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UBC-Nepal Expedition: Haemoconcentration underlies the reductions in cerebral blood flow observed during acclimatization to high altitude.
Howe, CA, Ainslie, PN, Tremblay, JC, Carter, HH, Patrician, A, Stembridge, M, Williams, A, Drane, AL, Delorme, E, Rieger, MG, et al
Experimental physiology. 2019;(12):1963-1972
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Abstract
NEW FINDINGS What is the central question of this study? The aim was to evaluate the degree to which increases in haematocrit alter cerebral blood flow and cerebral oxygen delivery during acclimatization to high altitude. What is the main finding and its importance? Through haemodilution, we determined that, after 1 week of acclimatization, the primary mechanism contributing to the cerebral blood flow response during acclimatization is an increase in haemoglobin and haematocrit. The remaining contribution to the cerebral blood flow response during acclimatization is likely to be attributable to ventilatory acclimatization. ABSTRACT At high altitude, an increase in haematocrit (Hct) is achieved through altitude-induced diuresis and erythropoiesis, both of which result in increased arterial oxygen content. Given the impact of alterations in Hct on oxygen content, haemoconcentration has been hypothesized to mediate, in part, the attenuation of the initial elevation in cerebral blood flow (CBF) at high altitude. To test this hypothesis, healthy men (n = 13) ascended to 5050 m over 9 days without the aid of prophylactic acclimatization medications. After 1 week of acclimatization at 5050 m, participants were haemodiluted by rapid saline infusion (2.10 ± 0.28 l) to return Hct towards pre-acclimatization values. Arterial blood gases, Hct, global CBF (duplex ultrasound) and haemodynamic variables were measured after initial arrival at 5050 m and after 1 week of acclimatization at high altitude, before and after the haemodilution protocol. After 1 week at 5050 m, the Hct increased from 42.5 ± 2.5 to 49.6 ± 2.5% (P < 0.001), and it was subsequently reduced to 45.6 ± 2.3% (P < 0.001) after haemodilution. Global CBF decreased from 844 ± 160 to 619 ± 136 ml min-1 (P = 0.033) after 1 week of acclimatization and increased to 714 ± 204 ml min -1 (P = 0.045) after haemodilution. Despite the significant changes in Hct, and thus oxygen content, cerebral oxygen delivery was unchanged at all time points. Furthermore, these observations occurred in the absence of any changes in mean arterial blood pressure, cardiac output, arterial blood pH or oxygen saturation pre- and posthaemodilution. These data highlight the influence of Hct in the regulation of CBF and are the first to demonstrate experimentally that haemoconcentration contributes to the reduction in CBF during acclimatization to altitude.
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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.
Kennedy, D, Wightman, E, Khan, J, Grothe, T, Jackson, P
Nutrients. 2019;(12)
Abstract
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 hours 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 hours 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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Misery perfusion and amyloid deposition in atherosclerotic major cerebral artery disease.
Yamauchi, H, Kagawa, S, Takahashi, M, Oishi, N, Ono, M, Higashi, T
NeuroImage. Clinical. 2019;:101762
Abstract
Although experimental studies have shown that global cerebral hypoperfusion leads to amyloid deposition in the hemisphere with carotid artery occlusion in rodents, the results of such occurrence are controversial in humans. Hence, we aim to determine whether global cerebral hypoperfusion leading to decreased blood flow relative to metabolic demand [increased oxygen extraction fraction (OEF), misery perfusion] is associated with increases in amyloid deposition in the hemisphere with atherosclerotic major cerebral artery disease in patients. We evaluated the distribution of β-amyloid plaques using positron emission tomography and a [18F]-pyridylbenzofuran derivative (18F-FPYBF-2) in 13 patients with unilateral atherosclerotic disease of the internal carotid artery (ICA) or middle cerebral artery (MCA) disease and no cortical infarction. The distribution volume ratio (DVR) of 18F- FPYBF-2 was calculated using dynamic data and Logan graphical analysis with reference tissue and was correlated with the cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and OEF, obtained from 15O-gas PET. The mean cortical value was calculated as the mean value within the frontal, posterior cingulate, precuneus, parietal, and lateral temporal cortical regions. Significant reductions in CBF and CMRO2 and increases in OEF were found in the hemisphere ipsilateral to the arterial lesion compared with the contralateral hemisphere. There was no significant difference for 18F-FPYBF-2 DVR between hemispheres. The ipsilateral to contralateral ratio of the 18F- FPYBF-2 DVR was increased in 3 patients, while the ipsilateral to contralateral OEF ratio was increased in 4 patients. The incidence of an increased hemispheric DVR ratio was significantly higher in patients with an increased hemispheric OEF ratio (3/4) than in patients without (0/9) (p < 0.02). Although the 18F- FPYBF-2 DVR in the ipsilateral hemisphere was positively correlated with OEF after adjustment for the 18F- FPYBF-2 DVR in the contralateral hemisphere using multiple regression analysis (p < 0.05), the contribution rate of OEF was small (R2 = 5.5%). Only one of the 4 patients with an increased hemispheric OEF ratio showed amyloid positivity based on the DVR value. In atherosclerotic major cerebral artery disease, misery perfusion accompanied only small increases of amyloid deposition at best. Misery perfusion was not associated with amyloid positivity.
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Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease.
de Jong, DLK, de Heus, RAA, Rijpma, A, Donders, R, Olde Rikkert, MGM, Günther, M, Lawlor, BA, van Osch, MJP, Claassen, JAHR
Hypertension (Dallas, Tex. : 1979). 2019;(2):413-420
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Abstract
Cerebrovascular changes, including reduced cerebral blood flow (CBF), occur early in the development of Alzheimer disease and may accelerate disease progression. This randomized, double-blind, placebo-controlled study investigated how 6 months of treatment with the calcium antagonist nilvadipine would affect CBF in patients with mild-to-moderate Alzheimer disease. CBF was measured with magnetic resonance arterial spin labeling in whole-brain gray matter and in a priori defined regions of interest including the hippocampus. Fifty-eight patients were randomly assigned (29 in each group), of whom 22 in both groups had no magnetic resonance exclusion criteria and were medication compliant over 6 months. Mean age was 72.8±6.2 years, mean mini-mental state examination was 20.4±3.4. Nilvadipine treatment lowered systolic blood pressure (Δ=-11.5 [95% CI, -19.7 to -3.2] mm Hg; P<0.01), while whole-brain gray-matter CBF remained stable (Δ=5.4 [95% CI, -6.4 to 17.2] mL/100 g per minute; P=0.36). CBF in the hippocampus increased (left: Δ=24.4 [95% CI, 4.3-44.5] mL/100 g per minute; P=0.02; right: Δ=20.1 [95% CI, -0.6 to 40.8] mL/100 g per minute; P=0.06). There was no significant change in CBF in the posterior cingulate cortex (Δ=5.2 [95% CI, -16.5 to 27.0] mL/100 g per minute; P=0.63) or other regions of interest. In conclusion, nilvadipine reduced blood pressure and increased CBF in the hippocampus, whereas other regions showed stable or small nonsignificant increases in CBF. These findings not only indicate preserved cerebral autoregulation in Alzheimer disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02017340.
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Dietary nitrate supplementation enhances cerebrovascular CO2 reactivity in a sex-specific manner.
Fan, JL, O'Donnell, T, Gray, CL, Croft, K, Noakes, AK, Koch, H, Tzeng, YC
Journal of applied physiology (Bethesda, Md. : 1985). 2019;(3):760-769
Abstract
Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction, and increased NO has the potential to enhance cerebral blood flow (CBF). Dietary supplementation with sodium nitrate, a precursor of NO, could improve cerebrovascular function, but this has not been investigated. In 17 individuals, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg-1·day -1) on cerebrovascular function using a randomized, single-blinded placebo-controlled crossover design. We hypothesized that 7-day dietary nitrate supplementation increases CBF response to CO2 (cerebrovascular CO2 reactivity) and cerebral autoregulation (CA). We assessed middle cerebral artery blood velocity (MCAv) and blood pressure (BP) at rest and during CO2 breathing. Transfer function analysis was performed on resting beat-to-beat MCAv and BP to determine CA, from which phase, gain, and coherence of the BP-MCAv data were derived. Dietary nitrate elevated plasma nitrate concentration by ~420% (P < 0.001) and lowered gain (d = 1.2, P = 0.025) and phase of the BP-MCAv signal compared with placebo treatment (d = 0.7, P = 0.043), while coherence was unaffected (P = 0.122). Dietary nitrate increased the MCAv-CO2 slope in a sex-specific manner (interaction: P = 0.016). Dietary nitrate increased the MCAv-CO2 slope in men (d = 1.0, P = 0.014 vs. placebo), but had no effect in women (P = 0.919). Our data demonstrate that dietary nitrate greatly increased cerebrovascular CO2 reactivity in healthy individuals, while its effect on CA remains unclear. The selective increase in the MCAv-CO2 slope observed in men indicates a clear sexual dimorphic role of NO in cerebrovascular function.NEW & NOTEWORTHY We found dietary nitrate supplementation improved the brain blood vessels' response to CO2, cerebrovascular CO2 reactivity, without affecting blood pressure in a group of healthy individuals. Meanwhile, the effect of dietary nitrate on the relationship between blood pressure and brain blood flow, cerebral autoregulation, was inconclusive. The improvement in cerebrovascular CO2 reactivity was only observed in the male participants, alluding to a sex difference in the effect of dietary nitrate on brain blood flow control. Our findings indicate that dietary nitrate could be an effective strategy to enhance cerebrovascular CO2 reactivity.
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Association Between Fatty Acids Profile and Cerebral Blood Flow: An Exploratory fNIRS Study on Children with and without ADHD.
Grazioli, S, Crippa, A, Mauri, M, Piazza, C, Bacchetta, A, Salandi, A, Trabattoni, S, Agostoni, C, Molteni, M, Nobile, M
Nutrients. 2019;(10)
Abstract
Polyunsaturated fatty acids (PUFAs) biostatus has been proposed as possible attention deficit hyperactivity disorder (ADHD) diagnosis biomarker. The present exploratory study aimed to investigate the association between PUFAs biostatus and cerebral cortex metabolism measured by functional Near Infrared Spectroscopy (fNIRS) in a sample of children with and without ADHD. 24 children with ADHD and 22 typically developing (TD) peers, aged 8-14, were recruited. Linoleic, arachidonic, docosahexaenoic and eicosapentaenoic acids levels were evaluated in whole blood. All children underwent fNIRS while performing an n-back working memory task. Between groups comparisons revealed lower levels of arachidonic acid in children with ADHD and stronger NIRS signal in TD participants, especially when completing more difficult tasks. Correlations conducted between fNIRS activation and PUFA biostatus revealed several associations between hemodynamic changes in the frontoparietal regions and fatty acids profile across participants. This result was also confirmed by the multiple hierarchical regression analyses that remarked an inverse effect of eicosapentaenoic acid levels on oxyhemoglobin values in right frontoparietal region. Such preliminary findings, if confirmed, would suggest that PUFAs could play a role in atypical neurodevelopment.
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Increased cerebral blood flow after single dose of antipsychotics in healthy volunteers depends on dopamine D2 receptor density profiles.
Selvaggi, P, Hawkins, PCT, Dipasquale, O, Rizzo, G, Bertolino, A, Dukart, J, Sambataro, F, Pergola, G, Williams, SCR, Turkheimer, F, et al
NeuroImage. 2019;:774-784
Abstract
As a result of neuro-vascular coupling, the functional effects of antipsychotics in human brain have been investigated in both healthy and clinical populations using haemodynamic markers such as regional Cerebral Blood Flow (rCBF). However, the relationship between observed haemodynamic effects and the pharmacological action of these drugs has not been fully established. Here, we analysed Arterial Spin Labelling (ASL) rCBF data from a placebo-controlled study in healthy volunteers, who received a single dose of three different D2 receptor (D2R) antagonists and tested the association of the main effects of the drugs on rCBF against normative population maps of D2R protein density and gene-expression data. In particular, we correlated CBF changes after antipsychotic administration with non-displaceable binding potential (BPND) template maps of the high affinity D2-antagonist Positron Emission Tomography (PET) ligand [18F]Fallypride and with brain post-mortem microarray mRNA expression data for the DRD2 gene from the Allen Human Brain Atlas (ABA). For all antipsychotics, rCBF changes were directly proportional to brain D2R densities and DRD2 mRNA expression measures, although PET BPND spatial profiles explained more variance as compared with mRNA profiles (PET R2 range = 0.20-0.60, mRNA PET R2 range 0.04-0.20, pairwise-comparisons all pcorrected<0.05). In addition, the spatial coupling between ΔCBF and D2R profiles varied between the different antipsychotics tested, possibly reflecting differential affinities. Overall, these results indicate that the functional effects of antipsychotics as measured with rCBF are tightly correlated with the distribution of their target receptors in striatal and extra-striatal regions. Our results further demonstrate the link between neurotransmitter targets and haemodynamic changes reinforcing rCBF as a robust in-vivo marker of drug effects. This work is important in bridging the gap between pharmacokinetic and pharmacodynamics of novel and existing compounds.
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Effects of acute prolonged sitting on cerebral perfusion and executive function in young adults: A randomized cross-over trial.
Stoner, L, Willey, Q, Evans, WS, Burnet, K, Credeur, DP, Fryer, S, Hanson, ED
Psychophysiology. 2019;(12):e13457
Abstract
Exposure to acute prolonged sitting reportedly leads to decreased cerebral blood flow. However, it is unclear whether this exposure translates to decreased cerebral perfusion and executive function or whether simple strategies to break up sitting can maintain cerebral perfusion and executive function. This study sought to answer two questions: in young, healthy adults, (a) does prolonged (3 hr) sitting lead to decreased cerebral perfusion and executive function? and (b) does breaking up prolonged sitting, using intermittent calf raise exercises, prevent changes in cerebral perfusion and executive function? Twenty young, healthy participants (21.7 [2.5] years, 70% female, 25.5 [6.1] kg/m2 ) were randomized to 3 hr sitting with 10 calf raises every 10 min (CALF) and 3 hr sitting without intermittent calf raises (CON). Prefrontal cortex perfusion was assessed using near-infrared spectroscopy to monitor total hemoglobin (tHB) concentration and tissue saturation index (TSI, oxygenated hemoglobin). Executive function was assessed using the Stroop word and color tasks. Following 3 hr sitting, tHb was significantly lower in CALF versus CON (-2.1 μM, 95% CI [-3.1, -1.1]). TSI was not significantly different between conditions (p = .667). Word (1.6 ms, 95% CI [0.7, 2.5]) and color (1.3 ms, 95% CI [-0.2, 2.8]) completion times were longer (worse) for CALF compared to CON. In conclusion, calf raises decreased both cerebral perfusion and executive function. Simple strategies, such as fidgeting or calf raises, which have been reported to preserve vascular function in the legs, appear not to be sufficient to benefit cerebral perfusion or executive function.
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Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency (CCSVI) in people with multiple sclerosis.
Jagannath, VA, Pucci, E, Asokan, GV, Robak, EW
The Cochrane database of systematic reviews. 2019;(5):CD009903
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Abstract
BACKGROUND Multiple sclerosis (MS) is a leading cause of neurological disability in young adults. The most widely accepted hypothesis regarding its pathogenesis is that it is an immune-mediated disease. It has been hypothesised that intraluminal defects, compression, or hypoplasia in the internal jugular or azygos veins may be important factors in the pathogenesis of MS. This condition has been named 'chronic cerebrospinal venous insufficiency' (CCSVI). It has been suggested that these intraluminal defects restrict the normal blood flow from the brain and spinal cord, causing the deposition of iron in the brain and the eventual triggering of an auto-immune response. The proposed treatment for CCSVI is venous percutaneous transluminal angioplasty (PTA), which is claimed to improve the blood flow in the brain thereby alleviating some of the symptoms of MS. This is an update of a review first published in 2012. OBJECTIVES To assess the benefit and safety of venous PTA in people with MS and CCSVI. SEARCH METHODS We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's Specialised Register up to 30 August 2018, CENTRAL (in the Cochrane Library 2018, issue 8), MEDLINE up to 30 August 2018, Embase up to 30 August 2018, metaRegister of Controlled Trials, ClinicalTrials.gov., the Australian New Zealand Clinical Trials Registry, and the World Health Organization (WHO) International Clinical Trials Registry platform. We examined the bibliographies of the included and excluded studies. SELECTION CRITERIA We included randomised controlled trials (RCTs) in which PTA and sham interventions were compared in adults with MS and CCSVI. DATA COLLECTION AND ANALYSIS Two authors independently assessed study eligibility and risk of bias, and extracted data. We reported results as risk ratios (RR) with 95% confidence intervals (CI). We performed statistical analyses using the random-effects model; and we assessed the certainty of the evidence using GRADE. MAIN RESULTS We included three RCTs (238 participants) in this update. One hundred and thirty-four participants were randomised to PTA and 104 to sham treatment. We attributed low risk of bias to two (67%) studies for sequence generation and two (67%) studies for performance bias. All studies were at a low risk of detection bias, attrition bias, reporting bias and other potential sources of bias.There was moderate-quality evidence to suggest that venous PTA did not increase the proportion of patients who had operative or post-operative serious adverse events compared with the sham procedure (RR 3.33, 95% CI 0.36 to 30.44; 3 studies, 238 participants); nor did it increase the proportion of patients who improved on a functional composite measure including walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity over 12-month follow-up (RR 0.84, 95% CI 0.55 to 1.30; 1 study, 110 participants); nor did it reduce the proportion of patients who experienced new relapses at six- or 12-month follow-up (RR 0.87, 95% CI 0.51 to 1.49; 3 studies, 235 participants). There was no effect of venous PTA on disability worsening measured by the Expanded Disability Status Scale, which was reported at follow-up intervals of six months (one study), 11 months (one study) and 12 months (one study). Quality of life was reported in two studies with no difference between treatment groups. Moderate or severe pain during or post venography was reported in both PTA and sham-procedure participants in all included studies. Venous PTA was not effective in restoring blood flow assessed at one-month (one study) or 12-month follow-up (one study). AUTHORS' CONCLUSIONS This systematic review identified moderate-quality evidence that, compared with sham procedure, venous PTA intervention did not provide benefit on patient-centred outcomes (disability, physical or cognitive functions, relapses, quality of life) in people with MS. Venous PTA has proven to be a safe technique but in view of the available evidence of its ineffectiveness, this intervention cannot be recommended in people with MS. All ongoing trials were withdrawn or terminated and hence this updated review is conclusive. No further randomised clinical studies are needed.
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Morning exercise mitigates the impact of prolonged sitting on cerebral blood flow in older adults.
Wheeler, MJ, Dunstan, DW, Smith, B, Smith, KJ, Scheer, A, Lewis, J, Naylor, LH, Heinonen, I, Ellis, KA, Cerin, E, et al
Journal of applied physiology (Bethesda, Md. : 1985). 2019;(4):1049-1055
Abstract
Preventing declines in cerebral blood flow is important for maintaining optimal brain health with aging. We compared the effects of a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks from sitting, on cerebral blood velocity over 8 h in older adults. In a randomized crossover trial, overweight/obese older adults ( n = 12, 70 ± 7 yr; 30.4 ± 4.3 kg/m2), completed three acute conditions (6-day washout); SIT: prolonged sitting (8 h, control); EX+SIT: sitting (1 h), moderate-intensity walking (30 min), followed by uninterrupted sitting (6.5 h); and EX + BR: sitting (1 h), moderate-intensity walking (30 min), followed by sitting (6.5 h) interrupted with 3 min of light-intensity walking every 30 min. Bilateral middle cerebral artery velocities (MCAv) were determined using transcranial Doppler at 13 time points across the day. The temporal pattern and average MCAv over 8 h was determined. The pattern of MCAv over 8 h was a negative linear trend in SIT ( P < 0.001), but a positive quadratic trend in EX + SIT ( P < 0.001) and EX + BR ( P < 0.01). Afternoon time points in SIT were lower than baseline within condition ( P ≤ 0.001 for all). A morning dip in MCAv was observed in EX + SIT and EX + BR ( P < 0.05 relative to baseline), but afternoon time points were not significantly lower than baseline. The average MCAv over 8 h was higher in EX + SIT than SIT ( P = 0.007) or EX + BR ( P = 0.024). Uninterrupted sitting should be avoided, and moderate-intensity exercise should be encouraged for the daily maintenance of cerebral blood flow in older adults. The clinical implications of maintaining adequate cerebral blood flow include the delivery of vital oxygen and nutrients to the brain. NEW & NOTEWORTHY This is the first study to measure the combined effects of an exercise bout with breaks in sitting on cerebral blood velocity in older adults. Using frequent recordings over an 8-h period, we have performed a novel analysis of the pattern of cerebral blood velocity, adjusting for concurrent measures of mean arterial pressure and other potential confounders in a linear mixed effects regression.