Reduction In Cerebral Blood Flow Research Articles

Hemodynamic Stroke in Simultaneous Cardio Cerebral Infarction: A New Term for Cardiologist

We report an uncommon case of simultaneous cardio-cerebral infarction, due to Inferior – right ventricle ST Segment Elevation Myocardial Infarction (STEMI) with acute ischemic stroke. Incidence of cardio cerebral infarction is exceptionally rare, with an incidence rate as low as 0.009%. Hemodynamic compromise in patients with acute myocardial infarction may result in the cerebral blood flow reduction that cause hemodynamic stroke. Due to the rarity of this condition, there were no recommended therapeutics strategy. Mechanical reperfusion with PCI procedure may be a superior choice in the settings of acute cardio-cerebral infarction for restoring hemodynamic stability.

Reactive oxygen species play a modulatory role in the hyperventilatory response to poikilocapnic hyperoxia in humans

The proposed mechanism for the increased ventilation in response to hyperoxia includes a reduced brain CO2 -[H+ ] washout-induced central chemoreceptor stimulation that results from a decrease in cerebral perfusion and the weakening of the CO2 affinity for haemoglobin. Nonetheless, hyperoxia also results in excessive brain reactive oxygen species (ROS) formation/accumulation, which hypothetically increases central respiratory drive and causes hyperventilation. We then quantified ventilation, cerebral perfusion/metabolism, arterial/internal jugular vein blood gases and oxidant/antioxidant biomarkers in response to hyperoxia during intravenous infusion of saline or ascorbic acid to determine whether excessive ROS production/accumulation contributes to the hyperoxia-induced hyperventilation in humans. Ascorbic acid infusion augmented the antioxidant defence levels, blunted ROS production/accumulation and minimized both the reduction in cerebral perfusion and the increase in ventilation observed during saline infusion. Hyperoxic hyperventilation seems to be mediated by central chemoreceptor stimulation provoked by the interaction between an excessive ROS production/accumulation and reduced brain CO2 -[H+ ] washout. The hypothetical mechanism for the increase in ventilation ( ) in response to hyperoxia (HX) includes central chemoreceptor stimulation via reduced CO2 -[H+ ] washout. Nonetheless, hyperoxia disturbs redox homeostasis and raises the hypothesis that excessive brain reactive oxygen species (ROS) production/accumulation may increase the sensitivity to CO2 or even solely activate the central chemoreceptors, resulting in hyperventilation. To determine the mechanism behind the HX-evoked increase in , 10 healthy men (24±4 years) underwent 10min trials of HX under saline and ascorbic acid infusion. , arterial and right internal right jugular vein (ijv) partial pressure for oxygen (PO2 ) and CO2 (PCO2 ), pH, oxidant (8-isoprostane) and antioxidant (ascorbic acid) markers, as well as cerebral blood flow (CBF) (Duplex ultrasonography), were quantified at each hyperoxic trial. HX evoked an increase in arterial partial pressure for oxygen, followed by a hyperventilatory response, a reduction in CBF, an increase in arterial 8-isoprostane, and unchanged PijvCO2 and ijv pH. Intravenous ascorbic acid infusion augmented the arterial antioxidant marker, blunted the increase in arterial 8-isoprostane and attenuated both the reduction in CBF and the HX-induced hyperventilation. Although ascorbic acid infusion resulted in a slight increase in PijvCO2 and a substantial decrease in ijv pH, when compared with the saline bout, HX evoked a similar reduction and a paired increase in the trans-cerebral exchanges for PCO2 and pH, respectively. These findings indicate that the poikilocapnic hyperoxic hyperventilation is likely mediated via the interaction of the acidic brain interstitial fluid and an increase in central chemoreceptor sensitivity to CO2 , which, in turn, seems to be evoked by the excessive ROS production/accumulation.

Invasive Multimodal Neuromonitoring in Aneurysmal Subarachnoid Hemorrhage: A Systematic Review.

Aneurysmal subarachnoid hemorrhage is a devastating disease leaving surviving patients often severely disabled. Delayed cerebral ischemia (DCI) has been identified as one of the main contributors to poor clinical outcome after subarachnoid hemorrhage. The objective of this review is to summarize existing clinical evidence assessing the diagnostic value of invasive neuromonitoring (INM) in detecting DCI and provide an update of evidence since the 2014 consensus statement on multimodality monitoring in neurocritical care. Three invasive monitoring techniques were targeted in the data collection process: brain tissue oxygen tension (ptiO2), cerebral microdialysis, and electrocorticography. Prospective and retrospective studies as well as case series (≥10 patients) were included as long as monitoring was used to detect DCI or guide DCI treatment. Forty-seven studies reporting INM in the context of DCI were included (ptiO2: N=21; cerebral microdialysis: N=22; electrocorticography: N=4). Changes in brain oxygen tension are associated with angiographic vasospasm or reduction in regional cerebral blood flow. Metabolic monitoring with trend analysis of the lactate to pyruvate ratio using cerebral microdialysis, identifies patients at risk for DCI. Clusters of cortical spreading depolarizations are associated with clinical neurological worsening and cerebral infarction in selected patients receiving electrocorticography monitoring. Data supports the use of INM for the detection of DCI in selected patients. Generalizability to all subarachnoid hemorrhage patients is limited by design bias of available studies and lack of randomized trials. Continuous data recording with trend analysis and the combination of INM modalities can provide tailored treatment support in patients at high risk for DCI. Future trials should test interventions triggered by INM in relation to cerebral infarctions.

P-BN004. Neuroprotective effect of edible bird's nest on chronic cerebral hypoperfusion induced neurodegeneration in rats

Introduction . Alzheimer’s disease is marked by insufficient blood supply to the brain, leads to progressive loss of memory and cognitive skills. Continuous reduction of cerebral blood flow as a result of chronic cerebral hypoperfusion leads to overproduction of reactive oxygen species that may cause cognitive decline. Until now there is no available curative treatment for Alzheimer’s disease (AD) and the only available option is symptomatic treatment. Recent alternative medicines have underscored the neuroprotective and antioxidant ability of the edible bird’s nest (EBN). The current study evaluates the effects of EBN on hippocampal neurons specifically in the CA1 hippocampal region by using chronic cerebral hypoperfusion- induced neurodegeneration in rat model. Methods . Chronic cerebral hypoperfusion was induced by permanent bilateral common carotid arteries occlusion (2VO) in rats that triggers the neuroinflammatory processes. The rats were divided into 4 groups: Sham group, 2VO group, and two 2VO groups treated with 2 different doses (60,120 mg/kg) of EBN, which was administered daily by oral gavage. After 8 consecutive weeks, rats were euthanized and the hippocampi were examined histopathologically by counting the viable neuronal cells and the level of F2 Isoprostane in hipoocampal tissue was measured by ELISA. Results . A significant decrease in the neuronal cell death and significant decline in F2 Isoprostane level was shown in the group of rats treated with EBN. Conclusion . CCH, which was triggered by 2VO, causes reduction in viable neurons in the hippocampal CA1 region. This damage could be ameliorated by administration of EBN, which exhibits a neuroprotective effect via increasing the viable neuronal cell count and decline in oxidative stress level. Our results underscored the possible effects of EBN in delaying the progression of dementia in AD patients if used early in the disease. It is safe supplement that could be used prophylactically for a long time.

A pilot study exploring the effect of repetitive transcranial magnetic stimulation (rTMS) treatment on cerebral blood flow and its relation to clinical outcomes in severe enduring anorexia nervosa

BackgroundRepetitive transcranial magnetic stimulation (rTMS) is a novel treatment option for people with severe enduring anorexia nervosa (SE-AN), but associated neurobiological changes are poorly understood. This study investigated the effect of rTMS treatment on regional cerebral blood flow (CBF) and whether any observed changes in CBF are associated with changes in clinical outcomes in people with SE-AN.MethodsAs part of a randomised sham-controlled feasibility trial of 20 sessions of high-frequency rTMS to the left dorsolateral prefrontal cortex, 26 of 34 trial participants completed arterial spin labelling (ASL) functional magnetic resonance imaging (fMRI) to quantify regional and global resting state CBF before (pre-randomisation baseline) and after real or sham treatment (1-month post-randomisation). A group of healthy females (n = 30) were recruited for baseline comparison. Clinical outcomes, including BMI, and depression and anxiety symptoms, were assessed at baseline, 1-, 4-, and 18-months post-randomisation.ResultsNo group differences in regional CBF were identified between the SE-AN and healthy comparison participants. A significant treatment-by-time interaction in a medial temporal lobe cluster with the maximal peak in the right amygdala was identified, reflecting a greater reduction in amygdala CBF following real rTMS compared to sham. Participants with the greatest rTMS-related reduction in amygdala CBF (i.e., between baseline and 1-month post-randomisation) showed the greatest sustained weight gain at 18-months post-randomisation. Higher baseline CBF in the insula predicted greater weight gain between baseline and 1-month post-randomisation and between baseline and 4-months post-randomisation.ConclusionsThis exploratory pilot study identified rTMS treatment related changes in CBF in adults with SE-AN and these were associated with changes in weight. Our preliminary findings also suggest that CBF (as measured by ASL fMRI) may be a marker of rTMS treatment response in this patient group. Future rTMS studies in AN should employ longitudinal neuroimaging to further explore the neurobiological changes related to rTMS treatment.Trial registrationISRCTN14329415, registered 23rd July 2015.

Optical manipulation of local cerebral blood flow in the deep brain of freely moving mice.

An artificial tool for manipulating local cerebral blood flow (CBF) is necessary for understanding how CBF controls brain function. Here, we generate vascular optogenetic tools whereby smooth muscle cells and endothelial cells express optical actuators in the brain. The illumination of channelrhodopsin-2 (ChR2)-expressing mice induces a local reduction in CBF. Photoactivated adenylyl cyclase (PAC) is an optical protein that increases intracellular cyclic adenosine monophosphate (cAMP), and the illumination of PAC-expressing mice induces a local increase in CBF. We target the ventral striatum, determine the temporal kinetics of CBF change, and optimize the illumination intensity to confine the effects to the ventral striatum. We demonstrate the utility of this vascular optogenetic manipulation in freely and adaptively behaving mice and validate the task- and actuator-dependent behavioral readouts. The development of vascular optogenetic animal models will help accelerate research linking vasculature, circuits, and behavior to health and disease.

Arterial Spin Labeling Imaging Assessment of Cerebrovascular Reactivity in Hypertensive Small Vessel Disease.

Objective: Cerebrovascular reactivity (CVR) represents the phenomenon where cerebral vessels dilate or constrict in response to vasoactive stimuli. CVR impairment may contribute to brain injury due to cerebral small vessel disease (SVD). We aimed to determine the CVR in hypertensive intracerebral hemorrhage (ICH) and to identify its vascular dysfunction.Methods: A total of 21 patients with spontaneous hypertensive ICH (strictly deep or mixed deep and lobar hemorrhages, mean age 62.5 ± 11.3 years) and 10 control subjects (mean age 66.1 ± 6.0 years) were enrolled for CVR measurement at least 3 months after the symptomatic ICH event. Each participant underwent a brain MRI study, and CVR was calculated as the cerebral blood flow (CBF) reduction using arterial spin labeling (ASL) between baseline and 10 min after an intravenous dipyridamole injection (0.57 mg/kg). Traditional MRI markers for SVD were also evaluated, including cerebral microbleed, white matter hyperintensity, lacune, and MRI-visible enlarged perivascular space, which were used to determine the total small vessel disease score.Results: Compared to control subjects, hypertensive ICH patients showed reduced CVR in the basal ganglia (CBF reduction 22.4 ± 22.7% vs. 41.7 ± 18.3, p = 0.026), the frontal lobe (15.1 ± 11.9 vs. 26.6 ± 9.9, p = 0.013), and the temporal lobe (14.7 ± 11.1 vs. 26.2 ± 10.0, p = 0.010). These differences remained significant in multivariable models after adjusting for age and sex. Within ICH groups, the CBF reduction in the basal ganglia was significantly correlated with the total small vessel disease score (R = 0.58, p = 0.006), but not with individual MRI markers.Conclusion: Patients with advanced hypertensive SVD demonstrated impaired vasoconstriction after dipyridamole challenge in the basal ganglia and the frontal and temporal lobes. Our findings provide safe approaches for whole-brain CVR mapping in SVD and identify a potential physiological basis for vascular dysfunction in hypertensive SVD.

Impaired Cerebral Autoregulation After Subarachnoid Hemorrhage: A Quantitative Assessment Using a Mouse Model.

Subarachnoid hemorrhage (SAH) is a common form of hemorrhagic stroke associated with high rates of mortality and severe disability. SAH patients often develop severe neurological deficits days after ictus, events attributed to a phenomenon referred to as delayed cerebral ischemia (DCI). Recent studies indicate that SAH-induced DCI results from a multitude of cerebral circulatory disturbances including cerebral autoregulation malfunction. Cerebral autoregulation incorporates the influence of blood pressure (BP) on arterial diameter in the homeostatic regulation of cerebral blood flow (CBF), which is necessary for maintaining constant brain perfusion during physiological swings in systemic BP. In this study, we quantitatively examined the impact of SAH on cerebral autoregulation using a mouse endovascular perforation model and a newly developed approach combining absolute and relative CBF measurements. This method enables a direct quantitative comparison of cerebral autoregulation between individual animals (e.g., SAH vs. control or sham-operated mice), which cannot be done solely using relative CBF changes by laser Doppler flowmetry. Here, absolute CBF was measured via injection of fluorescent microspheres at a baseline BP. In separate groups of animals, in vivo laser Doppler flowmetry was used to measure relative CBF changes over a range of BP using phlebotomy and the pressor phenylephrine to lower and raise BP, respectively. Absolute CBF measurements from microspheres were then used to calibrate laser Doppler measurements to calculate the relationship between CBF and BP, i.e., “cerebral autoregulation curves.” Un-operated and sham-operated groups exhibited similar cerebral autoregulatory curves, showing comparable levels of relatively constant CBF over a range of BP from ~80 mmHg to ~130 mmHg. In contrast, SAH animals exhibited a narrower autoregulatory range of BP, which was primarily due to a decrease in the upper limit of BP whereby cerebral autoregulation was maintained. Importantly, SAH animals also exhibited a marked decrease in CBF throughout the entire range of BP. In sum, this study provides evidence of the dramatic reduction in cortical CBF and the diminished range of autoregulation after SAH. Furthermore, this novel methodology should pave the way for future studies examining pathological mechanisms and/or therapeutic strategies targeting impaired cerebral autoregulation, a pathology common to many cardiovascular and cerebrovascular disorders.

Investigating the association between depressive disorders and cerebral haemodynamics

AimsAlterations in cerebral blood flow (CBF) may contribute to the development of depression, and serve as a novel biomarker. The aim of this review is to summarise and synthesise the available evidence on alterations in cerebral haemodynamics in depressive disorders relative to healthy control populations.MethodMEDLINE (1946- present), EMBASE (1947– present), Web of Science (1970–present), PsycINFO (1984–present), CINAHL (1976–present) and CENTRAL were searched using a predefined search strategy. Studies which compared the cerebral haemodynamics of adult patients (>18 years old) with depressive disorders against healthy controls (HC), by any imagining modality, were included. Studies with varying severity and chronicity of depressive disorder were included. A meta-analysis was conducted in four groups: 1) CBF (ml/min/100g) 2) Cerebral blood flow velocity (CBFv) (cm/s) 3) Combined CBF and CBFv 4) Ratio of uptake of radiotracer. A random effects model was used and heterogeneity and publication bias were assessed. Data are presented as mean difference (MD) or standardised mean difference (SMD) and 95% confidence interval (95% CI). A narrative synthesis of the remaining studies was performed.Result87 studies met the inclusion criteria. CBF (ml/min/100g) was significantly reduced in patients with depression compared to HC (15 studies, 538 patients, 416 HC, MD: −2.24 (95% CI −4.12, −0.36), p = 0.02, I2 = 64%). There were no statistically significant differences between patients and controls in the other three outcomes. CBFv (cm/s): 6 studies, 305 patients, 198 HC, MD: −1.23 (95% CI −6.10, 3.64, p = 0.62, I2 = 65%. Combined CBF and CBFv: 20 studies, 804 patients, 573 HC, SMD: −0.16 (95% CI −0.32, 0.01), p = 0.06 I2 = 51%. Ratio of uptake of radiotracer: 3 studies, 60 patients, 53 HC, MD: −0.11 (95% CI −0.11, 0.11), p = 1.00, I2 = 0%). The narrative synthesis revealed varying results, with many studies identifying a decrease in CBF in depressed patients compared to controls, but other studies identifying an increase, or mixed results. Multiple regions of impairment were identified, including the anterior cingulate cortex and prefrontal cortex.ConclusionThere was a statistically significant reduction in CBF in depressed patients compared to controls. The narrative synthesis revealed varying results, however specific regions of interest have been identified. Further research is needed to explore the effect of antidepressant medication, utilising different imaging modalities, and at different levels of disease severity.

211-OR: Differential Cerebral Blood Flow in Controlled and Uncontrolled Patients with Type 2 Diabetes Mellitus

Introduction: Patients with type 2 diabetes mellitus (T2DM) show variable brain tissue changes and mood and cognitive symptoms, which may result from altered cerebral blood flow (CBF). However, the regional CBF status in controlled and uncontrolled T2DM patients remains unclear, which can be examined with arterial spin labeling (ASL) imaging. Our aim was to examine regional CBF between controlled and uncontrolled T2DM patients using ASL imaging procedures. Methods: We collected hemoglobin A1c (A1C) data and 3D pseudo-continuous ASL data from 32 T2DM patients (16 controlled [A1C < 7%], age, 56.5±6.5 years; BMI, 29.6±6.2 kg/m2; 8 female; 16 uncontrolled [A1C ≥ 7%], age, 57.6±7.5 years; BMI, 30.0±5.1 kg/m2; 11 female) using a 3.0-Tesla MRI. A1C was measured by point-of-care testing. Whole-brain CBF maps were calculated, normalized to a common space, smoothed, and compared between groups (controlled T2DM patients vs. uncontrolled T2DM patients) using analysis of covariance (SPM12; covariates, age and sex; p<0.05). Results: No significant differences in age or sex appeared between groups. Multiple brain areas showed decreased CBF values in the cingulate, caudate, putamen, insula, hippocampus, amygdala, thalamus, hypothalamus, midbrain, cerebellum, prefrontal and frontal, and temporal cortices in uncontrolled T2DM patients over controlled T2DM patients. However, few brain sites in controlled T2DM patients, including the cerebellum, pons, medulla, parahippocampal gyrus, and temporal cortices showed reduced CBF over uncontrolled T2DM patients. Conclusion: Uncontrolled T2DM patients show significant reduction in CBF compared to controlled T2DM in areas that are involved in mood and cognition regulation. The findings suggest that uncontrolled levels may contribute to reduce regional CBF leading to site-specific tissue changes resulting to mood and cognition deficits in the condition. Disclosure S. E. Choi: None. B. Roy: None. M. Freeby: Research Support; Self; Abbott Diabetes, Novo Nordisk Inc. R. Kumar: None. Funding National Institutes of Health (1R01NR017190-03, 3R01NR017190-03S1)

Cerebral blood flow, cerebrovascular reactivity and their influence on ventilatory sensitivity

What is the topic of this review? Cerebrovascular reactivity to CO2 , which is a principal factor in determining ventilatory responses to CO2 through the role reactivity plays in determining cerebral extra- and intracellular pH. What advances does it highlight? Recent animal evidence suggests central chemoreceptor vasculature may demonstrate regionally heterogeneous cerebrovascular reactivity to CO2 , potentially as a protective mechanism against excessive CO2 washout from the central chemoreceptors, thereby allowing ventilation to reflect the systemic acid-base balance needs (respiratory changes in ) rather than solely the cerebral needs. Ventilation per se does not influence cerebrovascular reactivity independent of changes in . Alveolar ventilation and cerebral blood flow are both predominantly regulated by arterial blood gases, especially arterial , and so are intricately entwined. In this review, the fundamental mechanisms underlying cerebrovascular reactivity and central chemoreceptor control of breathing are covered. We discuss the interaction of cerebral blood flow and its reactivity with the control of ventilation and ventilatory responsiveness to changes in , as well as the lack of influence of ventilation itself on cerebrovascular reactivity. We briefly summarize the effects of arterial hypoxaemia on the relationship between ventilatory and cerebrovascular response to both and . We then highlight key methodological considerations regarding the interaction of reactivity and ventilatory sensitivity, including the following: regional heterogeneity of cerebrovascular reactivity; a pharmacological approach for the reduction of cerebral blood flow; reactivity assessment techniques; the influence of mean arterial blood pressure; and sex-related differences. Finally, we discuss ventilatory and cerebrovascular control in the context of high altitude and congestive heart failure. Future research directions and pertinent questions of interest are highlighted throughout.

Longitudinal Cerebral Blood Flow Changes in Normal Aging and the Alzheimer's Disease Continuum Identified by Arterial Spin Labeling MRI.

Cross-sectional studies have shown lower cerebral blood flow (CBF) in Alzheimer's disease (AD), but longitudinal CBF changes in AD are still unknown. To reveal the longitudinal CBF changes in normal control (NC) and the AD continuum using arterial spin labeling perfusion magnetic resonance imaging (ASL MRI). CBF was calculated from two longitudinal ASL scans acquired 2.22±1.43 years apart from 140 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). At the baseline scan, the cohort contained 41 NC, 74 mild cognitive impairment patients (MCI), and 25 AD patients. 21 NC converted into MCI and 17 MCI converted into AD at the follow-up. Longitudinal CBF changes were assessed using paired-t test for non-converters and converters separately at each voxel and in the meta-ROI. Age and sex were used as covariates. CBF reductions were observed in all subjects. Stable NC (n = 20) showed CBF reduction in the hippocampus and precuneus. Stable MCI patients (n = 57) showed spatially more extended CBF reduction patterns in hippocampus, middle temporal lobe, ventral striatum, prefrontal cortex, and cerebellum. NC-MCI converters showed CBF reduction in hippocampus and cerebellum and CBF increase in caudate. MCI-AD converters showed CBF reduction in hippocampus and prefrontal cortex. CBF changes were not related with longitudinal neurocognitive changes. Normal aging and AD continuum showed common longitudinal CBF reductions in hippocampus independent of disease and its conversion. Disease conversion independent longitudinal CBF reductions escalated in MCI subjects.

Entorhinal Perfusion Predicts Future Memory Decline, Neurodegeneration, and White Matter Hyperintensity Progression in Older Adults.

Altered cerebral blood flow (CBF) has been linked to increased risk for Alzheimer's disease (AD). However, whether altered CBF contributes to AD risk by accelerating cognitive decline remains unclear. It also remains unclear whether reductions in CBF accelerate neurodegeneration and development of small vessel cerebrovascular disease. To examine associations between CBF and trajectories of memory performance, regional brain atrophy, and global white matter hyperintensity (WMH) volume. 147 Alzheimer's Disease Neuroimaging Initiative participants free of dementia underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure CBF and serial neuropsychological and structural MRI examinations. Linear mixed effects models examined 5-year rate of change in memory and 4-year rate of change in regional brain atrophy and global WMH volumes as a function of baseline regional CBF. Entorhinal and hippocampal CBF were examined in separate models. Adjusting for demographic characteristics, pulse pressure, apolipoprotein E ɛ4 positivity, cerebrospinal fluid p-tau/Aβ ratio, and neuronal metabolism (i.e., fluorodeoxyglucose standardized uptake value ratio), lower baseline entorhinal CBF predicted faster rates of decline in memory as well as faster entorhinal thinning and WMH progression. Hippocampal CBF did not predict cognitive or brain structure trajectories. Findings highlight the importance of early cerebrovascular dysfunction in AD risk and suggest that entorhinal CBF as measured by noninvasive ASL MRI is a useful biomarker predictive of future cognitive decline and of risk of both.

Nightly Sustained Lower Body Negative Pressure Attenuates Reductions in Cerebral Blood Flow Associated with Simulated Microgravity

Background Cognitive impairment is a common maladaptation to space flight and may be related to microgravity-induced reductions in cerebral blood flow (CBF). One of the most prominent hemodynamic adjustments to microgravity that may contribute to cardiovascular impairment is a loss of plasma and blood volume that occurs to partially offset a cephalad fluid shift due to the loss of normal hydrostatic gradients. Lower body negative pressure (LBNP) may be an effective countermeasure to shift blood caudally, reduce central venous pressure, unload baroreceptors and partially restore diurnal hydrostatic gradients to preserve plasma volume and CBF. Hypothesis Sustained (8 hours) nightly LBNP will restore diurnal hemodynamic shifts, preserve plasma volume, and improve CBF during three days of simulated microgravity using a supine zero-degree bed rest model. Methods Nine healthy subjects (4 female; 30±9 years) completed three days of supine (0°) bed rest with and without eight hours of sustained nightly LBNP (-20 mmHg) in a randomized, crossover design. Total blood and plasma volume (carbon monoxide-rebreathing), and total CBF (combined ultrasound of vertebral and internal carotid arteries) were measured on the first and last morning of bed rest with LBNP off. Central venous pressure (CVP) was measured during spontaneous breathing with a peripherally inserted central catheter and end tidal CO2 (ETCO2) was monitored by nasal cannula. Values are presented as mean ± SD or mean and 95% CI where appropriate. Results CVP increased significantly from the seated to supine position (+9.1 ± 2.4mmHg, P < 0.001), and nightly LBNP caused a sustained reduction in supine CVP (5.7 ± 2.2mmHg to 1.2 ± 1.4mmHg, P < 0.001), indicating effective redistribution of blood volume. Plasma volume decreased similarly in the control and in the LBNP condition (Δ plasma volume: control: -394 ml [CI:-684 to -184], LBNP: -429 ml [CI -719 to -39; p=0.95). ETCO2 decreased similarly in both conditions (ΔETCO2: Control: -1.4 mmHg [CI: -3.2 to 0.32], LBNP: -0.4 mmHg [CI:-1.8 to 0.89]; P=0.27). However, LBNP attenuated the fall in total CBF by ~41% (Δ tCBF: control: -174 ml/min [CI: -107 to-241], LBNP: -102 ml/min [CI: -35 to -170]; P=0.04). Changes in plasma volume were directly correlated to changes in total CBF (Pearson r2=0.49; P=0.009). Conclusions Low level LBNP may be an effective countermeasure against microgravity-induced reduction in total CBF. While LBNP was not effective at preserving plasma volume, changes in total CBF were directly associated with changes in plasma volume. LBNP during sleep may be an effective counter measure against some but not all cardiovascular consequences of long-duration space flight.

Short‐term ketone monoester supplementation improves cerebral blood flow and cognitive function in adults with obesity: A randomized‐crossover trial

Background/Objectives Adults with obesity are at increased risk of neurocognitive impairments, due in part to reductions in cerebral blood flow (CBF) and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) are a purported therapeutic strategy for improving brain health in at-risk populations. We tested the hypothesis that short-term β-OHB supplementation will elevate CBF and BDNF, and in turn improve cognitive function in individuals with obesity. Subjects/Methods In a placebo-controlled double-blind crossover design 14 adults with obesity (10F; age=56±12 yrs; BMI=33.8±6.9 kg/m2) consumed 30 mL of either placebo or ketone supplement (12 g β-OHB) thrice-daily for 14 days. Participants were provided with all meals and snacks, which were matched between each 14-day period. CBF, cerebrovascular conductance (CVC), and shear rate were measured in the common carotid (CCA), internal carotid (ICA), and vertebral (VA) arteries by duplex ultrasound. Plasma and serum BDNF were measured by ELISA. Cognitive function was assessed by the digit-symbol substitution task (DSST), Stroop test, and task-switching test. All measures were taken in the fasting, non-supplemented state. Results CCA blood flow (25 mL×min-1 [12, 38], P=0.001), ICA shear rate (42 s-1 [15, 69], P=0.004), VA blood flow (18 mL×min-1 [10, 26], P<0.001), VACVC (0.08 mL×min-1×mmHg-1 [0.01, 0.15], P=0.027), and VA shear rate (34 s-1 [10, 59], P=0.008) significantly increased following 14-days of ketone supplementation. DSST performance (correct responses; CR) increased following ketone supplementation (+2.7 CR [1.3, 4.1], P<0.001) and this was positively associated with CCA blood flow (0.001 mL×min-1×CR-1 [0.001, 0.02], P=0.033) and CCACVC (1.24 ml×min-1×mmHg-1 CR-1 [0.24, 2.24], P=0.024), VA blood flow (0.034 mL×min-1×CR-1 [0.002, 0.066], P=0.039) and VACVC (3.32 1.24 ml×min-1×mmHg-1 CR-1 [0.20, 6.43], P=0.04). There were no differences in serum (301.8 pg/mL [-1033.4, 1637.2], P=0.65) and plasma BDNF (-380.4 pg/mL [-1023.9, 263.2], P=0.24) following ketone supplementation. Conclusions Short-duration ketone supplementation improved aspects of cognitive function, which may have been facilitated by enhanced CBF in adults with obesity. Ketone supplementation was well-tolerated and appears safe for cerebrovascular health, suggesting potential therapeutic benefits of β-OHB for brain health in adults with obesity.

Impact of Sleep Quality on Cardiovascular Responses to Simulated Hemorrhage in Humans

Introduction Sleep is an important determinant of cardiovascular health. Poor sleep quality, including sleep restriction, is associated with impairments in cardiovascular function, and may limit cardiovascular responsiveness to physiological stress. As hemorrhage is one of the leading causes of preventable civilian death, and a major cause of death from trauma in the military, it is important to assess the impact of sleep quality on cardiovascular responses to this stress. We hypothesize that human subjects who report poor sleep quality will be less tolerant to simulated hemorrhage, which will be associated with lower arterial pressure and cerebral blood flow, and higher heart rates compared to subjects who report good sleep quality. Methods Healthy human subjects (10F; 10M) participated in a graded pre-syncopal lower body negative pressure (LBNP) protocol to simulate hemorrhage. Sleep quality was assessed pre-experiment using the Pittsburgh Sleep Quality Index (PSQI). Subjects were categorized in two groups: POOR sleep quality (Global PSQI score ≥ 5) or GOOD sleep quality (Global PSQI score < 5). Arterial pressure, heart rate, stroke volume, and middle cerebral artery velocity (MCAv) were measured continuously throughout the LBNP protocol. The protocol was terminated if systolic arterial pressure was < 80 mmHg, or if subjects reported symptoms such as lightheadedness, nausea, dizziness, or vision disturbances. Results Of the 20 subjects tested, 5 were in the POOR sleep quality group (5M; 0F), and 15 were in the GOOD sleep quality group (5M; 10F). Sleep quality had no effect on tolerance to LBNP (POOR: 1453 ± 223 s vs. GOOD: 1535 ± 88 s; P = 0.34), and there were no differences in the magnitude of central hypovolemia at presyncope (%Δ stroke volume, POOR: -53 ± 8 % vs. GOOD: -49 ± 4 %; P = 0.32). However, there were differences in the magnitude of hypotension (%Δ mean arterial pressure, POOR: -18 ± 3 % vs. GOOD: -22 ± 2 %; P = 0.08), cerebral blood flow reduction (%Δ MCAv, POOR: -19 ± 6 % vs. GOOD: -28 ± 2 %; P = 0.03), and reflex tachycardia (% Δ heart rate, POOR: 103 ± 30 % vs. GOOD: 72 ± 9 %; P = 0.09). There was a moderate association between sleep quality and the magnitude of MCAv reduction at presyncope (r = 0.53; P = 0.02), where poorer sleep quality was associated with a smaller reduction in MCAv at presyncope. All 5 (100%) subjects in the POOR group terminated the experiment based on subjective symptoms (i.e., they did not reach the systolic arterial pressure threshold of 80 mmHg), compared to 2 of the 15 subjects (13%) in the GOOD group (P=0.001). Conclusion: Sleep quality did not affect tolerance to simulated hemorrhage in healthy human subjects. While there were differences in hemodynamic responses, this may be related to premature termination of the LBNP protocol based on the early onset of subjective presyncopal symptoms. A larger sample size may help to further investigate these observations.

Mild traumatic brain injury induces microvascular injury and accelerates Alzheimer-like pathogenesis in mice

IntroductionTraumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer’s disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored.MethodsIn a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, we examined the time courses of microvascular injury, blood–brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also evaluated the BBB integrity, amyloid pathology as well as cognitive functions after mTBI in the 5xFAD mouse model of AD.ResultsmTBI induced microvascular injury with BBB breakdown, pericyte loss, basement membrane alteration and cerebral blood flow reduction in mice, in which BBB breakdown preceded gliosis. More importantly, mTBI accelerated BBB leakage, amyloid pathology and cognitive impairment in the 5xFAD mice.DiscussionOur data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD.

IL-1β Antibody Protects Brain from Neuropathology of Hypoperfusion.

Chronic brain hypoperfusion is the primary cause of vascular dementia and has been implicated in the development of white matter disease and lacunar infarcts. Cerebral hypoperfusion leads to a chronic state of brain inflammation with immune cell activation and production of pro-inflammatory cytokines, including IL-1β. In the present study, we induced chronic, progressive brain hypoperfusion in mice using ameroid constrictor, arterial stenosis (ACAS) surgery and tested the efficacy of an IL-1β antibody on the resulting brain damage. We observed that ACAS surgery causes a reduction in cerebral blood flow (CBF) of about 30% and grey and white matter damage in and around the hippocampus. The IL-1β antibody treatment did not significantly affect CBF but largely eliminated grey matter damage and reduced white matter damage caused by ACAS surgery. Over the course of hypoperfusion/injury, grip strength, coordination, and memory-related behavior were not significantly affected by ACAS surgery or antibody treatment. We conclude that antibody neutralization of IL-1β is protective from the brain damage caused by chronic, progressive brain hypoperfusion.

Cerebral blood flow changes during aging process and in cognitive disorders: A review.

We aimed to summarize the available evidence on cerebral blood flow (CBF) changes in normal aging and common cognitive disorders. We searched PubMed for studies on CBF changes in normal aging and cognitive disorders up to 1 January 2019. We summarized the milestones in the history of CBF assessment and reviewed the current evidence on the association between CBF and cognitive changes in normal aging, vascular cognitive impairment (VCI) and Alzheimer’s disease (AD). There is promising evidence regarding the utility of CBF studies in cognition research. Age-related CBF changes could be related to a progressive neuronal loss or diminished activity and synaptic density of neurons in the brain. While a similar cause or outcome theory applies to VCI and AD, it is possible that CBF reduction might precede cognitive decline. Despite the diversity of CBF research findings, its measurement could help early detection of cognitive disorders and also understanding their underlying etiology.

Telmisartan prevents high-fat diet-induced neurovascular impairments and reduces anxiety-like behavior

Angiotensin II receptor blockers (telmisartan) prevent rodents from diet-induced obesity and improve their metabolic status. Hyperglycemia and obesity are associated with reduced cerebral blood flow and neurovascular uncoupling which may lead to behavioral deficits. We wanted to know whether a treatment with telmisartan prevents these changes in obesity. We put young mice on high-fat diet and simultaneously treated them with telmisartan. At the end of treatment, we performed laser speckle imaging and magnetic resonance imaging to assess the effect on neurovascular coupling and cerebral blood flow. Different behavioral tests were used to investigate cognitive function. Mice developed diet-induced obesity and after 16, not 8 weeks of high-fat diet, however, the response to whisker pad stimulation was about 30% lower in obese compared to lean mice. Simultaneous telmisartan treatment increased the response again by 10% compared to obese mice. Moreover, telmisartan treatment normalized high-fat diet-induced reduction of cerebral blood flow and prevented a diet-induced anxiety-like behavior. In addition to that, telmisartan affects cellular senescence and string vessel formation in obesity. We conclude, that telmisartan protects against neurovascular unit impairments in a diet-induced obesity setting and may play a role in preventing obesity related cognitive deficits in Alzheimer’s disease.