Effects of Daily Wild Blueberry Consumption on Cognitive and Vascular Function in Healthy Older Individuals: A Randomized Double Blind Controlled Trial (the Bluflow Study)

Abstract Objectives To investigate the effects of 12-week daily consumption of wild blueberry (poly)phenols on cognitive performance, vascular function, cerebral blood flow and gut microbiome in healthy older individuals. Methods A parallel, double blind, placebo controlled RCT was conducted in 61 healthy individuals, aged 65–80 years. The impact of wild blueberry (poly)phenols on cognition, vascular function (flow-mediated dilation; FMD, and blood pressure; BP), active and resting cerebral blood flow (CBF; using transcranial doppler ultrasound) was assessed. Measurements were taken at baseline and 12-weeks following daily consumption of 26 g freeze-dried blueberry powder containing 260 mg anthocyanins (equivalent to 178 g fresh wild blueberries) or a placebo powder matched for colour, taste, nutrients and fibre. Faecal samples were collected in both visits to measure changes in the gut microbiome using 16s rRNA sequencing. Blood and 24 h urine samples were also collected for the analysis of plasma and urinary (poly)phenol metabolites using LC-MS and authentic standards. Results Linear mixed modelling analysis with baseline performance as a covariate, revealed that accuracy scores for the switching task targeting executive function, significantly improved for the wild blueberry (WBB) group compared to placebo at 12 weeks (F(1,90,12) = 5.13, P = 0.026)). Additionally, immediate recall measure (AVLT) examining short-term recall memory revealed a significant improvement for the WBB compared to placebo at 12 weeks (F(1,46) = 4.321, P = 0.043)). FMD improved by 0.86% (F(1,54) = 32.8, P < 0.001) in the WBB group compared with the placebo group after 12-weeks daily consumption. Systolic 24 h ambulatory BP decreased by −3.59 mmHg (F(1,51) = 4.6, P = 0.037) in the WBB group compared to the placebo group. No changes in active or resting CBF were observed between groups. Conclusions This data suggests that daily consumption of wild blueberries may improve cognitive and vascular function in older adults. The role of circulating (poly)phenol metabolites and the gut microbiome on the effects observed is currently under investigation. Funding Sources Wild Blueberry Association of North America.

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Effects of Fermented Milk Containing Lacticaseibacillus paracasei Strain Shirota on Constipation in Patients with Depression: A Randomized, Double-Blind, Placebo-Controlled Trial

Nutrients ◽

10.3390/nu13072238 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2238

Author(s):

Xiaomei Zhang ◽

Shanbin Chen ◽

Ming Zhang ◽

Fazheng Ren ◽

Yimei Ren ◽

...

Keyword(s):

Mental Illness ◽

Placebo Group ◽

Rating Scale ◽

Controlled Trial ◽

Fermented Milk ◽

Daily Consumption ◽

Double Blind ◽

Tnf Α ◽

Significant Difference ◽

Factor Α

Probiotics have been shown to benefit patients with constipation and depression, but whether they specifically alleviate constipation in patients with depression remains unclear. The aim of this study was to investigate the effect of Lacticaseibacillus paracasei strain Shirota (LcS), formerly Lactobacillus casei strain Shirota, on constipation in patients with depression with specific etiology and gut microbiota and on depressive regimens. Eighty-two patients with constipation were recruited. The subjects consumed 100 mL of a LcS beverage (108 CFU/mL) or placebo every day for 9 weeks. After ingesting beverages for this period, we observed no significant differences in the total patient constipation-symptom (PAC-SYM) scores in the LcS group when compared with the placebo group. However, symptoms/scores in item 7 (rectal tearing or bleeding after a bowel movement) and items 8–12 (stool symptom subscale) were more alleviated in the LcS group than in the placebo group. The Beck Depression Index (BDI) and Hamilton Depression Rating Scale (HAMD) scores were all significantly decreased, and the degree of depression was significantly improved in both the placebo and LcS groups (p < 0.05), but there was no significant difference between the groups. The LcS intervention increased the beneficial Adlercreutzia, Megasphaera and Veillonella levels and decreased the bacterial levels related to mental illness, such as Rikenellaceae_RC9_gut_group, Sutterella and Oscillibacter. Additionally, the interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) levels were significantly decreased in both the placebo and LcS groups (p < 0.05). In particular, the IL-6 levels were significantly lower in the LcS group than the placebo group after the ingestion period (p < 0.05). In conclusion, the daily consumption of LcS for 9 weeks appeared to relieve constipation and improve the potentially depressive symptoms in patients with depression and significantly decrease the IL-6 levels. In addition, the LcS supplementation also appeared to regulate the intestinal microbiota related to mental illness.

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Neonatal Intracranial Hemorrhage and Phenobarbital

PEDIATRICS ◽

10.1542/peds.79.2.315 ◽

1987 ◽

Vol 79 (2) ◽

pp. 315-315

Author(s):

KARL C. K. KUBAN ◽

ELIZABETH BROWN ◽

ALAN LEVITON ◽

KALPATHY KRISHNAMOORTHY

Keyword(s):

Risk Factors ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Flow Pattern ◽

Intracranial Hemorrhage ◽

Double Blind Study ◽

Inclusion Criteria ◽

Blood Flow Pattern ◽

Double Blind ◽

Ultrasound Testing

In Reply.— We appreciate the comments by Dr Battisti et al. As noted in the inclusion criteria for our study,1 all intubated babies with birth weights less than 1,751 g were eligible for the study. One of the advantages of a randomized double-blind study is that babies with other risk factors, including presence of a fluctuating cerebral blood flow pattern on Doppler ultrasound testing, should have equal chances of being in the treated and placebo groups.

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Electro-Metabolic Sensing Through Capillary ATP-Sensitive K+ Channels and Adenosine to Control Cerebral Blood Flow

10.1101/2021.03.12.435152 ◽

2021 ◽

Author(s):

Maria Sancho ◽

Nicholas R. Klug ◽

Amreen Mughal ◽

Thomas J. Heppner ◽

David Hill-Eubanks ◽

...

Keyword(s):

Endothelial Cells ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Vascular Function ◽

Brain Activity ◽

List Type ◽

Capillary Endothelial Cells ◽

Metabolic Sensing ◽

Cellular Components

SUMMARYThe dense network of capillaries composed of capillary endothelial cells (cECs) and pericytes lies in close proximity to all neurons, ideally positioning it to sense neuro/glial-derived compounds that regulate regional and global cerebral perfusion. The membrane potential (VM) of vascular cells serves as the essential output in this scenario, linking brain activity to vascular function. The ATP-sensitive K+ channel (KATP) is a key regulator of vascular VM in other beds, but whether brain capillaries possess functional KATP channels remains unknown. Here, we demonstrate that brain capillary ECs and pericytes express KATP channels that robustly control VM. We further show that the endogenous mediator adenosine acts through A2A receptors and the Gs/cAMP/PKA pathway to activate capillary KATP channels. Moreover, KATP channel stimulation in vivo causes vasodilation and increases cerebral blood flow (CBF). These findings establish the presence of KATP channels in cECs and pericytes and suggest their significant influence on CBF.HIGHLIGHTSCapillary network cellular components—endothelial cells and pericytes—possess functional KATP channels.Activation of KATP channels causes profound hyperpolarization of capillary cell membranes.Capillary KATP channels are activated by exogenous adenosine via A2A receptors and cAMP-dependent protein kinase.KATP channel activation by adenosine or synthetic openers increases cerebral blood flow.

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The Acute and Chronic Cognitive and Cerebral Blood-Flow Effects of Nepalese Pepper (Zanthoxylum armatum DC.) Extract—A Randomized, Double-Blind, Placebo-Controlled Study in Healthy Humans

Nutrients ◽

10.3390/nu11123022 ◽

2019 ◽

Vol 11 (12) ◽

pp. 3022 ◽

Cited By ~ 3

Author(s):

David Kennedy ◽

Emma Wightman ◽

Julie Khan ◽

Torsten Grothe ◽

Philippa Jackson

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Single Dose ◽

Frontal Cortex ◽

Task Performance ◽

Performance Measure ◽

Controlled Study ◽

Double Blind ◽

Zanthoxylum Armatum ◽

Healthy Humans

Background: Zanthoxylum armatum DC. (ZA) is a traditional Asian culinary spice and medicinal compound, which is rich in monoterpenes and hydroxy α-sanshool. Mechanistic interactions with the monoamine, cholinergic and cannabinoid neurotransmission systems, as well as transient receptor potential (TRP) and potassium ion channels, may predispose ZA to modulate human brain function. Objectives: To investigate the effects of a single dose and 56-days supplementation with a lipid extract of ZA on cognitive function, mood and cerebral blood-flow (CBF) parameters in the pre-frontal cortex during cognitive task performance. Design: Double-blind, randomized, parallel groups study with N = 82 healthy males and females between the ages of 30 and 55 years. Assessments were undertaken pre-dose and at 1, 3 and 5 h post-dose on the first (Day 1) and last (Day 56) days of supplementation. Results: A single dose of ZA (Day 1) resulted in acute improvements on a ‘Speed of Attention’ factor and the Rapid Visual Information Processing (RVIP) task, in comparison to placebo. However, following ZA participants were less accurate on the name-to-face recall task. After 56 days of ZA consumption (Day 56), speed was enhanced on a global ‘Speed of Performance’ measure, comprising data from all of the timed tasks in the computerized battery. Participants also completed more correct Serial 3s Subtractions at the 3 h assessment and were less mentally fatigued throughout the day than participants consuming placebo. These effects were complemented on both Day 1 and Day 56 by modulation of CBF parameters, as assessed by Near Infrared Spectroscopy (NIRS). The primary finding here was a reduced hemodynamic response during the RVIP task. Conclusion: ZA improves aspects of cognitive performance, in particular the speed of performing tasks, in healthy humans and results in concomitant reductions in hemodynamic responses in the frontal cortex during task performance. The findings suggest an increase in neural efficiency following ZA.

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The Effect of Black Tea and Caffeine on Regional Cerebral Blood Flow Measured with Arterial Spin Labeling

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2013.40 ◽

2013 ◽

Vol 33 (6) ◽

pp. 963-968 ◽

Cited By ~ 24

Author(s):

Rishma Vidyasagar ◽

Arno Greyling ◽

Richard Draijer ◽

Douglas R Corfield ◽

Laura M Parkes

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Vascular Function ◽

Black Tea ◽

Cerebrovascular Reactivity ◽

Controlled Study ◽

Brain Vasculature ◽

Espresso Coffee ◽

Magnetic Resonance Imaging Mri ◽

Double Blinded

Black tea consumption has been shown to improve peripheral vascular function. Its effect on brain vasculature is unknown, though tea contains small amounts of caffeine, a psychoactive substance known to influence cerebral blood flow (CBF). We investigated the effects on CBF due to the intake of tea components in 20 healthy men in a double-blinded, randomized, placebo-controlled study. On separate days, subjects received a single dose of 184 mg caffeine (equivalent to one strong espresso coffee), 2,820 mg black tea solids containing 184 mg caffeine (equivalent to 6 cups of tea), 2,820 mg decaffeinated black tea solids, or placebo. The CBF and cerebrovascular reactivity (CVR) to hypercapnia were measured with arterial spin labeled magnetic resonance imaging (MRI) before and 2 hours after administration. We found a significant global reduction with caffeine (20%) and tea (21%) in gray matter CBF, with no effect of decaffeinated tea, suggesting that only caffeine influences CBF acutely. Voxelwise analysis revealed the effect of caffeine to be regionally specific. None of the interventions had an effect on CVR. Additional research is required to conclude on the physiologic relevance of these findings and the chronic effects of caffeine and tea intake on CBF.

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Tumor necrosis factor-α impairs cerebral blood flow in pregnant rats: role of vascular β-epithelial Na+ channel

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00744.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. H1018-H1027 ◽

Cited By ~ 2

Author(s):

Jeremy W. Duncan ◽

Subhi Talal Younes ◽

Emily Hildebrandt ◽

Michael J. Ryan ◽

Joey P. Granger ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Vascular Function ◽

Mapk Signaling ◽

Pregnant Rats ◽

Tnf Α ◽

Factor Α ◽

Placental Ischemia ◽

Necrosis Factor

Preeclampsia is a pregnancy-related disorder characterized by hypertension, vascular dysfunction and an increase in circulating inflammatory factors including the cytokine, tumor necrosis factor-α (TNF-α). Studies have shown that placental ischemia is associated with 1) increased circulating TNF-α, 2) attenuated pressure-induced cerebral vascular tone, and 3) suppression of β-epithelial Na+ channel (βENaC) protein in cerebral vessels. In addition to its role in epithelial Na+ and water transport, βENaC is an essential signaling element in transduction of pressure-induced (aka “myogenic”) constriction, a critical mechanism of blood flow autoregulation. While cytokines inhibit expression of certain ENaC proteins in epithelial tissue, it is unknown if the increased circulating TNF-α associated with placental ischemia mediates the loss of cerebrovascular βENaC and cerebral blood flow regulation. Therefore, the purpose of this study was to test the hypothesis that increasing plasma TNF-α in normal pregnant rats reduces cerebrovascular βENaC expression and impairs cerebral blood flow (CBF) regulation. In vivo TNF-α infusion (200 ng/day, 5 days) inhibited cerebrovascular expression of βENaC and impaired CBF regulation in pregnant rats. To determine the direct effects of TNF-α and underlying pathways mediating vascular smooth muscle cell βENaC reduction, we exposed cultured VSMCs (A10 cell line) to TNF-α (1–100 ng/mL) for 16–24 h. TNF-α reduced βENaC protein expression in a concentration-dependent fashion from 0.1 to 100 ng/mL, without affecting cell death. To assess the role of canonical MAPK signaling in this response, VSMCs were treated with p38MAPK or c-Jun kinase (JNK) inhibitors in the presence of TNF-α. We found that both p38MAPK and JNK blockade prevented TNF-α-mediated βENaC protein suppression. These data provide evidence that disorders associated with increased circulating TNF-α could lead to impaired cerebrovascular regulation, possibly due to reduced βENaC-mediated vascular function. NEW & NOTEWORTHY This manuscript identifies TNF-α as a possible placental-derived cytokine that could be involved in declining cerebrovascular health observed in preeclampsia. We found that infusion of TNF-α during pregnancy impaired cerebral blood flow control in rats at high arterial pressures. We further discovered that cerebrovascular β-epithelial sodium channel (βENaC) protein, a degenerin protein involved in mechanotransduction, was reduced by TNF-α in pregnant rats, indicating a potential link between impaired blood flow and this myogenic player. We next examined this effect in vitro using a rat vascular smooth muscle cell line. TNF-α reduced βENaC through canonical MAPK-signaling pathways and was not dependent on cell death. This study demonstrates the pejorative effects of TNF-α on cerebrovascular function during pregnancy and warrants future investigations to study the role of cytokines on vascular function during pregnancy.

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Acute cocoa flavanol improves cerebral oxygenation without enhancing executive function at rest or after exercise

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2016-0245 ◽

2016 ◽

Vol 41 (12) ◽

pp. 1225-1232 ◽

Cited By ~ 26

Author(s):

Lieselot Decroix ◽

Cajsa Tonoli ◽

Danusa D. Soares ◽

Semah Tagougui ◽

Elsa Heyman ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Executive Function ◽

Cognitive Function ◽

Near Infrared ◽

Acute Exercise ◽

Cerebral Oxygenation ◽

Cognitive Task ◽

Double Blind ◽

Exercise Induced

Acute exercise-induced improvements in cognitive function are accompanied by increased (cerebral) blood flow and increased brain-derived neurotrophic factor (BDNF) levels. Acute cocoa flavanol (CF) intake may improve cognitive function, cerebral blood flow (in humans), and BNDF levels (in animals). This study investigated (i) the effect of CF intake in combination with exercise on cognitive function and (ii) cerebral hemodynamics and BDNF in response to CF intake and exercise. Twelve healthy men participated in this randomized, double-blind, crossover study. Participants performed a cognitive task (CT) at 100 min after acute 903-mg CF or placebo (PL) intake, followed by a 30-min time-trial. Immediately after this exercise, the same CT was performed. Prefrontal near-infrared spectroscopy was applied during CT and exercise to measure changes in oxygenated (ΔHbO2), deoxygenated (ΔHHb), and total haemoglobin (ΔHbtot) and blood samples were drawn and analyzed for BDNF. Reaction time was faster postexercise, but was not influenced by CF. ΔHbO2 during the resting CT was increased by CF, compared with PL. ΔHbO2, ΔHHb, and ΔHbtot increased in response to exercise without any effect of CF. During the postexercise cognitive task, there were no hemodynamic differences between CF or PL. Serum BDNF was increased by exercise, but was not influenced by CF. In conclusion, at rest, CF intake increased cerebral oxygenation, but not BDNF concentrations, and no impact on executive function was detected. This beneficial effect of CF on cerebral oxygenation at rest was overruled by the strong exercise-induced increases in cerebral perfusion and oxygenation.

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Dietary nitrate facilitates an acetazolamide-induced increase in cerebral blood flow during visual stimulation

Journal of Applied Physiology ◽

10.1152/japplphysiol.00797.2013 ◽

2014 ◽

Vol 116 (3) ◽

pp. 267-273 ◽

Cited By ~ 6

Author(s):

Rasmus Aamand ◽

Yi-Ching Lynn Ho ◽

Thomas Dalsgaard ◽

Andreas Roepstorff ◽

Torben E. Lund

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Dietary Intake ◽

Vascular Function ◽

Visual Stimulation ◽

No Production ◽

Positive Interaction ◽

Healthy Human ◽

Cerebrovascular System

The carbonic anhydrase (CA) inhibitor acetazolamide (AZ) is used routinely to estimate cerebrovascular reserve capacity in patients, as it reliably increases cerebral blood flow (CBF). However, the mechanism by which AZ accomplishes this CBF increase is not entirely understood. We recently discovered that CA can produce nitric oxide (NO) from nitrite, and that AZ enhances this NO production in vitro. In fact, this interaction between AZ and CA accounted for a large part of AZ's vasodilatory action, which fits well with the known vasodilatory potency of NO. The present study aimed to assess whether AZ acts similarly in vivo in the human cerebrovascular system. Hence, we increased or minimized the dietary intake of nitrate in 20 healthy male participants, showed them a full-field flickering dartboard, and measured their CBF response to this visual stimulus with arterial spin labeling. Doing so, we found a significant positive interaction between the dietary intake of nitrate and the CBF modulation afforded by AZ during visual stimulation. In addition, but contrary to studies conducted in elderly participants, we report no effect of nitrate intake on resting CBF in healthy human participants. The present study provides in vivo support for an enhancing effect of AZ on the NO production from nitrite catalyzed by CA in the cerebrovascular system. Furthermore, our results, in combination with the results of other groups, indicate that nitrate may have significant importance to vascular function when the cerebrovascular system is challenged by age or disease.

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Pseudocontinuous Arterial Spin Labeling Reveals Dissociable Effects of Morphine and Alcohol on Regional Cerebral Blood Flow

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.234 ◽

2011 ◽

Vol 31 (5) ◽

pp. 1321-1333 ◽

Cited By ~ 33

Author(s):

Najmeh Khalili-Mahani ◽

Matthias JP van Osch ◽

Evelinda Baerends ◽

Roelof P Soeter ◽

Marieke de Kam ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Repeated Measures ◽

Arterial Spin Labeling ◽

Randomized Study ◽

Spin Labeling ◽

Statistical Testing ◽

Anterior Cingulate ◽

Double Blind ◽

Mixed Effect

We have examined sensitivity and specificity of pseudocontinuous arterial spin labeling (PCASL) to detect global and regional changes in cerebral blood flow (CBF) in response to two different psychoactive drugs. We tested alcohol and morphine in a placebo-controlled, double-blind randomized study in 12 healthy young men. Drugs were administered intravenously. Validated pharmacokinetic protocols achieved minimal intersubject and intrasubject variance in plasma drug concentration. Permutation-based statistical testing of a mixed effect repeated measures model revealed a widespread increase in absolute CBF because of both morphine and alcohol. Conjunction analysis revealed overlapping effects of morphine and alcohol on absolute CBF in the left anterior cingulate, right hippocampus, right insula, and left primary sensorimotor areas. Effects of morphine and alcohol on relative CBF (obtained from z-normalization of absolute CBF maps) were significantly different in the left putamen, left frontoparietal network, cerebellum, and the brainstem. Corroborating previous PET results, our findings suggest that PCASL is a promising tool for central nervous system drug research.

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