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A Review of Phytochemicals that Enhance Human Brain Function 
Kennedy DO, Wightman EL. Herbal extracts and phytochemicals: plant secondary metabolites
and the enhancement of human brain function. Adv Nutr. January 2011;2(1):32-50.

There is a limited number of drugs that can help people slow the cognitive decline associated  with aging, and these drugs have undesirable side effects. Many people turn to herbal products  to help preserve memory and cognitive abilities. Plants have many chemicals that influence  brain function, yet few have been thoroughly tested in humans. The purpose of this article was  to review current knowledge about plant extracts and phytochemicals which have been tested in  humans and assess their effectiveness in improving brain function. Many secondary metabolites affect the central nervous system in insects and animals.
Secondary metabolites that have central nervous system effects and that have been studied in humans include alkaloids, terpenes, and phenolic compounds.

Alkaloids
Humans have used alkaloid-containing plants medicinally for thousands of years. Medicinal and social alkaloids include atropine, ephedrine, cocaine, morphine, nicotine, and caffeine.
Caffeine is the most widely consumed psychoactive substance in the world. It is an antagonist  of the inhibitory adenosine A1 and A2 receptors, which is responsible for the stimulation, and  also causes constriction of blood vessels in the brain. Caffeine also increases activity in  dopamine neuronal systems. At low doses, caffeine increases alertness and improves  performance on tests of attention. At high doses, caffeine can cause anxiety, insomnia, rapid  heart beat, and agitation.
Nicotine is found in tobacco (Nicotiana tabacum). Nicotine binds to acetylcholine receptors and  increases the release of acetylcholine, serotonin, and other neurotransmitters. It increases  dopamine activity, which is associated with its addictive effect. Clinical trials in smokers and  non-smokers show that nicotine improves performance on tests of memory and attention.

Terpenes
Terpenes are a diverse group of lipid-soluble compounds. Some terpenes are non-toxic and are  common in foods and spices; others are toxic.

Ginkgo (Ginkgo biloba) leaves contain a number of terpenes, including bilobalide and  ginkgolides A, B, C, and J. Effects of ginkgo leaf extracts in the central nervous system include  modulation of several neurotransmitter systems, enhanced blood flow in the brain, and  scavenging of free radicals. Ginkgo is one of the most popular herbal products, and it is used to  improve cognitive performance. More than 30 clinical trials have tested the effects of ginkgo on  cognitive function in people with dementia or age-related cognitive impairment. One metaanalysis concluded that the evidence for cognitive improvement with ginkgo supplementation is inconsistent, while another meta-analysis concluded that ginkgo improves attention, executive
function, and long-term memory.

Lemon balm (Melissa officinalis) contains a variety of monoterpenoids and sesquiterpenes.  Effects of lemon balm on the central nervous system include binding to specific cholinergic  receptors, increased activity of the neurotransmitter gamma-aminobutyric acid (GABA), and  antioxidant activity. Limited clinical trials have shown that lemon balm has anti-anxiety effects,  improves agitation and quality of life in people with severe dementia, but has inconsistent effects on memory.

Asian ginseng (Panax ginseng) roots contain 40 or more triterpene saponins known as  ginsenosides. Ginseng root extracts have neuroprotective effects, modulate the neuroendocrine  system and the synthesis of nitric oxide, which relaxes blood vessels and influences many  cellular activities. Clinical trials have shown that ginseng improves accuracy on memory tests  and improves the speed of performing attention tasks. The impact of ginseng on mood has been  inconsistent in clinical trials to date. Sage (Salvia officinalis) contains a range of monoterpenes. Effects on the central nervous  system include anti-inflammatory activity and decreased breakdown of the acetylcholine  neurotransmitter. Clinical trials have demonstrated improved memory, attention, and alertness  in healthy people after single doses of sage extract and improved cognitive function in people  with Alzheimer's disease after 16 weeks of an alcoholic tincture of sage. 

Valerian (Valeriana officinalis) root contains a variety of terpenes, including the valepotriates and valerenic acid. Valerian compounds modulate serotonin receptor subtypes, GABA, and adenosine receptors and have anxiolytic activity. Some clinical trials suggest that valerian improves sleep quality; others were not conclusive.

Phenolics
Phenolics are ubiquitous in plants and they are important components in the human diet. They range from simple, low molecular weight compounds to complex, large structures such as flavonoids, tannins, and anthocyanins.

Curcumin is a polyphenol from turmeric (Curcuma longa). Curcumin prevented cognitive deficits and improved learning and memory in mouse models of Alzheimer's disease. Curcumin also reversed amnesia in rats. Many small pilot studies have been conducted in humans, but there are few controlled clinical trials to support a benefit of curcumin in brain function.

Epigallocatechin-3-gallate (EGCG) and related polyphenols are present in tea (Camellia sinensis). In vitro and animal studies suggest that EGCG may have protective effects in Alzheimer's disease and Parkinson's disease. EGCG improved cognitive performance and increased antioxidant capacity in rats. In epidemiological studies, greater consumption of green tea is associated with reduced risk of cognitive impairment and neurodegenerative disorders.

St. John's wort (SJW; Hypericum perforatum) extract contains a variety of phenolic compounds that have an impact on brain function, including phenolic acids, flavonoids, hyperforin, and hypericin. SJW extracts have been reported to inhibit reuptake of serotonin, dopamine, and GABA, but this finding is highly doubtful. Other reports include increased neurotransmitter sensitivity and altered receptor binding. Clinical trials have established that SJW is an effective treatment in people with mild to moderate depression.

Resveratrol is found in the skin of red grapes (Vitis vinifera) and in some other edible plants. Resveratrol preserved behavior and cognitive performance in older rats with brain injuries. In healthy humans, single doses of resveratrol increased blood flow and oxygen uptake in the frontal cortex of the brain, suggesting it may have benefits in Alzheimer's disease and other neurological disorders.

Soy (Glycine max) extract contains isoflavones such as genistein, daidzein, and glycetin that have very weak estrogen-like effects. Several clinical trials have shown that soy isoflavones modestly improve neurocognitive function and mood in postmenopausal women, but other clinical trials showed no improvement. Compared to a diet with no soy isoflavones, a diet rich in soy isoflavones was associated with improved short-term and long-term memory in men and women.

Conclusion
The authors conclude that the literature describing the effectiveness of herbal extracts for improving brain function is "somewhat equivocal." Research on caffeine and nicotine has been hampered by the addictive nature and serious adverse effects attributed to these alkaloids.
Research is progressing among plants containing terpenes, particularly ginkgo and valerian. However, the methodological quality of some of the clinical trials has been poor, and results have been inconsistent. Interest in the potential cognitive benefits of curcumin, EGCG, resveratrol, and soy isoflavones is relatively recent, and human clinical trials are still in the early stages.
The authors describe challenges in developing plant-based products to prevent or reverse agerelated cognitive decline. Challenges include identifying the active components, understanding the synergism among the active components, defining the environmental stressors and growing conditions under which plants produce increased amounts of secondary metabolites, and standardizing plant products to provide beneficial amounts of active compounds.



Antioxidanten en geheugen

Oxidatieve stress speelt een belangrijke rol bij veroudering van de hersenen. Verhoging van de inname van antioxidanten (zoals vitamine E, vitamine C, bètacaroteen, resveratrol, polyfenolen uit Ginkgo biloba, curcumine, ubiquinol) kan bijdragen aan de preventie en vertraging van cognitieve achteruitgang en dementie. De inname van vitamine E uit voeding en voedingssupplementen is geassocieerd met vertraging van cognitieve veroudering en uitstel van de ziekte van Alzheimer.1,23 Vitamine E beschermt de neuronale membranen en beschermt het zenuwweefsel tegen toxiciteit door amyloïd-β. Co-enzym Q10 beschermt zenuwcellen tegen beschadiging en apoptose door oxidatieve stress.24

Resveratrol (een polyfenol in druivenschil en rode wijn) bootst de gunstige effecten van calorische restrictie na door het stimuleren van sirtuïnes en beschermt de hersenen mogelijk mede door de vorming van amyloïde plaques tegen te gaan en de verwijdering van amyloïd-β te bevorderen.1 

Ginkgo biloba stimuleert het denkvermogen, bevordert de doorbloeding van hersenweefsel, moduleert neurotransmitters en hun receptoren, heeft een ontstekingsremmende en antioxidieve werking en remt mogelijk de aggregatie van amyloïd-β.1 Helaas kon in een studie van DeKosky waarin ruim 3000 ouderen boven 75 jaar gemiddeld 6, 1 jaar werden gevolg, niet worden aangetoond dat suppletie met Ginkgo biloba extract (2x 120 mg/dag) invloed heeft op de kans op de ziekte van Alzheimer bij cognitief gezonde ouderen en ouderen met milde cognitieve achteruitgang.25 In een Cochrane Database systematische review wordt eveneens geconcludeerd dat er onvoldoende wetenschappelijk bewijs is dat Ginkgo biloba extract cognitieve achteruitgang en dementie significant kan vertragen.26 Toch zijn er ook meta-analyses die wel een gunstig effect van Ginkgo extract bij dementie vaststellen.27,28

24. Somayajulu M et al. Role of mitochondria in neuronal cell death induced by oxidative stress; neuroprotection by Coenzyme Q10. Neurobiol Dis. 2005;18(3):618-27.
25. Ives DG et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA 2008;300:2253-2262.
26. Birks J et al. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003120.
27. Weinmann S et al. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr. 2010 Mar 17;10:14.
28. Wang BS et al. Effectiveness of standardized ginkgo biloba extract on cognitive symptoms of dementia with a six-month treatment: a bivariate random effect meta-analysis. Pharmacopsychiatry. 2010;43(3):86-91.



Voeding en geheugen

Epidemiologisch onderzoek bevestigt dat een gezond eetpatroon - niet teveel calorieën, gebalanceerde en gevarieerde (liefst onbewerkte) voeding - bijdraagt aan succesvolle cognitieve veroudering.1 Het is heel lastig om te bepalen welke specifieke voedingsfactoren de kans op cognitieve achteruitgang en dementie verlagen. Matige alcoholconsumptie (1 glas per dag voor vrouwen en 1-2 voor mannen, vooral rode wijn) heeft waarschijnlijk een beschermend effect, luidt de conclusie van een recente meta-analyse van 22 longitudinale studies naar het verband tussen alchoholconsumptie en cognitieve achteruitgang/dementie.1,11 Door matige alcoholconsumptie wordt de kans iets kleiner dat milde cognitieve achteruitgang uitmondt in klinische dementie.

Grootschalig longitudinaal bevolkingsonderzoek in Singapore suggereert dat het drinken van thee - met name zwarte (gefermenteerde) thee en oolong (semi-gefermenteerde) thee - eveneens helpt om cognitieve achteruitgang tegen te gaan.12 De studie sluit aan bij dierexpermenteel onderzoek waarin is aangetoond dat thee een neuroprotectieve werking heeft. Polyfenolen in thee (catechines, theaflavines, theanine) hebben antioxidatieve, neuroprotectieve en ijzerchelerende effecten en beschermen mogelijk tegen de vorming en toxiciteit van amyloïd-β. De onderzoekers konden geen beschermend effect van koffie aantonen.12

Een mediterraan voedingspatroon is gunstig voor de gezondheid van de hersenen.13,14 In een vier jaar durende studie hadden zelfstandig wonende ouderen die het mediterrane dieet strikt volgden (hoge inname groenten en fruit, enkelvoudige vetten uit olijfolie, vis, noten, granen, relatief weinig rood vlees) minder kans om de ziekte van Alzheimer te krijgen dan degenen die vaak afweken van dit eetpatroon. Ouderen met milde cognitieve achteruitgang hebben baat bij mediterrane voeding: de kans op verslechtering en klinische dementie gedurende een studieperiode van 4,5 jaar daalde significant door het gebruik van deze voeding.15 Via elke mechanismen mediterrane voeding de hersenen precies beschermt, is nog niet onderzocht.
Het hoge gehalte aan antioxidanten in mediterrane voeding en de hoge inname van vis en groenten spelen waarschijnlijk een belangrijke rol. Wetenschappers hebben geconstateerd dat ouderen (vanaf 65 jaar) die veel antioxidanten (vitamine C, vitamine E, bètacaroteen) uit voeding binnenkrijgen, een beter geheugen hebben dan leeftijdsgenoten met een lage antioxidantinname.8 De consumptie van vis vertraagt waarschijnlijk het proces van cognitieve veroudering.1,16 Vergeleken met ouderen die geen vis eten of minder dan een keer vis per week eten, verloopt cognitieve veroudering 10% trager bij mensen die een keer per week vis eten en 13% tragen bij degenen die twee of meer keer per week vis eten. De onderzoekers schrijven het beschermende effect niet uitsluitend toe aan omega-3 vetzuren in (vette) vis.

11. Peters R et al. Alcohol, dementia and cognitive decline in the elderly: a
2. systematic review. Age Ageing 2008;37:505-512.
12. NG TP et al. Tea consumption and cognitive impairment and decline in older Chinese adults, Am J Clin Nutr 2008;88:224-31.
13. Scarmeas N et al. Mediterranean diet and risk for Alzheimer's disease. Ann Neurol. 2006;59:912-921.
14. Scarmeas N et al. Physical activity, diet, and risk of Alzheimer's disease. JAMA 2009;302:627-637.
15. Scarmeas N et al. Mediterranean diet and mild cognitive impairment. Arch Neurol. 2009;66:216-225.
16. Morris MC et al. Fish consumption and cognitive decline with age in a large community study. Arch Neurol. 2005;62(12):1849-53.
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