Many human intervention studies have therefore focused on middle-aged and elderly adults at increased vascular risk who are also known to be at increased risk of cognitive impairment and dementia, allowing for improvement by lifestyle-based intervention strategies.CBF is defined as the volume of arterial blood delivered to a unit mass of brain tissue per unit of time. The different imaging techniques to assess brain perfusion will be mentioned briefly, as they have already been critically reviewed. The direct methods discussed below have been developed to measure the delivery of arterial blood to the capillary bed. A frequently observed value in human gray matter is about 60 mL/100 g/min, corresponding to the delivery of approximately 1 mL of blood to 100 g of brain tissue per second. Assuming an average brain tissue density of 1 g/mL, this means that approximately 1% of the total tissue volume is provided with freshly delivered blood each second. In earlier studies, radioactive tracers were used to measure the absolute blood flow in the brain. However, CBF measurements using radio tracers require a specialized imaging unit, and time intervals between repeated measurements are also required to minimize overexposure to radiation. These delays significantly reduce the usefulness of radioactive CBF measurements in human intervention studies. Therefore,dutch bucket hydroponic increasing attention has now been directed to recent developments in magnetic resonance imaging that enable the non-invasive measurement of cerebral perfusion in human volunteers.
Direct methods for measuring CBF in human subjects include, but are not limited to, single-photon emission computed tomography , positron emission tomography , MRI with contrast agents, and arterial spin labeling MRI. All these methods are based on the measurement of the amount of a tracer delivered to the human brain tissue by blood flow. PET using injection of 15O-labeled water radio tracers is still considered the gold standard approach. Important limitations, however, include the need for an on-site cyclotron and the invasive nature and complexity of the measurement. As a promising alternative, ASL is a relatively new, non-invasive MRI method that uses magnetically labeled water molecules in arterial blood as a tracer. This method is currently available on MRI systems produced by the major manufacturers. The general principles have been described in detail before. Briefly, this non-invasive measurement of CBF works by manipulating the magnetic resonance signal of in flowing blood in feeding arteries before it is delivered to the capillary bed of the different areas in the brain. Separate “label” and “control” images are acquired, and the resulting signal difference can be scaled to yield highly repeatable quantitative measures of CBF. Figure 2 shows an example of an ASL CBF map. Recently, human studies that performed both PET and ASL MRI to measure brain perfusion were systematically reviewed. It was concluded that ASL is a promising method for accurate and reproducible CBF measurements, and comparative studies show that ASL is a validated method for non-invasive perfusion imaging in humans. Dietary nitrate, which is found in high concentrations in red beetroot, lettuce, and spinach, may improve CBF through beneficial effects on vascular endothelial function, which is an important mechanistic determinant of cerebral perfusion. In the mouth, dietary nitrate can be reduced to nitrite by facultative bacteria from the dorsal surface of the tongue.
Once in the blood, nitrite can be further converted into nitric oxide in the human vasculature, thereby improving endothelial function via an increased NO bio-availability. Several human intervention studies have examined the acute effect of dietary nitrate intake on measures of CBF . Presley and colleagues measured cerebral perfusion using ASL MRI after administering a high versus low-nitrate diet for 24 h to a group of elderly humans . The test diet included beetroot juice and provided 773 mg of nitrate compared to 5.5 mg for the low-nitrate diet. The authors demonstrated that the diet high in dietary nitrate did not significantly increase global CBF, while regional cerebral perfusion improved in frontal lobe white matter, especially between the dorsolateral prefrontal cortex and the anterior cingulate cortex, which are known to be involved in executive functioning. However, whether the observed increase in regional CBF in coincides with concurrent improvements in cognitive functioning remains to be elucidated. A single dose of 500 mL nitrate-rich beetroot juice acutely increased MCA mean blood flow velocity, measured non-invasively with transcranial Doppler ultrasonography during submaximal exercise in twelve healthy, normotensive young adult females. More recently, Wightman et al. investigated the acute effects of 450 mL of beetroot juice on prefrontal cortex CBF parameters in 40 apparently healthy adults. It was found that a single dose of beetroot juice modulated the NIRS-monitored CBF hemodynamic response during the performance of tasks, which activated the prefrontal cortex. In fact, an initial rise in prefrontal cortex perfusion at the start of the task period was followed by consistent reductions in cerebral perfusion during the least demanding task, while performance on one of the three cognitive tasks—requiring resources in terms of working memory, psychomotor speed and executive functioning—was improved.
Polyphenols are predominantly found in fruits and vegetables, as well as red wine, tea and chocolate. These phytochemicals may exert beneficial effects on brain health due to their positive impact on endothelial function and other aspects of the vasculature through an increased NO bio-availability, which may translate into increased CBF. Acute intake of trans-resveratrol, which is present in the skin of a range of foods including red grapes, raised CBF in healthy adults . In a randomized, placebo-controlled, crossover study, trans-resveratrol administration resulted in dose-dependent increases in prefrontal cortex CBF during task performances which activated this brain region, as assessed with NIRS. The performance of cognitive tasks was not changed. These results were in line with those of another clinical trial on the acute effects of 250 mg trans-resveratrol co-supplemented with 20 mg of piperine, which increases the bio-availability of polyphenols. More recently, the effects of long-term trans-resveratrol supplementation on CBF were investigated in 60 adult subjects between the ages of 18 and 30 years. In that study, a single 500 mg dose of trans-resveratrol on the first day of the study increased the CBF response in the frontal cortex during tasks which activate this brain region. However, this effect was not observed with transcranial Doppler ultrasound parameters after 28 days of daily supplementation of 500 mg of trans-resveratrol. In addition, no unambiguous evidence was provided to support that the intake of trans-resveratrol improved cognitive function. The effects of trans-resveratrol intake have also been investigated in populations at an increased risk of accelerated cognitive decline. In 36 older type 2 diabetic patients, acute consumption of 75 mg of trans-resveratrol significantly improved hypercapnia-induced mean blood flow velocity responses in major cerebral arteries by about 13%. Also, Evans and colleagues reported the beneficial effects of long-term trans-resveratrol supplementation in postmenopausal women aged 45–80 years. In that study, increases of 17% were found in the MCA mean blood flow velocity response to cognitive stimuli and hypercapnia. In addition, performance of a cognitive task in the domain of verbal memory and in overall cognitive performance improved, which correlated with improvements in transcranial Doppler ultrasound parameters. A smaller number of intervention trials has assessed the cerebral hemodynamic effects of other dietary polyphenols . In a double-blind, placebo-controlled,dutch buckets system crossover study with 27 healthy adults, the acute effects of a single oral dose of epigallocatechin gallate—the most abundant polyphenol found in green tea—were investigated on CBF. The administration of 135 mg of epigallocatechin gallate reduced cerebral perfusion in the frontal cortex during performance of cognitive tasks activating the frontal cortex, but no changes in cognitive performance were observed. More recently, a human crossover trial was conducted on the cerebrovascular effects of flavanol-rich cocoa. Regional CBF was measured using ASL prior to and two hours following consumption of a high flavanol drink or placebo. In agreement with an RCT involving healthy young men and a pilot trial of four healthy females consuming 516 mg of cocoa flavonoids, acute improvements in resting CBF were observed following the consumption of the high cocoa flavanol drink in eight men and ten women aged 50–65 years. More specifically, higher resting CBF was observed in both the anterior cingulate cortex and the central opercular cortex of the left parietal lobe. Unfortunately, the effects on cognitive performance were not evaluated. In another study with elderly subjects, a single dose of cocoa increased hypercapnia-induced MCA blood flow velocity.
The effects, however, were not evident after a daily supplementation of 900 mg of cocoa flavanols for one week. Finally, Bowtell and colleagues investigated the effects of twelve weeks of blueberry concentrate supplementation on cerebral perfusion using ASL MRI in healthy elderly adults. The concentrate provided 387 mg of anthocyanins . They found improvements in gray matter CBF in the parietal and occipital lobes, as well as some evidence suggesting an improved working memory after blueberry versus placebo supplementation.Haast and Kiliaan recently summarized the effects of the n-3 long-chain polyunsaturated fatty acids , eicosapentaenoic acid , and docosahexaenoic acid , which are predominantly found in fatty fish and fish oils, on indicators of brain health. These dietary fatty acids can be incorporated in all lipid fractions. In fact, LC-PUFAs may have anti-inflammatory effects and increase the fluidity of cell membranes. They may also improve vascular endothelial function and arterial stiffness, which are both important mechanistic determinants of CBF. Two human intervention trials investigating the longer-term effects of these fatty acids on CBF were discussed by Haast and Kiliaan. One study indeed showed that regional cerebral perfusion in the prefrontal cortex improved during the performance of nine computerized cognitive tasks. In the study, 65 healthy adults received for 12 weeks a daily DHA-rich fish oil supplement of either 1000 or 2000 mg. The total daily dose of LC-PUFAs for the 1000 mg fish oil group was 450 mg DHA + 90 mg EPA, and for the 2000 mg fish oil group, these amounts were 900 mg DHA + 180 mg EPA. Relative changes in the concentration of hemoglobin were assessed in the prefrontal cortex using NIRS. However, no beneficial effects on cognitive performance were found. Furthermore, PET experiments in humans that were injected intravenously with labeled DHA showed that the rate of DHA incorporation into brain lipids correlated with the regional CBF in that particular region. Konagai and colleagues provided further evidence of the beneficial modulation of cerebral hemodynamics in the prefrontal cortex during working memory task completion, when 45 elderly men were supplemented for 12 weeks with n-3 LC-PUFAs from krill oil. However, these findings could not be replicated in a recent large RCT. In 86 healthy older adults who reported memory deficits, no effects of long-term supplementation of 2000 mg DHA-rich fish oil alone or in combination with other nutrients were observed on NIRS measures during task performance or on cognitive demand battery task outcomes. These results, however, should be interpreted with caution. As discussed by the authors, the study was limited by the fact that the utilized methodology only provides a measure of acute changes that have taken place during each discrete recording session. This limitation should be taken into account in long-term supplementation studies, because long-lasting changes in hemodynamic parameters between consecutive recording sessions—undetectable by NIRS—might be induced. The most widely consumed psychoactive compound is caffeine, which is found in various drinks and foods, such as coffee, tea, soft drinks and chocolate. Caffeine is a well-known cerebral vasoconstrictor, which significantly reduces resting cerebral perfusion by antagonizing adenosine receptors in the human brain, especially A1 and A2A subtypes that mediate vasodilation. By using PET methodology, Cameron et al. quantified the magnitude of the decrease in CBF in 1990. A single dose of 250 mg caffeine reduced resting CBF, with decreases ranging from 22% to 30%; this is in line with later studies using ASL and PET. Recently, Turnbull and colleagues evaluated the literature with respect to the effects of acute caffeine intake on CBF in adult subjects. Trials investigating intakes of ≥175 mg observed significant decreases in CBF in all study populations. Studies that administered lower doses only reported significant decreases in caffeine-naïve or low-caffeine consumers, but not in habitual consumers. Altogether, the authors of the recent review concluded that there is some evidence for a dose-response relationship between caffeine intake and CBF, with greater sensitivity in caffeine-naïve study subjects as compared to habitual caffeine consumers.