure of cerebrovascular function, which accounts for such diversity, is needed to differentiate between healthy young and old adults. Methods: We tested the effect of aging on cerebrovascular function by comparing healthy young adults aged 18–30 and older adults aged 60–75, without cognitive impairments. Cerebrovascular blood flow velocity was assessed using transcranial Doppler ultrasound. Parameters included resting middle cerebral artery velocity (MCAv), neurovascular coupling, cerebrovascular reactivity to CO2 (hypercapnia and hypocapnia), and the pressure-flow response during a sit-to-stand procedure. Results: MANOVA revealed that collectively, the parameters discriminated the groups (p < .001). MCAv and pressure-flow responses were lower in the older group (p < .001). While there were no differences in hypercapnic responses (p = .908) and neurovascular coupling (p = .517), hypocapnic responses were elevated in the old (p = .002). Conclusions: Collectively, cerebrovascular parameters can distinguish between healthy young and older adults, with aging leading to reductions in MCAv, and altering cerebrovascular reactivity and pressure-flow responses under hypotensive conditions. [ABSTRACT FROM AUTHOR]

Task-evoked Blood-oxygenation-level-dependent (BOLD-fMRI) signal activation is widely used to interrogate eloquence of brain areas. However, data interpretation can be improved, especially in regions with absent BOLD-fMRI signal activation. Absent BOLD-fMRI signal activation may actually represent false-negative activation due to impaired cerebrovascular reactivity (BOLD-CVR) of the vascular bed. The relationship between impaired BOLD-CVR and BOLD-fMRI signal activation may be better studied in healthy subjects where neurovascular coupling is known to be intact. Using a model-based prospective end-tidal carbon dioxide (CO2) targeting algorithm, we performed two controlled 3 tesla BOLD-CVR studies on 17 healthy subjects: 1: at the subjects’ individual resting end-tidal CO2 baseline. 2: Around +6.0 mmHg CO2 above the subjects’ individual resting baseline. Two BOLD-fMRI finger-tapping experiments were performed at similar normo- and hypercapnic levels. Relative BOLD fMRI signal activation and t-values were calculated for BOLD-CVR and BOLD-fMRI data. For each component of the cerebral motor-network (precentral gyrus, postcentral gyrus, supplementary motor area, cerebellum und fronto-operculum), the correlation between BOLD-CVR and BOLD-fMRI signal changes and t-values was investigated. Finally, a voxel-wise quantitative analysis of the impact of BOLD-CVR on BOLD-fMRI was performed. For the motor-network, the linear correlation coefficient between BOLD-CVR and BOLD-fMRI t-values were significant (p<0.01) and in the range 0.33–0.55, similar to the correlations between the CVR and fMRI Δ%signal (p<0.05; range 0.34–0.60). The linear relationship between CVR and fMRI is challenged by our voxel-wise analysis of Δ%signal and t-value change between normo- and hypercapnia. Our main finding is that BOLD fMRI signal activation maps are markedly dampened in the presence of impaired BOLD-CVR and highlights the importance of a complementary BOLD-CVR assessment in addition to a task-evoked BOLD fMRI to identify brain areas at risk for false-negative BOLD-fMRI signal activation. [ABSTRACT FROM AUTHOR]

The sulfonylurea 1 transient receptor potential melastatin 4 (Sur1-Trpm4) receptor is selectively expressed after intracerebral hemorrhage (ICH). This upregulation contributes to increases in intracellular sodium. Water follows sodium through aquaporin channels, leading to cytotoxic edema. Even after edema is thought to have resolved, ionic dyshomeostasis persists, as does blood-brain barrier (BBB) damage. Glibenclamide, a hypoglycemic agent that inhibits Sur1-Trpm4, has been shown to reduce BBB damage and edema following infusion of autologous blood into the brain (ICH) as well as after other brain injuries. In order to further assess efficacy, we used the collagenase ICH model in rats to test whether glibenclamide reduces edema, attenuates ion dyshomeostasis, improves BBB damage, and reduces lesion volume. We tested a widely-used glibenclamide dose shown effective in other studies (10 μg/kg loading dose followed by 200 ng/hr for up to 7 days). Early initiation of glibenclamide did not significantly impact edema (72 hours), BBB permeability (72 hours), or lesion volume after ICH (28 days). Recovery from neurological impairments was also not improved by glibenclamide. These results suggest that glibenclamide will not improve outcome in ICH. However, the treatment appeared to be safe as there was no effect on bleeding or other physiological variables. [ABSTRACT FROM AUTHOR]

We report a study on twenty-two healthy human subjects of the dynamic relationship between cerebral hemoglobin concentration ([HbT]), measured with near-infrared spectroscopy (NIRS) in the prefrontal cortex, and systemic arterial blood pressure (ABP), measured with finger plethysmography. [HbT] is a measure of local cerebral blood volume (CBV). We induced hemodynamic oscillations at discrete frequencies in the range 0.04–0.20 Hz with cyclic inflation and deflation of pneumatic cuffs wrapped around the subject’s thighs. We modeled the transfer function of ABP and [HbT] in terms of effective arterial (K( a )) and venous (K( v )) compliances, and a cerebral autoregulation time constant (τ(AR)). The mean values (± standard errors) of these parameters across the twenty-two subjects were K( a ) = 0.01 ± 0.01 μM/mmHg, K( v ) = 0.09 ± 0.05 μM/mmHg, and τ(AR) = 2.2 ± 1.3 s. Spatially resolved measurements in a subset of eight subjects reveal a spatial variability of these parameters that may exceed the inter-subject variability at a set location. This study sheds some light onto the role that ABP and cerebral blood flow (CBF) play in the dynamics of [HbT] measured with NIRS, and paves the way for new non-invasive optical studies of cerebral blood flow and cerebral autoregulation. [ABSTRACT FROM AUTHOR]

Myocardial perfusion abnormalities are the first sign of the ischemic cascade in the development of coronary artery disease (CAD). Thus, the early detection of myocardial perfusion abnormalities is significant for the prevention of CAD. Recently, a novel noninvasive method named Cardiodynamicsgram (CDG) has been proposed for early detection of CAD. This study aims to evaluate the predictive value of CDG in myocardial perfusion abnormalities for suspected ischemic heart disease. In the study, 86 suspected patients were enrolled. Standard 12-lead ECG and CDG were performed simultaneously before single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). Diagnostic accuracy of CDG for myocardial perfusion abnormalities detection is assessed using SPECT MPI as the reference standard. Of these 86 suspected patients, 37 patients were positive in CDG, 49 patients were negative in CDG. Diagnostic accuracy of CDG at presentation for myocardial perfusion abnormalities was 84.9%, sensitivity 84.0%, and specificity 89.4%. Furthermore, of the 10 patients whose SPECT MPI results are reverse redistribution, 9 patients were positive in CDG. Underlying causes of false positive CDG findings included the factors that can change the stability of cardiac electrical conduction and measurement noise. Myocardial remodeling in patients with old myocardial infarction might be the major cause of false negative findings. Results show a good consistency between the CDG and SPECT MPI in evaluating myocardial perfusion abnormalities. It suggests that CDG might be used as a cost-effective tool for assessing the myocardial perfusion abnormalities in the clinic. [ABSTRACT FROM AUTHOR]

Objective: Rheoencephalography is a simple and inexpensive technique for cerebral blood flow assessment, however, it is not used in clinical practice since its correlation to clinical conditions has not yet been extensively proved. The present study investigates the ability of Poincaré Plot descriptors from rheoencephalography signals to detect apneas in volunteers. Methods: A group of 16 subjects participated in the study. Rheoencephalography data from baseline and apnea periods were recorded and Poincaré Plot descriptors were extracted from the reconstructed attractors with different time lags (τ). Among the set of extracted features, those presenting significant differences between baseline and apnea recordings were used as inputs to four different classifiers to optimize the apnea detection. Results: Three features showed significant differences between apnea and baseline signals: the Poincaré Plot ratio (SDratio), its correlation (R) and the Complex Correlation Measure (CCM). Those differences were optimized for time lags smaller than those recommended in previous works for other biomedical signals, all of them being lower than the threshold established by the position of the inflection point in the CCM curves. The classifier showing the best performance was the classification tree, with 81% accuracy and an area under the curve of the receiver operating characteristic of 0.927. This performance was obtained using a single input parameter, either SDratio or R. Conclusions: Poincaré Plot features extracted from the attractors of rheoencephalographic signals were able to track cerebral blood flow changes provoked by breath holding. Even though further validation with independent datasets is needed, those results suggest that nonlinear analysis of rheoencephalography might be a useful approach to assess the correlation of cerebral impedance with clinical changes. [ABSTRACT FROM AUTHOR]

Despite their wide-spread use, only limited information is available on the comparative test-retest reliability of task-based functional and resting state magnetic resonance imaging measures of blood oxygen level dependence (tb-fMRI and rs-fMRI) and cerebral blood flow (CBF) using arterial spin labeling. This information is critical to designing properly powered longitudinal studies. Here we comprehensively quantified and compared the test-retest reliability and reproducibility performance of 8 commonly applied fMRI tasks, 6 rs-fMRI metrics and CBF in 30 healthy volunteers. We find large variability in test-retest reliability performance across the different tb-fMRI paradigms and rs-fMRI metrics, ranging from poor to excellent. A larger extent of activation in tb-fMRI is linked to higher between-subject reliability of the respective task suggesting that differences in the amount of activation may be used as a first reliability estimate of novel tb-fMRI paradigms. For rs-fMRI, a good reliability of local activity estimates is paralleled by poor performance of global connectivity metrics. Evaluated CBF measures provide in general a good to excellent test-reliability matching or surpassing the best performing tb-fMRI and rs-fMRI metrics. This comprehensive effort allows for direct comparisons of test-retest reliability between the evaluated MRI domains and measures to aid the design of future tb-fMRI, rs-fMRI and CBF studies. [ABSTRACT FROM AUTHOR]

The aim of this study was to validate the possibility of using functional Near-Infrared Spectroscopy (fNIRS) to measure changes in cerebral blood flow in response to a hand being placed on a participant’s back, and to identify the areas of enhanced activity in the brain. Nineteen female adult volunteers participated in the study. An experienced school nurse touched the center of the participant’s back between the shoulder blades with the palm of her hand. Cerebral blood volume dynamics were measured with a 52-channel fNIRS system. Significantly higher oxygenated hemoglobin (oxy-Hb) concentration levels were recorded by channels 11, 14, 21, 22, 24, 32, 35, 45, 46, and 49 during the touching period than during the resting period. These channels indicated enhanced activity in the supramarginal gyrus, the middle frontal gyrus, the superior temporal gyrus, and the inferior frontal gyrus. The ability to detect changes in cerebral blood flow using this method indicates the possibility of measuring changes in cerebral blood flow using fNIRS when a person is touched on the back. fNIRS has been shown to be useful for studying the effects of touch. [ABSTRACT FROM AUTHOR]

Neurological dysfunction has been reported in Gulf War Illness (GWI), including abnormal cerebral blood flow (CBF) responses to physostigmine challenge. However, it is unclear whether the CBF response to normal physiological challenges and regulation is similarly dysfunctional. The goal of the present study was to evaluate the CBF velocity response to orthostatic stress (i.e., sit-to-stand maneuver) and increased fractional concentration of carbon dioxide. 23 cases of GWI (GWI+) and 9 controls (GWI) volunteered for this study. Primary variables of interest included an index of dynamic autoregulation and cerebrovascular reactivity. Dynamic autoregulation was significantly lower in GWI+ than GWI- both for autoregulatory index (2.99±1.5 vs 4.50±1.5, p = 0.017). In addition, we observed greater decreases in CBF velocity both at the nadir after standing (-18.5±6.0 vs -9.8±4.9%, p = 0.001) and during steady state standing (-5.7±7.1 vs -1.8±3.2%, p = 0.042). In contrast, cerebrovascular reactivity was not different between groups. In our sample of Veterans with GWI, dynamic autoregulation was impaired and consistent with greater cerebral hypoperfusion when standing. This reduced CBF may contribute to cognitive difficulties in these Veterans when upright. [ABSTRACT FROM AUTHOR]

Objective: This study analyzed variability in cerebral blood flow velocity (CBFV) and its association with emotional, clinical and functional variables and medication use in fibromyalgia syndrome (FMS). Methods: Using transcranial Doppler sonography, CBFV were bilaterally recorded in the anterior (ACA) and middle (MCA) cerebral arteries of 44 FMS patients and 31 healthy individuals during a 5-min resting period. Participants also completed questionnaires assessing pain, fatigue, insomnia, anxiety, depression and health-related quality of life (HRQoL). Results: Fast Fourier transformation revealed a spectral profile with four components: (1) a first very low frequency (VLF) component with the highest amplitude at 0.0024 Hz; (2) a second VLF component around 0.01-to-0.025 Hz; (3) a low frequency (LF) component from 0.075-to-0.11 Hz; and (4) a high frequency (HF) component with the lowest amplitude from 0.25-to-0.35 Hz. Compared to controls, FMS patients exhibited lower LF and HF CBFV variability in the MCAs (p < .005) and right ACA (p = .03), but higher variability at the first right MCA (p = .04) and left ACA (p = .005) VLF components. Emotional, clinical and functional variables were inversely related to LF and HF CBFV variability (r≥-.24, p≤.05). However, associations for the first VLF component were positive (r≥.28, p≤.05). While patients´ medication use was associated with lower CBFV variability, comorbid depression and anxiety disorders were unrelated to variability. Conclusions: Lower CBFV variability in the LF and HF ranges were observed in FMS, suggesting impaired coordination of cerebral regulatory systems. CBFV variability was differentially associated with clinical variables as a function of time-scale, with short-term variability being related to better clinical outcomes. CBFV variability analysis may be a promising tool to characterize FMS pathology and it impact on facets of HRQoL. [ABSTRACT FROM AUTHOR]

The study aimed at evaluating the effects of combined aerobic and resistance exercise training on cardiac morphometry and function, oxidative stress and inflammatory parameters in diabetic ovariectomized rats. For this, female Wistar rats (10 weeks-old) were divided into 4 groups (n = 8): euglycemic (E), diabetic (streptozotocin, 50 mg/kg, iv) (D), diabetic ovariectomized (DO) and trained diabetic ovariectomized (TDO). The combined exercise training was performed on a treadmill and in a ladder adapted to rats (8 weeks, at 40–60% of maximal capacity). The left ventricle (LV) morphometry and function were evaluated by echocardiography. Oxidative stress and inflammatory markers were measured on ventricles tissue. The sedentary diabetic animals (D and DO) showed impaired systolic and diastolic functions, as well as increased cardiac overload, evaluated by myocardial performance index (MPI- D: 0.32 ± 0.05; DO: 0.39 ± 0.13 vs. E: 0.25 ± 0.07), in relation to E group. Systolic and MPI dysfunctions were exacerbated in DO when compared to D group. The DO group presented higher protein oxidation and TNF-α/IL-10 ratio than D groups. Glutathione redox ratio (GSH/GSSG) and IL-10 were decreased in both D and DO groups when compared to E group. Exercise training improved exercise capacity, systolic and diastolic functions and MPI (0.18±0.11). The TDO group showed reduced protein oxidation and TNF-α/IL-10 ratio and increased GSH/GSSG and IL-10 in relation to the DO group. These results showed that combined exercise training was able to attenuate the cardiac dysfunctions, probably by reducing inflammation and oxidative stress in an experimental model of diabetes and menopause. [ABSTRACT FROM AUTHOR]

Background and purpose: Arterial spin labeling(ASL)with magnetic resonance imaging (MRI) is an effective method for estimating cerebral blood flow (CBF). Furthermore, assessing perfusion territories of arteries is useful for determining the treatment strategy of patients with carotid artery stenosis. ASL with selective vessel labeling is an effective method to obtain perfusion mapping, however, the application for selective labeling is not installed on all MR scanners. The purpose of this study is to establish a method to selectively mask in the labeling area using material with high susceptibility instead of selectively labeling to obtain a partial perfusion image. Materials and methods: ASL perfusion images were performed in five volunteers. Masking was applied by placing a stainless-steel bolt and nuts on the neck. The area of artifacts extended to the carotid artery was confirmed by the localizer image. In the obtained masked ASL, blood flow of the left and right cerebrum and cerebellum was measured and compared with control ASL without masking. By subtracting masked ASL from the control ASL, the perfusion territory of the carotid artery on the masked side was identified. Results: Mean CBF which was 39.6 ml/(100 g × min) in control ASL decreased to 16.1 ml/(100 g × min) in masked ASL, and the masking ratio was 59.6%. There were no significant differences in the CBF of non-masked areas under the control ASL condition (39.6± 5.2 ml/[100 g × min]) btween that under the masked ASL condition (39.4 ± 7.0 ml/[100 g × min]). By subtracting masked ASL from control ASL, we successfully visualized the hemilateral carotid artery’s perfusion territory. Conclusion: Intentional susceptibility artifacts with non-magnetic metals on the neck can mask spin labeling of the carotid artery. Furthermore, hemilateral carotid artery perfusion territories can be visualized in hemilaterally masked ASL. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to investigate the components of day-to-day variability of repeated phase contrast mapping (PCM) magnetic resonance imaging measurements of global cerebral blood flow (gCBF). Materials and methods: Two dataset were analyzed. In Dataset 1 duplicated PCM measurements of total brain flow were performed in 11 healthy young volunteers on two separate days applying a strictly standardized setup. For comparison PCM measurements obtained from a previously published study (Dataset 2) were analyzed in order to assess long-term variability in an aged population in a less strictly controlled setup. Global CBF was calculated by normalizing total brain flow to brain volume. On each day measurements of hemoglobin, caffeine and glucose were obtained. Linear mixed models were applied to estimate coefficients of variation (CV) of total (CVt), between-subject (CVb), within-subject day-to-day (CVw), and intra-session residual variability (CVr). Results: In Dataset 1 CVt, CVb, CVw and CVr were estimated to be 11%, 9.4%, 4% and 4.2%, respectively, and to 8.8%, 7.2%, 2.7% and 4.3%, respectively, when adjusting for hemoglobin and plasma caffeine. In Dataset 2 CVt, CVb and CVw were estimated to be 25.4%, 19.2%, and 15.0%, respectively, and decreased to 16.6%, 8.2% and 12.5%, respectively, when adjusting for the same covariates. Discussion: Our results suggest that short-term day-to-day variability of gCBF is relatively low compared to between-subject variability when studied in standardized conditions, whereas long-term variability in an aged population appears to be much larger when studied in less a standardized setup. The results further showed that from 20% to 35% of the total variability in gCBF can be attributed to the effects of hemoglobin and caffeine. [ABSTRACT FROM AUTHOR]

Background: Coronal suture synostosis is a condition which can have deleterious physical and cognitive sequelae in humans if not corrected. A well-established animal model has previously demonstrated disruptions in intracranial pressure and developmental abnormalities in rabbits with congenital craniosynostosis compared to wild type rabbits. Objective: The current study aimed to measure the cerebral blood flow (CBF) in developing rabbits with craniosynostosis who underwent suturectomy compared to those with no intervention and compared to wild type rabbits. Methods: Rabbits with early onset coronal suture synostosis were assigned to have suturectomy at 10 days of age (EOCS-SU, n = 15) or no intervention (EOCS, n = 18). A subset of each group was randomly selected for measurement at 10 days of age, 25 days of age, and 42 days of age. Wild type rabbits (WT, n = 18) were also randomly assigned to measurement at each time point as controls. Cerebral blood flow at the bilateral hemispheres, cortices, thalami, and superficial cortices was measured in each group using arterial spin-labeling MRI. Results: At 25 days of age, CBF at the superficial cortex was significantly higher in EOCS rabbits (192.6 ± 10.1 mL/100 mg/min on the left and 195 ± 9.5 mL/100 mg/min on the right) compared to WT rabbits (99.2 ± 29.1 mL/100 mg/min on the left and 96.2 ± 21.4 mL/100 mg/min on the right), but there was no significant difference in CBF between EOCS-SU (97.6 ± 11.3 mL/100 mg/min on the left and 99 ± 7.4 mL/100 mg/min on the right) and WT rabbits. By 42 days of age the CBF in EOCS rabbits was not significantly different than that of WT rabbits. Conclusion: Suturectomy eliminated the abnormally increased CBF at the superficial cortex seen in EOCS rabbits at 25 days of age. This finding contributes to the evidence that suturectomy limits abnormalities of ICP and CBF associated with craniosynostosis. [ABSTRACT FROM AUTHOR]

While the cerebral autoregulation sufficiently protects subcortical brain regions during hypoxia or asphyxia, the cerebral cortex is not as adequately protected, which suggests that regulation of the cerebral blood flow (CBF) is area-specific. Hypoxia was induced by inhalation of 5% oxygen, for reoxygenation 100% oxygen was used. Cortical and subcortical CBF (by laser Doppler flowmetry), blood gases, mean arterial blood pressure (MABP), heart rate and renal blood flow were constantly monitored. Low dosed urapidil was used for α1A-adrenergic receptor blockade. Western blotting was used to determine adrenergic receptor signalling mediators in brain arterioles. During hypoxia cortical CBF decreased to 72 ± 11% (mean reduction 11 ± 3%, p < 0.001) of baseline, whereas subcortical CBF increased to 168±18% (mean increase 43 ± 5%, p < 0.001). Reoxygenation led to peak CBF of 194 ± 27% in the subcortex, and restored cortical CBF. α1A-Adrenergic blockade led to minor changes in cortical CBF, but massively reduced subcortical CBF during hypoxia and reoxygenation–almost aligning CBF in both brain regions. Correlation analyses revealed that α1A-adrenergic blockade renders all CBF-responses pressure-passive during hypoxia and reoxygenation, and confirmed the necessity of α1A-adrenergic signalling for coupling of CBF-responses to oxygen saturation. Expression levels and activation state of key signalling-mediators of α1-receptors (NOSs, CREB, ERK1/2) did not differ between cortex and subcortex. The dichotomy between subcortical and cortical CBF during hypoxia and reoxygenation critically depends on α1A-adrenergic receptors, but not on differential expression of signalling-mediators: signalling through the α1A-subtype is a prerequisite for cortical/subcortical redistribution of CBF. [ABSTRACT FROM AUTHOR]

Arterial blood pressure (BP) can be measured directly using an invasive intra-arterial method. This method is considered a gold standard, however it is potentially hazardous and requires expensive equipment and professional skills. Therefore, two non-invasive methods–Doppler ultrasonic sphygmomanometry and oscillometry–have been introduced in veterinary medicine. Their accuracy has so far been reliably evaluated in various animal species, however only one study included a small group of goats. Therefore, we carried out a large-scale study which aimed to evaluate agreement between the two non-invasive methods and invasive intra-arterial BP measurement in anesthetized goats at various age. The study included 122 goats of two Polish local breeds (Polish White Improved and Polish Fawn Improved): 67 adult females, 35 adult males, and 20 two-month-old female kids. Goats were anesthetized with the intravenous mixture of xylazine and ketamine. BP was measured simultaneously with the three methods in each goat with 7 measurements on average taken. The study showed that according to the criteria of the American College of Veterinary Internal Medicine (ACVIM) oscillometric method yielded BP measurements sufficiently consistent with invasive intra-arterial method in anesthetized adult goats– 95% of oscillometric BP measurements were expected to differ from invasive BP measurements by at most ±20–25 mmHg. The agreement was worse in goat kids–oscillometry significantly overestimated invasive BP measurements, which resulted in highly asymmetrical 95% limits of agreement. Doppler systolic BP very poorly conformed to invasive systolic BP both in adult goats and in kids and all the ACVIM criteria were violated. Concluding, oscillometry, but not Doppler ultrasonic sphygmomanometry, may be regarded as an alternative to invasive BP measurement in large-scale scientific studies involving adult goats, however, individual oscillometric BP measurements should be treated with caution as estimated 95% limits of agreement were wide. [ABSTRACT FROM AUTHOR]

Background: Understanding how vascular and metabolic factors impact on cognitive function is essential to develop efficient therapies to prevent and treat cognitive losses in older age. Cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF) and venous oxygenation (Yv) comprise key physiologic processes that maintain optimum functioning of neural activity. Changes to these parameters across the lifespan may precede neurodegeneration and contribute to age-related cognitive decline. This study examined differences in blood flow and metabolism between 31 healthy younger (<50 years) and 29 healthy older (>50 years) adults; and investigated whether these parameters contribute to cognitive performance. Method: Participants underwent a cognitive assessment and MRI scan. Grey matter CMRO2 was calculated from measures of CBF (phase contrast MRI), arterial and venous oxygenation (TRUST MRI) to assess group differences in physiological function and the contribution of these parameters to cognition. Results: Performance on memory (p<0.001) and attention tasks (p<0.001) and total CBF were reduced (p<0.05), and Yv trended toward a decrease (p = .06) in the older group, while grey matter CBF and CMRO2 did not differ between the age groups. Attention was negatively associated with CBF when adjusted (p<0.05) in the older adults, but not in the younger group. There was no such relationship with memory. Neither cognitive measure was associated with oxygen metabolism or venous oxygenation in either age group. Conclusion: Findings indicated an age-related imbalance between oxygen delivery, consumption and demand, evidenced by a decreased supply of oxygen with unchanged metabolism resulting in increased oxygen extraction. CBF predicted attention when the age-effect was controlled, suggesting a task- specific CBF- cognition relationship. [ABSTRACT FROM AUTHOR]

Objective: To explore noninvasively the complex interactions of the maternal hemodynamic system throughout pregnancy and the resulting after-effect six weeks postpartum. Methods: Eighteen women were tested beginning at the 12th week of gestation at six time-points throughout pregnancy and six weeks postpartum. Heart rate, heart rate variability, blood pressure, pulse transit time (PTT), respiration, and baroreceptor sensitivity were analyzed in resting conditions. Additionally, hemoglobin, asymmetric and symmetric dimethylarginine and Endothelin (ET-1) were obtained. Results: Heart rate and sympathovagal balance favoring sympathetic drive increased, the vagal tone and the baroreflex sensitivity decreased during pregnancy. Relative sympathetic drive (sympathovagal balance) reached a maximum at 6 weeks postpartum whereas the other variables did not differ compared to first trimester levels. Postpartum diastolic blood pressure was higher compared to first and second trimester. Pulse transit time and endothelial markers showed no difference throughout gestation. However, opposing variables PTT and asymmetric dimethylarginine (ADMA) were both higher six weeks postpartum. Conclusions: The sympathetic up regulation throughout pregnancy goes hand in hand with a decreased baroreflex sensitivity. In the postpartum period, the autonomic nervous system, biochemical endothelial reactions and PTT show significant and opposing changes compared to pregnancy findings, indicating the complex aftermath of the increase of blood volume, the changes in perfusion strategies and blood pressure regulation that occur in pregnancy. [ABSTRACT FROM AUTHOR]

Cerebral autoregulation (CA) is the complex homeostatic regulatory relationship between blood pressure (BP) and cerebral blood flow (CBF). This study aimed to analyze the frequency-specific coupling function between cerebral oxyhemoglobin concentrations (delta [HbO2]) and mean arterial pressure (MAP) signals based on a model of coupled phase oscillators and dynamical Bayesian inference. Delta [HbO2] was measured by 24-channel near-infrared spectroscopy (NIRS) and arterial BP signals were obtained by simultaneous resting-state measurements in patients with stroke, that is, 9 with left hemiparesis (L–H group), 8 with right hemiparesis (R–H group), and 17 age-matched healthy individuals as control (healthy group). The coupling functions from MAP to delta [HbO2] oscillators were identified and analyzed in four frequency intervals (I, 0.6–2 Hz; II, 0.145–0.6 Hz; III, 0.052–0.145 Hz; and IV, 0.021–0.052 Hz). In L–H group, the CS from MAP to delta [HbO2] in interval III in channel 8 was significantly higher than that in healthy group (p = 0.003). Compared with the healthy controls, the coupling in MAP→delta [HbO2] showed higher amplitude in interval I and IV in patients with stroke. The increased CS and coupling amplitude may be an evidence of impairment in CA, thereby confirming the presence of impaired CA in patients with stroke. In interval III, the CS in L–H group from MAP to delta [HbO2] in channel 16 (p = 0.001) was significantly lower than that in healthy controls, which might indicate the compensatory mechanism in CA of the unaffected side in patients with stroke. No significant difference in region-wise CS between affected and unaffected sides was observed in stroke groups, indicating an evidence of globally impaired CA. These findings provide a method for the assessment of CA and will contribute to the development of therapeutic interventions in stroke patients. [ABSTRACT FROM AUTHOR]

After carotid artery stenting, the procurement of information about blood flow redistribution among brain-feeding arteries and its time trend is essential to understanding a patient’s physiological background and to determine their care regimen. Cerebral blood flow has been measured twice following carotid artery stenting in few previous studies, with some discrepancies in the results. The purpose of this study was to measure cerebral blood flow at multiple time points after carotid artery stenting, and to elucidate the time trend of cerebral blood flow and redistribution among arteries. Blood flow rates in 11 subjects were measured preoperatively, at one day, one week, and about three months, respectively after carotid artery stenting by using phase-contrast magnetic resonance imaging. The target vessels were the bilateral internal carotid arteries, the basilar artery, and the bilateral middle cerebral arteries. Lumen was semi-automatically defined using an algorithm utilizing pulsatility. The results showed that blood flow rates in the stented internal carotid artery and the ipsilateral middle cerebral artery increased following carotid artery stenting. Blood flow rates in the contralateral internal carotid artery and the basilar artery gradually declined, and they were lower than the preoperative values at three months after stenting. The sum of blood flow rates of the bilateral internal carotid arteries and the basilar artery increased after carotid artery stenting, and then decreased over the next three months. There was no significant change in the blood flow rate in the contralateral middle cerebral artery. From these results, it was concluded that redistribution among the bilateral internal carotid arteries and the basilar artery occurs after carotid artery stenting, and that it takes months thereafter to reach another equilibrium. [ABSTRACT FROM AUTHOR]

Motivation: Obstructive sleep apnea (OSA) can impair cerebral vasoreactivity and is associated with an increased risk of cerebrovascular disease. Unfortunately, an easy-to-use, non-invasive, portable monitor of cerebral vasoreactivity does not exist. Therefore, we have evaluated the use of near-infrared diffuse correlation spectroscopy to measure the microvascular cerebral blood flow (CBF) response to a mild head-of-bed position change as a biomarker for the evaluation of cerebral vasoreactivity alteration due to chronic OSA. Furthermore, we have monitored the effect of two years of continuous positive airway pressure (CPAP) treatment on the cerebral vasoreactivity. Methodology: CBF was measured at different head-of-bed position changes (supine to 30° to supine) in sixty-eight patients with OSA grouped according to severity (forty moderate to severe, twenty-eight mild) and in fourteen control subjects without OSA. A subgroup (n = 13) with severe OSA was measured again after two years of CPAP treatment. Results: All patients and controls showed a similar CBF response after changing position from supine to 30° (p = 0.819), with a median (confidence interval) change of -17.5 (-10.3, -22.9)%. However, when being tilted back to the supine position, while the control group (p = 0.091) and the mild patients with OSA (p = 0.227) recovered to the initial baseline, patients with moderate and severe OSA did not recover to the baseline (9.8 (0.8, 12.9)%, p < 0.001) suggesting altered cerebral vasoreactivity. This alteration was correlated with OSA severity defined by the apnea-hypopnea index, and with mean nocturnal arterial oxygen saturation. The CBF response was normalized after two years of CPAP treatment upon follow-up measurements. Conclusion: In conclusion, microvascular CBF response to a head-of-bed challenge measured by diffuse correlation spectroscopy suggests that moderate and severe patients with OSA have altered cerebral vasoreactivity related to OSA severity. This may normalize after two years of CPAP treatment. [ABSTRACT FROM AUTHOR]

Ketone bodies are neuroprotective in neurological disorders such as epilepsy. We randomly studied nine healthy human subjects twice—with and without continuous infusion of 3-hydroxybutyrate–to define potential underlying mechanisms, assessed regionally (parietal, occipital, temporal, cortical grey, and frontal) by PET scan. During 3-hydroxybutyrate infusions concentrations increased to 5.5±0.4 mmol/l and cerebral glucose utilisation decreased 14%, oxygen consumption remained unchanged, and cerebral blood flow increased 30%. We conclude that acute 3-hydroxybutyrate infusion reduces cerebral glucose uptake and increases cerebral blood flow in all measured brain regions, without detectable effects on cerebral oxygen uptake though oxygen extraction decreased. Increased oxygen supply concomitant with unchanged oxygen utilisation may contribute to the neuroprotective effects of ketone bodies. [ABSTRACT FROM AUTHOR]

Typical simultaneous blood oxygenation-level dependent (BOLD) and arterial spin labeling (ASL) sequences acquire two echoes, one perfusion-sensitive and one BOLD-sensitive. However, for ASL, spatial resolution and brain coverage are limited due to the T1 decay of the labeled blood. This study applies a sequence combining a multiband acquisition with four echoes for simultaneous BOLD and pseudo-continuous ASL (pCASL) echo planar imaging (MBME ASL/BOLD) for block-design task-fMRI. A multiband acceleration of four was employed to increase brain coverage and reduce slice-timing effects on the ASL signal. Multi-echo independent component analysis (MEICA) was implemented to automatically denoise the BOLD signal by regressing non-BOLD components. This technique led to increased temporal signal-to-noise ratio (tSNR) and BOLD sensitivity. The MEICA technique was also modified to denoise the ASL signal by regressing artifact and BOLD signals from the first echo time-series. The MBME ASL/BOLD sequence was applied to a finger-tapping task functional MRI (fMRI) experiment. Signal characteristics and activation were evaluated using single echo BOLD, combined ME BOLD, combined ME BOLD after MEICA denoising, perfusion-weighted (PW), and perfusion-weighted after MEICA denoising time-series. The PW data was extracted using both surround subtraction and high-pass filtering followed by demodulation. In addition, the CBF/BOLD response ratio and CBF/BOLD coupling were analyzed. Results showed that the MEICA denoising procedure significantly improved the BOLD signal, leading to increased BOLD sensitivity, tSNR, and activation statistics compared to conventional single echo BOLD data. At the same time, the denoised PW data showed increased tSNR and activation statistics compared to the non-denoised PW data. CBF/BOLD coupling was also increased using the denoised ASL and BOLD data. Our preliminary data suggest that the MBME ASL/BOLD sequence can be employed to collect whole-brain task-fMRI with improved data quality for both BOLD and PW time series, thus improving the results of block-design task fMRI. [ABSTRACT FROM AUTHOR]

The ability to discriminate between normal and impaired dynamic cerebral autoregulation (CA), based on measurements of spontaneous fluctuations in arterial blood pressure (BP) and cerebral blood flow (CBF), has considerable clinical relevance. We studied 45 normal subjects at rest and under hypercapnia induced by breathing a mixture of carbon dioxide and air. Non-linear models with BP as input and CBF velocity (CBFV) as output, were implemented with support vector machines (SVM) using separate recordings for learning and validation. Dynamic SVM implementations used either moving average or autoregressive structures. The efficiency of dynamic CA was estimated from the model’s derived CBFV response to a step change in BP as an autoregulation index for both linear and non-linear models. Non-linear models with recurrences (autoregressive) showed the best results, with CA indexes of 5.9 ± 1.5 in normocapnia, and 2.5 ± 1.2 for hypercapnia with an area under the receiver-operator curve of 0.955. The high performance achieved by non-linear SVM models to detect deterioration of dynamic CA should encourage further assessment of its applicability to clinical conditions where CA might be impaired. [ABSTRACT FROM AUTHOR]

Background: In acute ischemic stroke the status of collateral circulation is a critical factor in determining outcome. We propose a less invasive alternative to digital subtraction angiography for evaluating collaterals based on dynamic-susceptibility contrast magnetic resonance imaging. Methods: Perfusion maps of Tmax and cerebral blood flow (CBF) were created for 35 patients with baseline occlusion of a major cerebral artery. Volumes of hypoperfusion were defined as having a Tmax delay of > 4 seconds (Tmax4s) and > 6 seconds (Tmax6s) and a CBF drop below 80% of healthy, contralateral tissue. For each patient a ratio between the volume of the CBF and the Tmax based perfusion deficit was calculated. Associations with collateral status and radiological outcome were assessed with the Mann-Whitney-U test, uni- and multivariable logistic regression analyses as well as area under the receiver-operator-characteristic (ROC) curve. Results: The CBF/Tmax volume ratios were significantly associated with bad collateral status in crude logistic regression analysis as well as with adjustment for NIHSS at admission and baseline infarct volume (OR = 2.5 95% CI[1.2–5.4] p = 0.020 for CBF/Tmax 4s volume ratio and OR = 1.6 95% CI[1.0–2.6] p = 0.031 for CBF/Tmax6s volume ratio). Moreover, the ratios were significantly correlated to final infarct size (Spearman’s rho = 0.711 and 0.619, respectively for the CBF/Tmax4s volume ratio and CBF/Tmax6s volume ration, all p<0.001). The ratios also had a high area under the ROC curve of 0.93 95%CI[0.86–1.00]) and 0.90 95%CI[0.80–1.00]respectively for predicting poor radiological outcome. Conclusions: In the setting of acute ischemic stroke the CBF/Tmax volume ratio can be used to differentiate between good and insufficient collateral circulation without the need for invasive procedures like conventional angiography. [ABSTRACT FROM AUTHOR]

Background: Cerebral extraction of diffusively distributed substances like oxygen has been suggested to change according to the cerebral blood flow (CBF) and status of the microvasculature. The relationships between the cerebral extraction of diffusively distributed lipophilic tracers and the severity of cerebral ischemia has not yet been clarified. In the present study, we attempted to elucidate the association between the extraction fraction of the lipophilic tracer I-123 iomazenil (IMZ) (IMZ-EF) and the oxygen extraction fraction (OEF) derived from O-15 PET in patients with chronic steno-occlusive disease of internal carotid artery (ICA) or middle cerebral artery (MCA). Methods: Seven patients with unilateral chronic severe stenosis or occlusion of the middle cerebral/internal cerebral artery were prospectively recruited for this study. All the patients underwent both O-15 PET and quantitative I-123 IMZ SPECT. Parametric images derived from the PET and SPECT scans were anatomically normalized and evaluated by automated image analysis based on the volume-of-interest template. Results: The asymmetry index (AI) of IMZ-EF was shown to be significantly correlated with the AI of OEF (r = 0.562, P < 0.001) in the internal carotid artery perfusion area. Strong and significant correlation between the AI of the influx rate constant K1 of IMZ and the AI of the cerebral metabolic rate of oxygen (r = 0.552, P = 0.001) was clarified. Conclusions: Our results suggested that the transportation efficiency of I-123 IMZ into the brain tissue was an indicator for evaluating severity of cerebral ischemia in patients with chronic steno-occlusive disease of ICA or MCA. Cerebral metabolic state can possibly be estimated by I-123 IMZ SPECT without cyclotron. [ABSTRACT FROM AUTHOR]

Background: Neuroimaging may guide acute stroke treatment by measuring the volume of brain tissue in the irreversibly injured “ischemic core.” The most widely accepted core volume measurement technique is diffusion-weighted MRI (DWI). However, some claim that measuring regional cerebral blood flow (CBF) with CT perfusion imaging (CTP), and labeling tissue below some threshold as the core, provides equivalent estimates. We tested whether any threshold allows reliable substitution of CBF for DWI. Methods: 58 patients with suspected stroke underwent DWI and CTP within six hours of symptom onset. A neuroradiologist outlined DWI lesions. In CBF maps, core pixels were defined by thresholds ranging from 0%-100% of normal, in 1% increments. Replicating prior studies, we used receiver operating characteristic (ROC) curves to select thresholds that optimized sensitivity and specificity in predicting DWI-positive pixels, first using only pixels on the side of the brain where infarction was clinically suspected (“unilateral” method), then including both sides (“bilateral”). We quantified each method and threshold’s accuracy in estimating DWI volumes, using sums of squared errors (SSE). For the 23 patients with follow-up studies, we assessed whether CBF-derived volumes inaccurately exceeded follow-up infarct volumes. Results: The areas under the ROC curves were 0.89 (unilateral) and 0.90 (bilateral). Various metrics selected optimum CBF thresholds ranging from 29%-32%, with sensitivities of 0.79–0.81, and specificities of 0.83–0.85. However, for the unilateral and bilateral methods respectively, volume estimates derived from all CBF thresholds above 28% and 22% were less accurate than disregarding imaging and presuming every patient’s core volume to be zero. The unilateral method with a 30% threshold, which recent clinical trials have employed, produced a mean core overestimation of 65 mL (range: –82–191), and exceeded follow-up volumes for 83% of patients, by up to 191 mL. Conclusion: CTP-derived CBF maps cannot substitute for DWI in measuring the ischemic core. [ABSTRACT FROM AUTHOR]

Background: Serial assessment of right ventricular ejection fraction (RVEF) predicts the clinical outcome of patients with pulmonary hypertension (PH). Cardiac magnetic resonance imaging (CMRI) enables RVEF monitoring, but its applicability is limited in clinical practice. This study aimed to examine the correlation between changes in CMRI-derived RVEF with those in echocardiographic indices in patients with precapillary PH. Methods: CMRI and echocardiographic indices of RV systolic function were evaluated at baseline and follow-up in 54 consecutive patients with precapillary PH (pulmonary arterial hypertension (PAH), n = 23; non-PAH, n = 31). During follow-up, medical treatment was optimized according to the guidelines for PH. Using CMRI-derived RVEF as the gold standard, we examined the accuracy of five echocardiographic indices by correlation analysis and receiver operating characteristic (ROC) analysis and by calculating sensitivity, specificity, and positive and negative predictive values. Results: After an average period of 9.5 months, CMRI-derived RVEF improved from 30.2% ± 10.6% at baseline to 41.4% ± 11.3% at follow-up. These changes significantly correlated with those in the five echocardiographic indices, i.e., %RV fractional shortening (r = 0.27), %RV area change (r = 0.46), tricuspid annular plane systolic excursion (TAPSE) (r = 0.84), RV myocardial performance index (RVMPI) (r = −0.72), and systolic lateral tricuspid annular motion velocity (TVlat) (r = 0.66). Of these indices, %RV area change, TAPSE, and TVlat significantly correlated with those of CMRI-derived RVEF in both PAH and non-PAH subgroups. ROC analysis showed that improvement in echocardiographic indices predicted a pre-specified improvement in CMRI-derived RVEF (>2.9%), with TAPSE and TVlat showing better accuracy over the other three indices. Conclusions: Echocardiographic indices modestly correlate with the changes in CMRI-derived RVEF in precapillary PH patients. Comparison among the five echocardiographic indices revealed that TAPSE and TVlat provide better accuracy than %RV fractional shortening, %RV area change, and RVMPI. [ABSTRACT FROM AUTHOR]

Background: Premenopausal women have fewer cardiovascular disease (CVD) events than postmenopausal women and age-matched men, but the reasons are not fully understood. Coronary endothelial function (CEF), a barometer of coronary vascular health, promises important insights into age and sex differences in atherosclerotic CVD risk, but has not been well characterized in healthy individuals because of the invasive nature of conventional CEF measurements. Recently developed magnetic resonance imaging (MRI) methods were used to quantify CEF (coronary area and flow changes in response to isometric handgrip exercise (IHE), an endothelial-dependent stressor) to test the hypothesis that healthy women have CEF compared to men particularly at a younger age. Methods: The study participants were 50 healthy women and men with no history of coronary artery disease (CAD) or traditional CV risk factors and Agatston coronary calcium score (on prior CT) <10 for those ≥ 50 years. Coronary cross-sectional area (CSA) measurements and flow-velocity encoded images (CBF) were obtained at baseline and during continuous IHE using 3T breath-hold cine MRI-IHE. CEF (%change in CSA and CBF with IHE) comparisons were made according to age and sex, and all women ≥50 years were post-menopausal. Results: In the overall population, there were no differences in CEF between men and women. However, when stratified by age and sex the mean changes in CSA and CBF during IHE were higher in younger premenopausal women than older postmenopausal women (%CSA: 15.2±10.6% vs. 7.0±6.8%, p = 0.03 and %CBF: 59.0±37.0% vs. 30.5±24.5% p = 0.02). CBF change was also nearly two-fold better in premenopausal women than age-matched men (59.0±37.0% vs. 33.6±12.3%, p = 0.03). Conclusions: Premenopausal women have nearly two-fold better mean CEF compared to postmenopausal women. CEF, measured by CBF change is also better in premenopausal women than age-matched men but there are no sex differences in CEF after menopause. Fundamental age and sex differences in CEF exist and may contribute to differences in the development and clinical manifestations of atherosclerotic CVD, and guide future trials targeting sex-specific mechanisms of atherogenesis. [ABSTRACT FROM AUTHOR]

To identify suitable cell lines for a mimetic system of in vivo blood-brain barrier (BBB) for drug permeability assessment, we characterized two immortalized cell lines, ECV304 and bEnd3 in the respect of the tightness, tight junction proteins, P-glycoprotein (P-gp) function and discriminative brain penetration. The ECV304 monoculture achieved higher transendothelial electrical resistance (TEER) and lower permeability to Lucifer yellow than bEnd3. However, co-culture with rat glioma C6 cells impaired the integrity of ECV304 and bEnd3 cell layers perhaps due to the heterogeneity among C6 cells in inducing BBB characteristics. The immunostaining of ZO-1 delivered distinct bands along cell borders on both cell lines while those of occludin and claudin-5 were diffused and weak. P-gp functionality was only proved in bEnd3 by Rhodamine 123 (R123) uptake assay. A permeability test of reference compounds displayed a similar rank order (digoxin < R123 < quinidine, verapamil < propranolol) in ECV304 and bEnd3 cells. In comparison with bEnd3, ECV304 developed tighter barrier for the passage of reference compounds and higher discrimination between transcellular and paracellular transport. However, the monoculture models of ECV304 and bEnd3 fail to achieve the sufficient tightness of in vitro BBB permeability models with high TEER and evident immunostaining of tight junction proteins. Further strategies to enhance the paracellular tightness of both cell lines to mimic in vivo BBB tight barrier deserve to be conducted. [ABSTRACT FROM AUTHOR]

Background and objective: Changes in cerebral blood flow (CBF) immediately after cigarette smoking (CS) are still unclear. Our purpose was to evaluate the hemodynamic changes in each intracranial vessel after CS by using quantitative magnetic resonance angiography (MRA). Material and methods: Fifteen healthy male smokers less than 45 years old with more than 3 pack-year smoking history were enrolled in this study. The hemodynamic change in the vessels, represented by cerebral flow rate (CFR, ml/s) and flow velocity (FV, cm/s), was quantitatively measured in eleven vascular segments of the brain using phase-contrast MRA. Two sets of data at each vessel before and after CS were statistically analyzed by paired t-test. Three of 15 participants, as a control group, followed all the procedures but did not smoke. Results: Total CFR of the distal intracranial vessels (anterior, middle, and posterior cerebral arteries; ACA, MCA, and PCA) was significantly reduced after CS by 7.3% (847 vs. 785 ml/s, p = 0.024). Such flow changes were statistically more significant in the anterior circulation (ACA and MCA) compared to the posterior circulation (PCA). All distal intracranial vessels did not have significant FV change while peak systolic velocity and mean velocity dropped 7.4 and 4.3% and pulsatility index decreased 10.9% in the internal carotid artery. Regarding cross-sectional areas, all distal intracranial vessels showed diminished, and only MCA had a statistical significance (9.9 vs. 9.3 mm2, p = 0.016). Conclusions: There was a significant decrease of CFR after CS especially in the anterior circulation of twelve young male smokers. Considering the changes of FV and cross-sectional area all together, it can be suggested that cerebrovascular impedance increased after CS especially at the main trunk level of the distal intracranial vessels (ACA, MCA, and PCA). [ABSTRACT FROM AUTHOR]

Purpose: Current time—density curve analysis of digital subtraction angiography (DSA) provides intravascular flow information but requires manual vasculature selection. We developed an angiographic marker that represents cerebral perfusion by using automatic independent component analysis. Materials and methods: We retrospectively analyzed the data of 44 patients with unilateral carotid stenosis higher than 70% according to North American Symptomatic Carotid Endarterectomy Trial criteria. For all patients, magnetic resonance perfusion (MRP) was performed one day before DSA. Fixed contrast injection protocols and DSA acquisition parameters were used before stenting. The cerebral circulation time (CCT) was defined as the difference in the time to peak between the parietal vein and cavernous internal carotid artery in a lateral angiogram. Both anterior-posterior and lateral DSA views were processed using independent component analysis, and the capillary angiogram was extracted automatically. The full width at half maximum of the time—density curve in the capillary phase in the anterior-posterior and lateral DSA views was defined as the angiographic mean transient time (aMTT; i.e., aMTTAP and aMTTLat). The correlations between the degree of stenosis, CCT, aMTTAP and aMTTLat, and MRP parameters were evaluated. Results: The degree of stenosis showed no correlation with CCT, aMTTAP, aMTTLat, or any MRP parameter. CCT showed a strong correlation with aMTTAP (r = 0.67) and aMTTLat (r = 0.72). Among the MRP parameters, CCT showed only a moderate correlation with MTT (r = 0.67) and Tmax (r = 0.40). aMTTAP showed a moderate correlation with Tmax (r = 0.42) and a strong correlation with MTT (r = 0.77). aMTTLat also showed similar correlations with Tmax (r = 0.59) and MTT (r = 0.73). Conclusion: Apart from vascular anatomy, aMTT estimates brain parenchyma hemodynamics from DSA and is concordant with MRP. This process is completely automatic and provides immediate measurement of quantitative peritherapeutic brain parenchyma changes during stenting. [ABSTRACT FROM AUTHOR]

Arterial Spin Labeled (ASL) perfusion MRI enables non-invasive, quantitative measurements of tissue perfusion, and has a broad range of applications including brain functional imaging. However, ASL suffers from low signal-to-noise ratio (SNR), limiting image resolution. Acquisitions using 3D readouts are optimal for background-suppression of static signals, but can be SAR intensive and typically suffer from through-plane blurring. In this study, we investigated the use of accelerated 3D readouts to obtain whole-brain, high-SNR ASL perfusion maps and reduce SAR deposition. Parallel imaging was implemented along the partition-encoding direction in a pseudo-continuous ASL sequence with background-suppression and 3D RARE Stack-Of-Spirals readout, and its performance was evaluated in three small cohorts. First, both non-accelerated and two-fold accelerated single-shot versions of the sequence were evaluated in healthy volunteers during a motor-photic task, and the performance was compared in terms of temporal SNR, GM-WM contrast, and statistical significance of the detected activation. Secondly, single-shot 1D-accelerated imaging was compared to a two-shot accelerated version to assess benefits of SNR and spatial resolution for applications in which temporal resolution is not paramount. Third, the efficacy of this approach in clinical populations was assessed by applying the single-shot 1D-accelerated version to a larger cohort of elderly volunteers. Accelerated data demonstrated the ability to detect functional activation at the subject level, including cerebellar activity, without loss in the perfusion signal temporal stability and the statistical power of the activations. The use of acceleration also resulted in increased GM-WM contrast, likely due to reduced through-plane partial volume effects, that were further attenuated with the use of two-shot readouts. In a clinical cohort, image quality remained excellent, and expected effects of age and sex on cerebral blood flow could be detected. The sequence is freely available upon request for academic use and could benefit a broad range of cognitive and clinical neuroscience research. [ABSTRACT FROM AUTHOR]

Background: The invasive nature of the current methods for monitoring of intracranial pressure (ICP) has prevented their use in many clinical situations. Several attempts have been made to develop methods to monitor ICP non-invasively. The aim of this study is to assess the relationship between ultrasound-based non-invasive ICP (nICP) and invasive ICP measurement in neurocritical care patients.Methods and Findings: This was a prospective, single-cohort observational study of patients admitted to a tertiary neurocritical care unit. Patients with brain injury requiring invasive ICP monitoring were considered for inclusion. nICP was assessed using optic nerve sheath diameter (ONSD), venous transcranial Doppler (vTCD) of straight sinus systolic flow velocity (FVsv), and methods derived from arterial transcranial Doppler (aTCD) on the middle cerebral artery (MCA): MCA pulsatility index (PIa) and an estimator based on diastolic flow velocity (FVd). A total of 445 ultrasound examinations from 64 patients performed from 1 January to 1 November 2016 were included. The median age of the patients was 53 years (range 37-64). Median Glasgow Coma Scale at admission was 7 (range 3-14), and median Glasgow Outcome Scale was 3 (range 1-5). The mortality rate was 20%. ONSD and FVsv demonstrated the strongest correlation with ICP (R = 0.76 for ONSD versus ICP; R = 0.72 for FVsv versus ICP), whereas PIa and the estimator based on FVd did not correlate with ICP significantly. Combining the 2 strongest nICP predictors (ONSD and FVsv) resulted in an even stronger correlation with ICP (R = 0.80). The ability to detect intracranial hypertension (ICP ≥ 20 mm Hg) was highest for ONSD (area under the curve [AUC] 0.91, 95% CI 0.88-0.95). The combination of ONSD and FVsv methods showed a statistically significant improvement of AUC values compared with the ONSD method alone (0.93, 95% CI 0.90-0.97, p = 0.01). Major limitations are the heterogeneity and small number of patients included in this study, the need for specialised training to perform and interpret the ultrasound tests, and the variability in performance among different ultrasound operators.Conclusions: Of the studied ultrasound nICP methods, ONSD is the best estimator of ICP. The novel combination of ONSD ultrasonography and vTCD of the straight sinus is a promising and easily available technique for identifying critically ill patients with intracranial hypertension. [ABSTRACT FROM AUTHOR]

Background: Dengue can cause plasma leakage that may lead to dengue shock syndrome (DSS). In approximately 30% of DSS cases, recurrent episodes of shock occur. These patients have a higher risk of fluid overload, respiratory distress and poor outcomes. We investigated the association of echocardiographically-derived cardiac function and intravascular volume parameters plus lactate levels, with the outcomes of recurrent shock and respiratory distress in severe dengue. Methods/Principle findings: We performed a prospective observational study in Paediatric and adult ICU, at the Hospital for Tropical Diseases (HTD), Ho Chi Minh City, Vietnam. Patients with dengue were enrolled within 12 hours of admission to paediatric or adult ICU. A haemodynamic assessment and portable echocardiograms were carried out daily for 5 days from enrolment and all interventions recorded. 102 patients were enrolled; 22 patients did not develop DSS, 48 had a single episode of shock and 32 had recurrent shock. Patients with recurrent shock had a higher enrolment pulse than those with 1 episode or no shock (median: 114 vs. 100 vs. 100 b/min, P = 0.002), significantly lower Stroke Volume Index (SVI), (median: 21.6 vs. 22.8 vs. 26.8mls/m2, P<0.001) and higher lactate levels (4.2 vs. 2.9 vs. 2.2 mmol/l, P = 0.001). Higher SVI and worse left ventricular function (higher Left Myocardial Performance Index) on study days 3–5 was associated with the secondary endpoint of respiratory distress. There was an association between the total IV fluid administered during the ICU admission and respiratory distress (OR: 1.03, 95% CI 1.01–1.06, P = 0.001). Admission lactate levels predicted patients who subsequently developed recurrent shock (P = 0.004), and correlated positively with the total IV fluid volume received (rho: 0.323, P = 0.001) and also with admission ALT (rho: 0.764, P<0.001) and AST (rho: 0.773, P<0.001). Conclusions/Significance: Echo-derived intravascular volume assessment and venous lactate levels can help identify dengue patients at high risk of recurrent shock and respiratory distress in ICU. These findings may serve to, not only assist in the management of DSS patients, but also these haemodynamic endpoints could be used in future dengue fluid intervention trials. [ABSTRACT FROM AUTHOR]

Background: Cerebral hyperperfusion syndrome (HPS) is a potentially life-threatening complication following carotid artery stenting (CAS) and carotid endoarterectomy (CEA). Early prediction and treatment of patients at risk for HPS are required in patients undergoing CAS because HPS occurs significantly earlier after CAS than CEA. Near-infrared spectroscopy (NIRS) is often used for monitoring, and indocyanine green (ICG) kinetics by NIRS (ICG-NIRS) can detect reductions in cerebral perfusion in patients with acute stroke. However, whether ICG-NIRS can predict postoperative hyperperfusion phenomenon (HP) after carotid revascularization is unclear. Objective: Here, we evaluated whether the blood flow index (BFI) ratio calculated from a time-intensity curve from ICG-NIRS monitoring can predict HPS after CAS. Methods: The BFI ratio was prospectively monitored using ICG-NIRS in 135 patients undergoing CAS. Preoperative cerebrovascular reactivity (CVR) and the postoperative asymmetry index (AI) were also assessed with single-photon emission computed tomography before and after CAS, and the correlation was evaluated. In addition, patients were divided into two groups, a non-HP group (n = 113) and an HP group (n = 22), and we evaluated the correlation with hemodynamic impairment in the ipsilateral hemisphere and clinical results. Results: Twenty-two cases (16%) showed HP, and four (3%) showed HPS after CAS. The BFI ratio calculated from ICG-NIRS showed a significant linear correlation with preoperative CVR and postoperative AI (r = −0.568, 0.538, P < 0.001, <0.001, respectively). The degree of stenosis, the rate of no cross flow, preoperative CVR, and the incidence of HPS were significantly different between the groups. Conclusions: Measurement of ICG kinetics by NIRS is useful for detection of HPS in patients who underwent CAS. [ABSTRACT FROM AUTHOR]

Objectives: Tuberculous meningitis is characterized by elevated levels of matrix metalloproteinase 9 (MMP9) in the cerebrospinal fluid (CSF). However, it is unclear whether elevated MMP9 levels are associated with poor treatment outcome. We tested the hypothesis that pretreatment MMP9 levels in the CSF would be higher in tuberculous meningitis patients experiencing a poor treatment outcome. Methods: We prospectively assessed the treatment outcome in a consecutive sample of human immunodeficiency virus-negative patients with tuberculous meningitis. We defined good outcome as survival without severe neurological disability (modified Rankin scale scores 0–2). We estimated levels of MMP9 and its tissue inhibitor (TIMP1) on pretreatment CSF samples. We used albumin index to assess blood-brain barrier permeability. Results: We studied 40 patients (23 males [58%]) with tuberculous meningitis. Sixteen patients (40%) had stage 3 disease. On follow-up, 18 (45%) patients had a poor treatment outcome—15 patients died and 3 had severe neurological disability. Pretreatment MMP9 levels were not associated with treatment outcome (median [interquartile range], 254 [115–389] vs. 192 [60–383] ng/mL in good vs. poor outcome groups; P = 0.693). MMP9 levels did not correlate with the albumin index (Spearman’s rho = 0.142; P = 0.381). However, MMP9 levels significantly correlated with CSF glucose levels (rho = −0.419; P = 0.007) and admission Glasgow coma scale score (rho = 0.324; P = 0.032). Likewise, TIMP1 levels also did not differ by treatment outcome (1239 [889–1511] vs. 1522 [934–1949] ng/mL; P = 0.201). MMP9/TIMP1 ratio that reflects net proteolytic activity was also not different between the two groups (0.191 [0.107–0.250] vs. 0.163 [0.067–0.34]; P = 0.625). Conclusion: Our findings do not support the hypothesis that pretreatment levels of MMP9 would be higher in tuberculous meningitis patients experiencing a poor treatment outcome. Further, MMP9 levels in the CSF did not correlate with blood-brain barrier permeability in patients with tuberculous meningitis. [ABSTRACT FROM AUTHOR]

Background: We introduce and demonstrate that the AC biosusceptometry (ACB) technique enables real-time monitoring of magnetic nanoparticles (MNPs) in the bloodstream. We present an ACB system as a simple, portable, versatile, non-invasive, and accessible tool to study pharmacokinetic parameters of MNPs, such as circulation time, in real time. We synthesized and monitored manganese doped iron oxide nanoparticles in the bloodstream of Wistar rats using two different injection protocols. Aiming towards a translational approach, we also simultaneously evaluated cardiovascular parameters, including mean arterial pressure, heart rate, and episodes of arrhythmia in order to secure the well-being of all animals. Results: We found that serial injections increased the circulation time compared with single injections. Immediately after each injection, we observed a transitory drop in arterial pressure, a small drop in heart rate, and no episodes of arrhythmia. Although some cardiovascular effects were observed, they were transitory and easily recovered in both protocols. Conclusions: These results indicate that the ACB system may be a valuable tool for in vivo, real-time MNP monitoring that allows associations with other techniques, such as pulsatile arterial pressure and electrocardiogram recordings, helping ensuring the protocol safety, which is a fundamental step towards clinical applications. [ABSTRACT FROM AUTHOR]

The dynamics of BBB permeability after AIS in humans are not well understood. In the present study we measured the evolution of BBB permeability after AIS in humans using MRI. Patients presenting to our institution with a diagnosis of AIS underwent a single dynamic contrast-enhanced MRI (DCE-MRI) sequence to measure BBB permeability during their initial workup. Forty-two patients were included in the final analysis. The patient sample underwent DCE-MRI at a mean time of 23.8hrs after the onset of AIS symptoms (range: 1.3–90.7hrs). At all time-points the BBB permeability within the infarct region of the brain as defined on DWI/ADC was higher compared to the homologous region of the contralateral hemisphere (p<0.005). BBB permeability, expressed as a ratio of infarct permeability to contralateral permeability, was greatest at 6-48hrs after the onset of AIS. Although the data was not acquired longitudinally, these findings suggest that the permeability of the BBB is continually elevated following AIS, which contradicts previous assertions that BBB permeability after AIS follows a biphasic course. Knowledge of BBB dynamics following AIS may provide insight into future treatments for AIS, especially BBB stabilizing agents. [ABSTRACT FROM AUTHOR]

Blood-brain barrier (BBB) disruption is thought to facilitate the development of cerebral infarction after a stroke. In a typical stroke model (such as the one used in this study), the early phase of BBB disruption reaches a peak 6 h post-ischemia and largely recovers after 8–24 h, whereas the late phase of BBB disruption begins 48–58 h post-ischemia. Because cerebral infarct develops within 24 h after the onset of ischemia, and several therapeutic agents have been shown to reduce the infarct volume when administered at 6 h post-ischemia, we hypothesized that attenuating BBB disruption at its peak (6 h post-ischemia) can also decrease the infarct volume measured at 24 h. We used a mouse stroke model obtained by combining 120 min of distal middle cerebral arterial occlusion (dMCAo) with ipsilateral common carotid arterial occlusion (CCAo). This model produced the most reliable BBB disruption and cerebral infarction compared to other models characterized by a shorter duration of ischemia or obtained with dMCAO or CCAo alone. The BBB permeability was measured by quantifying Evans blue dye (EBD) extravasation, as this tracer has been shown to be more sensitive for the detection of early-phase BBB disruption compared to other intravascular tracers that are more appropriate for detecting late-phase BBB disruption. We showed that a 1 h-long treatment with isoflurane-anesthesia induced marked hypothermia and attenuated the peak of BBB disruption when administered 6 h after the onset of dMCAo/CCAo-induced ischemia. We also demonstrated that the inhibitory effect of isoflurane was hypothermia-dependent because the same treatment had no effect on ischemic BBB disruption when the mouse body temperature was maintained at 37°C. Importantly, inhibiting the peak of BBB disruption by hypothermia had no effect on the volume of brain infarct 24 h post-ischemia. In conclusion, inhibiting the peak of BBB disruption is not an effective neuroprotective strategy, especially in comparison to the inhibitors of the neuronal death signaling cascade; these, in fact, can attenuate the infarct volume measured at 24 h post-ischemia when administered at 6 h in our same stroke model. [ABSTRACT FROM AUTHOR]

Background: Although dementia is associated with both global and regional cerebral blood flow (CBF) changes, little is known about cerebral perfusion in the early pre-clinical stages of cognitive decline preceding overt cognitive dysfunction. The aim of this study was to investigate the association of early sub-clinical cognitive decline with CBF. Materials and Methods: The study participants were recruited from a cohort of Danish men born in 1953. Based on a regression model we selected men who performed better (Group A, n = 94) and poorer (Group B, n = 95) on cognitive testing at age 57 than expected from testing at age 20. Participants underwent supplementary cognitive testing, blood sampling and MRI including measurements of regional and global CBF. Results: Regional CBF was lower in group B than in group A in the posterior cingulate gyrus and the precuneus. The associations were attenuated when corrected for global atrophy, but remained significant in regions of interest based analysis adjusting for regional gray matter volume and vascular risk factors. No influence of group on global CBF was observed. Conclusions: We conclude that early sub-clinical cognitive decline is associated with reduced perfusion in the precuneus and posterior cingulate gyrus independently of regional atrophy and vascular risk factors, but cannot be statistically separated from an association with global atrophy. [ABSTRACT FROM AUTHOR]

Exposure to blast overpressure (BOP) activates a cascade of pathological processes including changes in intracranial pressure (ICP) and blood-brain barrier (BBB) permeability resulting in traumatic brain injury (TBI). In this study the effect of single and multiple exposures at two intensities of BOP on changes in ICP and BBB permeability in Sprague-Dawley rats was evaluated. Animals were exposed to a single or three repetitive (separated by 0.5 h) BOPs at 72 kPa or 110 kPa. ICP was monitored continuously via telemetry for 6 days after exposure to BOP. The alteration in the permeability of BBB was determined by extravasation of Evans Blue (EB) into brain parenchyma. A significant increase in ICP was observed in all groups except the single 72 kPa BOP group. At the same time a marked increase in BBB permeability was also seen in various parts of the brain. The extent of ICP increase as well as BBB permeability change was dependent on intensity and frequency of blast. [ABSTRACT FROM AUTHOR]

Therapeutic hypercapnia has the potential for neuroprotection after global cerebral ischemia. Here we further investigated the effects of different degrees of acute systemic hypoxia in combination with hypercapnia on brain damage in a rat model of hypoxia and ischemia. Adult wistar rats underwent unilateral common carotid artery (CCA) ligation for 60 min followed by ventilation with normoxic or systemic hypoxic gas containing 11%O2,13%O2,15%O2 and 18%O2 (targeted to PaO2 30–39 mmHg, 40–49 mmHg, 50–59 mmHg, and 60–69 mmHg, respectively) or systemic hypoxic gas containing 8% carbon dioxide (targeted to PaCO2 60–80 mmHg) for 180 min. The mean artery pressure (MAP), blood gas, and cerebral blood flow (CBF) were evaluated. The cortical vascular permeability and brain edema were examined. The ipsilateral cortex damage and the percentage of hippocampal apoptotic neurons were evaluated by Nissl staining and terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate-biotin nick end labeling (TUNEL) assay as well as flow cytometry, respectively. Immunofluorescence and western blotting were performed to determine aquaporin-4 (AQP4) expression. In rats treated with severe hypoxia (PaO2 < 50 mmHg), hypercapnia augmented the decline of MAP with cortical CBF and damaged blood–brain barrier permeability (p < 0.05). In contrast, in rats treated with mild to moderate hypoxia (PaO2 > 50 mmHg), hypercapnia protected against these pathophysiological changes. Moreover, hypercapnia treatment significantly reduced brain damage in the ischemic ipsilateral cortex and decreased the percentage of apoptotic neurons in the hippocampus after the CCA ligated rats were exposed to mild or moderate hypoxemia (PaO2 > 50 mmHg); especially under mild hypoxemia (PaO2 > 60 mmHg), hypercapnia significantly attenuated the expression of AQP4 protein with brain edema (p < 0.05). Hypercapnia exerts beneficial effects under mild to moderate hypoxemia and augments detrimental effects under severe hypoxemia on brain damage in a rat model of hypoxia-ischemia. [ABSTRACT FROM AUTHOR]